ALS Crowd Radio S2:E6 Dr. Avindra Nath, MD: An Activated Virus Causing ALS?

Dr. Avindra Nath, MD
National Institutes of Health, Clinical Director of National Institute of Neurological Disorders and Stroke (NINDS)
Interview Date: May 17, 2016

Dr. Nath is an expert in viruses and retroviruses.  He speaks about studying human endogenous retrovirus-K (HERV-K) in the context of ALS, and why it could be important.  HERV-K is normally dormant, but Dr. Nath’s study found that in ALS patient brains it has been activated at fairly high levels. HERV-K creates proteins that are toxic to neurons, and points to a possible cause for sporadic ALS.  Dr. Nath believes that antiviral drugs could be used to inhibit HERV-K, and possibly alter the course of ALS.  More research and testing is underway, along with an intense search for an ALS biomarker to use in human clinical trials to prove effectiveness of these treatments. Many antiviral drugs are already FDA approved and commonly prescribed for use in HIV treatment.

ALS Crowd Radio Show with Dr. Nath:

Full Transcript: (available one week after the show)

Dr. Avi Nath joined NIH as the Clinical Director of NINDS in February 2011. Prior to this, he was the Director of the Division of Neuroimmunology and Neurological Infections at Johns Hopkins University for 9 years. His current responsibilities are to oversee and build the clinical research program at NINDS. He is also the Director of the Translational Neuroscience Center. The office has a clinical trials unit that provides assistance in all stages of protocol development and monitoring. It also oversees a unique training program for clinical fellows and residents in Neurology and Neurosurgery. The office oversees a variety of specialized clinics and provides services for investigation and consultation for patients with neurological disorders.

He graduated from Christian Medical College in Ludhiana, India, in 1981, completed a residency in Neurology in 1986 and a fellowship in Neuroimmunology from University of Texas in Houston in 1988. He was a clinical fellow in Neurovirology at NINDS from 1988-90. He held faculty positions at University of Manitoba (1990-97), University of Kentucky (1997-2002) and at Johns Hopkins University (2002-11).

His research has focused on the neuropathogenesis, neurological manifestations and treatment of HIV infection, Progressive Multifocal Leukoencephalopathy and Multiple Sclerosis. He has published over 300 articles and reviews. He has served on the editorial board of several journals and is currently is the Associate Editor of the Journal of Neurovirology and has edited a book on Clinical Neurovirology.

He is the past Chair of the Section of Neuroinfectious Diseases of the American Academy of Neurology and the current President of the International Society of Neurovirology.

ALS Crowd Radio S2:E5 Barbara Newhouse & Dr. Lucie Bruijn: ALS Advocacy

Barbara Newhouse, President and CEO
Lucie Bruijn, Ph.D.
ALS Association
Interview Date: May 9, 2016

S2:E5 ALSA President and CEO Barbara Newhouse and Chief Scientist Dr. Lucie Bruijn spoke live from Washington DC at the National ALS Advocacy Day and Public Policy Conference.  They shared the advocacy work on Capitol Hill that the National ALS Association and medical updates that are happening.

Full Transcript will be available in one week from date of show.   

Barbara Newhouse has over 35 years of success in leading strategic initiatives resulting in operation growth and market strength. Her specialties are aligning the needs of a varied group of constituents with the overall mission and working with the grassroots chapter and volunteer network while maintaining a strategic business operations focus.

Prior to the ALS Association, her background included executive roles with the American Cancer Society, the Alzheimer Association, the Autism Society of America, and the Arthritis Foundation.

Barb holds a Bachelor degree in Social Work and a Master’s degree in Health Care Administration. She received a Certificate with the Leadership Institute of Aging in 1994 and has attended various continuing education courses with the Kellogg School of Non-Profit. Barb has recently completed a Certificate in Leadership program through the University of Notre Dame on leading transformational organizations.

Throughout her career, she has served on numerous non-profit Boards of directors including chairing both a community mental health center as well as the Governor’s Conference on Alzheimer’s disease for the state of Iowa.

Lucie Bruijn, Ph.D. joined The ALS Association in January 2001 and is currently the Chief Scientist.  Prior to that Dr. Bruijn led a team at Bristol Myers Squibb developing in vitro and in vivo model systems for neurodegenerative disease. Her team worked with experts in academia to establish stem cell studies at Bristol Myers Squibb.

Dr. Bruijn received her Bachelor’s degree in Pharmacy at Rhodes University, South Africa.  She received a Master’s degree in Neuroscience and a Ph.D. in Biochemistry, at the University of London, United Kingdom. She received her MBA at Imperial College, London, United Kingdom. She joined Dr. Don Cleveland’s laboratory in 1994 where she developed and characterized a mouse model of ALS (mice expressing the familial-linked SOD1 mutation).  Using this model her studies focused on disease mechanisms.  In addition, in collaboration with Dr. Robert Brown she looked for neurofilament mutations in familial and sporadic ALS patients.

At The ALS Association, Dr. Bruijn leads a global ALS research effort, called Translational Research to AdvanceTherapies for ALS (or TREAT ALS™) with the goal to move treatment options forward.  It is her strong belief that only through collaboration among a wide range of disciplines will we be successful in changing the course of ALS and finding a cure.

ALS Crowd Radio S2:E4 Dr. Richard Bedlack,MD, PhD, MS Duke University: ALS Reversals

Dr. Richard Bedlack, MD, PhD, MS
Duke University
Interview Date: May 4, 2016

S2:E4 Dr. Richard Bedlack defines an ALS Reversal, in which a patient with a confirmed diagnosis of ALS regains motor function.  He describes his search for these cases, which has revealed 23 to date.  He started the ALS Reversals Program which includes two parts: 1)Replication of ALS Reversals (ROAR) and 2)Study of ALS Reversals (STAR).  Dr. Bedlack’s first replication pilot study is underway with Lunasin and is different from other clinical trials because it can include most ALS diagnosees. He describes this method of studying ALS from the patient side, rather than from the lab.  He hopes to collect enough ALS reversals to mine the data and find similarities, an approach that brought success in HIV treatment.  Dr. Bedlack believes there are many research breakthroughs happening; that this is the most exciting year for ALS in his 16 years in the field.   

ALS Crowd Radio Episode with Dr. Bedlack:

Full transcript:

Seth: Hello and welcome to ALS Crowd Radio Season 2 Episode 4. I am your host Seth Christensen here with my co-host Lori Wangsgard.

Lori: We are excited to interview Dr. Bedlack today. If you have a question, please call in at 516-590-0362 and press 1 to indicate that you have a question. Now I would like to introduce our guest.

Dr. Richard Bedlack, grew up in a small town in central Connecticut. He went to college at William and Mary in Virginia, then back to Connecticut for an MD and PhD in Neuroscience at UConn. Finally, he came to Duke where he completed his Medicine Internship, Neurology Residency, Neuromuscular Fellowship, and Masters in Clinical Research Science. He is currently a tenured Associate Professor of Medicine/Neurology at Duke, Director of the Duke ALS Clinic, and Chief of Neurology at the Durham Veterans Affairs Medical Center. He has won awards for teaching and patient care, including best Neurology teacher at Duke, Health Care Hero, Strength Hope and Caring Award, America’s Best Doctor, the American Academy of Neurology Patient Advocate of the Year and the Rasmussen ALS Patient Advocate of the Year. He has received ALS research grants, participated in ALS clinical trials, published more than 60 ALS articles and recently edited a new book called ALS: A Patient Care Guide for Clinicians. He is the outgoing Chairman of the North American ALS Research Group and leader of the international ALSUntangled program which utilizes social networking to investigate alternative and off label treatment options for patients with ALS. He lives in Durham, North Carolina with his wife Shelly and two mischievous kittens.

Seth: Dr. Bedlack. Welcome to this show.

Dr. Bedlack: Well thanks for having me back, Seth.

Seth: We’re thrilled to have you. I believe we had you on the last about a year-and-a-half ago, to talk about your work with ALSUntangled. How is that work going?

Dr. Bedlack: I think it’s going great. The program is getting bigger. I think it’s getting better. Since the last time that I was on, we have refined the way that we actually do our reviews. So we have always had a way to gather information sort of a standard operating protocol by which we gathered our information for our reviews but now we have got something called the table of evidence. So it’s a structure that we try to use for all of our reviews. We try to make sure that everything we look at, we grade it according to five categories.

We grade it according to its mechanism of action, in other words this particular treatment is it actually do anything that might be relevant in ALS. We grade it in terms of its preclinical data. So was this thing ever given to any sort of model of ALS either a test tube model or animl model? We grade it in terms of its effect on individual patients. Those are kind of like case reports that we might find on the internet like in chat rooms or that maybe one of us has seen in our clinic. We grade it in terms of any clinical trials that were done. Unfortunately, many of the things that we look at don’t have any clinical trials. And then finally we grade each one of these things according to their risks. And for each of these five categories, we assigned a letter grade ranging from A to F. A is the best, F is the worst and there is very specific things you have to achieve to get the next best grade in each of those categories. We have tried to make this process very objective.

Seth: Wonderful. For those of our listeners new to ALSUntangled, what is the program in a nutshell?

Dr. Bedlack: Yeah. So back in the beginning of my career, it became obvious to me that many patients with ALS were going home from clinic and going on the internet. The internet is just full of things that are advertised to potentially be useful in the treatment of ALS and you could understand why patients with ALS would do that. I mean here I am in my clinic trying to provide them with as many options as I can but I still don’t have the bullet that stops or reverses ALS. Folks wants to believe that maybe there is something better out there.  They that go on the internet and there are a lot of websites that make extraordinary claims about treatments for ALS and unfortunately there is no internet police to go around and try to validate these claims.

You could open up a stem cell clinic in Siberia and say that you have treated a thousand people with ALS with your stem cell and that every single person got better and you never had a single side effect. Who can actually hold you to do that? There is nobody that’s in charge of doing that. So we created this program to try to help patients and families make more sense of all these different alternative options. There are three parts to it.

First, how do we get our information and that is that patients can send it to us in a variety of ways. If you want to hear about a particular alternative therapy that you saw on the internet, the first thing I would suggest is go on our website, see if it’s something that we already reviewed or something that’s on our list of open reviews, something that we have got scheduled. If it’s on the list of open reviews, click the button that says vote and it will move up the list and that’s how we prioritize. We try to get the reviews that have the most votes next.

Then second, how we do our reviews and we talked a little bit about that with the table of evidence. And then the third part of it is how do we get the information back to patients and families. So we write articles, scientific articles which have a hundred authors. There are a hundred people like me around the world that are part of this program and this article gets circulated amongst all 100 authors and everyone kind of weighs in and we go around it around with different drafts. When we finally have it to a point where we can all agree that it’s publishable, we send it into the ALS Journal and they do a final review, their editor reviews it. And if they have no more comments then they publish it and these articles are all published free open access. So patients and families can read any of them for free. They don’t have to pay anything.

Seth: Wonderful. We are out on right now. We see that many of the topics covered in recent episodes are trending as open reviews with your team right now. We’re very excited and encourage our listeners to go to and read more about many of the topics we have all heard about. Thank you for that explanation.

Dr. Bedlack: Sure thing.

Seth: We’re thrilled to talk a little bit more about a bit of a different topic, but Im sure related.  You are a bit of a celebrity in ALS reserach right now and one of the topics that you speak on is ALS Reversals.   Can you explain to us what a reversal is?

Dr. Bedlack: Sure. Well I’ll tell you how I got interested in this. A few years back around 2010, I was doing ALSUntangled review on an energy healer by the name of Dean Craft. And I was going through his website which is really just a treasure trove of letters from people all over the world to claim that they saw this man do something that should not be physically possible like move a pendulum that was underneath a glass jar using only his mind. Of course, it’s interesting but there is no way to really validate any of these letters. But on that website, there was a video about a patient who was said to have been diagnosed with ALS at one of America’s top medical centers was said to have progressed to the point where she was completely paralyzed and near death, the video I think verbatim says her family was picking out her outfit to be buried in.

Then she went to Dean Craft and two years later she is back to normal. She can run. She can throw snowballs with her grandchildren. When I saw that, I didn’t know what to think. I have never seen anything like that before. My first thought was let me see if I can find this person, see if this person is even real and sure enough with social networking I was able to find some friends of hers who connected me to her. I spoke to her on the phone and she was nice enough to not only corroborate the story but also to send me a whole box of her medical records.  

I’ll never forget going through those records; as I got about halfway through and I had the goosebumps. I turned to my wife and I said, “You know how people already think I’m kind of crazy. They’re going to be really be amazed when I stand up at the next meeting and say I think I might have found the cure for ALS, energy healing. Because I’m absolutely sure reading through those records that she had ALS. I mean she had all the right story, all the right exams, all the right EMGs, all the testing that should have been to rule out mimickers. I’m sure she progressed to where she was quadriplegic and unfortunately near the end of her life. And now I’m sure that she is, if not 100% normal, pretty close.  And so I didn’t know what to think.

My first thought was, well it must have been this treatment, but it’s so surprising. Then the more I thought about it and searched the literature and talked to colleagues, there are other people that are out there that have had stories like this that did completely different things or in some cases didn’t really do anything at all. She is not the only ALS reversal and it led me to start thinking you know there is probably different possibilities for these ALS reversals. One possibility is that maybe there is another ALS mimicker out there that none of us knows about something very rare that we don’t usually test for. Another possibility is maybe some patients are genetically resistant to ALS. In other words, their bodies can figure out a way around it. And that may sound crazy but it turns out there is a president for that.

In the HIV field, there have long been a group of people called elite controllers. They get infected with the HIV virus, can measure it in their blood but they never get sick. They don’t take any medicine. For years people kind of shrugged their shoulders and didn’t know what to make of those folks and then somebody put them all in the same database and did some genetic testing and found that many of them have the same genetic abnormality. And when they figured out what that gene does, it codes for a protein. It’s in the surface of all of our cells that HIV needs to get in. Because of their genetic abnormality, that protein looks different and HIV cannot use it to get it to their cells.

We learned something very important about the biology of HIV by studying this very odd subgroup and now a company Pfizer has developed a drug which blocks that pathway that works for everybody with HIV. So maybe if I could find what makes some people resistant to ALS, maybe I could learn something about the disease that I could give to other folks.  Then the last possibility Seth is that maybe some of these unusual treatments really do work. I can’t discount that. So I started this whole program called ALS Reversals to try to work my way through these three different hypotheses and there are really two arms to this.

There is something called the Star Program, the STudy of ALS Reversals. There I’m trying to gather as many of these patients as I can.  If I can get as much clinical information on them into the same database to see what they might have in common with each other that might look different from other people.  Say for example, they all have a disease like Myasthenia Gravis, that would be very interesting. I don’t know yet because I don’t have them all in the database. I’m also trying to get blood on them to see if I could do some genetic testing like they did in the HIV field.

Then the second arm in my program is called ROAR, Replication Of ALS Reversals.  In that particular program, I am doing small pilot trials of the exact same treatments that some of these patients tried when they had their reversals. You probably have heard the story about Lunasin and the associated ALS Reversal and that’s my first ROAR pilot trial, the Lunasin trial.

Seth: Well for those new to Dr. Bedlack’s work please go to and read more.  Dr. Bedlack how many ALS Reversals are you looking at? Are these five people globally or is this a larger number?

Dr. Bedlack: Well I have 23 confirmed ALS Reversals now where I have enough medical information to be reasonably sure that the diagnosis is correct and that the reversal is very obvious. At 23, it’s not really enough probably to do the kind of genetic testing that I’m interested in doing. I’m going to have to find more. So part of what I’m trying to do right now is survey my colleagues around the world so that they’ll send me their cases of ALS Reversals. I’m trying to find more online and I do have at least six more that I’m looking at that I found on various websites but I don’t have records on. I’m trying to find those people. I’m trying to communicate with them to see if they’ll send me their records so I can try to confirm what it is that they are saying about themselves.

And then I’m also trying to work on a definition of ALS Reversal so that it doesn’t have to be so nebulous. Right now my definition is well, if they obviously got a lot of motor function back, that’s not supposed to happen so that’s an ALS Reversal. But it would be nice to be able to say something like, you know, if their course was two standard deviations better than it should have been by our predictive models or if they regained four points on the ALS functional rating scale after 12 months then we’ll call that a reversal. I still haven’t got that definition yet that I’m really excited about that the scientific community agrees as a good definition. But right now, my definition is you have to have a confirmed diagnosis of ALS and it has to be really obvious that you have regained motor function.

Seth: Excellent and to clarify, those are 23 currently living people?

Dr. Bedlack: Good question. So a couple of these people I don’t know if they’re still alive. Some of these folks I found back in 2010 and I have not been back in communication with them since. Once I get this Star Program up and running which I’m supposed to get a helper this fall and once I get that helper, we’ll be able to actually get this database built and get some surveys out there and really ramp this up, give it the amount of time that it really deserves. Right now, this is kind of a nights and weekends type of project. But once I get a helper, we’ll have somebody who’s devoted at least part time to really helping me grind through this.

I have been focusing more on the other arm, the ROAR arm because I know that there are so many folks who want to try things.  I have spent really the last year of nights of weekends trying to get that Lunasin trial off the ground. It actually took me quite a bit longer than I expected.  There were a lot more unexpected delays getting that off the ground but it’s finally up and running. We have been up for about a month and we have enrolled our first 16 patients in that now.

Seth: Excellent, I will invite Lori now to tell listeners how to ask a question.

Lori: Thank you. We have callers from around the nation. If you are already listening by phone, you can press one to indicate you have a question. If you are listening on computer, the best way is to dial in to the phone 516-590-0362 and then press 1 to indicate you have a question. You will be on hold and can still hear the show on the phone.

Seth: Excellent. Thank you, Lori. Though this is quite a night and weekend project, Dr. Bedlack tell us a little about your end vision for this project.  Will one assistant be enough or do you envision this being a larger program?

Dr. Bedlack: Well you know, Seth. I think it depends on how many of these reversals I can find. I’m hoping I could find a hundred reversals by some definition that other scientist will accept  as valid because I think if I can find a hundred, then I have got a big enough number to actually do some of that fancy genetic testing that I was talking about, something that’s called whole genome sequencing. Twenty-three is a pretty small number. I mean if they all had the exact same genetic abnormality, I might get lucky. But you know how things go.

The chances are if I’m lucky, most of them like the elite controllers will have the same genetic abnormality but it may be a stretch to think that they all have the exact same problem or the exact same abnormal gene that’s actually turning out to make them resistant to ALS. But yeah, no I mean it’s — I would love to be able to really devote the majority my non-ALS clinic time to this project. I am incredibly excited about it. I think it’s something totally different. As I said, I think there is a blue print in another field, HIV where this type of approach was very successful. I don’t think it’s completely crazy to think that this might lead us somewhere.

Seth: If it is completely crazy, we applaud this lunacy.

Dr. Bedlack: Well thanks.

Seth: It’s a creative approach and we are hungry for it. Just for our education, can you share any more cases studies that you’re working on besides the Dean Craft example?

Dr. Bedlack: Yeah. So I can tell you about some other reversals that I know about that are amongst the 23 that I have collected. So there is an ALS Reversal that was associated with the drug Aims Pro, A-I-M-S P-R-O, which is also known as hyper-immune goat serum. There is an ALS Reversal, a famous rabbi that’s been in the news that was just associated with the Brainstorm cell trial. There is an ALS Reversal associated with the Neural Stem, stem cell trial. There is an ALS Reversal associated with Lunasin which is the one that I have based my whole first trial around. There is an ALS Reversal associated with Protandim. There is an ALS Reversal associated with the drug NP001.

And the latest ALS Reversal that I came in contact with is detailed in the most recent ALSUntangled article on hyperbaric oxygen and this is a man who has put himself out online, so there is no problem revealing his name. His name is Kim Cherry and he’s got a website called ALS Winners. He really does appear to have ALS from his medical records and he really does appear to be getting better. The complicated thing about Mr. Cherry is that he is doing a lot more than just hyperbaric oxygen. He’s doing a very complicated cocktail including intravenous ozone, a number of nutritional supplements, dietary changes and attitude changes. And it would be a challenge to try to do a trial of exactly what he has done to himself. It’s been a challenge even to do this Lunasin trial because Lunasin is actually three products in order to do exactly what the ALS Reversal did on its three different products.

That is part of why this thing took so long to get off the ground. You know imagine trying to do a trial that had ten different major changes including things like hyperbaric oxygen and intravenous ozone and special diets and things like that, it would be difficult to get started, never mind difficult to actually measure the compliance of. There is a lot of interesting things out there that people are doing but those are the ones so far that I have seen at least one ALS Reversal with.

Seth: Thank you. At least by my count, four of those happened during the course of a regular phase two or phase three trial. I’m curious as a researcher, can you talk about why those reversals would not have approved the use of those drugs further?

Dr. Bedlack: Well I think, I wasn’t in charge of any of those trials but I think the reason that there wasn’t a lot more excitement about those particular cases was that it was just one case. I mean I think if you had three or five reversals, then I think you really could make an argument that there is definitely a subset of people that seems to be benefitting from this therapy. But when it’s just one, you have to wonder like go back to my different hypothesis. I mean was this person, did it just so happen to occur during this particular treatment? Might it have occurred anyway if the person wasn’t even in the trial? Again you would hope that if there was one of these things out there that is really causing ALS Reversals that we could find something that had two or three reversal and not just one.

I don’t know which of the three hypothesis is right but I think the fact that none of these treatments have more than a single reversal, it makes me think that one of the other two hypotheses, either the mimicker hypothesis or the genetic resistance hypothesis, is more likely to be accurate than the treatment hypothesis. But we are going to keep all of our avenues open and we’re going to explore them all.

Seth: Excellent. I will ask Lori to invite more questions.

Lori: Thank you. Again the phone number is 516-590-0362 and press 1 to indicate you have a question.

Seth: Thank you. Dr. Bedlack, how has this side project been reacted to in your ALS research circles?

Dr. Bedlack: You know I’m pleased to say that the people that are working on ALS around the world are very open minded and very collegial.  The first time I really kind of mentioned this in a public forum at a research meeting was this past December at the international symposium in Orlando.  It was met with a lot of very positive responses and a lot of good constructive criticism including this idea that I need to try to think more about how I define these reversals because at that time I was thinking about defining them as this four-point improvement in the ALS FRS score lasting a year and that was — I mean I don’t think that was met with a tremendous amount of enthusiasm. So I appreciate that people are open-minded enough to consider this as a legitimate way to look for treatments and also care enough to be able to give me some good constructive feedback to keep going back to the drawing board and making this better.

Seth: Can you share with us why that definition is so important? Isn’t any improvement good enough?

Dr. Bedlack: Well, Seth I a published this paper last year; this is what I was presenting at the meeting.  It shows that the natural history of ALS is not always a straight line in people. It turns out that it’s not that uncommon for people to have what’s called a plateau where they might go several months without getting any worse. And it’s even not that uncommon for people to have a small ALS Reversal lasting a short period of time like for example you know, a one or two-point improvement that lasted a few months. That’s a surprise to people because I think a lot of folks have this idea that patients with ALS they’re just going to keep getting worse. You know everyday they’ll be a little worse than they were the day before and that’s not necessarily true. The disease does bounce around a little bit.

We are trying to find something here that’s a little more robust than just that noise in the disease and that’s where it gets tricky. These 23 patients just telling their story is enough to make it obvious that something dramatic happened to them that is very, very unusual. But trying to pull patients out of a giant database, you’ve got to have some sort of way to define what you’re looking for to be able to pull it out of there. What I’m kind of shifting more toward is we have got these predictive algorithms, like this company called Origent has won the Prize for Life to be able to predict within a big database called ProAct, how patients with ALS are going to progress with very high accuracy. But it’s not 100% accurate.

And so one of my ideas for a definition is what if we changed the term from ALS Reversal to ALS Resistance? And we say, let’s look for people who do two standard deviations better than the model predicts they should have. That might be an easy way to pull out a large number of folks from a database and say now what is different about these people? What can we see? I mean were they older? Did it start in a different place? Were they on some different nutritional supplement that was captured in the original study that they participated in. So that’s kind of where I’m focusing my efforts now on the STAR part of the program is trying to figure out how to define this and just kind of playing around with different definitions and seeing what that does in ProAct in terms of numbers of people that it pulls out for me.

Seth: Excellent. For those new to the term ProAct, this is a Harvard generated database built of big data collected over the course of medical drug trials.  And it is currently, I believe, the largest single ALS database in existance. Thank you for that.  Does that definition, Dr. Bedlack, include those ALS patients who are living 15 and 20 years?

Dr. Bedlack: Yeah. That’s one thing I like about it Seth. I’m of course most interested in the people that got dramatically better but I don’t know if there is enough of them to give me the kind of information I need. So maybe if we could add to that mix, people that had really long plateaus.  Many of your listeners may know the story of Steven Hawking and I have seen the movie, the Theory of Everything. It seemed like you know for the first decade or so, he progressed pretty obviously and then it seemed like for the next four decades, if he progressed at all, it seemed like he was really slow. So he is one of those people that you would have built a predictive model and he would have beat it significantly. There is something different about people like that and maybe the term ALS Resistance is a better term than ALS Reversal in terms of getting the right numbers of people to do these kinds of studies that I’m envisioning.

Seth: Excellent. Thank you again. We will take an opportunity now to get a question from one of our listeners. Listener ending in 9832, you are on the air.

Caller: Hi, Dr. Bedlack.

Dr. Bedlack: Hello.

Caller: My question — just to continue with that conversation, ALS seems to be a big box that you get the symptoms, you get tested and then you’re kind of thrown in even though your progression for many patients are so different from each other. Do you feel like these are actually different diseases, someone who dies within six months or someone who can live six, seven, years or 14 years?

Dr. Bedlack: Yes, I do think that the term ALS is probably more than one different disease. The clear evidence for that is that we know 10% of patients with ALS actually have a bad gene that caused their disease and that 10% of patients, there is now more than 40 different genes that can cause what we call familial ALS.  Those are different genes. They cause different pathways to be abnormal and yet they all kind of lead to the same place in upper and lower motor neuron disease that’s disabling and life shortening. They all have different progression rates. So if we know familial ALS is heterogeneous, well then sporadic ALS probably is too. I mean there is probably more than one cause of sporadic ALS and there is probably more than one pathway that drives progressions in people with sporadic ALS.

What you are getting at is really sort of the difference between patients right from the start of the illness. I think that may be a separate question, but I think it’s an important one and I think biomarkers are what’s finally going to allow us to be able to tease that apart. So for the 10% of people of familial ALS, we have a biomarker. We know what sort of disease they have. We do genetic testing. We know that this person has C9 orf 72 ALS and that person has SOD1 ALS and the types of drugs that we try on those patients might be different. But maybe in people with sporadic ALS, a biomarker would be something like what Dr. Atassi at Mass General Hospital is working on with his PET Scan tracer that’s only picked up by activated microglia cells so that we can identify the subset of people who have that as the primary mechanism that’s driving their progression. Drugs that attach that mechanism, we would only test it in those people that have that mechanism active.

But I wonder though if it’s a separate question, there are clearly differences between people. What I’m interested in are the differences within people like why are there people who seemed to progress just like the average person with ALS for a while and then they either stop progressing or they are completely reverse and get better? You know that, I don’t know what that is. I mean that may be a different form of a disease or it could be like I say some host factor that makes them resistant to the same form of disease and lots of other people have or it could be one of the treatments that they tried that actually turned things around. I don’t know. I almost see that as a separate question but it’s a very important one.

Caller: I’m not familiar with your Lunasin trial. Could you expand on that and talk about the criteria to meet that trial? To be in that trial?

Dr. Bedlack: Yeah. So this trial is unusual for a lot of reasons. First of all, it’s unusual because of the way that we got the idea. Most of the time in ALS trials, our ideas come from things that we saw in a test tube or in cell cultures or in our animal models which are based on genetic mutations. As I said before, the idea for this trial came from a person who appeared to have sporadic ALS and did something and then got dramatically better. So that’s a model that we really haven’t used before in ALS.

Other things that are different about this, it’s very open. We’re allowing almost anyone with ALS to be in this. There are of course a few rules. I mean it is a one-year long study. Unfortunately if your doctor doesn’t think that you can survive a year, I can’t put you in the study because I need a year’s worth of data in order to get an answer. You also have to be able to use a computer and have internet access because we’re making patients full partners in this and we’re going to actually teach them how to measure things in themselves and how to enter their own data on a website. So the first thing that’s unusual is that it’s so wide open and part of why we can do that is with most trials we are looking for a tiny signal in a very noisy disease. If you are looking for 10% slowing in the rate of progression on the scale like the ALS function or rating scale, well you got to really try to homogenize your population as much as you can. We’re looking for a gigantic signal. We’re looking to see if anyone gets better on this. Do they actually regain motor functions over the course of a year? So we don’t have to worry so much about the noise.

We are also not going to have a placebo group. We definitely appreciate the need for placebo groups in phase three trials and especially when you are looking for small effects. But again this is a pilot study and we’re looking for a huge effect. So if at the end of a year, if five out of 50 patients have an ALS reversal, I’m not sure that anyone is going to say, well gee, you didn’t use a placebo. How could that be a placebo effect if people are actually reversing their ALS?

We’re also going to have very few visits required. Many trials are too burdensome for patients. Patients sometimes in my clinic look at trials and say, “Man, I don’t know if I can keep making monthly visits for an entire year and spend all that time in your clinic getting all those measurements.” So in this trial, we only have three visits, the screening visit, the one month visit and then the one-year visit. And everything in between is going to be patients on their own home computer entering their own data.  If they are not entering it, we get a little prompt from the system and we call them to try to find out what’s going on and they’re having trouble with their computer, have they just given up on the study? What is it?

And then finally, because we’re using Patients Like Me and because that’s publicly available information, anybody anywhere in the world can take a live look at our study. A lot of times patients tell me, “Gee, this study that you want to do, it’s a yearlong and you’re telling me it’s going to take a year to enroll. That means I won’t have any information about whether this drug worked or not for two years? That’s pretty frustrating.” Well, you can look at our data anytime you want. You can just go and Patients Like Me and type in Duke Lunasin study and you could see what’s happening to the people in our study, see if anyone is having an ALS reversal.

Caller: Wow. That sounds incredible. We’ll watch closely. Thank you for your time.

Dr. Bedlack: You bet. Thanks for your questions.

Seth: Thank you, caller, for the great question. Dr. Bedlack, before we wrap up, our callers are always curious about how they can personally support your research. How can we do that?

Dr. Bedlack: Well as far as the ALSUntangled program, we’re fortunate now to have two great sponsors, the ALS Association and the Motor Neuron Disease Association. With their help, I think we have all the financial resources we need but we definitely need those ideas to keep coming in. If you get ideas about things that we haven’t thought about yet, be sure to send those in. You can see on our website all the different ways you can get those ideas to me. Be sure to go on there and vote under the open review so that we know which of the more than 200 things that people have asked us about, do the most folks care about? And be sure to download and read our reviews because that’s one of our measurements that we used to determine if the program is actually useful. You know how many people are actually reading our reviews.

