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 ALSuntangled.com 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 ALSuntangled.com 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 ALSreversals.com 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
ethnomedicine.org
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 ethnomedicine.org. 

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 ethnomedicine.org which is E-T-H-N-O- medicine.org. 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 ethnomedicine.org. 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.