And then when it comes to ALS Reversals, this is right now an entirely patient funded project. We’re blessed to have a family, the Larry Vance Hughes ALS Foundation that is the primary sponsor of that program.  As the program grows, we probably will need some additional help there and certainly if we get some interesting pilot data, we’ll be able to apply for grants like to the ALS association and the NIH. And the other thing is if you’re out there and you hear about ALS Reversals please let people know that I’m interested.

One thing that’s been amazing to me is a lot of these folks are — they are sort of anti-doctor now. Some of these folks that I think might have ALS reversals that I haven’t been able to confirm yet, what I hear through the grape vine is that they are not interested in talking to doctors or scientists anymore, because I guess in the past, they were just kind of rebuffed. I do still hear that sometimes patients — their ideas are not taken seriously.  But I am genuinely interested in these folks and I’m coming at this with a totally open mind. I just want to hear their story and ideally get their records and see if I can confirm what happened to them because I do think there could be something important if we can get all these patients together. Those are some ideas that I have Seth along those lines.

Seth: Thank you. One final question, but do want our callers to have every opportunity, Lori?

Lori: The phone number is 516-590-0362 and press 1 to ask a question. We’re going to take our next question at this time from caller ending in 3662. Go ahead, you’re on the air with Dr. Bedlack.

Caller: Hi Dr. Bedlack. I was just wondering if you had any experience or opinion on this new Japanese approved drug called Radicut.

Dr. Bedlack: Yeah. So it’s also known as Edaravone. It’s a free radical scavenger and it’s an interesting history. So you may know that there were some preliminary studies on the drug in ALS that didn’t show any benefit and then they kind of went back and tried to pull subgroups out of those preliminary studies and see if there was a subgroup that might have benefited. After some manipulation of the data you are able to find a sub group and then they designed another study just of that subgroup, that’s called enrichment. And it’s an interesting way to do things. The problem is knowing whether the results then generalize to everybody else with ALS.

In my opinion I think because this is such an unusual paradigm, the results of that study really do need to be replicated. Hopefully somebody in United States is going to take the lead on that. I think they are. Unfortunately, it’s not the cure for ALS but there is a suggestion that it could slow it down. I definitely think it’s something that needs that needs to be studied further, be replicated. But in my opinion, I don’t think right now that the data is strong enough to say that everybody with ALS should take that. I think that there are still a lot of questions that I have about it than I’d like to see it replicated in a more traditional study.

Caller: Great. Thank you. I can’t wait to pour through the website and see all the other information on there.  

Dr. Bedlack: Well, I hope you like it.

Caller: I appreciate your work.

Dr. Bedlack: Sure thing. Thanks for your call.

Seth: Thank you, caller. Now to wrap up Dr. Bedlack, we have talked a lot about your specific focus but stepping back and looking at ALS as a community and as a larger problem, is there a great single opportunity for ALS families to contribute and get involved? Or should we simply focus researcher by researcher?

Dr. Bedlack: No. I mean I think it would be awesome if everybody with ALS tried to get involved in a study. So sometimes people say well I can’t find a study that I can be. Well there are some studies that everybody with ALS can be in for example the National ALS Registry and there is a group called Create, C-R-E-A-T-E. If people want to know what that’s about, just Google the word Create and then the words Rare Disease Clinical Research Network. It’s a national institute to help sponsor a group that is very interested in trying to do a whole genome sequencing in as many people with ALS and other motor neuron diseases as possible and try to tease out why do they look different?

And it goes back to that other caller’s question about “Can we identify ALS subtypes?” That would be so helpful. And then there are clinical trials. I mean there is more clinical trials going on now that I have ever seen in the history of ALS and some of these are just incredibly exciting. You probably saw some of these papers that have me with a big smile on my face. I mean one of them is a paper from a doctor at John Hopkins that was trying to identify the cause of sporadic ALS.  He was looking at something called Human Endogenous Retro Virus- K. Did you ever talk about that on your show?

Seth: On an upcoming episode, we will cover that. But no, we have not yet.

Dr. Bedlack: Well I don’t want to steal anyone’s thunder but it’s a very preliminary finding but it could turn out to be the most important paper in the history of ALS if this can be replicated, because it might have told us what the cause of at least some sporadic ALS is. And it might have identified a way to actually stop that form of sporadic ALS. Stay tuned on that. Then I’m incredibly excited about some of the things that I see in terms of biomarkers. I personally think that once we have some biomarkers, the field is going to really explode because then we’ll be able to subtype people and we’ll be able to pull out folks that are much more likely to respond to a particular drug that attacks a particular mechanism. So yeah, I have been in ALS for 16 years Seth, and I think this is the most exciting — this particular year that we’re having right now is the most exciting that I have ever seen.

Seth: Given that this listener base is not very good at being a patient or staying tuned, can you speak a little bit more about that finding and that paper?

Dr. Bedlack: Yeah, sure. So again we have struggled to fix sporadic ALS in my opinion, in large part because we don’t know the cause of sporadic ALS. It’s hard to fix something when you don’t why it’s happening in the first place. A clue that Mother Nature gave us 20 years ago was that there were a bunch of young men who were coming forward with what looked like ALS but were also HIV positive. And in those patients, when they were put on what was at that time the new cocktail therapy for HIV, not only did their HIV virus titers drop way down but their ALS like disease went away.

Everyone got real interested and said wow, could there be a retrovirus, which is what HIV is, that actually causes sporadic ALS? They started looking and looking for retroviruses in patients with sporadic ALS but what everybody was looking for was called an exogenous retrovirus, a retrovirus like HIV that comes from outside of us.

Unbeknownst to me, we actually all have retroviruses inside of us. I did not know this until I read this paper by this group from Hopkins. Our ancestors all got exposed to retroviruses and they either died or they incorporated those retroviruses into their DNA and they became what is referred to ask junk DNA. And no one has thought anything of it. They just thought it was just kind of sitting there not doing anything. This guy at Hopkins said “I wonder if one of these endogenous retroviruses could become reactivated to cause sporadic ALS?” And so, it is a very small study, but in 10 out of 10 people with sporadic ALS, there was evidence of reactivation of a retrovirus called the HERV-K and in nobody that they looked at without sporadic ALS was this retrovirus active.

When they took that retrovirus and they put it on motor neuron in a dish, the motor neurons died. When they gave that retrovirus to animals, the animals developed what looked like ALS. And so, this could be huge. It needs to be replicated in a much bigger sample but they are already in the process of doing that at John Hopkins and furthermore, when they find now people with sporadic ALS who have the activation of this retrovirus, they are starting anti-viral therapy on them, an HIV-like cocktail in them. So I think this is an awesome study to keep our eyes on. I’m incredibly excited about it.

Seth: We are too.  Dr. Avindra Nath will be on our show May 17th to talk more. Thank you for that.

Dr. Bedlack: Yeah, that’s going to be great. He’s a brilliant guy.  You’ll really like him.  

Seth: Thank you. Dr. Bedlack, we are incredibly grateful for your work in making time today.

Dr. Bedlack: It’s my pleasure, Seth.

Seth: Well we look forward to hearing more about your breakthoughs. Lori, can you talk a little about our next episode?

Lori: Our next show for ALS Crowd Radio will air on Monday 9th at 4:30 PM Eastern Time. It will be live from Washington DC at the National ALS Advocacy Day and Public Policy conference. We will interview both Barbara J. Newhouse, President and CEO of the ALS Association and Dr. Lucie Bruijn, Chief scientist for ALSA.

Seth: For now again thank you to Dr. Richard Bedlack for his nights and weekends and days. We’re grateful to have you on the team Rick.  

Dr. Bedlack: Well thank you so much, Seth.

Seth: All right, until next time.

Dr. Bedlack: Thank you.

ALS Crowd Radio S2:E3 Dr. Paul Cox, PhD, Institute for Ethnomedicine: Environmental Causes of ALS

Dr. Paul Cox, PhD
Brain Chemistry Labs – The Institute for Ethnomedicine
Interview Date: April 28, 2016

S2:E3 Dr. Paul Alan Cox, Ph.D. speaks about his research approach in studying people to find and fight the environmental causes of ALS.  His research has proven the strong correlation between exposure to an environmental toxin called BMAA and ALS related symptoms.   Large doses of the dietary amino acid called L-serine may reduce the risk of BMAA exposure and delay the onset of symptoms.  Dr. Cox explains the phase 1 trials that have already taken place for L-serine and the urgency to move to phase 2 trials in 65 patients.  For more information, see 

ALS Crowd Radio Episode with Dr. Cox:

Full transcript:

Seth: Hello and welcome to ALS Crowd Radio Season 2 Episode 3. I am your host, Seth Christensen, here with my co-host, Lori Wangsgard.  

Lori: Welcome to this show. Throughout our discussion with Dr. Cox if you have a question please dial in at 516-590-0362 and then press 1 to indicate that you have a question and we will get to you. Now, I would like to give a proper introduction to our guest.

Dr. Paul Alan Cox is a Harvard Ph.D., Paul Alan Cox has spent his career searching for new medicines by studying patterns of wellness and disease among indigenous peoples. For these efforts, TIME magazine named Cox one of 11 “Heroes of Medicine.” His work with indigenous peoples in preserving their island rain forests won him the Goldman Environmental Prize. Cox has published over 200 scientific papers and four books.

He has held academic appointments at the University of California, Berkeley, Brigham Young University, the University of Melbourne, Uppsala University, the Swedish Agricultural University, and the University of Illinois, Chicago, and served as Director of the Congressionally-chartered National Tropical Botanical Gardens in Hawaii and Florida.

Cox founded Seacology, the world’s premier environmental non-profit organization for island conservation, headquartered in Berkeley, California. Through partnerships with indigenous people, Seacology has now saved over 1.3 million acres of island rainforests and coral reefs in 56 nations. Throughout Polynesia, he is known by the chiefly title Nafanua.

Cox currently serves as the Executive Director of the Institute for Ethnomedicine in Jackson Hole, Wyoming. His research there is focused on finding and fighting the causes of neurodegenerative disease including ALS and Alzheimer’s disease. Welcome, Dr. Cox.

Dr. Cox: Thank you very much.

Seth: It’s an honor to have you with us Dr. Cox. Thank you for making time in your busy schedule.

Dr. Cox: Of course, Seth. It’s a pleasure to be with you. Thank you for inviting me.

Seth: Well, I’m thrilled to have you with us. Lori went over a formal introduction but we don’t know from that bio how you came to study ALS. Could you share that with us?

Dr. Cox: Sure. I’m an ethnobotanist. My training is — I had to work with indigenous people to study their patterns of wellness and disease with an idea or an eye to coming up with new pharmaceutical treatments that can benefit people everywhere. I began in cancer research, moved in the 1980’s to HIV AIDS, and that was a deeply moving experience to me. HIV AIDS was a different sort of disease in the 1980s than it is now. Many people were dying and there seemed to be more than death sort of a loss of them being treated as persons and being treated with the dignity and respected that all people deserve. So I became emotionally attached to the HIV AIDS community.

For a while I think I was only one or two straight members of the AIDS Research Alliance Board. And it was a deeply emotionally moving thing to me. We discovered a new drug candidate called Prostratin in my work with indigenous people. Once that got launched down the pharmaceutical pipeline, I wanted to find another disease that I could work on that had the same sort of sense of hopelessness, maybe a sense that there hadn’t been any useful drugs discovered, maybe the possibility that a new approach that new eyes could shake loose some new ideas. I’m also very willing to work on what I call high risk research, any research that has only a very small chance of success and a high risk of failure. So I started thinking about different diseases and decided to study ALS.

So in the 1990’s, late 1990’s I quietly read everything I could find about ALS. I tried to educate myself about the illness. I decided that I would start my research by studying indigenous people who had the highest rates of ALS in the world. So with my colleagues I began very quietly in the late 1990’s and early 2000 taking expeditions to remote villages in Guam where people suffered from an ALS-like disease at about a rate of 100 times what it occurs here. One of the villagers were in about 25% of the people were dying of an ALS type disease. And so I thought perhaps if I could figure out what was going on in that village that it would give greater insights into ALS in general.

Seth: Wow. Over these years has the field progressed or have there been major milestones that have propelled your research forward?

Dr. Cox: Well yeah. The first objective was to try and understand what was happening in these villages and I think that’s a very different approach to the disease and traditional research. The only drug that’s been approved by the FDA for treatment of ALS is riluzole, also marked at Rilutek. That was approved by the FDA in 1994 and I just really didn’t see much coming out of the drug pipeline. A typical research program would be to develop a mouse model of the disease and of course in 1993 we saw the advent or 1994, the SOD1 mouse model. And then you screen a whole host of different pharmaceutical compounds against that model to see if you can improve the animal model of disease.

This was very different. We were dealing with people. It turned out there had not been prior ethnobotanical work of studies with these people although there had been a lot of neurologists through the years that had become very interested in Guam. They were all clinicians. As an ethnobotanist, I’m trained to live with the indigenous people to conform my lifestyle to their culture, to attempt to learn their language and we like to think that people tell us things that — and we gain, understand this way, that would not be gained in a clinical setting.

I think the first milestone that we gained is one that we brought the table because of my botanical training. We became very interested in a neurotoxin called BMAA. This had been isolated from the seeds of cycads. These are trees that people used the seeds to make tortillas. They make flower out of the seeds and use it to thicken stews and make dumplings.  We found two things. First of all, we were very interested that the indigenous people eat flying foxes. These are very large bats. This had not turned up in any previous studies by medical researchers. And then we also found that they have specialized roots in these trees that harbor photosynthetic bacteria called cyanobacteria.

So we cultured these roots in our laboratory.  The cyanobacteria we found produces the toxin BMAA. We then looked at museum tissues of these flying foxes and found a very strong accumulation of BMAA in the flying fox tissues. So that was really sort of the first milestone I guess would be to confirm suspicion of previous researchers that this toxin, an environmental toxin might play a role. But this research came at some cost because we realized really to our horror that cyanobacteria just don’t occur in this little island in Guam. They occur throughout the world. We got our colleagues around the world to send us laboratory samples of cyanobacteria, isolated from lakes in New Zealand, the Baltic Ocean, the streams in Bermuda, everywhere. And we found that of 30 different types we sampled I think 29 contained the toxins.

It was a bit frightening to me at the beginning to realize that people could be exposed to this toxin anywhere in the world. They wouldn’t have to live in this village in Guam. These people in Guam got a very high dose, but low dose exposures might be different elsewhere. We then were very fortunate being able to obtain autopsy tissues from Chamorro people in Guam who had died of this ALS-like disease. We found that all of them had high amounts of the toxin in their brains. This work was replicated and extended by the Miami Brain Bank, Dr. Deborah Mash who found that in 13 out of 13 ALS patient brains she studied in Miami, that all 13 had significant amounts of this toxin, BMAA. So this did not prove that BMAA exposure could trigger ALS, but  it certainly encouraged us to continue the research.

Seth: Incredible  As a side question, are there other hot spots worldwide other than Guam for  ALS?

Dr. Cox: They are indeed. Yes, there are. There is a hot spot in a remote part of Japan, called the Kii Peninsula. We have traveled there several times. We have been studying carefully the diet and lifestyle of these people. We have found BMAA in their food supplies and water supplies but are not quite ready to publish that. We have not yet confirmed BMAA in brain tissues with patients who are in Kii, so we are still working on that. There is another place in New Guinea that has a high rate of ALS. We would very much like to get there. It’s been in a bit of a military area and it’s difficult for us to get permission to go there.

The other thing that was quite interesting to me, and I was fascinate Seth, with reports of US Military personnel who had been deployed in the first Gulf War in 1992 through 1993. About ten years later when they returned, many of them started experiencing ALS and it was about two to three times the rate of soldiers that had been trained in the same way but not deployed to the gulf. Together with ALS researcher Dr. Walter Bradley who was chairman of the department of neurology at the University of Miami Medical School. We went to the gulf. I thought this might be a way of disproving our hypothesis because we typically think of cyanobacteria as the sort of the blue green scum that occurs on ponds or reservoirs during warm weather and here we’re in the desert area. But we got into Qatar, I saw an unusual soil crust, I poured my water on it. It immediately started photosynthesizing.

We since discovered that parts of the low-lying areas of the gulf, deserts are up to 87% are covered with cyanobacteria crust, which produced BMAA. So our hypothesis was that soldiers marching behind tanks going through the desert, were inhaling aerosolized cyanobacteria and getting exposed to the toxin that way. The epidemiology is quite interesting. The ground troops indeed did experience this sort of sudden spike ten years later of ALS, but so did helicopter mechanics. We puzzled, why helicopter mechanics? It turns out that the helicopters in that first deployment could only fly 24 hours or so before their engines were clogged with dust. When they land the helicopter mechanics were just covered with dust from the rotor blast and from ripping the part of the engines.

So we include US Military Personnel now in our studies and we have been very interested in the possibility that people could be exposed to the toxin either by inhaling dust from cyanobacteria in the deserts or by inhaling aerosolized cyanobacterially contaminated water from lakes and reservoirs or by eating shellfish that had been contaminated with BMAA. So we have been working very carefully trying to figure out what are the most likely exposure roots of people with these toxins.

The picture that’s emerging Seth is that we believe that at least some points of ALS result from gene environment interactions, their interaction between having a vulnerable genotype and then having exposure to this toxin that serves as trigger. The BMAA hypothesis is that the genotype is like a gun and the environmental toxin is the trigger. So our focus, which is quite different from mainstream ALS research, is to try to find drugs that can block that trigger. That’s led to our current investigations of the amino acid L-serine.  

Seth: Thank you for that answer. We want to dig further into the unique approach of the Center for Ethnomedicine.  But first we’ll pause.  Our listeners are listening both by phone and over the computer. For those who have a question for Dr. Cox I’ll have Lori tell you how to ask.

Lori: To ask a question, dial 516-590-0362 and press 1 to indicate that you have a question and you will be on hold while you listen.

Seth: Thank you, Lori. Now as you mentioned you’re a bit different in your efforts from mainstream research. As Lori mentioned you are located not at a university, but we know you are associated with other researchers around the world.  Could you tell us a little more about how the center for ethnomedicine works?

Dr. Cox: Sure. Unfortunately, we have just rebranded ourselves. We call ourselves now the Brain Chemistry Labs because people were struggling trying to figure out what on Earth ethnomedicine is. So we’re the Brain Chemistry Labs at the Institute for Ethnomedicine in Jackson Hole, Wyoming. What I did, when I started realizing that we had a lot of different interesting aspects of the story that was immerging I felt that we needed to have an interdisciplinary global group of researchers all working together. I felt that no single discipline could succeed in trying to discover a new ALS drug.

And so I have gone around the world to various researchers in different areas including chemistry, neurology, synthetic chemistry, oceanography — I cherry picked the top minds in the world. So I said you know, you’re doing a wonderful work now. I asked them would you please stop and come join with me? I’m trying to find a cure for ALS. I Tell a little bit about our research to the person, and they have always agreed. So we have 50 researchers now around the world in 28 different universities or government labs. I think we’ve got 12 or 13 countries represented. Everybody checks their egos at the door because you may be good in neurology but not know a whole lot about oceanography. It’s been sort of fun to see researchers share and help each other.

One of my frustrations with drug research in general is that in a typical pharmaceutical model, the scientists are siloed up. They’re not sharing information. I have worked with now five or six pharmaceutical firms during my career. They’re great research organizations but you have to sign a pile of confidentiality agreements about six inches thick. And I don’t think that’s a good way to find drugs. It’s to sequester information. Furthermore, I have been concerned about using the for-profit model as a mechanism of drug discovery. A lot of people say to me wow, given your result, why don’t you form a biotech? And the answer is well because I care more about patients than profits. I don’t really don’t want to worry about some costs. If we find something that doesn’t work, we just drop it that day, we don’t pursue it. I never want to worry about a shareholder. I worry about the patients. That’s our whole goal here.

The 50 of us are communicating all the time. I mean this morning I was talking to about 12 researchers ranging from Miami to San Francisco and Phoenix. We share experiments. We get together at least once a year, all of us for a no-holds conference and basically we just have one single wish which is to find new therapies for ALS. We basically created a virtual pharmaceutical firm without investing the brick and mortar and all the cost of marketing. We have a faculty of 50 on our little virtual pharmaceutical firm and it’s been a terrific experience for all of us.

Seth: Wonderful. We love to see new ways of attacking this problem. Now, does this mean that you do not pursue FDA approved trials or something different.

Dr. Cox: Well that’s been the great thing is that the FDA has been fabulous with us. If we discover something, our goal is to go immediately as soon as possible to human clinical trials because that seems to me to be the major stumbling block in translating new research discoveries at the lab bench to this patient bedside. So we have now — let’s see, we’ve had two different trials approved by the FDA. The first one took us five to six weeks. The second one took us four days which I think was a record. We’re just finishing that trial up and now we’re moving towards a phase 2. I think part of this is because the FDA contrary to some rumor, not the bad guys. They just want to protect people and patients particularly from hokey stuff and things that can hurt your health or damage them. We give the FDA the information they need.

Our clinical workers and researchers are topnotch. Again our clinicians are really four centers now, Dr. Walter Bradley at the Miller School of Medicine University of Miami, Dr. Robert Miller the Forbes Norris ALS MND Clinic in San Francisco, Dr. Elijah Stommel Department of Neurology in Dartmouth Medical School and Dr. Todd Levine, Dr. David Saperstein at Phoenix Neurological Associates. These guys are all really well regarded in the research community, well-regarded by the FDA and so — no, we are pursuing and have been granted licenses by the FDA to conduct human clinical trials. It’s just that our trials are coming from a very different place. They’re not coming from mice models. They’re coming from studies of indigenous people. So far, we’re pretty excited about the progress we have made.

Seth: Thank you. We will paue again to tell our listeners how to ask a question.

Lori: The phone number to call in is 516-590-0362 and push 1 on your phone so we know you have a question.

Seth: Thank you. So Dr. Cox, once you formulated the BMAA theory, how do you proceed to test that theory?

Dr. Cox: Well maybe I can give you a little bit of sense of our first FDA approval of L-serine to test in human clinical trials. We discovered with our colleagues in Australia Dr. Rachael Dunlop and Dr. Ken Rodgers that BMAA can be mistaken by our cell machinary as  a normal amino acid and insert itself in the proteins and cause them to misfold, untangle, to aggregate. In fact, ALS is considered a tangle disease along with Alzheimer’s disease, Parkinson’s, Supranuclear Palsy, Pick’s Disease and a half dozen others. And we got very interested in how this tangling is caused. We discovered together with our Australian colleagues that by increasing the amount of one of the normal dietary amino acids, L-serine in cell culture that we could actually stop neuronal cells from dying and these proteins from misfolding.

We then contacted Dr. Joy Goto who is chair of the Chemistry Department at Cal State Fullerton. Dr. Goto although she’s a chemist is an expert on studying fruit fly responses to toxic insult. And so she quickly confirmed these in vitro results with a fruit fly model. When exposed to BMAA within three days, fruit flies start having inability to fly, gait paralysis. When we added L-serine to the fruit fly chow, they didn’t have that problem and we found that we could even – rescue some of them up to 24 hours after hitting them with BMAA.  So armed with that in vitro data and the in vivo fruit fly data, we went immediately to the FDA.

Now we sort of do everything backwards at our laboratory because the typical academic program is first of all, you get the idea, then you write a grant and you wait a year or two to get your grant approved and then you do the research and then after a year, you publish and then after you publish maybe you somehow find some way to work with a clinical researcher and live in the clinic. Here, we do everything backwards. We immediately took these results straight to the FDA, said please approve our request to begin human clinical trials, FDA approved within a week. We brought in our team of clinical researchers Dr. Todd Levine and Dr. David Saperstein at Phoenix Neurological Associates in Arizona and then Dr. Robert Miller and his team at the Forbes Norris ALS MND Clinic.

We begin dosing patients with L-serine in different doses. As you know, a phase 1 trial is basically to confirm that the drug does not harm patients or worsen their disease. We have just finished this trial now. We are working on the publication. The good news is that it really doesn’t appear to us that they’re really serious or significant complications to patients from taking orally L-serine and we’re now preparing a phase 2 trial. We’re trying to raise 1.5 million dollars to do a 60-patient trial to see if L-serine can slow the progression of ALS disease symptoms. And we’re all pretty excited. I mean we don’t — we really won’t know until it’s been proven in a clinical that it works. But that led us to do some interesting primate trials in the island of Saint Kitts.

Seth: Wow. Now is L-serine an approved drug or is it a supplement? Tell us more about L-serine.

Dr. Cox: Well what we decided to do is I wanted to see — I mean I have some reservations about the mouse models and rodent models. I mean my hat is off to all the great people who work on them. So this is no way a critic of their work. But where our focus is on moving so quickly to human clinical trials, we wanted something that was closer to human beings to get a heads up on how L-serine might work. So we started studying vervets on the island of Saint Kitts. Saint Kitts is a Caribbean Island. Vervets were introduced there from Africa maybe 100 years ago. They have gone wild. They don’t belong in the island. There is 30 or 40,000 and so there is a couple of research colonies on Saint Kitts. These are very nice places where the animals are housed in groups and big enclosures. It really feels more like a zoo than a research facility. The animals are happy. The wild vervets try to break in there.

We went through an institutional review board, raised the funds from our board of trustees in the John and Joseph P. Lewis Foundation because it’s expensive to do primate trials. So we started supplementing, feeding these vervets on an extended period. What we noticed in the village, and this is work done by Ralph Garruto and others at NIH, if these villagers left these villages in Guam had such a high rate of this ALS-like disease that they could move to California and be there for 15 or 20 years and then come down with the paralysis and muscle denervation characteristics of ALS, meaning that there is a long latency to this disease. So what we tried to do is compress into 140 days about 15 to 20 years of Chamorro exposure to the toxin.

Each day the animals would be handed. We just give him a banana. Inside the banana would be a place to powder test substance. It’d be either BMAA or rice flour for placebo or BMAA plus Serine and then we had a very low dose of BMAA. We did this for 140 days. We are astonished by the results, replicated the study and we just published that at the end of January in the Proceedings of the Royal Society of London, series B. We’re pretty excited about the publication. What we found was that after 140 days of chronic dietary exposure to BMAA that these animals started developing neuropathology that’s strikingly similar to what the Chamorro people have in the villages. We also found that when we added L-serine to their diet that that significantly reduced the amount this neuropathology.

Armed with that and our findings from the phase 1 trial that it’s safe for ALS patients to take Serine in oral doses up to 30 grams a day, we now prepared the protocols for a phase 2 clinical trial on L-serine to determine if it can actually slow disease progression in ALS patients. There have been a few anecdotal reports of patients that claim that it’s helped them or it slowed their progression but we really won’t know until we see if it works under a really rigorous clinical setting. And that’s what we have designed. We’re hopeful that as soon as we can raise the funds that we can get permission from the FDA and launch this trial. And I have to push a cautionary note here which is that we totally support the FDA process and it’s really important for us to know if it works or not in the clinical setting before we get everybody all excited because at this point don’t know.

So please I’m not encouraging patients to add L-serine or go out and buy anything else to take. What I’m saying is that we really want to find out as soon as possible if this shows a benefit. And if it does then of course, we’ll be pushing the FDA for preliminary approval. Then if it doesn’t then we’ll drop this and move on to the next drug candidates. That’s the way our research works and it really doesn’t matter if we can cure every fruit fly or mouse or monkey in the world unless it works in the clinic. Again our focus has been to accelerate human clinical trials as quickly as possible.

Seth: Do you recall the numbers from your primate research?  Were all of the vervets dosed with BMAA or would those — did they develop symptoms?

Dr. Cox: Well that’s a really good question Seth and the answer is none of the animals developed symptoms. What we found was neuropathology that would be preclinical that would be consistent with Chamorros who will get sick but haven’t done so already. So our findings were based on neuropathology and not signs in terms of behavior.  What sort of astonished us I guess was that all of the BMAA fed animals developed neuropathology but those that we had supplemented their diet with L-serine had a 50% to 80% reduction of neuropathology. So we all feel very strongly that this is something we need to follow-up quickly on now to see if we can see if it works in the clinical and human beings are not and we are ready to go as soon as we can raise the 1.5 million dollars.

Seth: Thank you for that clarification. At this point, we will pause to take the question of an online listener.

Dr. Cox: Thank you.

Lori: We have a question from a caller ending in 6431. Go ahead. You’re on the air with Dr. Cox.

Caller: Thank you so much. You can hear me?

Dr. Cox: Yes, I can. Thank you.

Caller: Okay. Dr. Cox, thank you so much. It is so exciting to hear about your work as a person who has an ALS relative, I just can’t thank you enough for your collaboration across the globe with people concerned not about the bottom line profit but about helping people. Thank you. Now, my question is, does ALS manifest itself the same way, did it in Guam as it has in other places as it does here in the US? Is it the same nature?

Dr. Cox: Oh, that’s a really good question. The answer is the Guam disease is somewhat unique. What happened was in the aftermath World War 2, when the United States retook Guam from the Japanese who controlled it, US Army physicians started noticing these patients with ALS-like symptoms and started counting them up and realized to their horror that is 50 to 100 times the rate of ALS elsewhere. But the disease has some distinct differences in Guam and elsewhere. Sometimes the patients in Guam show symptoms of Alzheimer’s disease. Sometimes the patient shows symptoms of Parkinson’s. Some unfortunate individuals have symptoms of all three.

Clinically it was different and neuropathologically is different too because the Chamorro people show in their brain tissues those who have the disease brain plaques and tangles that are quite characteristic of Alzheimer’s disease but which we typically don’t see in abundance in ALS patients. And what we reported in our paper in the Royal Society of London in January was that we had found these brain tangles and plaques in the brains of these vervets that had been chronically exposed to through their diet to BMAA. We’re still continuing work with the Miami Brain Bank looking now very carefully for Neuropathology consistent with ALS and we don’t know yet but we are excited to find out if that occurred.

Caller: Thank you. My final question would be you say that you’re in need of funding to go to the next step. Will this happen by huge grants or is there any way individuals can participate in this? What will be helpful to you?

Dr. Cox: Right. Well thank you very much. And again Seth let me say that my purpose here in participating this call is not to raise funds. Look we are in a not for profit organization. And so when ALS patients come and see us or talk to us, I tell them we look forward for you. That’s it. There is nobody else. I mean I think there is very few people in the world who wake up every morning, thinking about ALS other than ALS patients and families, and we’re there. So the message really here Seth for the listeners is one of hope that there is a group of people in Wyoming that are augmented by 50 people around the world. We are all over from a variety of disciplines and we are very, very determined to keep pushing forward.

That said, as a non-profit organization, we’re supported about 40% of our funding comes from our board of directors. None of whom have ALS or ALS in their families but they are just public spirited people. About 20% comes from research foundations and a remainder from well meaning individuals. Everybody that donates a dollar to us, I sent him a letter every month, to keep them up on the research. But so far, we have been very fortunate, we have a fairly small budget. We have been spending about 1-1/2 million dollars a year plus whatever it costs for the clinical trials. But at this point, we need to do a clinical trial. I have been looking for 2.5 million for 120 patients. None of those funds would be used by us. It all goes to cover hospital cost and clinical cost and trial.

That’s a bit daunting. So we have reduced it now to 65 patients to 1.5 million dollars and as soon as we can get these funds, we’d be able to go forward and I’m quite hopeful that we can find this from private sources. Our research is so different from mainstream ALS research. Most of the mainstream researchers have been studying genetic determents of ALS and as you and your listeners know about 8 to 10% of ALS patients have a family history and about half of those have an identified mutation, like SOD1, or TP43, or FUS.  

Our focus is on sporadic cases where there is no family history but we are outside not only of the mainstream research. We’re outside of mainstream funding. And so we have been raising the funds on our own and it’s been just a wonderful thing. There is a family and Logan Utah. Lee Badger was a beloved member of the Logan Utah Community who owned Lees Marketplace, the chain of grocery stores.  When he passed away from ALS his family decided to fight it. So they started a golf tournament in Logan Utah and I think that’ll be June 3rd this year and everybody comes up and has a good time in that golf tournament in Logan called the ALS Challenge has been supporting our research now for four or five years. And there is just other people that do wonderful things to try this out.

But again Seth, it was not to try to raise money through this interview but just to let people first of all that there is hope, secondly that there’s people that are thinking outside the box and approaching this for a very different angle and third that we have made some success now. We have really seen some real progress particularly with the primate study and particularly with the phase 1 clinical study that’s pushing us forward now to do a phase 2 study. Once we get the funding, I’m quite hopefully that we can finish that study within 12 months and we’ll know yes or no can L-serine help slow the loss of muscle and neurons experienced by ALS people.

My personal goal was to — I don’t know if I can cure ALS but I think we got a shot at slowing it down buying patients more time with their family and their loved ones and buying more time for where they can stay functional and my real dream would be to change the landscape of ALS so it can be managed as a chronic disease much like multiple sclerosis is already. I think that’s possible. I think that’s within our grasp and I’m optimistic and I want to pursue every avenue I can to see if we can achieve that.  And if we fail, well we fail. But it’s a great cause and one that we’re fully invested in.

Seth: Thank you. Thank you, caller for your question. Now Dr. Cox, many of our listeners are unable to speak or call in over the phone. We have a number of online questions that Lori will read.

Lori: Thanks. We have a series of three questions from a listener that kind of go together. What does the L-serine treatment look like in humans? What would the dose would be? What are the side effects that it may have and how can an ALS diagnosee get involved in your clinical trials?

Dr. Cox: Well let me start with the first one. L-serine is a common amino acid in our diet. It’s rich in soybeans and soy products like edamame. It’s rich in sweet potatoes and pork and eggs, bacon. So we’re already getting on average about 3-1/2 grams of L-serine from all forms of our diet. That’d be average for Americans. In our phase 1 trial have orally dosed patients up to 30 grams per day and doing it twice a day and what we’re still working on the manuscript. We want to publish it and of course take to a peer review. But the preliminary result suggests that patients tolerate that well. Side effects that we have noticed in patients include bloating, nausea in a couple of patients.

I cannot recommend a dosage because I don’t know and furthermore it’s not been approved by the FDA. So again my advice is to just stay tight until we can find out if it’s working or not because I don’t want to do anything to suggest any practice that people would adopt that has no efficacy. For the phase 2 trial, if we can get the funding quickly and get it approved quickly and I’m optimistic that maybe we can do both of these things. The trial will occur at a couple of centers. I think it’ll occur at Dartmouth Medical School, occur at the Forbes Norris ALS Clinic in San Francisco and occur at Phoenix Neurological Associates and a couple of others.

Basically my best advice is to just stay in close touch with your physician and as these opportunities become available, I’m sure your physician will let you know. The other place you can look for news is we have a website which is E-T-H-N-O- People are happy to look there. We always are delighted to welcome ALS patients at our laboratory in Jackson Hole, we’re just off at Town Square opposite the elementary school. Although we can’t advise people with medical conditions because we’re all PhDs, we are not MDs, we delight in sharing our research with patients. We have a number come up and see us and we’re not in a position to diagnose or prescribe but we do have this really heavy hitter neurologists in Dr. Walter Bradley.  He’s sort of like Yoda in terms of the ALS Community. I mean he has been awarded as the top ALS clinician researcher. Dr. Robert Miller in San Francisco, it’s the same thing. We’re like having Yoda and Obi-Wan Kenobi on the team here. Dr. Miller’s clinic in San Francisco is so fabulous.  What has really impressed me is the deep respect and dignity they accord to patients. So we have got the right team. We have got an unusual approach and unusual idea but we have some promising preliminary results and our goal is to see if we can — see if they work in the clinic or not and we aim to do so in a very rapid fashion.

Seth: Wonderful. In time we should not stay away from bacon and eggs for breakfast, correct?

Dr. Cox: Well, any guilt that you feel on eating bacon and eggs, you are hereby resolved. In my own life, I have changed my diet. I’m eating a lot more edamame. I buy little packets that I throw in the microwave from the frozen vegetable section and I eat them for breakfast and I eat them for lunch. So I’m jacking up my own L-serine content and again if it doesn’t pan out in the clinic, well so be it. But it’ll be so wonderful if it works because this is a relatively non-toxic treatment and we just love to know if it can help people or not.

Seth: Excellent. Thank you for that removal of my guilt. Now we would like to talk briefly about what other ways will your reserach progress? Is it solely through the trial?

Dr. Cox: Well I have pretty deep feelings about ALS and we put pictures of patients up in our laboratory. My team is so amazing.  We went out canoeing; we took one day off one year in the afternoon,  and went canoeing on the Snake River.  Then we brought the canoes back and I asked Dr. James Metcalf, my key cyanobacterial specialist “Can I take you back to your home?” He said, “Well no. Could you drop me at the lab?” I said “Why? It’s 10 PM.” And he said, “Well I still think I have time to make one more experiment.” So that’s the sort of spirit here is that there is one more experiment.

That being said, I can’t speak for patients and their families but it seems to me that if I were the patient I would take heart in people trying all sorts of different approaches to ALS. The current approach, again the last drug for ALS came out in 1994. I mean that’s what, 22 years ago. That’s just outrageous. I’m really frustrated by this. I think there should be as many different approaches as possible, all carefully screened by the FDA and under rigorous clinical conditions and hope that one of those would yield a new drug, a new treatment that could be a benefit for patients. And so I would like to see obviously more approaches rather than narrower and more highly focused approaches.

Again, I think everybody in the ALS Community is working very hard and there has been some spectacular advances made in understanding the genetic basis of familial ALS. But as far as I’m aware, our consortium, we’re the only groups working on environmental triggers and yet the teams we have, I mean William Camu, neurology at University of Montpellier, Christian Conradie at Karolinska Institute. I think we have got a shot. I don’t know how bit a shot it is but we have got a chance and we’re going to take that shot and the way to take the shot is to complete a phase 2 clinical trial to see if it’s efficacious in slowing progression of disease symptoms in ALS patients.

Seth: Excellent. We have one final question for you. But before we go I’m going to ask that Lori tell our listeners about our next episode.

Lori: Our next episode for ALS Crowd Radio will be Wednesday May 4th at 11 AM Mountain Daylight time with Dr. Richard Bedlack speaking about ALS Reversal.

Seth: Thank you, Lori. Dr. Cox, we’ve covered a lot of ground in this hour and how people can get involved in your research. But from your perspective what is the greatest opportunity in ALS for people who care to get involved?

Dr. Cox: You know it’s such an interesting question. One thing I’ve really felt is that it’s a real gift for me to have been able to meet such wonderful patients. There is something special about ALS patients, not just that they’re facing a desperately devastating disease but they tend to be very nice people and what I have noticed is that the patients that get involved in clinical trials do better even if the drug doesn’t work and that’s because they’re under observation all the time by a physician.

People that are very proactive in fighting it seem to do better and again, I would encourage your listeners to go on to our website at There is a film, a short film clip there. They can get an idea of our research and research papers and I guess what I really want to say is thank you because we have received so many encouraging notes and messages from ALS patients and their families and it’s been a very deeply moving experience for me to get involved in this community and I just — my prayer is that something that we do in Wyoming with our colleagues will turn into benefit for ALS patients. If that happens, we’d be delighted.

Seth: Thank you. Thank you for your time, Dr. Cox. It’s an honor to speak with you and please relay to your staff our gratitude for their work and sacrifice on our behalf.

Dr. Cox: I’d be pleased to do that, Seth. Thank you.

Seth: All right, thank you, listeners. This has been a great episode. Please tune in and join the next episode. Thank you again to Dr. Paul Cox of Jackson Hole, Wyoming.

ALS Crowd Radio S2:E2 Dr. Joseph Beckman on Stopping ALS in the Lab

Dr. Joseph Beckman, PhD

Oregon State University, Linus Pauling Institute

Interview Date: April 19, 2016

Dr. Joseph Beckman has been studying ALS for 23 years. He shares exciting results in the lab of treating SOD1 mice with a copper compound that extends their life from four months to over two years. His hypothesis seems proven: that a copper deficiency is being created in the brain of the ALS mice. Dr. Beckman treated them with copper ATSM and saw remarkable improvements.   The compound will begin human Phase 1 trails in Australia in two months, and shortly after in the US. Copper-ATSM is currently used in humans as an imaging tool which can detect brain tumors, or other damaged cells.  Dr. Beckman believes that both familial and sporadic ALS can benefit from this treatment, although much research will be needed from this point forward.  As his important research continues, he speaks with hope of turning the tide against this horrible disease.  

ALS Crowd Radio Show with Dr. Beckman

Full Transcript:

Seth: Hello and welcome to the Season 2 Episode 2 of ALS Crowd Radio. I’m your host, Seth Christensen, here today with our ALS Crowd Director of the Health Education, Lori Wangsgard. I will have Lori introduce our guest for today.

Lori: Thank you, Seth. We would like to welcome Dr. Joseph Beckman as a Distinguished Professor of Biochemistry and Biophysics in the College of Science at Oregon State University. He is the Director of the Environmental Health Sciences Center and Principal Investigator and the Burgess and Elizabeth Jamieson Chair in Healthspan Research at the Linus Pauling Institute.

Dr. Beckman received a Bachelor’s Degree in Molecular Biology and Master’s Degree in Population Biology both from the University of Colorado, and then received a PhD in Plant Physiology and Biochemistry from Duke University. Dr. Beckman served as a Professor at the University of Alabama at Birmingham in the Departments of Anesthesiology, Biochemistry and Molecular Genetics, and Neurobiology.

Before coming to Oregon State University in 2001, he was also a Guest Professor at the Swiss Federal Institute of Technology in Zurich, and also Universität Konstanz in Germany. Dr. Beckman has been the recipient of many research grants. A major research project in his lab is aimed at understanding how oxidative stress, superoxide dismutase, and zinc are involved in ALS. We would like to welcome Dr. Beckman to the show.

Dr. Beckman: Hello everybody.

Seth: Hi. Dr. Beckman, thank you for being with us. We’re honored to have you here today. Thank you for your willingness. Dr. Beckman, this is the first time we’ve had you on our show. I wonder if you could tell us what originally brought you to ALS as a career.

Dr. Beckman: I’m a researcher doing basic science in the field of oxidative stress, and I was interested in using the enzyme superoxide dismutase as a protective agent. In 1993, mutations to superoxide dismutase were discovered as the first known cause of ALS, and that created a lot of mystery of how an enzyme and a protein that’s expressed in every cell of the body from birth can cause a very selective death of motor neurons and cause ALS many, many years later. But in tracing that down, I’ve been working in the field since 1993, basically, trying to understand how does this protein cause the disease.

Seth: Amazing. All right. In those 23-odd years, how has the field progressed or changed?

Dr. Beckman: I’m sorry, there’s an echo in the background. I’m just having a little trouble hearing you.

Seth: My apologies. My question was over those 23-odd years, how has the research you’ve done progressed or changed? Have there been milestones that propelled us forward?

Dr. Beckman: In understanding the disease, I’m a Biochemist by training, so we’ve tended to work with pure proteins and with cultured cells and then we started to work with transgenic mice. I’ll talk a little bit about the transgenic mice because they’re very important for understanding ALS research, and a transgenic mouse is a mouse that a scientist has genetically engineered in some way to change the DNA or the material involved in inheritance.

I mentioned that there are mutations, genetic causes to a protein called superoxide dismutase. Mark Gurney and his colleagues in 1994 had a major accomplishment where they could take the DNA from a human that encode this gene and put it into a mouse, and now that mouse inherited the human gene and it developed ALS in about four months. And what’s remarkable is these mice really do recapitulate the human disease pretty well. The mice died very consistently in four and a half months, and we’ve had the mice for over 20 years but no one has been able to effectively treat the mice. They even offered a million-dollar prize if you could extend life by 25%. In other words, add a month of life to the mice.

That’s been a huge puzzle in the field. Why does this protein, why does this mutation to a protein cause the disease and why the heck can’t we treat it? Why can’t we stop it? I’ll be happy to stop there and we can expand further.

Seth: Wonderful. Yeah. We have to have other guests to speak about the SOD1 mouse model. We’re eager to understand them further. Is it the only mouse model in ALS?

Dr. Beckman: No, but it was the first and it recapitulates the disease better than any other mouse that’s been created so far. In the ‘90s, there was just a little progress that momentum was building to discover new genes that cause ALS. But after that, a lot of different genes have been identified and people have made mouse and rat models, and they’re studying those at this point. But the mouse model, the SOD1 mouse, is still the best model we have of the disease, and it recapitulates the disease. And the question is, why can’t we figure out how to treat it effectively? In many ways, like being run over by a Mack truck, it’s just so severe that it’s very hard to stop.

Seth: Yes. This brings us to the meat of our interview today. We have all heard rumors that you have been able to make progress in treating the SOD1 mice. I’ll allow you to talk about that.  All callers who have a question for Dr. Beckman out there, after his explanation, dial in 516-590-0362 and press the number 1 if you have a question. We’ll now give Dr. Beckman the chance to explain about his progress.

Dr. Beckman: I’ll start by explaining a little bit about the paper we just published and what we showed. Basically, my colleagues in Australia at Melbourne, at the Florey Institute, they came up with an interesting compound that contains copper, and they were getting as good a protection as anybody had gotten in the SOD mice. We had taken a different attack, instead of asking, how do you cure the disease? We were investigating what makes the disease worse. So if you understand what makes it happen faster, what accelerates the disease, I can give you other clues of where to look. And that’s where we made the progress.

Dr. Elliott and son in Texas had shown that there was a very unusual finding. There’s a protein that associates with SOD that helps insert copper into the protein. They had this remarkable and surprising result that if they took the human CCS gene and put that into a mouse, the mice were just fine. But if that gene was co-expressed at the same time with the mutant SOD, the mice die ten times faster. This acceleration was really dramatic and never seen to that extent in any other way.

We figured out that there was probably a copper deficiency being created in the brain. So we tried the Australian compound and to our surprise, the mice responded remarkably well. And what we published in January was that the mice had actually lived for about two years. So the life extension had gone from four months to over two years.

Now, we’ve argued that this mouse model, in many ways, represents what goes on in humans more because humans do express both the CCS protein and the SOD1. And that gives us hope that we could take this compound and actually try it in humans and see if we’d be able to treat ALS with it. So that’s the progress so far. The compound has actually been made and clinical trials for safety should start in about two more months. That was the latest word I got this morning.

Seth: Thank you for that explanation. Since the publication of the paper, we have all begun to eat three more pennies to get the copper, but I’m told that is probably not the right way to go.  Can you tell us what the magic of copper is and how you get that across the blood-brain barrier?

Dr. Beckman: Okay. You raised an excellent point. The question is, copper is a micronutrient, and why not just take free copper? Why do you need this compound? The problem is the copper itself is required in small amounts but it becomes toxic in larger amounts. It’s required by every cell in the body in order to be able to use oxygen. All the energy we get from taking in oxygen, breathing it, is only possible because there’s a copper atom that’s interacting with the oxygen in a place in the body, an organelle called mitochondria.

You have to have copper, but copper is pretty reactive and it can catalyze, it can cause a lot of different types of damage, and there’s certainly a number of diseases that are caused by copper overload or copper mishandling. If you just try to take free copper, it’s not going to help. One is it will cause some damage, and two, the brain really strictly regulates the way copper is taken up. And that was what we discovered from our work in the mice was just how careful, how slow copper is taken into the brain, and how getting the right amount there is critical.

Now, the compound is actually already used in humans for imaging experiments. There are experiments that use PET scanners, that use radioactive copper to detect tumors, and also to diagnose Parkinson’s. And this particular compound was know to leave copper in tumors or in damaged regions of the brain, because of the way the copper gets released from the compound. So it’s extremely fast at crossing the blood-brain barrier. It doesn’t need a protein or anything to do it. And usually, it carries the copper back out of the brain harmlessly. It’s only released in cells that are damaged and seem to have a need for the copper.

What we found was this compound, Copper-ATSM, worked really well. But if we removed one methyl group, one carbon atom, the compound no longer works, and in fact, it could become toxic. So the structure is really important to its function, and you have to be really careful in how you dose and how you use it in order for it to work.

Seth: For a context, how long ago did you begin to first dose SOD1 mice with this compound?

Dr. Beckman: We started about three years ago. It was just a trial set of experiments and we had some pretty amazing results of the mice responding very quickly. But then we designed much more complex experiments that were blinded, which means that we didn’t know which mouse was getting which treatment, and started to see how long they would survive and they kept living and living. So after they have lived for about a year, we started to try to publish the studies, and then there is enough skepticism in the field from one or two reviewers that it took over a year to get the data published.

Seth: Please go ahead with the background.

Dr. Beckman: I’m sorry, I had trouble understanding you.

Seth: I interrupted you. You were saying the background.

Dr. Beckman: I’m sorry I still couldn’t quite understand.

Seth: That’s all right. We understand that, in the SOD1 mouse model a developed breakthough like this has never happened before. I wonder how a research staff react when they begin to have mice live beyond the four-and-a-half-month period. Are you able to get excited in the lab or do you feel like you need to reserve excitement for a later time?

Dr. Beckman: I’m sorry I’m still having an awful time understanding what you were saying. There’s kind of an echo that we weren’t getting earlier. You’re asking about, is this the first time the mice have lived beyond four and a half months?

Seth: Yes. We can start there.

Dr. Beckman: Okay. Yeah. There have been one or two reports of mice that have lived substantially beyond four months but they were never repeated. And then if we treat the standard model with our compound, they only live to be about a month longer, a little longer than that. They hit 25%. So it’s only when they have the combination of the chaperone protein in the SOD, both human proteins together, that the copper compound is protective.

Now, the good news is that humans already have the human CCS gene, the copper chaperone expressed. So in many ways, I believe our result more closely represents what would happen in humans than the mouse model. And we’ll have to just tell it by clinical trials and see whether or not the compound works.

Seth: Thank you for that. Can you talk to us for a moment about that timeline for clinical trials?

Dr. Beckman: Okay. When we knew we had the protective results, the mice were living for a long time, we started to contact people. My colleagues in Australia, actually, had already licensed the compound to a company called Procypra. So I contacted the CEO and we’ve been in contact for quite a while now. So they are the company that’s involved in actually doing all the work that’s needed to get a molecule like this for mouse studies into humans. And it takes a fair amount of money and resources and it has to be done in a very strict way.

I’ve tried to explain the process but they’ve worked down through the steps. So the first is, how do you make the compound? How do you make the chemical in a way that’s safe and that it’s known to be pure and it’s not contaminated? And that’s a very detailed and complicated process. We can make the chemical in our lab but we have to be able to prove it would be safe enough to get to humans and you could make more of it. Then you have to figure out how do you put it together as a pill or a drug or how do you actually give it. Then we have to figure out, is it toxic to mice and rats? And then is it toxic to larger animals before you go into humans?

All of those studies have been completed now, and the compound is ready to go to what’s called a Phase 1 study. And usually, Phase 1 studies are done in healthy male volunteers to see whether or not the compound has any toxicity or any side effects. The company went forward and they got permission to actually go directly into ALS patients and test the drug in patients. And they’re going to do the first studies in Australia, for a number of reasons, but they could actually get them together a little bit faster than the United States, although they’re working on that too. In the Phase 1 study, we’ll be giving the compound starting with very small doses and they’ll be given for 28 days and the doses will be increased if there’s no risk of damage, if there’s no sign that people are getting sick from taking the drug.

That’s where the studies are now, they’re trying to figure out, is the compound safe enough to give to humans? Are there things that we just don’t know that start to happen in humans that you don’t see in other species? And that’s a possibility. Then from there, they start to do more studies that will be called Phase 2 or possibly Phase 3 to start to test these compounds. Are they still protective? Do they have any protection in ALS? Do they have any benefits? And so those will take probably one to two years to complete and decide whether or not there’s a benefit there.

Actually, from the announcement of our success in mouse studies, we’re much closer to getting into humans than previously. But I also realize that it’s still too damn slow for a lot of people who suffer from the disease now. So I’d be happy to expand further if you like.

Seth: Thank you. We will pause for a moment and allow Lori to invite callers.

Lori: If you have a question for Dr. Beckman, you can call in at 516-590-0362 and press 1 to indicate that you have a question so we can connect you with Dr. Beckman.

Seth: Thank you, Lori. We have callers from all over the country at this point, but none that have indicated that they have a question. We will continue for a moment to allow those to press the number 1. Dr. Beckman, do we know whether this compound is effective in non-SOD1 cases of ALS?

Dr. Beckman: We have no idea, and this is one of the big arguments I get into when I write grant applications. Only about 3%, anywhere from 2% to 7% of people with ALS have SOD mutations. So the question is, would a drug that treats SOD actually have an effect in people without the mutations? A lot of people say, “Well, they could be completely separate diseases and the drug will have no effect.” And they may be right.

I tend to believe that the mutations don’t really cause the disease. They just make it more likely for the protein to malfunction, and that they’re an indicator of what goes wrong, and the same thing could go wrong in sporadic patients. And we have some evidence that the processes are closely related. The flipside of it is, I would argue that the drug might work better in sporadic patients than familial patients, people with the SOD mutations. But that’s purely a hypothesis, a conjecture or what my colleagues would say a wild-ass guess. The only way to tell is actually give the drug and see if it works, which fortunately, the drug company is going to do sporadic, as well as familial patients, and we’ll see how that turns out.

Seth: Yeah. I love to hear that. Thank you. Again, callers can press the number 1 if they have a question. Dr. Beckman, while we are waiting the Austrailian trials, how does your work continue in Oregon?

Dr. Beckman: We are continuing in a couple of directions. One is there’s a chance that there’s something with copper-ATSM, that it may not be the best chemical to test. So we’ve made lots of different versions changing the structure, and we’re trying to see, can we find something that works better? We’re trying to understand how does the drug really work, which will give us the insights into how you could test it or how you would know it’s working in humans. We’re working on trying to test the compound in dogs because it turns out that many breeds of dogs have mutations to SOD1 and they develop a disease that looks very much like ALS.

And then we’re also testing other types of compounds, and one of the ones that we’ve been working on is something called masitinib. And the exciting news is that in Phase 3 trials in Europe, and an interim analysists suggests that this chemical, actually, was effective in ALS patients in slowing the disease.

There is a lot of different things happening in ALS and people have been talking about making progress, and I think you’re starting to see the first fruits of it come now. It’s not just the compound we’re working on but there are other things that are maybe turning the tide and offering some hope.

Seth: Thank you. We feel that hope and are thrilled to have researchers like yourself on the team. With that, we will take our first caller. Caller ending in **35. You are on the air with Dr. Joseph Beckman.

Caller: Hi, Dr. Beckman. My name is Stephen Finger. I’m in South Carolina. When you think about what you’ve seen in mice and if you think the mechanisms work similarly in patients, would you anticipate this slowing progressions or do you think if everything works perfectly, you would see improvements?

Dr. Beckman: Okay. The question is if the drug worked, a huge if, would it just slow down the further progression of the disease or would you see improvement? To be honest, I would be dancing a jig if either happens. We have been able to do the experiment in a mouse. We can take the drug away and let the mice develop the disease and then start the treatment again. And you’re not able to replace motor neurons that have already died, but what we did see is the mice did show some improvement in how they moved. They started to gain weight. So we’re able to actually stop further progression for a long time.

Unfortunately, the mice, after about eight months, they did start to progress further and got sick and eventually died of ALS symptoms. Our hope is that we can understand what stops the progression of the disease and stops to spread. And we’re not going to be able, with this type of therapy, to actually reverse a huge amount of the injury, but the goal would be to do something like happens in post-polio syndrome where people have lost a lot of motor neurons. They can have very severe mobility issues and challenges but they have a good quality of life and the disease doesn’t progress. That would be our goal.

Caller: Thank you.

Dr. Beckman: Okay. Any other questions?

Caller: What would you expect to see in terms of endpoints in the trial?

Dr. Beckman: I’m sorry, the question was what are the endpoints in the trials?

Caller: Yes. If you expect, it would simply slow progression or halt progression, what do you think would be an appropriate endpoint?

Dr. Beckman: That’s really not my expertise, and I won’t be involved in actually designing the trial. And there’s certainly a lot of different debates as to what it would be. Generally, they’re following the progression of the disease using various scales that monitor the further progression of the disease. And the challenge with that has been that it’s usually presented ALS is a relentless progressing paralysis, but there are periods where it slows down for some patients and then accelerates in others.

All of that has to be taken into account in the design and making sure that you follow enough patients long enough that you know that the drug is working. There’s a huge surge now for surrogate markers or biomarkers that would tell you whether or not the drug is actually engaging a target and whether you can tell you got enough of the drug in. And even that in itself is a pretty tough problem that we spend a lot of time working on and still don’t have a great answer for it yet.

That’s a great point. The success of the trial depends very much on the endpoints you’re searching for, and that is a continuing debate as to how do you treat with this compound or any compound in ALS.

Seth: Go ahead, Dr. Beckman.

Dr. Beckman: I’m sorry, was there another question?

Seth: No. You were saying you would add one point.

Dr. Beckman: Oh, okay. Yes. I’ve been very impressed with how the medical community has come together to study and work with ALS. I’ve watched this evolve over 20 years and there’s a huge amount of knowledge that’s been gained about how you test drugs in ALS, what are the difficulty with it. And it’s basically, there haven’t been successes in drugs that really treat the disease to speak of, but there’s been a huge amount learned about how you test it and how do you evaluate it. So there is progress in studying the disease and there’s been huge progress in how you manage the disease, which also helps with the quality of life quite a bit.

When I say that that’s not my expertise, that’s in part because there are a couple of hundred physicians that debate that and think about it very carefully.

Seth: Thank you for that. How can our listeners support your research?

Dr. Beckman: Well, I think the ice bucket challenge in many ways helped a lot of people. In Oregon the ALS Association has provided a grant. It’s just helped raise the awareness of the disease enough that it’s become higher profile. So I think that was a success and it’s trying to figure out how do you keep the momentum going? How do you keep awareness about ALS improving? And then what I’m hoping that the results we publish show is that we are making progress. It was actually very frustrating when people were dumping ice on their heads that we knew we had compound that worked really well but they were all locked in the laboratory. And you just had to keep going, keeping the experiment blinded and progressing.

And I think there’s a lot of different people. I know there are a lot of different projects and a lot of different approaches to treating many different aspects of the disease. Keeping hope up is really the key part in understanding that the work that people have done to support this disease is helping in making a difference.

Seth: Thank you. We have one final question for you but do not want to cut off questions from our callers. Callers, please press number 1 if you have a question for Dr. Beckman. Caller ending in **32, you are on the air.

Caller: Hi, Dr. Beckman.

Dr. Beckman: Hi.

Caller: You mentioned earlier that they used copper in other sorts of treatments. I wondered about your research if you’ve seen side effect, adverse side effects. I don’t know how you can do that with mice, but if you can project any side effects with this treatment for humans as well.

Dr. Beckman: It’s a great question. If you’re giving copper, what are the side effects and can you reduce the toxicity? And that’s actually where a lot of our researcher is going now, is trying to understand what they might be and how might you counter it. One way that you can counter copper toxicity is giving zinc. We know that zinc is also important for the disease and zinc is important for the SOD1 gene. We’re also investigating ways of giving zinc and keeping the balance of the two chemicals together.

The other part of what other side effects there are, basically, we have to determine what they would be in larger animals because there’s very few effects in mice and rats. But larger species, including humans, handle copper quite a bit differently than smaller animals, which is key because we live much longer and effects can have much longer consequences. We’re just going to have to see what happens when you do those experiments and it becomes really costly and you have to think very carefully when you’re using large animals as to what the effects would be. Did that answer your question?

Caller: Yes, thank you, and thank you for your research. This is really interesting and exciting.

Dr. Beckman: We’re very thrilled with it too. It’s a horrible disease but it’s a great puzzle to be working on, and very challenging. I didn’t expect it to be this hard.

Caller: Well, thank you for your effort.

Dr. Beckman: Okay.

Seth: All right. Dr. Beckman, wrap-up question is always the same. What is the greatest opportunity you see today for our listeners to help solve the ALS riddle?

Dr. Beckman: What is the greatest challenge or the greatest work?

Seth: Greatest opportunity for us all to help?

Dr. Beckman: Oh, what’s the greatest opportunity? I don’t have a great answer for that. I do think that what I try to encourage people that are newly diagnosed with ALS is get in touch with either the ALS Association or the Motor Neurone Disease Associations around the world because there’s a huge amount of knowledge about how you manage the disease that’s come along. And then it’s working through local groups that can help a lot of people make further progress. It doesn’t hurt to let your federal government senators and representatives know that ALS is still on the radar and it is important to continue research.

I think the last thing I’d say about it is that doing research is something that we seem to be losing sight of in this country as being not valuable. It has to produce goals and we have to have an immediate societal impact and show the significance, and it’s really important that we also continue basic research. If you remember from Lori’s introduction, my PhD is in Botany and yet I’m working in ALS. And everything that I studied that turned out to be fairly important in this was for things that nobody thought was very important at the time.

The dollars that are donated for research to the different associations, they helped enable people like myself who are at the edges of the field come into it and bring in new insights, and that’s really important for making progress in the disease. There’s an old saying of, if the federal governments went off to cure polio, what we would have today are portable computer-controlled iron lung machines instead of a Salk vaccine.

I think that’s also true for ALS. A lot of seed money allows people to try things. And 99.9% of the things that are tried are going to fail. But the one in a thousand chance still can unlock the disease and help make further progress. So a bit longer than I thought but —

Seth: No. Thank you. Before we sign off with you, we’ll have Lori share the information about our next botanist. 

Lori: Thank you. Next week on ALS Crowd Radio, we will be talking with Dr. Paul Cox, PhD from the Institute of EthnoMedicine about the environmental causes of ALS. It will be Thursday, April 28 at 1:00 Mountain Standard Time.

Seth: Thank you, Lori. And thank you, Dr. Joseph Beckman for his ongoing service to the ALS community. It has been an honor to have you with us today.

Dr. Beckman: It’s been my pleasure. So good luck.

Seth: Thank you. Goodbye.

Dr. Beckman: Okay. Goodbye.



ALS Crowd Radio S2:E1 Dr. Merit Cudkowicz on ALS Research: Progress Since the Ice Bucket Challenge

Dr. Merit E. Cudkowicz, MD, MSc
Massachusetts General Hospital
Interview Date: April 12, 2016

Dr. Cudkowicz is a leading expert in the field of ALS and is involved in all aspects of research, clinical trials, and patient care. She gives an update of ALS breakthroughs that have occurred over the last two years, since the Ice Bucket Challenge. The increased awareness and attention brought more resources, especially more doctors, companies and researchers working on the ALS puzzle. Dr. Cudkowicz tells of a new drug called Radicut® (aka Edaravone) which has been approved in Japan to treat ALS. The last two years also brought approval for Nuedexta in treating emotions and can help improve speech and swallowing. iPCS has also taken off, which is collecting blood samples from a patient then making motor neurons specific for that patient. This will lead to better individualized treatments. Answer ALS is currently undertaking a large coordinated effort to collect blood samples. A new company called Origins is creating a prognostic equation to see if they can test drugs in a better and quicker way. Promising stem cell therapy results have been released by Brainstorm and will be released soon from Neurostem. There is hopeful progess in finding biomarkers in three areas: imaging, electrophysiology, and blood & spinal fluid. New technology is also making it possible for outcomes to be measured from home, so patients don’t need to travel to a clinic as often. There are many ways patients can become involved in research and advocacy. Dr. Cudkowicz shares her expertise from being right in the middle of this important time for ALS discoveries.

ALS Crowd Radio Show with Dr. Cudkowicz

Full Transcript:

Seth: Hello and welcome to another episode of ALS Crowd Radio. I’m your host, Seth Christensen. Here with my good friend and a fellow ALS diagnosee, Whitney Hill. Hi Whit.  Good to have you with us. We are honored today to kick off Season 2 of our radio show. Our show began almost two years ago with the Ice Bucket Challenge.  Now, we are honored to have back with us our original guest, Dr. Merit Cudkowicz from Harvard University. I will pause for a moment to have Amy introduce Merit.

Amy: Dr. Merit Cudkowicz is the Professor of Neurology at Harvard Medical School, the Chief of Neurology Services at Massachusetts General Hospital, Director of Massachusetts General Hospital, MDA ALS Clinic, Co-director of the Neurological Clinical Research Institute, and the Co-director of Neuromuscular Division at Massachusetts General Hospital. She is the Julianne Dorn Professor of Neurology at Massachusetts General at Harvard Medical School. Dr. Cudkowicz completed medical training at Harvard Medical School and was a resident in Neurology at MGH. She obtained her master’s degree in Clinical Epidemiology from the Harvard School of Public Health.

Dr. Cudkowicz’s research and clinical activities are dedicated to the study and treatments of patients with neurodegenerative disorders, in particular, ALS. She directs the MGH ALS clinic and the Neurology Clinical Trials Unit. She is one of the founders and co-directors of NEALS, or the Northeast ALS Consortium, a group of 92 clinical sites in the United States and Canada dedicated to performing collaborative academic lead clinical trials in ALS. Dr. Cudkowicz received the American Academy of Neurology 2009 Sheila Essey ALS Award. Dr. Cudkowicz is on the Research Council of the American Academy of Neurology and the Medical Advisory Boards for the Muscular Dystrophy Association.

Seth: Thank you.  Dr. Merit, are you with us?

Dr. Cudkowicz: Yes, and thank you very much for your kind words, Amy, and it’s great to be here. And thank you, Seth, for inviting me.

Seth: Well, I’m honored to have you back. Merit, we’re grateful to have you today and wondered if we could start off by where we left off two years ago. We interviewed you last right before the ice bucket challenge. And know that a lot of our world changed.  Could you tell us at a high level, in your view, has anything changed for ALS since our last interview?

Dr. Cudkowicz: Yeah. So much has happened since our last interview. It says the ALS field is finally on fire with progress and hope and a lot of people studying it. I was thinking about this; whar are the top things that have happened since I last spoke to you.  We’ve have progress in lots of areas. The most exciting, obviously, is on the therpaies.  I’ll definitely talk a little bit about that, but we’ve had progress on therapeutics for the people with ALS. There’s been progress in understanding the underlying biology of the disease and how this might be different in different groups of people. And huge progress in what is really known as big data of making the most of all the data out there on people with ALS and how we can learn about the illness and develop treatments. I think those would be the three areas that have changed a lot since we last spoke two years ago.

Seth: Well, we would love to dive into those areas a little more if you have a minute for each one.  

Dr. Cudkowicz: Oh yes, absolutely. So therapeutic.  There is now another drug approved for ALS since we last spoke, and that drug is approved in Japan but it’s still an approved drug for people with ALS, and it’s called edaravone, also known as Radicut. And I think that’s just a huge news. The last time a drug was approved for ALS to slow down the illness was Riluzole in the mid-‘90s.

It’s really good news to have another drug. This drug now has been reported by the company at international meetings. They’ve shared the data that shows that it slows down the illness, and particularly effective taken kind of early in the illness. So it’s great news. It’s not obviously yet approved in Europe and the U.S. but the hope is that that’s where it’s going to be moving so it’s available to people really all over the world, just like Riluzole is.

That’s I think huge news. And related to that, there’s also another drug that is on the market for ALS called Nuedexta, which is on the market for a symptom of ALS called pseudobulbar affect when sometimes people with ALS might have extra emotions. That can be disabling and we know it works well for that, but in the trial for that symptom, the participants were telling the doctors that their speech and swallowing was better.

Dr. Smith, who was leading that study, Richard Smith, then did another study with NEALS just to see could Nuedexta improve what we call our bulbar symptoms or symptoms with speech, abnormalities or swallowing difficulties?  And he also reported in December his results where he showed that 75% of the people in the study had improvement in their swallowing and speech. That’s huge also because those are symptoms that are really important for patients to try to see if we can find ways to improve them.

I think those are two positive things in the right direction for therapeutics. And also, there is other positive news out there in therapies of reports of a few other treatments that have had initial positive results in what we call the early development trials, the early phase of testing. For example, methylcobalamin was reported to have some positive effects in the phase 2 study. And there was a recent report of Masitinib having some positive effects.

I think we’re finally turning the corner on therapies. We’re finally giving some hits; that’s just phenomenal on my end. So there’s a lot more to do in that but at least it’s going in the right direction.

Whitney: That sounds wonderful. Hi, Dr. Cudkowicz. This is Whitney Hill, Seth’s co-host. We met a couple of years ago when I came to you as a patient.

Dr. Cudkowicz: Good to hear you.

Whitney: Good to talk to you. When you say that those new drugs are showing some promise, how has the research came since the introduction of the money from the ALS ice bucket challenge? Has the focus changed a little bit? Are we seeing things heading in a new direction? Are we hitting olf things and trying to make those work? What do you see?

Dr. Cudkowicz: I think what we’re seeing since the ice bucket is basically global awareness of the illness and ALS research happening in more places than it used to. I think the ice bucket challenge kind of brought the awareness and it certainly brought resources. But it also got people all over the world excited about studying ALS, and other foundations contributing to ALS research. We’re in an unusual time, and I hope it stays for a long time where there are a lot of people interested in funding ALS research.

There are drug companies interested in it, there are investigators all over the world that are opening up parts of their lab to study ALS. The more people you have focused on it from different backgrounds, it’s just I think the more likely that you’re going to have some successes. I really think the ice bucket challenge awareness was almost even bigger than obviously the resources that brought in.

Whitney: I agree. In researching lately, I’ve been noticing that there’s been a lot of news in more of the genetic component of ALS. Certain genetic components that — it kind of seems like the researchers had — we’ve seen a lot more focus on that. Do you agree with that or do you think that there is — that’s only about 5% to 10% of the population, isn’t it, of the ALS patients?

Dr. Cudkowicz: Yeah. I think the genetic form is less than about 10% of the population, and there’s certainly very exciting work going on in genetic forms, but there’s also a ton of work going on in the sporadic forms. In the genetic form, the excitement is that the tools to modify or block genes of mutations from making them mutated protein that causes illness, those tools are now ready to go into people.

There are some trials, for example, patients with SOD1 ALS or C9 ALS, some of the genetic forms. There are trials geared just for those patients and they’re right on target of the cause to try to stop that disease. So you did see a lot of news about that and a lot of research on the models of those diseases, but there’s also a huge emphasis on the other 90%. Some of the work going on in the sporadic ALS is to try to understand, is that one disease or is it ten diseases? Is ALS all one disease or is it a syndrome?

I always give the example of blood pressure. There’s a lot of reasons why people have a high blood pressure and you treat people differently based on their cause of their high blood pressure. We think that that might be the case in ALS too. So where the resource and the researcher going for sporadic ALS is to try to understand that disease heterogeneity. And that was the second area I think has really changed a lot since we spoke two years ago that the tools to understand that disease heterogeneity, exists now where they didn’t exist before. And those are technology tools.

For example, we’re partnering with GE Healthcare and another ALS foundation called ALS Finding a Cure to bring all imaging technology GE has to ALS to see if we could actually image the brain in the MRI and see the underlying biology. If we can, that gives us tools to screen drugs much faster in people and to put the right therapies in the right patients based on their biology. That’s brand new since the last time we talked and looking incredibly hopeful.

The other technology that’s being used to really get at this, is this one disease or is this a syndrome with lots of different biologies,  is a technology called IPSC or Induced Pluripotent Stem Cells. The idea is taking people’s own blood and taking their stem cells in their blood and being able to make from that stem cell the person’s individual motor neuron. It’s a way to study a person’s individual disease. And that technology is relatively recent.

There’s a big study that’s funded by several groups including this ALS Finding a Cure and Team Gleason and Travelers to do big data study where you ask a thousand people with ALS to come in and donate a sample of blood so that we can make people’s motor neurons and study everything there is about it and then really try to get at this question of, is this one disease or many? And once we do that, that’s going to make developing therapies much, much faster for people and much smarter.

Whitney: Dr. Cudkowicz, how do we have access to that process as an ALS patient to have access to the IPSC and to be able to give you our information and have that mapped out? I mean I haven’t even heard of this.

Dr. Cudkowicz: Yeah. Good question. So there is an Answer ALS website that Team Gleason is hosting. And on that website, it’s list of centers that are currently enrolling those five right now, but the hope is that will grow. That will be the first place to start, kind of Googling Answer ALS. And also, the patients ask their ALS neurologists, how can you participate in research? NEALS has really tried to lower those barriers so that any ALS clinic that wants to be part of research and wants to contribute blood samples or clinical data from their patients can do that very easily.

Seth: This is incredible.  We thank you for those answers. I’d like to go to a topic that you mentioned here briefly. It is one of the major outcomes of our original interview. At that time, you talked about big data. A number of these projects are beginning to merge onto that idea.  How far are we out from a true centralized database of ALS patient information?

Dr. Cudkowicz: There’s been huge progress in that as well. I think there’s still more to do but since we spoke, a couple initiatives have taken place to really try to learn from every person with ALS and to be able to share their data with any researcher. One of them is something called PRO-ACT, and that just continues to grow. And what PRO-ACT is, it’s a database of all past clinical trials. The companies have agreed to share the data, particularly, for sure the data from people who are in placebo and sometimes also from people who are on treated drug. And that’s an open source database for anyone to mine, and that continues to grow.

There’s now data from 11,000 people with ALS in PRO-ACT and there have been over 1,000 people who have downloaded the data and about 20 plus papers. But the most, I think, important thing that has come out of that so far is that there are companies actually been formed from it called the Origent to develop a prognostic equation for ALS. Why that’s important is this might be a way to screen drugs faster.

If you could take a few clinical data points, make maybe a prediction of what would happen to someone with this illness, and then see if your drug can change that trajectory. And there have been discussions already with the FDA. Would they accept this type of clinical trial design? These are new people never in the ALS field. They are computer scientists who have come into the field to see if they can help improve and speed up the whole process of how we develop drugs. And that wouldn’t have been possible without this kind of open source huge dataset. So that’s clinical trial data.

The other data we want to really capture is the clinical data because people with ALS are going to the clinics, are giving information to their physicians. Obviously, they’re getting care, but if there was a way to collect that data as well and make it anonymized so it’s safe but available to researchers, that would be fantastic. We are using a system called NeuroBANK for that and working closely with companies that have electronic health record systems like Epic to see if we could make it part of the electronic record that all these hospitals have. There’s been big progress there as well.

Seth: Excellent. Now, are we including non-clinical data in those efforts? For example, environmental data or geographical data?

Dr. Cudkowicz: Yes. The way NeuroBANK is built is that there’s a list of a library of forms and they include all the epidemiology forms that the ALS field has created, as well as forms for other clinical characteristics. The investigator, for example, maybe someone’s doctor, if they want to start collecting information on their patients, they can go to NeuroBANK, it’s free, and download the forms that they want and start entering their patient’s data.  And it becomes part of a much bigger system and can be added to data entered by another doctor in another place. And we’re also building it so that patients can enter their own data, some of their own data in this as well.

I think it’s really important. We should be learning from everybody. That will only speed up the process, if we can find a way and an easy way so there’s not a burden to patients and families to learn from everybody so that their data can be shared and anonymized with the researchers.

Seth: All right. We will pause for a moment to allow callers to get the information they need to ask a question.

Amy: If you have a question for Dr. Cudkowicz, if you could press number 1 on your keypad and that will notify us that you have a question for her. I know with all this information we’ve got a lot of questions out there. And if you need to call in, the number is 516-590-0363 and then press 1 to indicate you have a question.

Seth: Thank you, Amy. Merit, how has the resources you’ve talked about from the ice bucket been applied to reserach today?

Dr. Cudkowicz: A lot of the money has been applied to research, and not just in the U.S. but in all these other countries, Canada and U.K. The number of applications for grants has gone up four-fold in the field, which was just tremendous. There have been a few special initiatives, for example, the ALS Association earmarked some of the funds with this other partner, the ALS Finding a Cure, to fund trials for therapies that were ready to go into what we call Phase 2 study, the initial study to look for preliminary efficacy and that you got the right dose.

They’ve now funded three studies that without the ice bucket money, those studies wouldn’t have been funded. They’ve also funded collaborative groups that studied the basic cause of ALS. They’ve brought in new people to the field and new partnerships, researchers from other areas like Alzheimer’s or Parkinson’s and attracted them to the ALS field.

It’s actually impossible to list all the things that the ice bucket money has helped fund. It’s pretty huge. I think the other key thing is that it forged partnerships. So there are a lot of foundations now working together and saying, “All right, this is a big project that will answer some important questions, how can we work together and pool our funds so that we fund the best science rapidly?” That’s a huge change in the field.

Seth: Thank you. We will now take a question from our first caller. Caller one, go ahead and ask your question.

Caller: Is that me?

Seth: Yeah, it’s you.

Caller: Oh okay, great. Dr. Cudkowicz, in regards to these earlier questions, is there a mouse model being developed for sporadic ALS, a non-SOD1 mouse model being developed? Or part two of the question is, will the iPSC replace mouse model studies altogether?

Dr. Cudkowicz: Those are great questions. Right now, all the mouse models are based on different genetic mutations. And that’s purely because the field does know how to make a mouse model of a non-genetic form. But those models are important because a lot of biology that happens in genetic forms happens in the sporadic form. You can learn a lot about all forms of ALS from those models. People are also making fly and worm models as well.

But I think your second question with where the field is going, especially for sporadic ALS.  Can you use this new technology, this iPSC, induced pluripotent stem cells, where you take someone’s blood or their skin and you can make their own motor neurons? There’s a lot of effort to use that approach to study sporadic ALS. I don’t know yet if it will replace completely mouse models. I think we need to wait to have a few more drugs that work in people where you can then go back and see what was the best predictive model. But that’s the hope is that the iPSC approach will help us screen therapies for groups of people or individuals more effectively.

Caller: Great. Thank you very much. I’m in a study at ALS TDI, in your neighborhood, and it’s been over a year since I gave my sample but it seems that — well, they haven’t gotten my stem cell line created yet.  How long is that typically from your patient to give a skin sample until there would be new cell line generated from the iPSCs?

Dr. Cudkowicz: Very good question. So the time keeps getting shorter and shorter as the technology gets more widespread. It can take 20 weeks or so to go from the skin to the stem cell that the skin cell came from and then to the motor neuron. I mean, it varies by lab but it’s usually in that order of a couple of months. People are trying to make that even faster but it’s still a relatively new technology. It really requires some specialized skill. So there aren’t that many facilities that have the know-how to do this at the moment. I think that will change and it will get faster over time.

Caller: Great. Thanks for your answers.

Dr. Cudkowicz: Sure. Thank you for calling in.

Seth: Thank you, caller. I’m glad that we’ve talked about iPSC. Merit, are we making any progress in stem cell therapy?

Dr. Cudkowicz: Since the last time we spoke; we don’t have a lot of new data yet but we’re close. There’s a study by a company called BrainStorm that has now fully enrolled in the United States and is almost complete. People are waiting for the results of that trial. That’s the trial that uses people’s own stem cells taken from their bone marrow and then injects them in the spinal fluid and the muscle to see if they can deliver proteins that are good for motor neurons that can make motor neurons healthier.

Then there’s Neuralstem that also finished their second trial and they’ve reported out the results of good safety. They actually used some of these datasets that were available through PRO-ACT to compare how people did in their trial to natural history or because they didn’t have a placebo in their group. They reported that 7 out of 15 people in their trial had, at least by one measure, no progression over nine months. And then if you look at PRO-ACT, you would expect to see that more like in 20% of people.

That’s not the same analysis as when you have a concurrent placebo group but it does show the power at least in the early pilot studies of using large datasets, data on people as a comparison group to help you decide whether to go forward with the treatment or not. So that is now in the stage of thinking about what would be the next step that would be needed to get an approved therapy.

Whitney: Wait, Dr. Cudkowicz, is that stem cell therapy available here, and what stage is it in the United States?

Dr. Cudkowicz: Yes. So both Neuralstem and BrainStorm are investigational treatments. Neither today is enrolling participants but they both did studies in the United States. BrainStorm is waiting to have the results of the current U.S. trial to know what the next step would be. Neuralstem, we have their initial pilot results and they are working on what the next step would be, the next trial would be in the United States.

I don’t have any dates today of when this will happen, but hopefully, it will be soon. And a good place to look up about trials are obviously the ALS Association, the MDA listed, and our NEALS Consortium also lists. As soon as we hear a trial is going to start, we list it there.

Whitney: Thank you. We have an online question regarding Nuedexta. I realize that it’s for emotional things and for swallowing; can you use it when you have one and not both? Are they showing that it’s effective to swallowing issues? And then what are the side effects of it?

Dr. Cudkowicz: Very good question. In the clinical trial for swallowing and speech, it worked also in people who didn’t have any of the emotion. So it definitely works on these symptoms separately. If someone didn’t have any of the emotional symptoms and have only swallowing, you could try it for swallowing. It’s a fairly safe drug. There are certain medications you can’t take with it because of the part of Nuedexta that is called quinidine. You definitely have to check with your physician to screen the therapies you’re on to make sure they don’t interact with that part of Nuedexta. Some people get some stomach upset with it, but for the most part, it’s a very safe drug, but definitely one that you need to do with your physician.

Seth: Excellent. On another topic, we spoke in our last interview a lot about biomarkers. Do we have any new biomarkers for ALS in the last few years?

Dr. Cudkowicz: Yes. I think there are several new biomarkers. They’re all under development. It means that they are hopeful but they’re not 100% this is the biomarker for ALS, but there has been a lot of progress. And I’d say they’re in maybe three buckets. One is imaging, and I’d come back to that because in other fields that if you can see the disease, it makes it a whole lot easier to screen therapies. You can think of a cancer treatment. You look and does the tumor shrink or not? In multiple sclerosis, do the lesion shrink or not?

A lot of progress on imaging, and imaging in particular, something called neural inflammation. There are some studies again working with GE to look at inflammation in the brain and spinal cord of people with ALS. That’s looking at the moment like it’s potentially going to be a really good biomarker and a tool to screen drugs that block information. But there are also other efforts really globally to develop tools to the image of spinal cord, which is not an easy task but really important in ALS since a lot of the illness is in the spinal cord.

That’s one category. The other is I would say electrophysiology; measuring how the motor neurons are firing. There’s been some new tools developed largely in Australia called TMS to measure something called hyperexcitability. They’ve shown that sometimes even before symptom onset, you can start to have some hyperexcitability. They do that by looking at people who carry the gene mutation. But that very early in the illness, the motor neurons are firing too much. That gives us a way again to measure the illness, a biomarker of that, and then you can screen drugs against that.

And then the last one I would say is biomarkers in blood and spinal fluid. The most promising at the moment is something called neurofilament heavy chain, where it looks like that’s elevated in the spinal fluid of people with ALS. And it might be correlated to disease progression so that the more someone has of it, the faster the course.

Now a lot of the clinical trials are adding that as a marker to see if their drug can reduce the neurofilament and does that correlate with the improvement in the illness. And if we could find something like that, that means you can screen drugs quickly in a few people. If it lowers neurofilament, then you know that that might be the drug to bring forward fast. So a lot of progress, but I don’t think anyone say we’re done but it’s certainly a lot more than two years ago.

Whitney: It seems to me that there might be a hindrance in getting a lot of this information and people’s willingness and ability to travel to where the clinical trials are being done. Is there more of an effort being made for someone to do it at their ALS clinic and the information be gathered thereand sent to the central location so that information can be gathered and shared but it’s not dependent on person’s ability to travel or to relocate?

Dr. Cudkowicz: Yes. There are a couple of initiatives on this and I think we’re with a field where we need even more ideas. So a couple of things that are being developed are to make it really easy for any center to be part of a trial so if the doctor wants to on trial to lower the barrier. For that, for example, there are protocols that a doctor could just download from NeuroBANK to collect samples from their patients and put them in a repository like blood and spinal fluid and share the clinical data. And that there are some resources provided from this Foundation, ALS Finding a Cure, to make it easier for people anywhere in the country to be part of these biomarker studies. That’s one initiative out there.

The other, for clinical trials is, can we develop tools to measure the illness in the home using mobile devices so that people don’t have to come back to the clinic for their outcome measures to make it a lot easier for people? That’s all a new technology. It’s being done in other illnesses like Parkinson’s, and there’s a big team kind of thinking about how to do this in ALS, what will make sense to measure and how to do that but to bring the visit more to people’s home.  I think ultimately, that’s the way to lower the barriers; it can be done pretty much in your home and you don’t have to travel that far to be part of a study.

Seth: Thank you for those answers. I’ll have Amy remind us of the way to ask the questions.

Amy: If you’re listening online you can dial 516-590-0362 and press 1 to let us know that you have a question for Dr. Cudkowicz. Again, press 1 to indicate you have a question.

Seth: Thank you, Amy. So one follow-up question on the blood and spinal fluid biomarker. Is this being studied as a way of differentiating between quick or fast or a slow progress?

Dr. Cudkowicz: Yeah. The biomarkers can be used in different ways, and one is for kind of prognostication, what you described of, are there markers that are faster or higher or different in people who have a faster course or a slower course? And can that teach you something about the illness or give you a target for a therapy? That’s one use of the biomarker. Another is maybe even diagnostic. Is there a test like, for example, cholesterol for heart disease, something that you can measure in the blood or the spinal fluid that would say this is most likely motor neuron disease? So that’s another type of biomarker.

And then I think the third type would be a biomarker that measures the disease and then when you give a treatment, you can get rid of that biomarker. So that’s what a lot of the effort is focused on. For example, the neurofilament heavy chain I mentioned, the hope is that that might be a marker of the illness, and that if a drug gets rid of it or lowers it that that might be predictive of the clinical effect of the drug.

Seth: So can you lay out specifically, where the spinal fluid study that you mentioned is being led?

Dr. Cudkowicz: I didn’t entirely understand the question. Was it where the spinal fluid is?

Whitney: Where the spinal fluid study is being led. Where is it they direct from; where it’s headed?

Dr. Cudkowicz: I think one of the key things is we need to develop really large bio sample repositories of spinal fluid. There are some studies already ongoing. There is one that NEALS is doing at six centers where over 100 people now have enrolled and are kindly providing spinal fluid about every four months, as well as clinical data. And that’s a really important biorepository that’s being shared with scientists really all over the U.S., as well as in drug companies. But it’s a finite set of sample, so we’re always trying to again build protocols and bring in centers who will approach their patients and ask if they’d be willing to donate a spinal fluid for ALS research. I think it’s a really important sample that can really help the field move forward.

Whitney: That’s great. I think as an ALS patient myself, I’m often saying, “Just take it. Take my spinal fluid. Take my blood. What do you need?” But because of where we are located, we don’t learn about it or know that we should be sending those samples in. So this is great information. What is our greatest need today as an ALS community?

Dr. Cudkowicz: I think we’ve touched on some of them. It’s always hard to say what the one greatest thing is. I think we need to find a way that all patients or 80% of people can be part of research whether it’s giving a blood sample or spinal fluid or being in a clinical trial. That just becomes part of ALS, so we can keep learning and keep developing treatments. We have to figure out what were those, keep lowering those barriers so it’s easy for people to be part of research.

The other is we still need a whole lot of funding. I mean I expect it was tremendous and these other groups that are forming are great, but there are more questions and more ideas of how to conquer this illness then there’s funding available. It’s certainly a lot better than it was two years ago. I mean it’s fantastic now compared to two years ago where there were lot of ideas and was no funding. But I think we have to keep them advocating for money from the government and working together on philanthropy.

We make sure that the funding agencies are funding different things in complementary studies and no duplication. Those groups are all doing that. They are meeting around in circle and talking and comparing and working together to fund research. I think that’s also something that we have seen more in the last two years as well.

Seth: How, again, can we get more involved more actively in the process that you’ve mentioned?

Dr. Cudkowicz:  There are a couple of ways to get involved I think in different levels depending on how much people want to get involved. I think one, the local level of going to your ALS physician, and if they’re not involved in research, asking them to get involved and directing them to the NEALS website, and we can help them on getting these tools to be able to start doing some research. That’s one way.

And then the other, I think advocacy is still really critical. That’s at the government for funding to keep going to ALS. There I would work through the ALS Association or the Muscular Dystrophy Association. They have teams that are going down to the hill and advocating; but lending your voice. There’s nothing better or more moving than a voice of a patient to Congress and the people making the decisions about federal funding.

Seth: Thank you for that. We are thrilled at that. We have a great [0:46:45] [Indiscernible], but we are thrilled to have our season take off with you. Thank you for your ongoing work on our behalf.

Dr. Cudkowicz: Thank you for your role in advocacy. It’s really a pleasure to be on the call.

Whitney: Our next ALS Crowd Radio episode will be in one week, Tuesday April 19th at noon, Mountain Standard Time. Dr. Joseph Beckman from Oregon State University will be our guest about stopping ALS in the lab.

Seth: Okay. We want to thank Dr. Merit Cudkowicz for her time today and we look forward to solving this puzzle we call ALS. Thank you, Merit.

Dr. Cudkowicz: Thank you very much. Have a good day.

Seth: All right. Take care. Bye.

ALS Crowd Radio Episode 11: Dr. Alfred Goldberg, PhD, Harvard Medical School

Dr. Alfred Goldberg, PhD
Harvard Medical School
Interview Date: January 7, 2016

 Dr. Goldberg’s knowledge and discoveries about proteasome inhibitors, used to treat multiple myeloma, are making the development of new drugs against ALS possible.  His insight about cellular mechanisms can be used for both ALS and multipule myeloma; but it opposite ways.  One disease needs a proteasome inhibitor, one disease needs a proteasome activator.  His studies using this target are about to start on ALS mouse models.  Dr. Goldberg explains how new ideas coming from other areas of research are giving a great deal of hope. 


ALS Crowd Radio Show with Dr. Goldberg

Full Transcript:

Jenny: Welcome to ALS Crowd Radio, a show helping ALS patients understand the latest in research. My name Jenny Ahlstrom and I am co-hosting a show today with Seth Christensen.

Seth: Good morning, everyone.

Jenny: Today, our show is about a unique topic taking a drug that is currently approved for something else particularly cancer in this case and applying it to a different disease like ALS. For today, we have Dr. Alfred Goldberg with us. We welcome you Dr. Goldberg.

Dr. Goldberg: Thank you. Pleased to be here.

Jenny: Let me give an introduction for you to begin with. Dr. Alfred Goldberg is a Professor of Cell Biology at Harvard Medical School, where he has been on the faculty for his entire academic career. His important discoveries have concerned the biochemical mechanisms and physiological regulation of protein breakdown in cells and the importance of this process in human disease. His laboratory first demonstrated the non-lysosomal ATP-dependent pathway for protein breakdown, now termed the ubiquitin-proteasome pathway. They first described the roles of the 26S and 20S proteasomes in the degradation of ubiquitinated proteins and discovered the ATP-dependent proteases responsible for protein degradation in bacteria and mitochondria. 

In addition, their lab has elucidated their novel biochemical mechanisms and mode of regulation Also of wide impact have been Dr. Goldberg’s studies showing that the ubiquitin-proteasome pathway is critical in the clearance of misfolded aggregation-prone proteins, in the excessive protein breakdown causing muscle atrophy in many disease states, as well as in antigen presentation to the immune system. He and his colleagues also first introduced proteasome inhibitors widely used as research tools (e.g. MG132), and he initiated the development of the proteasome inhibitor, Bortezomib/Velcade, now used worldwide for the treatment of multiple myeloma.

Dr. Goldberg received his AB degree in Biochemistry and his PhD in Physiology in 1968 from Harvard University, after attending Cambridge University as a Churchill Scholar and Harvard Medical School. His research accomplishments have been recognized with many honors, including the Novartis-Drew Award for Biochemical Sciences, Severo Ochoa Award (New York Univ), Knobil Prize for Medical Research (Univ Texas), the Gabbay Award for Biotechnology and Medicine (Brandeis Univ.), the Gordon Alpert Prize for Medical Research (Harvard Univ) and the Ernst Beutler Prize for Basic Research (American Hematological Society). 

He is a Fellow of the American Academy of Arts & Sciences and a member of the National Academy of Medicine and the National Academy of Sciences. He has also received honorary doctoral degrees from Cold Spring Harbor Laboratories (Watson Graduate School), the University of Maastricht and University of Barcelona and is among the 1% most cited authors in the life sciences.

Welcome again Dr. Goldberg.

Dr. Goldberg: Thank you. I’m happy to be here. How can I help you?

Jenny: Well, I think I’d like to give a little background about how we discovered you. I am a Multiple Myeloma patient who runs a foundation and have an advocacy group for Myeloma which is a blood cancer and I attended the recent American Society in Hematology meeting in Orlando Florida where you were receiving an award and giving a presentation. I know it was intended for a scientific audience. I understood a part of it but not all and I was very impressed in the thing that just gave me chills at the end as that you said this drug that has been used in cancer for over a decade and now multiple proteasome inhibitors are coming out for cancer and multiple myeloma specifically.

But you saw a use for them in Neurological Disorders like Parkinson’s or MS or ALS. I have to say, it really electrified me to ask you about the application of a currently FDA approved drug for another disease like ALS. So maybe you want to start by giving us a background of your work on proteasome inhibitors for myeloma and then the work that you have done understanding how to apply these other disease states.

Dr. Goldberg: Well, I’d be delighted to spend time on both topics but I should make it clear from the outset that there’s a little misunderstanding. The drugs that are being used for myeloma that affect the proteasome, we are not developing for neurodegenerative diseases such as ALS. The insights and the knowledge about the proteasome is making possible progress in development of drugs against ALS, we believe. The information in the cellular mechanisms are the same but the drugs themselves will have to be different. I will explain that a little more clearly I hope.

Our work for many years has been concerned about basic cellular processes. What happens when cells make a mistake in protein assembly? What happens if cell proteins get damaged or if there’s a mutation that happens for example in many ALS patients and is happening all the time to generate cancers? The cells make a protein at fails to function or even fold up correctly and we’re interested in how evolution has enabled us ourselves to recognize those proteins and destroy them, at least destroy them most of the time.

This protection mechanism which we have been studying the biochemistry of is basically a cellular sanitation system in which cells have the ability to recognize an abnormal protein and destroy it, eliminate it the way a good vacuum cleaner will do to clean problems in our household. So we’re interested in how cells were able to recognize the abnormal proteins and destroy them selectively and we discovered this structure we named the proteasomes which is where the destruction takes place.

Now, in one kind of disease, multiple myeloma, is the cancer with uncontrolled growth of cells, normally make antibodies. These are the plasma cells that produce protective antibodies in all of us. In the myeloma patients unfortunately, these cells have become cancerous and they do two things. They grow like mad and they happen to generate an abnormal protein that your physicians monitor. What we have found is that the drugs that we were developing to block the proteasome actually interfere with that, the cellular sanitation system in the myeloma cells where they already have so many abnormal proteins that take the accumulation of the misfolded proteins and kills them, in other words, the proteasome inhibitors Carfilzomib, Bortezomib. Now the new one is Ixazomib are interfering with the cell sanitation system which drive cells into basically a non-functional suicidal mode.

It has turned out that the very basic process that we were trying to understand and for which we were developing inhibitors is particularly sensitive to this kind of drug. When we were developing it, we actually didn’t understand it. The drugs were tried against many cancers and the myeloma responded dramatically for many patients. That’s the basis for the development of these two or three drugs. It’s also the basis for their combination therapies with other drugs. But the point is really that myeloma is a cancer where the cells are producing a huge amount of garbage protein.

Because the garbage breakdown mechanism is blocked, they’re not viable and we can help patients in this fashion. That’s why these drugs have been successful. Is that at all clear and we could talk about the neurological disease afterwards. But is that pathological mechanism and is the drug action clear or can I do a better job of explaining it?

Jenny: Oh, I think you did an excellent job explaining it.

Seth: Dr. Goldberg, how successful have these drugs been in myeloma?

Dr. Goldberg: Well, it all depends. Myeloma is still a terrible disease as you’re a listening audience or as Jenny can tell you much better than I. Or, my wife is a physician and I hear about the cases where the drugs are not as successful. But certainly, the longevity of the patients has been dramatically increased and the cocktails, that is the mixtures of two or three drugs with different modes of action, has been able to add years to the life of what used to be viewed as a hopeless disease.

The exact benefits are almost hard to say because new and improved ways of using these drugs keep emerging and this real reason to believe that from what’s in the pipeline of many drug companies, there are going to be further improvements even over the present mixtures. But I think this is one now, one of the more successfully treated cancers for many patients, for most patients certainly compared to the way that disease was ten years ago. Others can attest to that better than I because I am still the basic science. I’m the grandfather of the drug. I don’t give it to patients or see patients. I think the statistics are very clear that it has been very successful but certainly not as successful as we would hope and there are always improvements left to be done.

Jenny: Well it is a basic drug class that’s always used now in myeloma treatments no matter what type of treatment combination therapy, you always have a proteasome inhibitor added to that treatment in my experience.

Dr. Goldberg: I think that is definitely true and the combination of those drugs with the imids and glucocorticoids, I think well over 95% shows some benefit. But for how long, it depends on genetic factors we don’t understand probably. But the improved ways of using are continually emerging thanks for the effort of many physicians.

Seth: Great. Can you clarify for those of us new to this space. Do the drugs interfere with a haywire process, or are they more targetet at restoring the natural order of a healthy cell?

Dr. Goldberg: Well, if I understand the question, these are very selective drugs. They are not like the traditional chemotherapy where patients or every cell in the body that’s dividing patients to not see loss of hair or have the GI problems — These are specifically affecting one structure in a cell and myeloma cells are particularly sensitive. At the moment, the success has been with treatment of myeloma. For other malignancies or rather even hematological malignancies, we were hoping they would probably be more successful than they have been so far. Much of that is still understudied.

Now, I’m not sure if that answered your question though.

Seth: Yeah. My question in general is about that vacuum cleaner you mentioned. Are we restoring a broken vacuum cleaner or are we —

Dr. Goldberg: Oh, I understand now. Yes. Now, that’s a very profound question. In fact, we are not in this case restoring a broken vacuum cleaner. We are making a vacuum cleaner stop working in the cell without a vacuum cleaner dies. The reason the myeloma problem is, why those cells are particularly affected, is because they are making all the garbage. The rest of our cells are doing very well. This is definitely saying, let’s take away the vacuum cleaner in the myeloma cells instead of them taking over the body are dying. That’s good. This is the case where the offending cells are very sensitive to a drug.

Now, this is in real contrast to the areas we’re working on now for neurodegenerative diseases such as ALS but also in Alzheimer’s and in Parkinson’s, cells that have functioned very well for many years specifically neurons, either neurons in a spinal cord. If it’s ALS or neurons in our brains, if it’s Alzheimer’s, they are accumulating specific abnormal proteins inside of them. That’s causing the cells to stop functioning and eventually die.

In other words, the proteasomes, the pathway that we have been studying works very well in most of us until our 70s or 80s in getting rid of the garbage. There is something that goes wrong in either the brain or the spinal cord of patients that in these diseases causes the accumulation of toxic amounts of abnormal proteins that precipitate out in the cells. What we’re talking about in this as our challenge and what our lab is working on to these diseases is the exact opposite of myeloma. We want the garbage collection system to work even better. We want to eliminate these proteins just like we did when we were young. That is a scientifically harder thing. To make a better vacuum cleaner, you have to really understand how it works.

To mess it up or stop it from functioning, you only have to understand a little. The past ten years and in the last couple of years, we think we have learned a lot about the pathway and then we have some exciting new hints on how we can activate the proteasome so we can enhance the garbage collection and presumably stop the progression of these diseases if the research is successful. It looks very encouraging in the test tube at the moment. Now the point is to go to animals and humans with specific drugs. But we have a rationale that looks very promising that we didn’t have in the past.

Is that distinction clear? Because I certainly didn’t want in my lecture to say that the kind of impression I may have given because it was a short talk. We are working. We are focusing on the neurodegenerative diseases but it’s not with the same molecules. It’s with the same target. It’s the same concern with the proteasome.

Jenny: I think I jumped ahead too much making that connection. What you’re saying is using the current drugs would possibly have the opposite effect of what you want.

Dr. Goldberg: You have really gotten a very important point. Using the present drugs, it might have been — have very negative consequences and we worried about this 12 years ago when we developed the first proteasome inhibitors. In those drugs like Carfilzomib, Bortesomib, Ixazomib actually do not get across through the blood brain barrier. They will not cause the same problems that you might see. Maybe I should explain this.

In our bodies, between the nervous system and the brain and the rest of the body is a barrier which we call the blood brain barrier that stops many drugs from entering the brain. It’s something that protects the brain against many things we view as toxins. Certainly many drugs do cross it, but many do not. The drugs that we’re talking about here do not enter the brain and therefore, there are no side effects of the kind that you have perceptibly notice. If you actually study nerves in a dish or in a test tube as we do in the laboratories, then you’re absolutely right. The drugs can cause — or would make a model of ALS, they would make a model of Alzheimer’s worse because they would make the garbage collection that minimizes disease non-functional. But this is not a worry for patients or for any humans who are taking these drugs.

Jenny: Right, because their usual drugs are completely different application.

Dr. Goldberg: They don’t enter the brain. That’s what I meant by the blood brain barrier. Those drugs, if they got into the nerves would do what you say but they don’t get across into the brain because of this barrier. We are definitely in, to think about these diseases have to study molecules that actually do get into the brain and we are doing that.

Jenny: The lessons that you have learned over this very deep extremely exceptional research is now being applied to these. What are the key lessons that you gain in the neurological diseases like ALS that really stand out to you?

Dr. Goldberg: Well, I think it’s hard to say. I think the most important point is that you learn from myeloma. From this way of thinking about the neurodegenerative diseases such as ALS is that new ideas coming from other areas are giving a great deal of hope. People studying myeloma or a blood cancers premier lymphoma would never have been worried about the proteasome or that pathway where that was a very fundamental bit of biochemistry with basic research advancing our knowledge, then molecules that could be drugs became available.

It was almost a surprise to find out the myeloma patients were so sensitive because research in myeloma hadn’t focused on this area. The same thing is true about the group of diseases to be called neurodegenerative diseases or ALS. If one just studied how nerve or muscle worked or even how memory work, you would almost, as many neurologist do, forget that the nervous system is made up of cells in very basic biochemical processes that tell us how white cells or liver cells work also apply to the nervous system.

The new insights that we’re bringing or people who think about these issues, are bringing to thinking about neurological diseases are coming from a general biological background and are a good example of the unanticipated benefit of very basic research. Whether they’ll be coming as fast as patients would like or as we would hope, that we can’t say. But these new approaches are being applied and they’re coming from outside of the traditional discipline. They’re coming from work that the NIH has sponsored as undirected research for many years and now the insights can be directed to specific diseases such as ALS.

Jenny: It’s foundational work.

Dr. Goldberg: We hope so. We hope it’s relevant someday. But we’re optimistic that we’re on the right track.

Jenny: Seth, do you have a question? I have other questions but I don’t want to prevent you from asking yours.

Seth: Yeah, Dr. Goldberg, my mind is filled with questions. I’m curious in myeloma, how long ago was the vacuum cleaner discovered and how long did it take to make a drug based on that model?

Dr. Goldberg: That’s also an important insight. I mean in broader points to discuss our research related to how cells breakdown proteins goes back. I started it in the ’70s. The field really starts growing in the ’80s or ’90s. But in the early 1990’s, we were convinced that inhibitors of the proteasome could be drugs. We did not have myeloma in mind at all. When we actually started a company, our first goal was to build up muscle, muscle atrophy for example, what you see when you injure a nerve or an ALS patient. When a nerve dies, the wasting of those muscles is a case where we have too much protein breakdown and we were able to show that excessive protein breakdown was the vacuum cleaners working too fast.

Our first goal was if we got molecules to slow down the vacuum cleaner to use this metaphor, we would have applications to build muscle and to stop the wasting you see in cancer patients, the neurodegenerative patients. Drugs were developed and the first evidence was 20 years ago that a small molecule could do this. By the early ’90s, we started a company because in the University, there was no way for basic scientists and chemists and physicians to work together and we actually had a small venture capital firm in a small company. By the mid ’90s, we were able to get molecules that look like they could be turned into drugs. The clinical trials were started in about 2003 and in truth, they were tried against cancers.

For various reasons, we knew that we could kill cancers with these drugs more easily than we could slow muscle atrophy. In other words, as the research progressed, we reoriented our research towards a different group of diseases and when it went into patients in a phase one trial, this was about 2003, 2004. Within one year, there was dramatic results and phase two approval was achieved. First as a fallback drug then a phase two was confirmed it became approved as the drug of choice in phase one. That’s really only about I think eleven years ago.

I would say from when we had real molecules to when it was widely used was about 13 or 14 years. That’s a lot longer than I think a sick patient would hope for. But for some patients, this was three or four years from when it was still an idea until it first was used as a drug. I think if an agent is really able to have an effect and the clinical trials are well designed, this process can go much quicker than it does for many drugs. But still to prove efficacy in an impartial way unfortunately takes time and sometimes science is a prolonged frustrating process. But the myeloma case, it went fairly rapidly. Does that clarify?

Jenny: I think part of Seth’s question is what you addressed. But ALS has had maybe one new drug approved in the last hundred years. And so they have a great sense of urgency to say okay, how can we get things into the clinic to try that looked like they are potentially effective. With your research that you have done on the foundational research that you have done, how long do you think it would take to try to create a small molecule, proteasome inhibitor or maybe not proteasome inhibitor, just something — yeah, a proteasome activator that would affect ALS per se.

Dr. Goldberg: Yes. This is always the kind of question that a careful scientist and a careful physician does not like to face because even though with absolutely and appropriate and natural question that they are thinking themselves. One wants to not get hopes irrationally encouraged and also wants to be realistic. The truth of the matter is, in this case, the molecules that we are investigating and find to inactive that proteasome and have effects in cells are well-known agents that is in a sense that we are not developing molecules of a kind that have never been drugs or that a totally going to require new chemistry, which occurs in many areas.

We have a lot of information we can build on and there are some molecules already available to try in cells and the test tube and already in mice. My collaborators have shown that this works in mice against a model of it’s called frontal temporal dementia. It’s an early onset Alzheimer’s condition for which there is a specific abnormal protein well-studied. And so it has been used as a model and this has already worked in a mouse. The situation here is that we are about ready to study animal models which our models of ALS. We have started such studies in collaboration with Dr. Robert Brown who is one of the persons who identified SOD1 mutants as one of the causes of ALS.

We are about to start on some such studies on a different ALS model and mouse caused by mutations in the Fos protein. We are farther along than we ever were in other projects such as the myeloma one. We’re not at the outset. We’re at a position where if animal models are encouraging and there are some pretty good animal models to try this on. Then one could consider human trials within a few years, a couple of years. This isn’t an immediate possibility but it’s much more tractable than when one reads about an exciting new gene target and one has to start with new chemistry and even develop animal models.

When it comes to the animal studies, I have to work with neurologists and we are just starting those for people who are really experts in thinking about the practicalities of handling disease models and patients also. Because we don’t have other treatments available, they’re also — It should be much easier to bring new ideas and new drugs into clinical trials which isn’t true of conditions for example where there are five competing trials and they’re harder to establish. I think there is a reason to be relatively optimistic. Although it’s hard to say that to any person, any community of patients. Physicians are very sympathetic too but don’t have miracles to offer.

Seth: Dr. Goldberg, we’ll ask about how we can help speed up that process but perhaps then I know we have a number of callers. Could you remind them how they can ask a question.

Jenny: Oh, sure. If you are online listening to the show and you’d like to ask a question to Dr. Goldberg, you can call 516-590-0362 and press 1 on your keypad.

Dr. Goldberg, I think you make a really important point that you’re not starting at the absolute onset of research. It sounds like there is a process. I’m familiar with it but I don’t know if everyone is that you do this research in the lab first and you move it to the mouse models and then you start phase one, two and three clinical trials. A new drug will have to go through that process to be able to get FDA approved. What you’re saying is you’re in the middle of that process because you’re almost to the point of starting to work in mouse models. Is that correct?

Dr. Goldberg: Yes, that’s absolutely correct and mainly because we’re building on a lot of valuable insights into this area of chemistry and to this area of biology and because the initial experiments, which have just been published, have been very encouraging. Yes, we have colleagues who work and are very expert on animal models and develop that and they will be pursuing these more translational research building on our cellular biochemical insights testing whether the ideas are really helpful. But then the question is how to optimize the utility and whether that goes quickly or not, it’s almost unpredictable.

Seth: Are there anything that the ALS community can do help speed up that model?

Dr. Goldberg: There is no question that in science, like many other things our government does or foundations do, it requires money. ALS has recently through the efforts of many patients and their families and well wishers has gotten an infusion of research funding that has been very helpful. This is the new area to me in the sense that I’m not a long term investigator in the area, long term interested. But for example, in the past year, we have applied for research grants to one group called Target ALS, one group called Project ALS, and also to Jenitech, the company which gives some funds for basic scientists.

All have chosen our projects as particularly promising in wanting to fund. We have entered from the outside without credentials in ALS directly but what looks to us and the people who have read it as a novel and exciting idea and we have gotten support. There is no question that kind of money from foundations makes the world go round. Sometimes, money comes without good applications or good ideas or good ideas that don’t work. But without those ideas, there has never really been progress.

Now, I think there are a lot of innovative ideas available to Seth. I think the small foundations have recognized that. Further support would only help without a doubt and that means more people could be working on this area. Whether we can convince companies to put resources into it or not, that would further accelerate it. That’s exactly what happened with the case of myeloma, what was looked at as a drug that was very unlikely to succeed and no one wanted to pursue it. As soon as patients were responding, then at least four companies jumped in and now there are at least four proteasome inhibitors in trials and the possibility with each step of success you would encourage shall we call financial capitalist’s interest which means more valuable research.

I think resources will only help. Now it certainly helps what we do directly and will help with the field. Thankfully our government just passed regulation to give more money to science for these diseases which had been cut back to the last few years in economic downturns but the politics seems to now be changed as both democrats and republicans realize that helping people should be a priority.

Seth: Excellent. To put a fine point on it, how can the individual members of the ALS community determine where best to focus their time and money. I know that is a bit explicit but do you have any recommendations?

Dr. Goldberg: I feel like I’m somewhat knowledgeable as a scientist. The idea of evaluating organizations or their relative strengths, I have 1) no qualifications in very good experience. My limited knowledge has left me impressed that the major foundations that exist are certainly well-motivated in doing their best. In these areas, I don’t think I can comment with any knowledge. In fact, all of you probably have much more experience with the specific foundations, what they do with the patient. In terms of specific scientific projects which are highly technical issues then I have strong opinions and I don’t think those are issues that one can distinguish one’s foundation from another from anything I know.

Seth: Great.

Dr. Goldberg: I feel very confident talking about my research but what foundations they’re doing is really someone else’s concern. But these are not — I don’t know any are organizations that aren’t doing good. Whether they are doing as best as they can, I don’t know enough.

Jenny: Well I want to make the point too that now that we have talked to many, many doctors and understand more about the lab work that’s being done at specific facilities, it’s quite possible, and happens very frequently, that people donate directly to a lab at a facility, if it’s a project that they see is very helpful. Someone could do that for you. Someone could do that for another physician or another researcher and that’s done really all the time. It’s possible.

Dr. Goldberg: Yeah, there is no question. If people with means are interested in supporting work, there is no question we would be delighted. We have young scientists in training that have careers taking off. To encourage and to go directly would certainly be something that we would welcome but it would have to be with the absolute understanding as that we are not working with patients. We are working to make treatment of patients possible one of these days.

Jenny: It’s foundational work, yes.

Dr. Goldberg: Yes. It’s definitely work that we think is important in a reason for being optimistic but it’s very hard to say anything certain in the kind of life that I lead. We know a good idea but we don’t know whether it will necessarily be beneficial.

Jenny: Well you have to take it all the way through the process. That’s part of entrepreneurship and that’s part of science. I think that’s pretty common. Anytime you have a new idea, Seth understands and we both understand the entrepreneurial process and that’s very similar. You have to take a risk to see if it will work or not.

Dr. Goldberg: Yes. This is definitely risky but I am not sure if I would call the word entrepreneurial in a sense that we’re not working for a profit the way a venture capital is — We are working for personalal reward or intellectual reward to do something helpful but these are not — Then the research we do, we don’t directly profit from. To some extent, it’s not the — This is not an entrepreneurial company. Few scientists work on that basis.

Jenny: That’s not typical. Seth, do you have another question?

Seth: No. I really appreciate your work Dr. Goldberg. I look forward to hearing more about it as we make advances in our understanding of the biology of ALS.

Dr. Goldberg: Well, if there are any specific questions that you or people listening have, I’d be glad to try answering them or putting them in touch with people who have expertise that’s relevant, if mine isn’t. If anyone is interested in supporting for the research, I’d love to talk about how that’s possible.

Jenny: Well I like to ask one last question. You mentioned earlier in the show about how new ideas coming from other areas do help people. What can be done to help support that cross disease foundational work that people like you are doing to help make those connections? I guess myeloma is a good example in that one patient, one time, they knew about Fulton and the work he was doing on angiogenesis and demanded that a certain drug be used for her husband. And it didn’t work for him but it became part of the class which is a whole class of drugs that’s now typically used with the proteasome inhibitors for myeloma.

Those type of flukes chance happening in disease, from your perspective, since you have been on a corporate side and you have also just been assigned to doing such fonation work for such a long time, how do you see those connections being improved or what could we do to speed those up or make those better?

Dr. Goldberg: What you have defined is a major challenge for education of our young scientists. It’s also a major challenge for drug companies and foundations which often gets dominated by existing expertise, people who for example have thought about myeloma or a cystic fibrosis or ALS and know as much as possibly knowable about that condition. But since they have gone to medical school or graduate school, major advances have come in about important factors that will eventually influence therapy. Those are very hard challenges.

I mean I try teaching PhDs about medical problems and we always have the challenge of teaching physicians about basic research. It’s not obvious that there is a simple solution at the moment that many of us are not struggling with that very problem. The case of individual diseases to bring, we have a neurobiologist and people interested in memory together with people who are interested in keeping cells alive. Those are very different areas of science and to get them to talk to one another may be where real insights come from. Some drug companies really are doing that continually.

Sometimes, we get buried in our own special walls with notes around it and we don’t communicate with the areas where we can have an impact. I’m not sure if there is a general way to do that. The best most open companies and the best most open foundations bring together a variety of talents and have them talk to each other whether it’s geneticists who studied those few patients with ALS repeatedly in the family, with people who are able to analyze what’s special about their genes, and then test them in a cell. Those are different expertise that you have to bring together.

In some places, it’s done routinely. In many place, it isn’t. I don’t know if I have a specific solution but realize that it is a continued challenge and try keeping our eyes open for new technologies that we might apply. I think drug companies are getting much, much better in this realm than in the past and small biotech companies have been much more innovative in this respect than drug companies in the past, which is I think a real reason for hope.

Jenny: Well, I would agree. I see that in many different diseases including ALS. I know for patients who have limited options, what you’re doing is very exciting. They are looking forward to seeing more about what you’re doing and so we hope you will keep us posted.

Dr. Goldberg: Thank you very much for the invitation. I look forward to more contact in the future.

Seth: Thank you.

Dr. Goldberg: Good bye.

Jenny: Thank you so much, Dr. Goldberg for joining us and thank you for your deep research and all the effort that you put in to helping people and curing diseases over the course of your very prestigious career.

Dr. Goldberg: Thank you very much. Bye-bye.

Jenny: Thank you so much.

ALS Crowd Radio Episode 10: Dr Jonathan Katz, M.D., Sutter Pacific Medical Foundation

Dr Jonathan Katz, M.D.,

Sutter Pacific Medical Foundation

Interview Date: February 26, 2015

Dr. Katz speaks about the complex issue of the right to try for patients with ALS.  Can an ALS patient be allowed to try an experimental drug before it is approved by the FDA?  Dr Katz explains why it can take up to ten years for drug development, and the reason for exclusions in clinical trials.  He shares his vision for a shared database of information between the 90+ ALS clinics around the country that can make a huge impact for the ALS community.

ALS Crowd Radio Show with Dr. Katz

Full Transcript:

Seth: Hello and welcome to episode 10 of ALS Crowd Radio. I am your host, Seth Christensen. I have the delight to introduce a new co-host today, a fellow pal, Whitney Hill. Whitney, can you introduce yourself?

Whitney: Sure. I am Whitney Hill, a friend of Seth’s. I have been diagnosed with ALS starting in November of 2012. I am still not quite sure that I agree with that diagnosis, wishful thinking maybe. And I live here in the Salt Lake area. I’m a wife and a mom.

Seth: Thank you, Whitney, for being here. We have the pleasure of having Dr. Jonathan Katz here with us today as our guest. I’ll have Whitney introduce Dr. Katz.

Whitney: Dr. Jonathan Katz is the director of neuromuscular program at Forbes Norris ALS Center in San Francisco, one of the largest centers on the West Coast. He is currently the national principal investigator in multicenter clinical trials of — I don’t want to butcher this — Rasagaline and diaphragm pacing. He’s also the current president of ALS-RG, a national organization of clinical investigators that is tasked with improving efficiencies in clinical research.

Dr. Katz has written over 70 peer-reviewed articles in ALS and in other neuromuscular conditions and has given numerous lectures on ALS. He is the co-director of a busy social media website for neuromuscular physicians, which focuses on the dissemination of knowledge among those practicing in this area.

Prior to joining the Norris Center, he was an Associate Professor of Neurology at Stanford University School of Medicine. He did his neuromuscular training at the University of Texas, Southwestern Medical Center in Dallas, his neurology residency at University of Washington in Seattle, and Medical School at Tulane in New Orleans. He is a graduate of Johns Hopkins University. He is currently an Adjunct Professor of Neurology at Kansas University Medical Center. And even with all those accomplishments, probably the biggest one is that he is also could be the twin of Woody Harrelson. So all pretty impressive feat.

Seth: Thank you, Whitney. And Dr. Katz, are you with us?

Dr. Dr. Katz: I am here.

Seth: Great. Would you like to refute anything Whitney said?

Dr. Katz: I think she got it pretty much on the number. I’ve been all around the country, and I feel like the only city I miss was Salt Lake City.

Seth: Well, we will have you out there after this show. Thank you for joining us today. We are thrilled to have you.

Dr. Katz: Nice being here.

Seth: Thank you. Before I get to our main topic, I’d like to try to talk about your overall work in ALS and your focus areas. What can you tell us about what excites you in ALS?

Dr. Katz: Well, I come from the background of being the clinician. First and foremost, I have a clinic in San Francisco. I see a lot of patients so I try to take that patient perspective as much as possible and try to understand what people want and what the right thing to do is. Obviously, this is a frustrating disease in the sense that we’re trying to find a cure and trying to move the world forward.

So I see also the research side of everything. From a research end, personally I am interested in clinical trials and how to bring a drug that might be successful in ALS as fast as possible and as efficiently as possible to people. So I think a lot about that issue. I am not, just to be clear, a scientist in ALS, but I think there’s a lot of work to be done by the scientists to figure out exactly how the disease is happening. I try to stay in touch with that topic as much as possible. But I think it’s probably the most important part of all the puzzle together when it comes to solving this thing.

And then I think right now the things that excite me is I am directing, as you heard, a couple of clinical trials nationally, one with the diaphragm pacer and the other with this drug, Rasagaline. I am doing one with Jeremy Shefner who is in Arizona, and the other with Rick Barohn who is in Kansas. My pet project of all is I am very interested in data right now. So I’m working on a project that hopefully will allow all the ALS clinics in the country to start entering common data like if you were at a bank or something like that and you wanted a mortgage, say, at Wells Fargo or some bank, they wouldn’t let all the mortgage brokers enter your information haphazardly anyway they want to do it.

So I am working on a project right now that would get eventually the 90 or so ALS centers in the county to understand that it would be very useful to the field if we are all entering the same clinical information every time we saw a patient that would go into a database and help us begin to understand the disease a lot better. So that’s kind of where I am right now.

Seth: Well, we are excited about those things as well. And thank you for your work in those areas. I can tell our listeners that Dr. Katz is one of the most forward-thinking leaders in the country in data. We hope to have a lot more time on our future episode to address that topic in and of itself. Thank you for that intro.

Speaking on the first point, the bringing of drugs to market and to the ALS community, what is your interest in the right to treat or right to try?

Dr. Katz: Well, it’s a timely topic, right to try. It’s super interesting topic because for the one part it’s becoming reality. It’s a law. So the right to try is basically a legal movement that will give people the right and give companies the right to use drugs or give out drugs or sell drugs as long as the agent has been proven effective, it’s been proven safe in a Phase I trial.

So it’s an interesting movement because from the one side, from a patient perspective, it’s going to give people more opportunity to get to resources that they might think are important. On the other side, it’s going to make it easier to get drugs that haven’t necessarily been proven effective. So it’s a super interesting topic in the sense that I think it’s really important for people to understand all the different sides of this, the potential for good but also the potential for risk. Hopefully today, if people want to ask questions, we could open some of that discussion.

Seth: Great. I know here in Utah, there was bill passed yesterday on the right to try. So timely it is. We are told that we are having a significant static. I think we would like to try and call you back, Dr. Katz. If you could hang up and we will immediately call you back.

Dr. Katz: Hello.

Seth: Dr. Katz, we hope that this is better.

Dr. Katz: Sounds better.

Seth: All right. Great. And my apologies to our listeners. We hope that will clear up some static. So as I was saying, I know this is happening in a number of states including here in Utah yesterday. How from a regulatory perspective is this rolling out?

Dr. Katz: From a regulatory perspective, I think you have — I hope I answer the question the right way — but on the one side, you have some organizations tend to be somewhat conservative leaning, pushing the right to try from this standpoint of the government. In this case, the government would be perhaps considered the food and drug administration. From their point of view is that the government has been a bit of an impediment in slowing down process, making it hard for drugs to come to market. They should basically get out of the way. I use the term a conservative worldview because it tends to be that it’s the conservative side of the various think tanks or the conservative think tanks that ask for the government to get out of the way and decrease regulation in general.

In this particular case, there is a nice fundamental relationship to be had with people who really do in the immediate present of the world want these drugs because why would you want to go to the process of having to volunteer for clinical trials. And maybe you don’t meet criteria for clinical trials or you can’t get into clinical trial because there’s not one in your area or you’ve had the disease too long or for whatever reason or you don’t have enough abnormalities to have the disease to be qualified for a study or your disease is too mild or too severe and so on and so forth.

And then the other thing about people, PALS, is that they’re going to be in a clinical trial. The trial is going to take two or three years to get done. That’s not really fair that you’re being asked to enroll in a clinical trial for the benefit of the next generation of people who are struck with ALS. So there’s a real desire for people to get their hands on drugs. So the movement is a natural relationship between PALS and conservative think tanks.

So that’s I think who is pushing the legislation for the most part. It’s a legislation if you think about it that your liberal agendas are going to be in favor of because how are you going to say no to a bunch of people who really have a legitimate need for something. And on the other hand, the conservatives are going to be in favor of it because it’s anti-regulatory. So I think from a legal standpoint or from a fundamental legislative standpoint, it’s got pretty sound backing. Now, there is another side to it which I am sure somebody is going to ask me about.

Seth: No, please go ahead and preempt them. We will open the callers in a bit. But if you want to talk about this, go ahead.

Dr. Katz: So in a way, I am not a legal scholar but I am somewhat familiar with the term the slippery slope. So everything sounds good on its face that we can make drugs available to people, but there as some downsides to it because now if you cut out the regulatory center of the relationship between companies and patients, what’s to prevent a company from giving a drug that’s safe. I mean safe is not a very high bar really or charging money or getting people excited about taking a drug if you don’t even talk about the fundamental issues of cost or the fundamental issues of who’s going to pay for this. But now you have the issue of a drug that hasn’t been proven getting into people’s hands.

Well, how hard can a company push before you get into false advertising in that situation? What kind of press releases could a company release that gets people excited about something? If you think of any clinical trial or new drug, the reality is the only way you’re going to get people to fund the trial is if you get them very excited about it in the first place. But the reality is most drugs we’ve tried are not effective, so you need the hype machine turned on to get the drug even to be studied and to go to trial. But you really have to know the answer before you are really going to trust people having the drug.

So it opens up the door to a lot of behaviors that regulation might serve a purpose to prevent where a company over-hypes a drug and people get overexcited about it. The other potential downside to that is we have to enroll people in clinical trials still to find out if drugs are actually effective, like that problem doesn’t go away.

So what follows from that is we have to either be really clever in how we study drugs given the right to try. So if I am going to live in a world where everybody gets drug who wants it, I really would like a deeper ability to be able to predict the outcomes in the patients that are getting the drugs so I could see if what the expected outcome gets altered by the drug. So maybe with the right to try we have an outside chance especially something super effective of seeing it work because we’d say, “Hey, this was supposed to be the course of ALS patients.” But in fact they got the drug and it seems like the PALS all did better than we would have expected.

So we’d have to have some sort of ability to track what’s going on under the right to try to really get to understand things, and I am not sure that’s built into the legislation. The other solution with the right to try, I mean there’s a lot of things tossed around would be to say you have the right to try provided you don’t meet criteria to be in a trial. But then that’s not fair to the people who are in the trial because still it would only be the people who meet criteria that would be subject to having to possibly get placebo and that kind of thing.

So all I am really saying is there are definitely a lot of sides to this discussion I think things that get out into legislation. Personally, I don’t think that’s the right place to make decisions. I am not a big fan of government myself. So you really don’t want people who are not that educated in this topic and businesses pushing stuff through lobbyists in making decisions. I think the last thing I will say is the ALS community, ALSA, some of the other organizations, and you can ask me later about specific examples, but they’re in a bit of a though situation saying, “We really want to do trials the right way, but we really want patients to have access to drugs as much as possible.”

So trust me when I say there’s a lot of really good and really smart people in our field that are thinking really creatively and really openly about how we’re going to make this work for everybody. I am big fan of letting the people who are the stakeholders like the patients and some of the doctors that are involved in this being at the forefront of the decision making. Once it gets into legislation, I am always a little bit queasy that things are going to get out of our hands pretty quickly and who knows where it goes from there. But that’s just about as much background as I could give you right now.

Seth: Great. For those new to the drug development process, this is an old conversation. It seems that two gaining factors are time and money. We wouldn’t be having a conversation about being treated outside of trials if trials moved the speed of light and were all well funded, but that is not the case. Any thoughts on the time cycle required for drug development?

Dr. Katz: You hear all sorts of things and you just use the two magic words: time and money. And in ALS, I’ll answer the question two different ways. You could look at the time in a well-funded large pharma company for how long it takes a drug to get to market and those guys have to go through the initial development of the drug, all the preclinical research in test tubes and in laboratory rats, all the safety studies that have to go on after that to make sure that a new molecule is not going to hurt people. And the safety studies have to start off at the animal level and sometimes companies do see things, go slightly wrong.

And then after assessed risk, if you should keep things going forward, if maybe there is a little problem in an animal model and then you have to try small studies in humans, either with or without the condition you are interested in to make sure it’s safe and small, studies that require now communicating with the doctors and all the IRBs and the federal IRBs, meaning the review boards at all the individual institutions. And then you have the FDA to contend with. And then after all that is done and you’ve pumped in all the funds to get that started, then you might have to go to a small clinical trial to see if something is effective. And that could take a year and then you have to go back to the FDA after that. And then after you’re done with the FDA, now you have to do the really big study to prove that the drug is effective which could take a year or two.

And it’s an incredibly long and incredibly expensive procedure. I think it’s all geared towards diseases that are much less fearful. If you have a high blood pressure medicine and you’re going through that kind of process, who cares? Everybody is getting a high blood pressure taken care of fairly well. But if you have a disease like cancer or ALS, there is not really time for that sort of process so we need other strategies. So that process I just described could take 10 years.

And then to go back to what I said at the beginning, the other side of the whole thing is that in ALS sometimes it’s not big pharma that’s starting the process. It’s a little company that’s out there like in Silicon Valley or somebody who had an idea with the molecule and they want to test it. So there they’re going to have to scrounge up their money to do even the first stages of something. And by the time that they get done with the small trial which is already fairly far off the road, they’re broke and their funders may have disappeared. Significant time passed or the people that are funding them think a couple of million dollars is a giant amount of money to put up for risk.

So what happens is you get these results that might be optimistic in early phases, but you can never do the trial because the company can’t raise the funds for the later parts of the trial. And what happens there is we go through all the statistics and we say before we do the study, just like we do for everything, here’s what would be an important outcome and we create these terms like P values and this and that. And the study gets done and the issue has nothing to do with anything you’ve talked about for the first two or three years of putting the project together.

Now, you are just talking about is can the company get money to do the next phase of their trial? And if they can’t, it’s done. If there’s not enough excitement on the outcome, they can’t get funds for the second trial. In our particular field like a couple years ago, you had this gigantic study from Biogen on dexpramipexol that came out negative. After that, because it was such a big negative outcome, people get scared about putting the funds up for the next drugs. So immediately, after that we get into a period where everything slows down again because the optimism wanes because of a negative study and money is a big part of it. And like you said, time is a big part of it. So there really are so many different factors that go into this.

Seth: And the trial process, is a very complicated thing.

Whitney: I want to tell the listeners that if they want to call in with a question, the number is 516-590-0362, and press 1 to indicate that you have a question.

Dr. Katz, I have a question regarding trials from a patient’s point of view. I don’t understand why you basically have two years from diagnosis to be included in any trial and after that you don’t qualify. Why is that?

Dr. Katz: We got asked that question all the time, and there’s a really good answer to it from the perspective of somebody doing a trial and it seems really unfair. Obviously, to start up a thing, if we forget the trial altogether and we have a new drug out there, why can’t everybody just have the drug?

Whitney: Right.

Dr. Katz: Trial to people who have the disease for more than two years. But here’s the but side of it. Here’s what happens when you are doing it.

Whitney: Dr. Katz, we’re going to have you start your answer to that again. We lost you for a minute.

Dr. Katz: Oh. Where should I start?

Whitney: Right after I said, “Why is that?”

Dr. Katz: Okay. That’s great. Let me hit my rewind button for a second. So I think I start here. So anyway, the answer to that question — before I even answer the question, I just want to say it sounds really unfair that we cut the access to a drug in a clinical trial off at two years. So in other words, people who have the disease for more than two years just can’t get into a trial. Sometimes it’s three years for the cutoff. Sometimes it’s two years. And on its phase, from a really simplistic fairness perspective, one can argue it’s really wrong.

Now, if we don’t look at it from that perspective, if we look at it from the perspective of everything I just talked about which is the money that goes into a trial, the funding that goes into a trial, if I am the person paying for a clinical trial, I want to find out if a drug that I am interested in is effective or if I am a government funding agency that’s just going to say — I’ll make a number — 2 million dollars to somebody who can put together a trial for me, I have a limit to what I could spend on this trial. So I really do have to begin to think how best can I understand if the drug works at the end of the trial? How do I make sure that I am going to not spend those 2 million dollars and at the end of the day have no answer to my question?

Two million dollars which is often just a rough amount of funding for an early trial, sometimes it’s more, sometimes it’s even less, sometimes it’s 7 million dollars or whatever, but what you are talking about early trials here, at low levels of funding, I really do have to take into account the risk that I am going to blow it without answering the question. It just turns out that if you have the disease for more than two years and you are not so sick at two years that you are in desperate condition, that would mean you are a slow progressor. Your progression is very slow because you’ve lived a long time and you are still in pretty good shape to be part of a trial. So you are a slow progressor.

From a purely statistical point of view, the problem with slow progressors is that they’re not going to change much over the course of the trial or at least there is a big risk they are not going to change much over the course of the trial. If I am interested in studying whether a drug works, I don’t want to spend — again I am not talking about fairness, I am just talking about determining if a drug works. I don’t want to spend a lot of my resources on people that aren’t going to change over the one year I am observing them in trial because you don’t get any information from those people as far as just the raw statistics.

What I really want is people that are going to progress over the course of a year, and I am going to compare them, the people who are on placebo to the people on drug, and I am going to see if I could alter that progression. If I put a lot of people in my trial who are going to show no change over a year, then I really run the risk that since the change is so small, I have to put more people in the trial to be able to see that, to see the difference if I could slow it down with the drug if the change is very small which means I have to pay more. And as you know, the way I started this discussion is these trials frequently don’t have enough money to do that.

So it really is about what we call statistical power. It’s the ability to see that we’re making a difference. Now, on the other side is we also cut off the breathing limit in a lot of trials at a certain number and that’s because the other thing you don’t want to have happen is you know somebody in a trial and they pass before the trial is done because then you also lose a lot of information. So it really is one of those things where in the perfect trial — and again we are just talking about the trial itself — we need the kind of like the goldilocks of people that are going to progress enough that you are going to be able to see a difference but not progress too much that they’re not going to make it through the observation period. Does that make sense?

Whitney: Unfortunately, you made it sound so practical. I am kind of bugged. But yeah, that makes sense.

Seth: Now, we come to the topic of right to try, collection of data and proof of validity of a potential drug is a whole other topic. I know that overseas they do agree to treat people under the topic of compassion, but they have the same problem, the data collection and including the overall trial at risk. I know that if you simply go and do a Bing or Google search of the topic, ALS and right to try, you will come up with a number of people suggesting ways of collecting data outside of the trial from those who are using a drug under right to try. Do you ever see that gaining legs or accepting that by the FDA?

Dr. Katz: Well, I think the answer to that question is: absolutely. It’s not ideal. It’s not the best way to study drug. I think there will always be a place for the basic trial like we’re doing it now, but I also think that we could probably think more creatively and find ways to actually capture that information. Now, I’ll say one more thing. For that information, if we’re going to basically say anybody who wants to take a drug which I think is a great goal, we need to think completely differently about how we understand drugs. And I kind of hinted it this earlier in the conversation. If you want to give everybody the drug and know if the drug works, you’re going to have to be much more clever at predicting the outcomes of everybody who gets that drug.

So if I have a patient that comes to me and they say, “My ALS started in 2012 and I think I am in pretty good shape,” well, I could quickly do the math. That’s three years ago and they’re still in pretty good shape. So I probably say in the next three years, there’s not going to be a lot of change in that person. And if somebody comes to me and says, “My disease started at the end of 2014 and I am already in really bad shape,” I could predict that that person is probably not going to do great over the course of the next month.

Now, statistically, we should make the effort to take, say, a hundred patients and hear their stories about what’s happened up to the time they got the disease and be able to predict really, well, if I were to give drugs to these hundred patients, what would I expect the average rate of progression to be in those hundred patients? I think this could be done but we have to put the effort into studying the prognosis in patients to be able to do that. And so far, the problem we have is that most of the databases we have are only patients who have been in trials.

So we have to really extend it to the whole population if we’re going to really be able to make the effort to see what’s going on. We have to get much better at prognosticating and to do that, I think we have to get much better at collecting large amounts of data on patients and to understand this other thing that comes up all the time, their biomarkers. We have to understand what’s in their blood or maybe what’s in their DNA or what’s in their spinal fluid a little bit better to really understand how we’re making things change. I think eventually if everybody starts thinking together, this movement can have some success from a scientific standpoint, not just from an access standpoint.

Seth: Thank you. We’re going to have Whitney read the number again and invite callers.

Whitney: The number to call in is 516-590-0362, and press 1 to indicate that you have a question.

Seth: Now, we have a number of callers on the line. We’re going to pause for a moment to take our first caller. Caller ending in 4475, you are on the line with Dr. Jonathan Katz. Go ahead with your question.

Caller: Dr. Katz, I’ve got a question about on the right to try. Is there a differentiation between treatments that are approved for non-ALS issues versus brand new drugs, for example, Lipitor or Flomax or Viagra? Somebody got an idea that that might be effective and they started a study on it. Since they have to be FDA approved, is there an easier path of having right to try for those types of things or is it even an issue since you might be able to get your physician to prescribe it?

Dr. Katz: That’s a great question. We had that come up before. A few years ago there was Tamoxifen which is like a breast cancer drug that affects estrogen that people were super interested in trying for ALS. And if somebody out there wants to call me on it, maybe I am getting mixed up but I think it was Tamoxifen. And we had a bunch of patients because it a prescription drug. So we had a bunch of patients saying, “Can you please start me on that drug?” So we would. So it’s not really what right to try is about. Right to try is really much more about non-FDA approved drugs.

Now, I’ll add on to that that sometimes the insurance companies aren’t exactly going to pay even though something is FDA approved. So if we take what you just asked and make it a little bit more complicated which is, let’s say, let’s look at the diaphragm pacer which is probably a $25,000 to $50,000 procedure where you need a surgeon to put something into the body, there the FDA for certain ALS patients has approved the procedure but the insurance companies don’t always want to pay for it. So Medicare pays for it. A lot of the insurance companies pay for it. But Kaiser out here in California won’t pay for it.

So that get into that’s not really what the concept of right to try is, but it does get into the issues downstream of will insurance companies even pay for a drug or a procedure if it’s too expensive and whatever? So you don’t really always have the right to have what you want. But if it’s a cheap drug like Lipitor and you have this conversation with your doctor saying, “I’d like to try this,” I don’t see a problem there whatsoever. But the two big show stoppers are the drug is expensive or the procedure, so who’s going to pay for it? And then obviously, if it’s not FDA approved, that’s really what right to try is about.

Genervon has a drug right now, for example, that people want to get their hands on. And obviously, you’ll know about this from looking at the internet or from being part of it. But that’s really what right to try is about; it’s getting your hands on drugs that are not FDA approved.

Caller: Yeah, okay. Thank you.

Seth: Thank you, Caller 1, for the great question. We will take another caller ending in 0311. Caller 2, you are on the air with Dr. Jonathan Katz.

Caller: Hi. Thanks, Seth. I have a couple of questions. One is the right to try seems somewhat vacuous because for clinicians there’s still IRB to go through and the FDA. The FDA simplifies the compassionate use form from an hour to 45 minutes, but still they need to be complied with because state laws don’t trump the federal regulations. So is there any significance to right to try when it comes to experimental stuff?

Dr. Katz: Yeah, that was a very smart question because you still have the FDA in a way. But I don’t think that the groups that are pushing right to try have necessarily stopped the push at the state houses, right? I think there’s more push that’s going to go on and we’re just seeing the beginning of this movement.

Caller: Oh, so they want federal law?

Dr. Katz: Right. So the pressure is going to end up on the FDA eventually. I don’t know which way it’s going to spin out at the end of the day. I don’t know if there’s going to be a permissive FDA at the end of the day that says, “Yeah, people have a right to try. We’re not going to get in our way.” Or if the FDA is going to say exactly what you just brought up which is the current world because we’re not there yet where they’re going to say, “No, you can’t. Even though you have the right to try this drug you still need a permission slip from your doctor and the IRB of whichever center is prescribing it.”

Caller: People like ALS Emergency Treatment Foundation, they say the current regulations are fine because there’s expanded use trial provision for FDA and that was taken advantage of back in the day of AIDS treatments before for ACT and so forth and that’s enough, and that’s what needs to go forward instead of right to try.

Dr. Katz: Well, that is true, but then you have the issue where — in the expanded use question, it’s a totally different variable because now you have the question where all right, I am a company and I am interested in getting my drug approved. I could theoretically make expanded use part of this proposal. I’ll talk to the FDA. I’ll make sure that people who can’t be part of my trial can get access to the drug for whatever reason that I think that that’s the right thing to do.

But from a company’s perspective, that’s expensive and it’s also really risky because you are opening up the use of the drug in a way that’s out of control of your study. So you are taking on a lot of risk that could end up shooting you in the foot as you are going through a process because somebody has a side effect in Tuscaloosa, Alabama, and the study is not in Alabama and they end up in a hospital and it gets into the press. How do you know how that’s going to spin out? And it takes effort to get the drug out there.

So the easiest way to do it for a company is to say I am going to get my permission slip to do the drug in the trial, and I will only do what I am allowed to do on that permission slip. I am not going to put any resources into anything else because in fact all the resources I have need to go into the trial right now. So from a concept of risk, from a concept of cost, expanded use doesn’t always make sense. The AIDS epidemic was a little bit different in the sense that the voices were a little bit louder. I think in reality it was bordering on unethical to not give people expanded use because you are starting to really have successes of these drugs.

So ALS, we haven’t even talked about it, but we also have the issue that people in drug trials in the back of our minds or in the back of some people’s mind, they almost hate saying this, are always a little skeptical still that a drug is going to work. So AZT in the AIDS era, I think there was like a really legitimate belief that it could end up being effective. So the ethics just vary between the diseases if that makes any sense for reasons of belief of whether you think a drug is going to work or not, the deepest innermost levels.

Caller: Thank you.

Seth: And thank you, Caller 2. I believe our Caller 2 was a friend from Boston. Thank you. We would invite the other callers on the line to press 1 if you have a question for Dr. Katz on not just the right to try but anything related in his work in ALS.

Dr. Katz, thank you for the conversation so far. You brought up the topic of Genervon. Can you speak specifically about where we are in that trial?

Dr. Katz: Yes. I think anything I am going say about Genervon I am going to say carefully because it seems like a bit of like a multifaceted social event right now. But it’s a good case study on everything we’re talking about because I’ll say it from the standpoint of an honest ALS researcher. I look at the work that’s been done which I can summarize is their drug which has moderately interesting underlying scientific basis has been given to a really small number of patients. Their data to say, “Hey, this thing is really great,” is not there. In reality, I don’t look at what Genervon has done and say, “Boy, this is the most exciting thing and it’s going to work.”

So that’s just the background. I don’t want to completely throw the idea of Genervon’s drug out without saying I think drugs need a chance to be proven whether they work or not. But I just want to say that where Genervon is right now, they haven’t gotten over a bar to say, “Hey, this thing is great.”

Now, you moved away from the science for a second. What’s interesting with respect to our time is that now we have social media. It’s possible to raise a very loud voice about something. I think you start putting together what the ALS community wants with respect to drugs, which is to give people hope, to give people a chance to use a drug to make drugs available, to not have to deal with the FDA for 5 or 10 years. And you put together a company that is willing to press that button and willing to be part of that discussion, about fundamental access, instead of a company that wants to work with the proof of principle that a drug works in the usual manner.

You have a bit of a powder keg that could explode because historically the companies, because of the FDA, because of regulation, have stayed on the side of the scientist, of the clinical scientist. But here with the media, not surprising for companies, again money is involved or whatever, you begin to press some buttons that are a little different than the buttons that were pressed in the past. In this case, it’s the social media buttons and it’s the feeling that we’re not giving patients everything they need fast enough which is legitimate. And when you press those buttons, maybe you do end up approaching the FDA differently. Somebody sooner or later is going to get somebody at the FDA to say, “You are right. We have to make the access a lot greater and we have to give people a chance.”

But the flipside of that, like we said earlier, is well maybe Genervon starts pushing the drug in directions that we’re not used to, not through clinical trials but through access and maybe they get to profit from that. So you can see where I am going. It really is complicated and the last thing I want to see is for people — I want people to have access. I think that’s important. I think we have to think about it. But just to have a lot of access out there without a strategy to prove the drug is effective, it raises a lot of questions and in fact a lot of fear that somebody is going to take advantage of the system at some point.

So the last thing I will say is the ALS Association really tried to address this with a letter to let everybody know that the organization cares about this. But an organization that’s funding clinical research historically and wants to see the right thing happen which is both access and learning about drugs, has to be somewhat — is in a difficult position to say the right thing to everybody which is we really want you guys to all have what you want and we want drugs to be studied faster. But I think the steps forward from all of these are all about really going to be all about helping everybody think a little differently about how we’re going to study drugs as with the fighting right off the bat or letting a lot of hard feelings out there saying people don’t want what’s for the best. We just have to balance two slightly conflicting ideas.

Seth: Very much so. Thank you. We will now go to another caller. Caller ending in 6431, please go ahead with your question. Caller 3 ending in 6431, you are on the air.

Caller: Thank you so much. Dr. Katz, I just really appreciate your presentation. It’s so informative and considering the different directions that this whole issue has to be observed. I just need to express my appreciation for you to be sharing this with a group such as because if I understand this organization, their great direction is to improve data collection. And when you talk about the necessity with expert data collection, DNA awareness, the whole issue of understanding each patient were they to undergo one of these trials or results or one of these opportunities, the results, I think that data collection is paramount.

I am so excited to have you associate or have you speak through an organization such as because that is such a push on their — if I understand the organization correctly, that is their main thrust is to coordinate the data to make this applicable, to make it worthwhile for everyone. And I appreciate that so much. Thank you for working with them and sharing with us your information.

Dr. Katz: Well, thank you for saying that. I will plug both myself and them together. We look at this collection of data as extremely important. If I had to just talk for a second about like where data collection should go on the field, I think it’s a gigantic vision in the sense that, number one, what I said earlier, it’s kind of crazy if you think about it that we have 90 plus ALS centers in the country and everybody is just collecting at the bedside every time a patient comes in. Every week I see 15 ALS patients in my clinic. We’re just collecting notes in all 90 centers completely differently and passing the notes on to Medicare so they can bill. That makes no sense whatsoever. We have this great opportunity.

I mean what’s in a clinic? You have a doctor, a patient, sometimes all the other clinicians. You have the ability to order wheelchairs. You have the ability to — five years ago there wasn’t a computer in the clinic. Now, there’s a computer. You can feed information back to people, educate them on the disease. So we’re not taking advantage of these clinical centers which I think is a giant mistake and we have to fix it. I think a lot of the research we’re talking about, trials would flow from that because you understand patient outcomes better.

But there’s also just like the community that develops from being able to collect data together, and the opportunity for different people to get to know about each other and learn about the disease and learn about outcomes. And then there is all of the other places that ALS could connect to like making wheelchair ordering cheaper or making speech devices better. There’s just a ton to learn by having a structured internet. That doesn’t really go one way where we get the patient’s data because the other way where we can give the patient’s data.

I think Seth has a really great vision also, that’s the second plug, which is to begin to really hook ALS up. My interest is to do it from the bedside but his is to hook up ALS to the rest of the world and to really begin to use some really creative ways to put all this data, genetic information, blood information — I’m probably leaving out a thousand things — historical information, ancestry information to really create a very deep understanding of the disease. I think that’s where things really need to go. So I am glad you brought up that question.

Seth: And thank you, Caller 3. You’ve added us as the data go-to.  I can re-plug Dr. Katz. He is a very forward-thinking on how to get the data, one, standardized at the clinic level; and two, out into the open away from the clinic so that we can actually use that data as a community. And the community is critical here. We need to not reinvent the wheel but instead use all of the wheels that have been invented and use them for what they are designed to do which is solve this riddle. So I thank you both.

We will take another caller. Caller ending in 1034, you are on the air.

Caller: Hi, Dr. Katz. Thank you so much for doing this show today. I really appreciate it.

Dr. Katz: Thanks.

Caller: I have a follow-up question about the data. If you can wave a magic wand and maybe pick one of the most critical pieces, the standard process in clinical trials in drug development is an 8 to 10 year process. Drugs develop for potentially a particular target and it goes through the whole process and that many years later you get an FDA approved drug. What do you see as the biggest shortcut where you can develop hypothesis on a really rapid scale? Because without targeted biomarkers that you are going after in ALS, it’s even more of a challenge.

Dr. Katz: You said it right there. I mean the first answer is to find the biomarkers. It would make things a thousand times easier. If we had something we could just look at that would require fewer numbers of patients because there’s a lot of variability on functional scores, some people decline faster than others, if we had a biomarker that we could just measure, that would be fantastic because we could shrink the size of trials and speed them up. It would be a lot more trustworthy if you just had the blood test to measure things from a distance because when you are measuring functional decline from a distance, who knows what everybody is measuring and whatever.

A blood test is very objective. It’s very fast. So that’s the short answer to the question. But let’s say we don’t have a biomarker for a long time. It starts getting confusing because if you want to study biomarkers during clinical trials, which tends to be what happens, you want to figure out if a drug hits the target every time you do a clinical trial. In others words, your trial gets a lot more expensive, which is going to slow down the speed that you could do trials. So finding a biomarker actually makes it harder to do the other half of what your question was which is to fundamentally speed through trials. You are going to be slowed down until you have that biomarker.

So it just creates a big challenge. I think for every drug that wants to come to market, you have to have a different strategy. I toss this around in my mind all the time, but I think at one level you have to think of the cheap and dirty, fastest trial ever which would be to really understand disease outcomes, you put a hundred people on drug and you just figure out if the drug works and if it doesn’t, forget about it and move on to the next drug. That’s the way you do things fast.

If you have a drug you are really interested in and you have the funding, you’re going to want to learn about is it hitting this target? Learn about biomarkers. And then I think the other piece to it is there has to be a completely separate process to study biomarkers where we’re constantly testing ideas in ALS patients. And again, that gets back into creating the infrastructure at the bedside where we have a lot of station information. And we could take their blood samples or bio samples and give them to interested scientists and study them on a constant basis. What we’re doing right now though, we’re funding one thing at a time over and over again is really haphazard and small and disorganized and we’re not going to get there as fast as we can.

So I guess my answer would be create the infrastructure first that needs to be in place. Communicate a lot better which means having governance and ideas that are tossed about by patients and doctors, the infrastructure governance, and finally I think a real deep understanding of everybody into what our goals are with every single drugs that we could at least speed along as fast as possible. That’s as good as I can do.

Caller: That’s a great answer. But I wonder if it would be reasonable to go backwards and start out with patient outcomes that are working well and drive back down to the, let’s say, five or six of different hypotheses of what worked well and then try to drill down a little bit more on those. I don’t know if that’s possible.

Dr. Katz: Well, I think that that’s actually another really good point because — I am not sure I am going to answer what you said exactly on target. But I do think like another strategy for discovering the disease is to have a really strong hypothesis of what we think are the primary players. It gets into the whole question of what drugs should we be studying. I always envision that there is a meeting of great ALS minds of people that are actually detached from the funding, who would get together and tell us here is the fundamentally unifying hypothesis of this disease that we think is most interesting to test right now and develop drugs towards that hypothesis. I think what you did is bring up a whole another question which is, which drugs should we really be testing, which if we only have limited resources is an enormous question.

Caller: In time. Okay. Well, thank you so much.

Seth: Thank you for your question. We are almost out of time here but I do want to invite you, Dr. Katz, to plug any of your current trials, anything more to share about your diaphragm pacing trial or your drug trial right now?

Dr. Katz: So the diaphragm pacing trial, if anybody has any interest in the diaphragm pacing trial, email Seth, email me. I will get your name and we can see if you’re — after all this I almost hate saying it, but we could see if you are eligible for the procedure. And it’s an exciting procedure in the sense it’s a device that stimulates the diaphragm. And since the breathing muscle which is the diaphragm is super important for the longevity, if you could just make that muscle more functional, you may improve people’s life expectancies.

So that’s why we’re doing the trial. The trial is having a hard time enrolling because it’s a surgical procedure and also because I think some of the super excitement that was there at the beginning is kind of gone away with time. But we’re about 50 patients into 180-patient enrollment. So we’re pushing along. We still think it’s an exciting trial and we hope people would sign up for it. And then Rasagaline is a drug that was helpful in Parkinson’s disease. So we’re looking at it in ALS. It may have slowed down the progression of Parkinson’s disease. And that study is just about done but hopefully you’ll be hearing some results in the next six months or so. We’re done recruiting.

Seth: Thank you. If you could tell our listeners what you said the greatest opportunity to get involved either in your trials or in the ALS community. We’ll wrap up with that.

Dr. Katz: Well, in a nutshell, instead of answering the question exactly as you asked it, I think it’s something that Seth and I hopefully will continue to talk about, but I think we want to use shows like this and we want to use an internet portal to really make people aware of opportunities for trials and actually all of these issues that we’ve talked about. I think that in itself can bring the community together which in a way will make everybody’s voice louder, make people be able to hear the field better, and to make research projects faster and to ensure that we’re going to end up doing the right thing. So if I had to say anything, it’s anything that brings the community together is going to be extremely important.

Seth: Excellent. And lots more kind of on that topic. We want to thank Dr. Jonathan Katz for the time and insights and also, Dr. Katz, for your dedication to the community. We love having brilliant minds on board and it also helps when we really like the people attached to those minds. So thank you for your time today.

Dr. Katz: Thanks so much, everybody.

Seth: And thank you, Whitney Hill, for her exceptional co-hosting of today’s show. We look forward to our next episode. We’ll publish the full transcript from today’s episode in the next week. Thank you for listening.


ALS Crowd Radio Episode 9: Dr. Richard S. Bedlack, MD, PhD, MS, Duke University School of Medicine

Dr. Richard S. Bedlack, MD, PhD, MS

Duke University School of Medicine

Interview Date: November 19, 2014

Dr. Bedlack explains ALSUntangled, a program he started to give ALS patients scientific reviews about alternative and off-label treatments.  About 50% of patients with ALS try at least one of these treatments over the course of their illness; maybe something they heard about through friends, family, or the media.  He shares some “red flags” for treatments that are not likely to work.  ALSUntangled helps to educate and empower ALS patients to make educated choices about their care.  He encourages patients to be involved in research studies as well as clinical trials to increase the knowledge and lead to a cure for ALS.  

ALS Crowd Radio Show with Dr. Bedlack

Full Transcript:

Seth: Hello and welcome to episode 9 of ALS Crowd Radio. I’m your host, Seth Christensen, here with Amy Christensen. And we have the honor today of having as our guest, Dr. Richard Bedlack of Duke University. Amy?

Amy: Yes.

Dr. Richard Bedlack grew up in a small town in central Connecticut. He went to college at William and Mary in Virginia, then back to Connecticut for his MD and PhD in Neuroscience at UConn. Finally, he came to Duke where he completed his Medical internship, Neurology Residency, Neuromuscular Fellowship, and Masters in Research Science.

He started the Duke ALS Clinic, the Catfish Hunter ALS Clinic at East Carolina University, and the Durham VA Tele-ALS Clinic. He is currently a tenured Associate Professor of Medical Neurology at Duke and Director of the Duke ALS Clinic and the Durham VA Tele-ALS Clinic. He has won awards for teaching and patient care, including best Neurology teacher at Duke, Health Care Hero, Strength Hope and Caring Award, America’s Best Doctor, the American Academy of Neurology’s Viste Award for Patient Advocate of the Year, and the ALS Association’s Rasmussen Award for ALS Advocate of the Year.

He has received research grants, participated in clinical trials, and published more than 70 articles. He is past Chair of the North American ALS Research Group and current leader of the NEALS Patient Education and Advocacy Committee, and the international ALSUntangled program which utilizes social networking to investigate alternative and off-label treatment options for patients with ALS.

He lives in Durham North Carolina with his wife, Shelly, and two mischievous kittens.

Seth: Welcome. Dr. Bedlack. Thank you for joining us today.

Dr. Bedlack: Well, thank you, Seth, and thank you, Amy for that nice introduction. It’s great to be with you.

Seth: Hopefully those two mischievous kittens are behaving.

Dr. Bedlack: Never, never.

Seth: We appreciate your time today and know that we have a lot of folks interested in hearing your insights so we’ll jump right into it. Amy?

Amy: Yes. Callers and listeners, we would love to hear your questions today. Please call in to ask questions to Dr. Bedlack at 516-590-0362 and push number 1 to indicate that you have a question today.

Seth: Thank you, Amy.

Dr. Bedlack, we had the honor of meeting you recently and receiving your insights and wondered if you wouldn’t mind sharing the overall focus of your research.

Dr. Bedlack: Yeah! Well, Seth, it was my honor to meet you and Amy as well.

My research really is focused on trying to find new treatments that help people with ALS and overall, trying to speed our journey toward a cure for this disease. And so that kind of falls into three categories. One is I do clinical trials. Some of those trials are investigator-initiated, meaning they happen only at Duke. Some of them, I’m an investigator for a multicenter trial like a phase II trial for example, the Cytokinetics trials that were going on or even a big phase III trial like the dexpramipexole study.

Second group of things I do involves reviewing alternative and off-label therapies and by that, I mean treatments that are being proposed for use in ALS, may be advertised as slowing or stopping the disease, without a lot of mainstream evidence for those. So things like coconut oil and marijuana for example.

And in the third sort of research that I do is I’m trying to actually build an army of advocates, patient advocates for research and that’s where I met you and Amy at one of the clinical research learning institutes that I helped create and run through the North East ALS Consortium. And the importance of that is just trying to make sure that there aren’t any patients who don’t know what their research options are so we want the graduates of this program to go and speak at support groups and fundraisers and to go on Facebook and spread the word about studies that are open and make sure that people don’t have any misconceptions about research studies and make sure that funders always realize how important ALS research is.

Seth: Thank you for that overview. We have marketed today’s show as investigating alternative ALS treatment. But for one moment I want to touch on your third area, training patient advocates. Why is this important in the whole ALS ecosystem?

Dr. Bedlack: Well, Seth, one of the things that a lot of people probably don’t realize is that enrollment in ALS research studies is surprisingly low. So somewhere between 5% and 10% of patients who have ALS ever enroll in a research study and only about two patients per site per month are enrolled in multicenter trials.

So for example, at Duke, I might see 40 patients in a month and only enroll two. And so the questions are why is enrollment so low? It’s such a tough disease, we have some treatments to offer but nothing that stops or reverses the disease. You think people would want to sign up for research study in droves.

Well, there’s lots of reasons why people don’t sign up. One reason is that patients may not know that they have an option for research. Another is that they may have misconceptions about a research study. For example, one thing that I’ve heard from patients when they turn down a research study is they’ll tell me, “I feel like if I sign the piece of paper that informs consent, that I’m basically going to be a guinea pig and you can do whatever you want to me”, and that’s a misconception. And I understand why it happens because in the past, in the United States, there was research like that, there were things done to patients in trials without their knowledge. But nowadays, there’s a ton of oversight, there are tons of laws that protect patients from that happening again.

And so those kinds of misconceptions and those kinds of missed opportunities to get people in research, we really can’t afford that as a field. We’ve got to try to boost our enrollment rates so we can get through these studies faster and ultimately get to a cure for ALS faster.

Seth: Thank you. We as a patient community need to understand that and I think your work in training patient advocates is central to that. So thank you.

Dr. Bedlack: Pleasure.

Seth: Turning our focus to today’s topic now, investigating alternative ALS treatments, could you explain to us what ALSUntangled is?

Dr. Bedlack: Yes. So ALSUntangled utilizes social networking to try to provide a scientific review for alternative and off-label treatments for ALS. And again, alternative and off-label treatments would be things that somebody is advertising for use in ALS without mainstream data, so without phase I and phase II and phase III clinical trials. Again, some examples would be things like coconut oil and marijuana.

Seth: And why did you start this effort?

Dr. Bedlack: Well, so I noticed, Seth, when I started the Duke ALS Clinic in the year 2000 that a lot of my patients were trying these alternative and off-label therapies and it turns out when I looked in the literature, more than 50% of patients with ALS would try at least one of these over the course of their illness. And it seemed to me that there were three ways that this situation was handled by doctors in the ALS field and I’ll divide those into paternalism, autonomy, and shared decision making.

So a paternalistic way to handle this would be to say to your patients as if you were their parent, “That’s really not a good idea, you shouldn’t do that, it’s never going to work.” The problem with that is first of all, it’s not very respectful, and second of all, it’s dishonest. I mean we don’t know whether these things might work unless we actually look into them. You can’t just look at something and know that it won’t work, you have to actually do a little bit of research on it.

The second way we handled it was through autonomy where we’d say to the patient, “Okay. Well, good luck with that. Let’s turn our attention to the things that I can offer you in the clinic.” The problem there is that the patient is actually relying on the doctor I think in many cases to utilize their many years of training and experience to help them sift through whatever data is available on that thing and make an informed decision.

And so the final model was shared decision making where we do exactly that. The patient would ask us about a particular thing, maybe a stem cell clinic in China and we’d spend a few weeks researching it, trying to find out exactly what they were doing, trying to find a way to talk to the person who was in charge, trying to find patients who went there and find out what happened to them, and then get back and actually tell the patient what we found and make a recommendation based on that. And that’s great. Patients like that, doctors really enjoy that but the problem is it takes a ton of time. And the other problem with that is that next week, when someone down the street at another ALS clinic asks the same question to their doctor, they have to reinvent the entire wheel again.

So we created ALSUntangled to engage in what we call shared decision making. So we do all these reviews by committee and we publish the results so no one has to do the review again. We can all kind of point to that and say, yeah, that’s kind of what the field thinks about this particular alternative and off-label therapy.

Seth: So I am out on the website ALSUntangled right now and it appears we have completed 26 formal reviews and have, wow, quite a few under way.

Dr. Bedlack: Yes. That’s the mode of the challenges is that there’s a lot more of these than I ever realized and so we certainly want to put them all on a list and we’ll get to them one by one. But this so far has been a sort of a part time thing that most of us do nights and weekends. There’s no like protracted time, there’s no funded time to do this so this is a labor of love, if you will. We don’t crank this out nearly as fast as we’d like to.

Also the way that we do this, it’s challenging. This is not traditional research where you know exactly there’s a blueprint and exactly how to do a good mouse study or exactly how to a phase II trial. A lot of this stuff, we’ve kind of have to sort of pave the way and the whole process of doing research like this.

Seth: Let’s step for a minute into that process. You use Twitter to decide which studies to engage in, correct?

Dr. Bedlack: Yes. So there are three parts to this program: inputs, reviews, and outputs. The inputs come by any means necessary. So most of them now, as you pointed out, are coming from Twitter. We average about a tweet a day. Some of them come through email so my email is all over the internet. Some of them come from emails by my colleagues, like a patient in their clinic asked them face-to-face about something and they’ll email it over to me and it gets on the list that way.

And then there’s the reviews themselves. So we’ve long had a sort of standard operating procedure for doing these and it starts with making multiple attempts to contact the person that’s selling this particular AOTs so make sure we understand their side of it. We try to get any kind of materials they’re using to advertise this, figure out what the claims are. We do a PubMed search. PubMed is a database that has scientific publications to find out if there’s any scientific paper and a peer review journal about this thing. We do a Google search which is where we find a lot more of the information we look at and that’s where you find things like blogs.

We do a poll of all the ALSUntangled investigators and there are now 94 ALSUntangled investigators from across ten countries. The purpose of the poll is to find out if any of us take care of patients who’ve tried this and if so, what happened. We look at big shared database called PRO-ACT and we try to see if anybody in that database — and there’s almost 9,000 patients in that database — if anybody has ever said they were trying one of these things and then what did their outcome measures look like before and after they tried this.

We look on the website PatientsLikeMe and there we can find information about subjective outcome measures that patients input themselves. And then we try to visit the clinic, review the infrastructure of the clinic, interview people that are there, look at the medical records. Most recently, we’ve actually instituted something even one step beyond this which is something called the Table of Evidence. So we Crowd-Source this because again, there was no precedent to doing something like this for looking at this kind of data. And we decided that in ALSUntangled, we’re really looking at four types of data: mechanistic plausibility, preclinical data, case reports, sometimes trials, and then data on risk.

And so in those four categories, we’ve come up with an ordinal system for grading each AOT on each of those categories. So for example, under mechanistic plausibility, you’d get a grade A if you showed in a peer-reviewed publication that whatever is that you’re selling could act on a relevant mechanism in people with ALS; and you’d get an F if this thing that you were trying to sell violates known laws of physics and biology like for example, energy healing. We’d have to rewrite the textbooks if that existed. Now, it might work but still, as of right now, you’d get an F grade for mechanism because that mechanism is not recognized by science.

I think this is going to help us in a lot of ways. One is it makes it a lot transparent what we’re doing. Each one of our reviews from now on will get letter grades in all these categories. Second, it allows us to quickly update a review. So for example, the Deanna Protocol. When we first reviewed them, I think it was a little over a year ago, they didn’t have any animal data. Now they have one animal study, one small animal study so they get an upgrade there. And third, hopefully this allows people in other diseases to do something similar to what we’re doing because I’ve heard from other people like in MS and Parkinson’s that they would love to do something like this but it’s hard to get started. So hopefully, this provides a nice blueprint for how to get started reviewing evidence on AOTs.

Seth: Fascinating! Now, who of these, the 94 reviewers, who comprises that body? Is it international, is it only Western-trained, is it more on them?

Dr. Bedlack: So there are people from ten different countries, they’re mostly clinicians but some of them are like basic scientists, for example. And so the countries that are represented include United States, Canada, Ireland, Israel, Spain, Thailand, Sweden, Poland, France, and Russia. So we wanted this to be international for a lot of reasons but partly because some of these clinics are in faraway places and so if we’re going to try to visit clinics, it would be great to have people all over the world that are part of our team so it would be easier for them to get in there and review the clinic.

Seth: Is there an oversight board that decides who is in, is not on that review committee?

Dr. Bedlack: We don’t really have any kind of oversight board. So if you have a history of doing an ALS research, you send us an email and say, “Hey, I’d like to be in the ALSUntangled.” We do just a quick literature search to find out has this person done anything related to ALS research and if so, you’re in. We don’t have a big vetting process but at the same time, we do want to have some history of engaging in ALS research to be able to be part of the team.

Seth: We love it! And now, are you funded by anyone?

Dr. Bedlack: Right now we have a small amount of funding from the Motor Neurone Disease Association and what that funding does is it allows us to keep our website up to date. I don’t know much about building websites or keeping websites up to date so I have to hire somebody to do that. So that’s basically what the money pays for right now.

We’re hoping maybe to get a grant in 2015 that would allow somebody like myself to spend half-a-day doing nothing but ALSUntangled so that we could get through this list of over 130 open reviews a little faster.

Seth: Thank you. We will ask at the end of our show how people can donate and support this amazing method for researching alternative treatments.

Dr. Bedlack: Oh, thanks, Seth.

Seth: We’re huge fans of out-of-the-box thinking and think you are as out-of-the-box as we’re comfortable with.

Dr. Bedlack: I appreciate that.

Seth: Amy, could you remind callers of the number.

Amy: Yes, we have several callers online now. If you’re just joining us, please call in to 516-590-0362 and push number 1 to indicate that you have a question for Dr. Bedlack when we come to that point.

Seth: We realize that callers get nervous but we promise Dr. Bedlack will not chew you out on the air.

Dr. Bedlack: Never. Never.

Seth: All right. Dr. Bedlack, could you share a couple of your favorite reviews and subsequent findings?

Dr. Bedlack: Yeah, I’d be happy to.

There’s been some real surprises to me over the five years that I’ve been running this program. The first group of surprises deal with the people that are actually selling these AOTs. When I first started this, I had the impression that a lot of them we’re going to be kind of like the old Wild West snake oil salesmen just out to make a buck. And we certainly have found some of those, the most famous of those is actually a person named Dr. Larry Stowe. You can read more about him on the 60 Minutes webpage, they actually did a whole story about him called “21st Century Snake Oil”.

But surprisingly, there are many more people out there that I call true believers that are selling these things because they really believe that they work, they really believe that they’re helping people. And in fact, some of these folks are really good doctors, like the ALS community of physicians can learn a lot from the bedside manner of some of these folks. I’ve been to some of their clinics and I’ve watched them interact with patients and I’ve interviewed patients afterwards and ask, “How did you get here?” like “How did you get in this chelation clinic?” Many times patients say, “We started in a mainstream clinic but it was all gloom and doom. Nobody gave us any hope, they just wanted us to sell our living wills and people didn’t want to hear about our ideas and even when we would ask a question by email or telephone, it would be many days or sometimes weeks before we’d get an answer back.” And some of these folks that run these alternative clinics, well, they’re the most optimistic people I’ve ever seen. They’re incredible cheerleaders, they’re very respectful of their patients’ ideas and they’re very responsive.

I remember being at a chelation clinic in Hilton, had to be in late at night because the doctor told me that every night when clinic finished, he made sure every message was answered before he went home for the night. And I just think those are three key things that we need to be as ALS clinicians: optimistic, respectful, and responsive to our patients.

And then the other thing, Seth, are some of the actual treatments themselves. Again, when I first started this program, I was very skeptical that any of these things were going to be very useful. And certainly we have found a lot of things out there that are bogus. I can give the listeners some things that these share in common, I call these the red flags, things to watch out for if you’re thinking about a particular alternative therapy.

First of all, anybody who’s advertising something as dramatically effective or a cure for many of the world’s worst diseases — 20, 30, 40,  50 of the world’s worst diseases — you have to be a little skeptical of that. Like why would this person who says that they can cure 40 of the world’s worst diseases be practicing in a strip mall in India next to a Kentucky Fried Chicken? They should be one of the most famous wealthy people in the history of Medicine, it just doesn’t make sense.

Anything that’s advertised as perfectly safe, it doesn’t make sense. Nothing’s perfectly safe. If you’re in a stem cell clinic and you’re doing blood tests, bone marrow biopsies, and spinal taps and you write that you’ve seen 2,000 people and no one’s ever had a side effect, that’s just not possible. Someone’s going to have bruising, someone’s going to have pain, someone’s going to have an infection when you break the skin 2,000 times.

Anytime you’ve got a clinic where there’s no oversight; anytime you’ve got a clinic that’s run by somebody who doesn’t have any credentials; anytime you have a clinic where they’re not asking you to sign any kind of consent form so you’re not actually seeing in writing what the potential risks and benefits are. And maybe worst of all, anytime you have a clinic where they have no interest in following you after you pay and get the treatment — that’s a problem. If nothing else, we need to be able to track what happened to the people when they get these things. And if you’re at a clinic where they want to charge you a bunch to give you something and then never want to see you again, that’s probably not a very legitimate clinic.

But you know, Seth, some of these things actually look like they might be useful and probably do warrant further study. So just to tell you quickly about some of those, there’s one called AIMSPRO also known as hyperimmune goat serum. I won’t talk too much about that because the company, Daval International, is actually going to do its own follow up studies on that compound. There’s a supplement called GlutaMAX which is a combination of vitamins and flavonoids which are antioxidants. And there’s some very interesting anecdotal data to support that that seems to be reasonably safe and reasonably inexpensive.

Lunasin which is my most recent ALSUntangled investigation and that’s one that I personally am very excited about, excited enough to be launching a trial of it in 2015. It’s a peptide from soybeans. It’s taken orally and it supposedly has histone-altering properties. So if you alter histone acetylation, you change the pattern of genes that are on, possibly toward a more protective pattern. It’s also reported to have anti-inflammatory and antioxidant effects. And what’s very exciting about that is I’ve got one validated case of a person whose records I have. Three different neurologists diagnosed him with ALS, I believe he has ALS. He’s dramatically improved over the course of one year on this supplement so this is something that I call “a validated ALS reversal.” And when we find validated ALS reversals, whatever it is that they tried, we need to try that in more people. And we’ll figure out why it worked later but first we have to figure out if it’s working. And so that’s why I’m picking that one first because that’s one of the more dramatic cases I’ve seen.

And then lastly and the strangest of all, there’s something called fecal transplants. And Seth, when I first heard about this from one of our ALSUntangled tweets, I thought maybe there was a misspelling. I thought it was fetal transplants but no, fecal with a C literally is what it sounds like. Taking the stool from a person without a disease, making sure there’s no infection in there and then putting it into the colon of a person with a disease. And what’s the rationale here? Well, within all of us, there’s a family of bacteria in our gut called the microbiome and there’s pretty good evidence now that when the microbiome gets altered, when one particular bacteria overgrows, it can cause human diseases. And the best evidence is diseases of the gut like for example, clostridium difficile infection or even Crohn’s disease. Fecal transplants is now a mainstream treatment for those. It turns out there is a bacteria, a clostridial species that can secrete a toxin that can kill motor neurons. It can actually get out of the gut, cross the blood-brain barrier and kill motor neurons.

So wouldn’t it be interesting if there’s a subset of people with ALS who actually have their disease because they have an altered microbiome and if that were true, then a fecal transplant might actually stop the disease in them. So I’m hoping that at some point, we’ll see folks actually study the microbiome in people with ALS and see if there are subsets and if there is a subset with this clostridial species, try a fecal transplant and see what happens.

Seth: Well, I’ll add that to my list of favorite, non-favorite things to try.

That was an amazing list of your top candidates. As an ALS patient, you hear all the time the disease is very heterogeneous and we don’t know what causes it and how it proceeds so differently in different people. As the effect of diminishing our confidence in anything that we are regarded to try, thinking that “Wait, I may be different”, can we rely on scientific studies that are seeking a treatment there for all ALS patients or do we have to filter those through our own perception of our personal disease?

Dr. Bedlack: So I don’t think that right now we’re smart enough to know how to subdivide patients with ALS and that’s part of why there’s such an emphasis on finding biomarkers that might be able to tell us about different pathophysiologies in different patients. That’s one of the reasons I love that microbiome study. A microbiome is a biomarker that might lead you to a different cause for that person’s ALS and a completely different treatment. There’s got to be those. Those are going to happen. There’s going to be a genetic, there’s going to be imaging biomarkers, there’s going to biomarkers in the serum in the CSF, it will all happen over the next few years.

But until then, I think the best we can do is continue to do trials the way we’re doing them but look within our trials for groups of patients that might have responded. Don’t just give up on the trial when there’s no different overall between the treated and the placebo group. Look to see like the NP001 folks if there might be a subset of folks that actually responded and then try to figure out what’s different about them later.

Seth: Incredible! The biomarker study you mentioned, is it happening at one place or everywhere?

Dr. Bedlack: There’s a lot of different biomarker studies going on now and one of the really cool things is that for the first time, we’re really starting to share data. Not only are we putting data into the PROACT database, we’re putting data into the Neurobank database. We’re starting to require that funded trials use something called a global unique ID so that the patient basically would have one ID that they would carry with them no matter what study they ever participated in.

And that’s the kind of stuff we really need to do to beat this disease. We need to be able to share data across the whole world, that we get giant amount of information on one place.

Seth: Thank you. Amy?

Amy: Yes. Callers, the number to call in to ask questions is 516-590-0362 and press 1 for any questions for Dr. Bedlack.

Seth: Thank you. We’ll pause on this topic for a moment, Dr. Bedlack, and ask, stepping back, what other trials and research are you currently involved in?

Dr. Bedlack: Yes. I just found out that I’m going to be part of something called the CReATe Consortium. This is a rare disease clinical research network that’s sponsored by the NIH. And CReATe is actually an acronym, it stands for Clinical Research in ALS and Related Disorders for Therapeutic Development. And our lead investigator on this is Dr. Michael Benatar at Miami. But this is going to be an incredibly exciting program that tries to bring together patients with a lot of different kinds of motor neuron diseases — so ALS, PLS, progressive muscular atrophy, hereditary spastic paraplegia, and we’re also trying to bring patients with frontotemporal dementia into this mix as well.

So we’re trying to get them into the same studies, the same databases because we know there’s going to be overlap in what’s happening in their bodies. We’re also trying to get all the different advocacy groups to the same tables. So the ALS Association, the Muscular Dystrophy Association, the Spastic Paraplegia Foundation, the Association of Frontotemporal dementia all the same table so we can figure out how to synergize and how not to have too much overlap between what we’re all trying to do. So this is exciting on a lot of different levels but it’s an entire program, it’s not just a study.

And then I’ve also got a Cooperative Study Program through the VA Medical Center which is called Cooperative Studies 567. It’s a study of a brain computer interface for patients with ALS. So this is the way for folks who’ve lost most of their movement to be able to continue to communicate and possibly even continue to surf the internet and control devices using the electrical activity in their brains with no movement at all.

And then we’ve got upcoming in 2015, a nice trial of an antiepileptic drug called retigabine. And finally, my ALS Reversals program, I’m very excited about this. As I mentioned with Lunasin, over five years in the ALSUntangled program, one of my frustrations has been that once in a while, I run into a patient that I actually think had ALS and got much better. Some of them got completely well and I’ve never had the resources to follow up and study those patients. And I think we have to.

I think when you run into an ALS reversal like the one I mentioned in the Lunasin paper, there’s a lot of different possibilities. One is they were misdiagnosed so to we want to make sure we got records on those folks. Another is that they might have had something different about them that allowed them to beat the disease. You may have seen in the news last week, there’s a group of people that have HIV and they never progressed to AIDS. And in fact, sometimes in those people when you look down the road, the virus appears to be gone and those people never got any treatment. They call those people elite controllers and there’s been a lot of debate about whether it’s worth studying them. It’s a very rare group but there’s been a small tenacious group of investigators that have been studying them. And last week, they had a huge breakthrough. They actually figured out that at least some of those people, the way they beat the disease is they have an enzyme that allows them to incorporate the retrovirus DNA into their own DNA. In other words, they kind of absorb the virus into their own DNA and it becomes part of them, it becomes non-toxic, they bind with it.

And so imagine if some of these people who have ALS and get better have something that’s genetically different about them like these elite controllers that allows them to beat the disease. We need to know what that is. We need to try to give that to other people. And then finally, it’s just possible that some of these folks that have ALS reversals get them because they actually tried something that works. And so part of this program is going to be trying to actually give whatever these ALS reversals used on themselves, give it to other people and see if we can make anyone else better.

Seth: I’m fascinated that you, more than any of our previous guests, are interested in the outlier cases. We understand the economics of going for the largest group in a rare disease community but applaud your efforts in this area.

I wonder if you wouldn’t mind sharing your X Files reference that you shared with me, how that plays a role in how you think about this work.

Dr. Bedlack: Yeah. The whole reason that I really got ALSUntangled off the ground was because of a patient and I’ll call her Samantha. The reason I call her Samantha is I kind of think of this whole program as the X Files of ALS. And for those who remember the X Files, the TV show that ran for a little over ten years here and spawned a few movies, the premise of the show was there was a guy named Fox Mulder and when he was a kid, he saw his sister, whose name was Samantha, disappear. And the way he remembered it, she was kidnapped by aliens. And of course, nobody believed him and he felt all this guilt about the fact that his sister disappeared on his watch and he spent the rest of his life trying to investigate strange happenings in hopes that he would be able to prove to people that aliens really did exist.

The patient that kind of was the index case for me was a university professor that came to see me that had a pretty clear-cut diagnosis of ALS, didn’t seem to have an cognitive or behavioral problems. And I broke the news to her, I told her about the evidence-based options that I had for her and I invited her into some of the research studies that we were doing. She said she’d be happy to take riluzole and come to clinic and do the evidence-based things we had but she wasn’t going to do research. Instead she was going to try oral sodium chloride which she had read about on the internet on Good Morning America’s website.

And so driving home that day, that really left an impression on me that first of all, that people would try this and I did the research and found out that a lot of people try it. And second of all, that even very intelligent people try this without really a very thorough investigation of the evidence. This was a Good Morning America website, there was really almost nothing on the website about the mechanism of oral sodium chloride, whether it worked as well as IV sodium chloride, what kind of harms might come to a person, where they would get it.

That’s why there is a parallel with the X Files. I really wanted to help this patient like Fox Mulder really wanted to help prove what happened to his sister, and that motivation continues. For me the motivation are the patients that I see every Monday and Tuesday, ALS Clinic every Monday and Tuesday now, and they keep me motivated.

Seth: Thank you.

Before we go to our callers, I would remind callers, you need to press 1 to get in the question queue. Last question before we open the lines, are there any other projects in ALS you are excited about and would like to mention?

Dr. Bedlack: Absolutely.

So I think there are a lot of exciting things on tap for 2015. I’m hoping that Neuraltus Pharmaceuticals can get the funding that they need to do a study of NP001. As I mentioned before, this is an intravenous drug and it acts on part of the immune system called macrophages. And what was exciting about their phase II study was they appeared to find a subgroup of patients, about 30%, who took the drug and didn’t progress at all for six months. And that’s different than the natural history of ALS where about 10% of people would be expected not to progress for six months.

There’s another company out there called Cytokinetics and they have a drug called Tirasemtiv. It’s been through several small studies. The studies were regarded as “negative” studies because they weren’t able to show a benefit on the primary outcome measure which was the ALS Functional Rating Scale. But all the studies did show benefits on muscle strength and benefits on breathing measures and obviously, those are important. So even though it didn’t affect the ALS FRS, thankfully the company has decided to go back to the FDA and try to get permission to do a follow up study where strength and breathing measurements would be the primary measures. So I think that that’s got a really good chance of being something that we can use to help patients.

And then of course, there’s the stem cells studies, Brainstorm cell and Neuralstem. Those are exciting for a lot of reasons but to me personally, the reason why they’re exciting is each of those studies has an ALS reversal. So Brainstorm has a rabbi that took that product off-label, whose ALS got dramatically better. And Neuralstem has a very well-known American patient within the Neuralstem study who had dramatic measurable improvements in muscle strength and activities of daily living.

So I think those are all things we can look forward to in the next year.

Seth: Thank you for those.

We will now go to our first caller. Caller ending in 0559, you are on the air with Dr. Rick Bedlack.

Caller: Yes, Dr. Bedlack. I will need some additional information on the Lunasin. Is that an oral medication and could you reviewl a little bit more of how it worked and potential side-effects and how someone would go about getting into your study?

Dr. Bedlack: Sure. All the information that you just asked about is in that free article that’s on our website which is and it’s the last review on the website that says Lunasin.

So this is an oral substance and it actually comes in a variety of different forms. It’s overall a peptide that comes from soybeans. And the mechanisms that it appears to have in cell cultures, it can reduce free radical production by activated macrophages, it can scavenge free radicals, it can alter the release of inflammatory cytokines from macrophages, and it can alter the pattern of histone acetylation which in turn should be able to alter the pattern of gene expression hopefully toward a more protective pattern.

So at least in cell cultures, it’s got a lot of promising mechanisms. But the main reason that I’m personally going to study this is because there’s a patient from the New England area who took a combination of products containing Lunasin, and over the course of a year, had dramatic objective improvements in his speech, swallowing, and limb strength. The supplements that he took, it wasn’t just one, it was actually a series of things. They all came from a company called Reliv and the supplements included LunaRich X capsules, something called Reliv Now®, and something called ProVantage. And again, the exact regiment that he took is in that paper.

As far as the study goes, it’s probably going to be a fairly small study. It’s actually funded by a group of patients that contributed money to our clinic. We’re thinking that it’s going to be somewhere between 30 and 40 patients. I suspect it’s going to fill up pretty fast. It’s probably going to open around March.

There’s a few benefits from being in the study of course. One of the benefits is that you’re helping us figure out if this works or not, that’s the main reason to go into any research study. But also, folks who come into this study will be able to get these products for free. The company is actually going to supply them for our study and outside the study, these are rather expensive. So to do exactly what this patient did would be about $700 a month.

This study’s going to be unusual for a lot of reasons. We’re looking for the biggest effect that’s ever been seen in an ALS research study. So most of the time in an ALS research study, we’re looking for a very slight slowing in disease progression like a 20% slowing in the slope of the ALS Functional Rating Scale for example. And when you’re looking for a very small effect in a disease that’s very noisy, you need to try to make your patients look as similar as you can at the beginning of the study, that’s why the inclusion-exclusion criteria is so narrow for research studies. You need to have a lot of patients and you need to have a control group that you also enroll at the same time and treat exactly the same way — usually a placebo group.

So in this particular study, because we’re looking for such a huge effect, we’re actually looking for an ALS reversal. We don’t have to have any narrow inclusion-exclusion criteria, we don’t need a lot of patients, and we actually don’t need a placebo group. We can use a historical control group to figure out if anybody in the study got better. The downside of doing a study like this is if there’s a small effect, we’ll miss it. We’re looking for the home-run effect in this study and if there’s no home-run effect, we’re going to move on to the next thing than an ALS reversal trial. That’s what this program is all about.

Caller: Thank you.

Seth: And thank you, Caller, for that question. Going on to our next caller, caller ending in 0899, you are on the air.

Caller: Thank you, Dr. Bedlack, sure appreciate all of your work. You’ve mentioned on this CReATe project, you seem to have just an amazing grasp on the possibilities of what could happen and what could be done in the whole ALS fight.

Are there other disease communities that you admire as far as how they’ve attacked a disease that you like to look at as a model of how the ALS community can come together?

Dr. Bedlack: Yeah, that’s a great question.

I do admire a lot of other groups that are out there that has made progress in their disease like for example, the folks working in HIV. I think the amount of collaboration in that field and the fact that there are people studying these very rare HIV phenotypes, like the elite controllers, and having some success figuring out what it is that allows those folks to beat HIV. I think that we need to pay attention to that and that’s part of why I’m so excited about this ALS Reversals project.

Caller: Thank you.

Seth: Thank you, Caller. Going right along, caller ending in 1243, you are on the air.

Caller: Hello. Thank you, Seth,  for this great radio show and thank you, Dr. Bedlack, for all your hard work that you do.

Dr. Bedlack: My pleasure.

Caller: My question is I am vent-dependent but I can still speak and swallow. Would I be excluded from pretty much all of the clinical trials that are going on right now? Because I know there’s a shortage of people and I would be more than happy to participate.

Dr. Bedlack: Yup. So it’s important to take a step back and remember that this business about participating in research, there’s a lot of different kinds of research that are important. Clinical trials are only one type of research. So for example, we’ve got epidemiologic research, biomarker research, genetic research. All that research is going to be really important in helping us eventually beat this disease and there’s no reason why you would be excluded from many of those kinds of studies like for example the National ALS Registry or some of the genetic studies that are going on.

When it comes to trials, traditionally, like I said before, we’re looking for such a small signal in such a noisy disease that we have to try to homogenize the patients as much as we can and that’s part of why we have such narrow entry criteria in trials. It won’t always be that way. Someday we’re going to be able to subdivide patients based upon a blood test hopefully or an imaging study to figure out what subset of ALS they have and we’ll be able to have a lot less noisy disease when we do that and therefore a lot wider inclusion-exclusion criteria.

But for right now, unfortunately there aren’t many trials that folks with very far advanced ALS who are on ventilators can be in and that’s another reason why I’m excited about studies like the ALS Reversals project where we’re looking for big signals and we can bring just about anybody in as a result.

Caller: Okay, all right. What website can I go to to find something that I can participate in?

Dr. Bedlack: I think the most comprehensive place to go for research opportunities is The downside of that website is that it’s not the easiest to navigate but hopefully you’ll be able to get help maybe from your clinic that you go to and be able to type in ALS. Look for open studies and you can even put in a zip code to figure out how far you’re willing to drive to be in a research study and they’ll tell you what’s open and you can kind of look quickly through the inclusion-exclusion criteria and find out which ones you might qualify for.

Caller: All right. Well, thank you very much. Once again, thanks for all your hard work that you’re doing for us.

Dr. Bedlack: Well, thanks for listening today.

Caller: You bet. Thank you. Bye.

Seth: Thank you, Caller. Our next question came to us online. “How can one communicate with ALSUntangled other than through social media? Is there an email contact?”

Dr. Bedlack: Yes. So you can email me anytime. It’s And if you forget that, then you can also Google the Duke ALS Clinic and you can find my email on there.

Seth: Excellent. Thank you.

That brings us to the end of our caller queue. I did want to ask, Dr. Bedlack, if you have any closing thoughts you would like to share?

Dr. Bedlack: Yes. So a question that I get asked a lot is what’s the greatest opportunity for people to get more involved and I think there’s multiple parts to this. I think first of all, join every research study you can. Even if it’s not a trial, that doesn’t mean that’s not important. In fact, I would argue, based on kind of where we are in the history of ALS, studies that tell us more about what’s causing ALS and why people who get it keep getting worse are probably even more important than the trials because we need to understand this disease better before we have trials that are going to be curative.

I think you should try to become a research ambassador by signing up for one of our clinical research learning institutes and we’re going to have one of those in January that’s going to be virtual so people all over the world could potentially be research ambassadors without having to travel like you and Amy did, Seth, to Florida.

And then finally, I think if you’re one of the more than 50% people with ALS who are thinking about trying one of these alternative or off-label therapies, don’t be afraid to have a conversation with your doctor. And then maybe most important of all, if you do try it, make sure you sign up for a website like PatientsLikeMe and input your outcome measures so that the world knows what happened to you. Because I think that’s probably the most tragic of all the things I’ve seen in the past five years is that I know there are a lot of people who’ve tried these things and they never blogged about them and they never put their data in any place. So whatever happened to them is unknown and that’s a shame. I think we need to learn something from every patient with ALS especially those that are out there trying things. We need to learn from that.

Seth: I completely agree. And for those of us who wish to donate to your research, how do we go about that?

Dr. Bedlack: So there are a couple of different ways, we don’t actually have a formal donation program for ALSUntangled. But if you donate it to the Duke ALS Clinic and wrote on your check, you wanted this to be for the ALSUntangled account, we would certainly create an account. Again, the purpose of that, the next sort of thing we’re trying to get enough money to do is to protect some time so that I might be able to do like a half-day a week of nothing but ALSUntangled so it’s not just the nights and weekends part-time project anymore. I think it’s gotten to be almost too big for that now. So hopefully we’ll be able to make that happen in 2015.

Seth: Excellent, thank you.

We sincerely appreciate your time both on the show and in looking for a cure for us in the community. We applaud your work and encourage you to keep going. Thank you.

Dr. Bedlack: We’ll do it, Seth. Thanks to you and Amy.

Seth: You’re welcome.

For our listeners, a full transcript of today’s show will be available in coming days on Thank you to Dr. Richard Bedlack for his time. Bye for now.

ALS Crowd Episode 8: Dr. Eva Feldman on ALS stem cell research

Eva L. Feldman, M.D., Ph.D., F.A.A.N., F.A.N.A

Wednesday, November 5, 2014

Listen to Episode 8:


Full Transcript:

Seth: Hello and welcome to episode 8 of ALS Crowd Radio. I’m your host, Seth Christensen, here as always with my co-host, Amy Christensen.

We are thrilled today to have as our guest, Dr. Eva Feldman, of the University of Michigan. Amy?

Amy: Dr. Feldman received her MD and PhD from the University of Michigan and completed a neurology residency at the Johns Hopkins Hospital and returned to University of Michigan for a Neuromuscular fellowship.

In addition to her clinical practice and position as the Russell N. DeJong Professor of Neurology at the UM Medical School, Dr. Feldman is Director of the A. Alfred Taubman Medical Research Institute, and is the Director of Research for the University of Michigan ALS clinic. She runs her own 30-scientist laboratory, the Program for Neurology Research & Discovery, and is the Principal Investigator of the first-ever FDA-approved human clinical trial of an intraspinal stem cell implantation therapy for ALS.

Dr. Feldman has published more than 300 original peer-reviewed articles, 60 book chapters and three books and is the Principal Investigator on five major NIH grants. She is the Past President of the Peripheral Nerve Society and serves as President of the American Neurological Association from 2011 to 2013. She has been listed in The Best Doctors in America for the last 15 years.

Seth: Dr. Feldman, are you with us?

Dr. Feldman: Oh, yes. I’m definitely with you. Thank you so much for having me today.

Seth: Well, it is our honor and thank you for making time. I believe we already have a record number of callers on the line so that is a good sign for today’s discussion.

As our topic, we have chosen ALS stem cell research but thought we would open with a broader question. We have known about ALS for quite some time, are we learning new things about ALS today?

Dr. Feldman: Oh, we certainly are, Seth. Every day we are learning something new about ALS. In fact, in the last three to five years, I think the new data, the new research and the new clinical findings that are coming out probably surpass what we have learned in the previous 20 years. So now we understand new genetic causes of ALS and that’s given us new clues on why everyone who has ALS may get it, so the sporadic cases of ALS.

We are learning new imaging tools, we’re discovering new reasons that there may be environmental and occupational exposures to ALS and then new therapeutics. So the field is rapidly changing and in my 25 years as an ALS clinician-scientist — so it’s a long time — I have not seen such progress like the progress I’ve seen in the last three to five years. It’s really remarkable.

Seth: We have heard that sentiment echoed among your peers and are thrilled to hear it as an ALS patient community.

Now your particular focus on research is very broad and deep in a number of areas. Do you consider yourself a specialist in a particular area of ALS research?

Dr. Feldman: Well, I’m interested in three broad areas of ALS research. One area that I’ve been interested in for a very long time is if there’s an occupational or an environmental exposure that may predispose someone to developing ALS.

So we currently have a grant from the Center for Disease Control where we’re doing a very detailed study asking those very questions of our ALS patients and in parallel, measuring levels of like pesticides and different environmental exposures in their blood and their hair. And coming up with what I am certain will be new insights into answering that question. So that’s one area.

The second area I’ve been very interested in is developing new ways of imaging the brain and the spinal cord to better diagnose individuals very early in the course of ALS. Frequently it takes a long time, at least a year — the average is a year — to make the diagnosis. And if we could have a way to image the brain and the spinal cord with our new techniques, we can make the diagnosis sooner. And why do I want to make a diagnosis sooner? Well, that’s my third area of interest. I’m very interested in therapeutics, particularly cellular therapeutics or stem cells and I’m very interested in the potential beneficial role of stem cell therapy in ALS. And I have evidence, both based on my clinical studies in patients as well as my preclinical studies in animal models of ALS, that the earlier we can perform stem cell transplantation, the more likely it is to have the benefit for ALS patients.

So those are my three broad areas of interest.

Seth: Excellent! I know we could dedicate our show to each of those areas at least but for today, we’d like to focus in on your stem cell experience and ask why stem cells? What is the promise of this area of research?

Dr. Feldman: I will tell you a story, Seth. I turned to the idea of stem cells approximately seven years ago when I had spent almost ten years in a clinical trial that failed in ALS — a clinical trial with a drug known as myotrophin or IGF-1. And I had spent almost a decade doing the preclinical work and then working on developing the clinical trial and doing a series of clinical trials.

And I felt that that experience led me to believe that it’s going to be difficult for just one drug to be beneficial solely in ALS so we needed something, a combination of drugs, or what about stem cells. Because stem cells, in a way, are really quite remarkable in that they can go into an environment and in the case of ALS, the stem cells can enter the — I’ll call it — ALS environment, whether it’s in the brain or the spinal cord. They can secrete growth factors which are very good for disease tissue and makes it healthier. They can form synaptic contents, they can actually even produce neurotransmitters, they can become nerve cells, they can become supporting cells. So the promise of stem cells or my interest in stem cells began when I had the kind of realization that it’s never going to be just one drug that’s going to really truly provide long-term benefit in ALS. But we need to go away from the single drug idea to what I’ll call a cellular therapy and that’s where stem cells come in because they have so many beneficial aspects to them.

Seth: How long has the ALS research community been really interested in the stem cell research?

Dr. Feldman: I think for the last decade there’s been interest. For the last five years, there’s been a great deal of interest. We entered our first patient in our FDA phase I approved stem cell trial in January of 2010. We’ve now completed both a phase I and a phase II trial. There are now other very good individual ALS clinics and groups of ALS clinics that plan to do similar stem cell trials but maybe using different types of stem cells.

So the idea that stem cell therapy could potentially be both safe and beneficial in ALS has taken traction and so there are several other new proposed trials besides our own. So I’m very excited about that and look forward to not only now doing the next phase of our trial but also hearing and understanding new and different ALS stem cell trials that are coming on board.

Seth: Wonderful. Could we talk for a moment about your, now famous, Neuralstem trial? Could you outline that experience for those of us who are new to stem cell research?

Dr. Feldman: Of course. So the Neuralstem trial has now been completed in both what we’ll call a phase I trial and a phase II — those are the designations by the FDA. So a phase I FDA trial is completed for safety and it’s really safety alone which, really, not looking at efficacy but looking at if the procedure is safe. And in that particular trial, we entered 15 patients for a total of 18 surgeries. So three patients got double transplants and we were able to safely show that we can inject stem cells directly into the spine of ALS patients, in the lower spine called the lumbar spine area as well as the upper spine known as the cervical area. And in that trial, we injected up to 1.5 million stem cells and we continued to follow those individuals over time who remain active in the trial. So that is the phase I.

So the phase II trial then is designed to continue to look at safety but in this case, we also wanted to increase the dose of stem cells as well as do more stem cell injections into the cord. And I’m pleased to report in that trial which we completed July of this year. We again entered 15 patients and did 18 surgeries. Previously as I told you in the phase I trial, the most stem cells that one patient received was 1.5 million. In this phase II trial, we got up to 16 million stem cells, given 8 million stem cells in the low back, and 8 million stem cells in the upper back or the upper part of the cervical cord, the spinal cord. These patients are now being followed, again, safety. We have shown this procedure is safe in both phase I and phase II.

And now on phase II, we also begin to look at what we call exploratory clinical efficacy, kind of medical lingo for “Is there a signal, a therapeutic signal? Do we see a difference in the patients who’ve received 8 to 16 million stem cells in the course of their disease?” So now we’ve just completed this trial and we don’t have, we’ve not looked at the data yet. We will not look at the data until six months after the last patient was entered but that’s going to be very exciting information for us to have at the end of the phase II trial and has helped guiding us as we plan the next phase of the trial which we call phase II B.

Phase III, when we complete the phase III trial, that’s the definitive trial, and that will say whether or not this therapy can go out of the research arena into the more general clinical therapeutic arena where it could be available for all patients.

Seth: Thank you for that explanation. So it’s six months until we look at the data, what would be the ideal timing be for phase II B or a phase III?

Dr. Feldman: Well, I’d like to say six months from now if possible.

So the ideal timing will be we will need to carefully look at those data and we are hopeful to have an application in place in the winter-early spring of 2015 with the goal of beginning recruitment as soon as we can. Again — Seth, you need to hear this — we feel the same, I feel the same sense of urgency that you feel. Everyone who works with me does. Everyone who has spent their life trying to understand ALS and develop therapeutics feels and embraces the sense of urgency as the ALS community does, because we’re all part of the same community, the sooner the better but we need to look at the phase II results before we can put that next application in.

Seth: Excellent! Let’s keep the pedal to the metal on this.

Dr. Feldman: We definitely will.

Seth: You mentioned a moment ago other trials that are using different types of stem cells. We had Dr. Jeffrey Rothstein on a few weeks ago to talk about IPS cells.

Dr. Feldman: Wonderful.

Seth: Can you speak about the type of cells we used for the phase I and II Neuralstem trial?

Dr. Feldman: Yes. So interesting because the name of the biotech company who has generously supplied the cells and has funded a great deal of this trial is Neuralstem and these are actually neural stem cells. So these are stem cells that have the fate to become some type of nerve cell in the body when they’re transplanted. And what we find, Seth, is when we place these stem cells in the spinal cord of an ALS preclinical model, these stem cells, about half of them become nerve cells and the other half become supporting cells of the nerve cells.

And what’s also kind of a segue just to explain a little bit more about why these cells are likely so therapeutically potent is, again, in the ALS spinal cord, the large nerve cells are undergoing a death and the surrounding cells look very inflamed and angry so I call it kind of a bad neighborhood, the neighborhood looks like in disarray. And you put the stem cells in and the stem cells form again these contacts on the sick nerve cells and begin to nurse them back to health and also all the inflammation around the sick nerve cells go away, the stem cells kind of clean up the inflammation also.

So these neural stem cells become nerve cells and also these glial cells and they have very, very strong therapeutic potential in the spinal cord.

Seth: Now we hear a lot socially about embryonic versus other derived stem cells. Could you explain the difference between the promise of different cell lines?

Dr. Feldman: I’ll be happy to.

So first, I think it’s important to understand what embryonic stem cells, how they are created, because I believe there’s some misconception there. So in Invitro fertilization clinics, a man donates sperm, a woman donates egg; in a small petri dish the two are put together and embryos are formed. Many of those embryos are taken for transplantation into the woman to, of course, have children. Some are frozen but most are discarded, literally put down a disposal. And so those embryos that would otherwise be discarded can be donated.

So those donated embryos are then placed in a petri dish and on day 5, a small part of the donated embryo known as the inner cell mass is then taken and put in another petri dish and that’s the beginning of what’s known as an embryonic stem cell. And those cells have the ability to become any cell in the body. They’re called totipotent, meaning they can become any cell in the body. So that’s an embryonic stem cell.

Early on, Seth, in our work, in the preclinical and the animal models of ALS, we looked at embryonic stem cells as the source of therapy but come any cell in the body, when we put them in the spinal cord, many of them became nerve cells and glial cells but they also could become other types of cells that we didn’t want. So for our purposes, these cells were not good for therapies.

As I mentioned, in the dish you can grow the embryo to a later stage and or you can receive donated fetal tissue. And then tissue that’s been donated, you can take the small piece, for example an area that was going to become the spinal cord or the brain from a two- or three-week donation and those can become stem cells, those are called progenitor cells or, in this case, neural stem cells. Or you could take some that would definitely become a muscle cell, et cetera. So that’s another type of stem cell, a progenitor cell.

Another type, of course, are adult stem cells and the use of adult stem cells are mesenchymal stem cells which are from the bone marrow of patients. It’s currently being done and there’s a clinical trial about that, I’m happy to tell you about that, that that’s ongoing for ALS.

And then the fourth type that’s commonly discussed are these IPS cells and I know that Dr. Rothstein just talked about those. And that’s when you take a small, either your own blood cell or a small skin cell, and you turn that into an embryonic-type stem cell.

Seth: I’m sure we’re just scratching the surface here, thank you for that.

So to clarify the Neuralstem trial, were they progenitor cell trial?

Dr. Feldman: Yes, it is. It was and will continue to be. And this is a progenitor cell line, this is a stem cell line that was developed over ten years ago and has been thoroughly studied which is very good for us and is also made in what we call GMP grade, good manufacturing practice grade, which the FDA insists on before you can use it in a clinical trial.

So we chose this to work with Neuralstem because we saw these cells have been the type of cells that would be particularly therapeutically beneficial in ALS. And were ready to go too, I should throw in, and were ready to be used.

Seth: Excellent, excellent. We will pause for a second to have Amy invite listeners.

Amy: Hi, callers! Please call in to 516-590-0362. And to indicate that you have a question for Dr. Feldman, please push the number 1 and we’ll know you’re ready for the questions at the end of the show.

Seth: Thank you, Amy.

Now, Dr. Feldman, we have this exciting trial going on. What other trials are you involved with currently?

Dr. Feldman: You mean my own or the other ALS trials that we’re doing or do you want me to talk about the other stem cell trials that other individuals are doing, Seth? What do you think people would rather hear about? Maybe the other stem cell trials?

Seth: Perhaps that would be the best use of our focus area.

Dr. Feldman: Yes, I think so, because the other trials that I would discuss would be unique to our clinic while the stem cell trial, our own stem cell trial that I just discussed, the next phase will be more broadly available to everyone in the United States which I think is very exciting.

And there are three other trials, one that’s ongoing and two that are in the active planning stages that should begin shortly. The one trial that’s ongoing is a trial that’s been done by the University of Massachusetts. I also believe it’s Massachusetts General Hospital and Mayo Clinic and that’s the mesenchymal stem cell trial where a patient will come in, a bone marrow biopsy will be done. The mesenchymal stem cells, so the bone marrow stem cells are taken from their own bone marrow and then they are processed and they are injected back into the patient’s spinal fluid. It’s the fluid that surrounds the spinal cord and the brain. And so that is an active ongoing protocol currently. It’s a different type of approach that we are using in our Neuralstem trial, of course, but I think it’s an exciting new venue.

Two other trials that are proposed and I think will begin shortly. One is being done at Cedars-Sinai in Los Angeles by Drs. Clive Svendsen and Robert Baloh. This particular trial is similar to the trial that we have done with Neuralstem in that in this trial, they’re going to inject stem cells into the low back, the lumbar part of the spinal cord. But these stem cells, they’re not neural progenitors like the stem cells that I discussed with you. These are progenitors for the supporting cells of the nervous system known as astrocytes, so it’s a different type of stem cell. And another exciting part of these stem cells is that they produce a lot of one particular growth factor known as GDNF which is very neuroprotective to the spinal cord. So that stem cell trial, I believe, is going to start in the near future.

A third trial is actually being done at Johns Hopkins and maybe Dr. Rothstein mentioned it with Dr. Nick Maragakis and he too is doing a different type of stem cell and I believe that his approach is going to be similar to the approach that we both have used and Dr. Svendsen andBaloh are using in terms of directly injecting stem cells into the spinal cord.

So we go from no stem cell trials in 2009 and we fast forward five years and we now have one active trial doing intraspinal injections, our trial; the mesenchymal trial, doing the injections around the spinal fluid; and then two new proposed trials. So the field’s moving very quickly.

Seth: We love to hear that. I believe the mesenchymal trial is commonly known as the BrainStorm trial?

Dr. Feldman: Yes, it’s commonly known as the BrainStorm trial. I just wasn’t sure since I didn’t have BrainStorm’s permission to mention their name if I could but you did, Seth, so good.

Seth: Yeah. I hope they’re not too upset with me. And I am not aware of the other two common names but we can —

Dr. Feldman: This trial at Cedars-Sinai with Dr. Svendsen and Baloh, those cells were developed by Dr. Svendsen himself and that trial was being funded by you know how California makes a very large investment in stem cell work, and so it’s actually being funded by the State of California which I think is very exciting and very transformative. So that’s actually being funded by the State of California.

And then in a similar vein, the trial being done at Hopkins, I guess that trial I believe is being funded by a company known as StemCells, Inc. I believe that’s correct. We may need to fact-check that.

Seth: Okay. Excellent. Thank you for that high level of review. I know we have a record number of callers and I would like to get to those questions. I know you were very gracious and interested in answering questions.

We will go to our first caller. Caller ending in 0200, you’re on the air with Dr. Feldman. Please go ahead.

Caller: Hello.

Dr. Feldman: Hi!

Caller: Hi! I guess my biggest question is for those that have ALS and are interested in participating in trials, how do they become involved in them?

Dr. Feldman: So multiple different ways. For those patients who have ALS, they are likely being seen in an ALS Association-certified center or an MDA-certified center, and those certified centers, the centers themselves have a list of all the available trials. And for specifically about the stem cell trial that I’m telling you about the next phase, as I mentioned, we’re going to make that trial available nationally. Previously you have to be geographically located close to one of the three centers that were actually doing the surgeries, that’s now going to be more open.

And information on that trial will be available on the ALS Association website, is another good source and also, in our particular case, the Neuralstem website. But if you go to the ALS Association website, the MDA website,, that lists almost all the trials. Then your own physician will also of course be able to be helpful in the ALS or MDA clinic.

Caller: Thank you very much.

Dr. Feldman: Oh, you’re welcome.

Seth: All right. Thank you, Caller 1. We’ll keep going down the list and as a reminder, if you have a question for Dr. Feldman, please hit the number 1 and we will enter you in the queue.

Our next caller ending in 8760, you are on the air.

Caller: Hi, Seth, this is Allison. We met in Florida, hello. And hi, Amy, if you can hear me too.

And Dr. Feldman, I want to first thank you for dedicating your career to finding a treatment for ALS. My husband was diagnosed last year and he’s just 41 years old and so of course we are very dedicated in wanting to find a treatment for the disease. I know that you’re specifically talking about stem cells but I was really interested in one of the first things you talked about, about your clinical interest including the environmental and occupational factor that may be contributing to ALS. And I was wondering if there is anything that you have seen in the research that you have done or preliminary data that’s been collected.

Dr. Feldman: Right, that’s a wonderful question. Yes, we just published a paper. It’s a very preliminary paper, so I’m glad we’re both using the word preliminary, showing that pesticides particularly organophosphates, individuals who have had that exposure have a greater likelihood of developing ALS.

And so that’s like the first tick in the occupational environmental exposure box that we have fairly confirmed evidence on. And that’s only the beginning. We also have preliminary evidence on what are called flame retardants. So exposure to both organophosphates pesticides and flame retardants and individuals who had exposure to those two compounds or substances, their likelihood of developing ALS was up to two-to three-folds higher.

So this is preliminary, this brings up though a great point. Have you heard about the National ALS Registry?

Caller: Yes.

Dr. Feldman: Yes. So that is a fabulous thing that our government is doing. So that is a registry of all living ALS patients. And when you go to register, there’s about a one-and-a-half hours’ worth of forms to fill out or questionnaires and they’re surveys about occupation, surveys about your exposure, surveys about where you live in terms of is that meaningful if you live near a lake, near a toxic dump, et cetera.

So I encourage everyone to enter the National Registry because those data, along with I think our own study, are going to help answer these important questions.

Caller: Thank you so much.

Dr. Feldman: Oh, thank you for calling.

Seth: Thank you, Allison.

We will continue down our list. Caller 3 ending in 0899, you are on the line with Dr. Feldman.

Caller: Oh, hi! Thank you. Dr. Feldman, thanks for your work. It’s wonderful.

Dr. Feldman: Thank you for the comment.

Caller: I just wanted to know about the qualifications for an ALS patient to participate in a stem cell trial.

Dr. Feldman: Certainly, that’s a wonderful question. Thank you so much for asking.

We don’t specifically know yet because as I mentioned, we are in the next step of preparing the next application and we’ll of course again wait the phase II data for final preparation. But we anticipate, we would like to enter individuals earlier in the course of their disease so three years or less which brings me back to my very first point of the program, that’s why early diagnosis I think is so important, so three years or less. And we are interested in entering patients who have a forced vital capacity, a respiratory capacity of at least 60% and that’s something that patients are tested for in their clinic regularly. And we are interested in entering patients who do have good speaking and swallowing so they don’t have a great deal of trouble speaking and swallowing.

So those are going to be the entry criteria. I think the key one is less than three years of disease and then being able to have a forced vital capacity of 60%. I should tell you, again, we used to use to have to live in a certain place like Michigan or Georgia or Massachusetts in particular but that will no longer be a requisite at all.

Caller: I have one more follow up. In following some of what Seth and Amy are doing, looking at ALS Crowd, they’re looking at bringing in ways of collecting data and so I’m interested in your first point of that kind of early identification of the environmental factors and any thoughts on maybe how new ways of collecting data.

Dr. Feldman: Yeah. I think that’s just a great question.

I’ll go back to the National ALS Registry because they just published their very first paper on the National Registry. And that is going to be a way for us to collect big data on all currently living ALS patients and that is going to be extremely valuable and they’re going to make that data open to all interested individuals and academia so that we’ll all be able to access that data to better understand. Again, this in particular, environmental occupational exposures. But they also have a subset of individuals who are going to their homes and they’re actually drawing blood like we are doing, accessing hair, nails, and trying to understand in the home environment more the occupational exposure.

So now you couple that registry with what’s also being done by the National Institute on Aging as one example where they are trying to collect blood and do genome sequencing looking at all of your genes, that 16 billion reads as we call it, I mean, it’s a huge set. And they’ve done that now in over 5,000 patients and they are hopeful to triple that number. So if you combine the data of the genes with the data of the exposures and the Registry data, we might really begin to get new insights into ALS. So combining and looking at big data are very, very important.

And if I may add and then I’ll stop is I think organizations such as PatientsLikeMe can also be very pivotal in providing data for academia and for these big data sets.

Seth: Thank you, Caller, for your question.

Dr. Feldman, we could spend hours on any of these topics but I wonder, as we wrap up over the next few minutes, if there are any other projects that you are excited about and feel we should mention?

Dr. Feldman: Yeah. I’ll mention one last before we close for the afternoon. Before I do mention I want to thank you again for having me and tell you what really an honor it is to talk to you and to get to talk to other individuals from the ALS community as together as a team we try to better understand what causes ALS and come up with new therapies. So thank you, Seth and Amy, very much.

And so to end, I’ll tell you another project that I’m pretty excited about. And it definitely ties in with the environmental exposure project in that what we now know is that you and I are born with one set of genes, one set of DNA. But over time, what we do, what we’re exposed to changes that DNA and that field is known as epigenetics. And epigenetics is how our DNA changes over time due to what we’re exposed to as during our lifetime and those changes in the DNA actually then result in changes in what are known as RNA and protein that come from the DNA.

And so what we have seen is that in patients with ALS, there’s a clear what I’ll call epigenetic signature, a clear change in their DNA. And we believe again it’s due to environmental exposures but that is helping us try to understand how, for example exposures to pesticides and flame retardants, how that would cause a result in developing ALS so to understand what I’ll call the mechanism of the disease. So this field of epigenetics is an area that my laboratory is very invested in and we think will lead to new therapeutic targets in ALS.

So I can end with that, with my enthusiasm for cellular therapy, stem cells, but also then for this understanding of occupational exposures and this field of epigenetics.

Seth: Thank you for mentioning that project.

If we could ask one final question that we ask on all our shows is what is the greatest opportunity for our listeners to get involved?

Dr. Feldman: I believe the greatest opportunity is to get involved locally, so to get involved locally with either your ALS chapter, your ALSA chapter in particular or possibly your MDA chapter and or in your local ALS clinic and or any very local groups that are involved. Like here we have something called Ann Arbor Against ALS, A2A3 we call it, and it’s a local group that works with the ALS Association and the MDA.

And I think local involvement is very important. Why get locally involved? To raise awareness. This Ice Bucket Challenge has taken a disease that you and I know well but many people have never heard of and is now made nationally understood. So when you get locally involved, you increase awareness. You may or may not increase funding for the disorder but importantly you connect with other individuals who know and understand the disorder. So the more that we can increase awareness, I think, it’s extremely important. If everybody who listens to this program could, if they’re not part of the National ALS Registry, register and tell two or three other ALS pals to register, that could make a tremendous importance.

So local, local, local. I think to get involved locally with your organizations and what they are doing is by far the most important thing one can do. And I really do think together we can really come up with an understanding of this disease and I always say, “Wouldn’t it be great to have an ALS-free world?”

Seth: Indeed, indeed. And thank you for dedicating your career to our community. We deeply appreciate your dedication, creativity, and life focus and we applaud your efforts.

Dr. Feldman: Thank you so much. It is truly an honor, I have to tell you, and a pleasure to work with the ALS community. You are the reason I do what I do every day, Seth, so thank you so much for everything you do for the ALS community. And you too, Amy, thank you so much.

Amy: Thanks.

Dr. Feldman: Okay. Well, goodbye, everyone. Okay. Thank you again.

Seth: For our listeners, a full transcript of this episode will be available on ALS Crowd over the next couple of days. Thank you to Dr. Eva Feldman your time.

Bye for now.