S3, E04: From Humble Beginnings to Potential Treatment for ALS

Josh Cohen:
One of the nurses came up to Justin and I and said, you know, one of my main jobs is to talk to people about the fact that they might only have a few years left and what they might do, how they might best preserve function, and kind of maintain what they have. When you guys announced positive data, for one day in the clinic, all my conversations were about how ALS is changing and how it might be different.

Chris Garcia:
Myotrophic lateral sclerosis, or ALS, is a rare neurological disease that primarily affects the neurons responsible for voluntary muscle movement. The disease is progressive. While patients may initially experience mild symptoms, they eventually lose the ability to chew, walk, talk, and even breathe. The average life expectancy is just three to five years from symptom onset. With no known cure or effective treatment on the market, patients battling ALS are counting on their research community to develop novel therapies as quickly as possible. I'm Chris Garcia and in this episode of Vital Science, Gina catches up with Josh Cohen and Justin Klee, CEOs of a Amylyx Pharmaceuticals to hear about the progress they've made with their groundbreaking ALS therapy. We'll discuss the company's recent clinical trial success, partially funded by the 2014 Ice Bucket Challenge, their moves to commercialize in the US, Canada and Europe, and the role optimism has played in getting them to where they are today.

Gina Mullane:
Well, you were one of our first Vital Science podcast guests, and you joined us for the Humble Beginnings episode, which was held in early 2020, just before the pandemic. And as we take pause to reflect now, how much has changed since we last spoke?

Josh Cohen:
So it's been a busy year and a half or so since we last spoke. There's been a lot of developments at the company. We've gone from, I think when we spoke, we were probably about a seven or eight person company, we're now just under a hundred people. So there's been pretty rapid growth at the company and also over that time, we've submitted for approval for the drug in Canada and in the United States. And we're working hard towards a submission in Europe as well. So, I'd say the mission has very much stayed the same of trying to make a dent and change the lives of people with ALS and other neurodegenerative diseases but we've been excited to bring a lot more people along on that mission as well. And, hopefully that allows us to do even more.

Gina Mullane:
Can you tell us a little bit about the journey to get to that big point of submitting for a new drug application, or NDA to the FDA? I know that's a pretty significant milestone and wondering what that involved for you.

Justin Klee:
So I would say it's been a very exciting journey and one where I think we've learned a lot as well. And I think one that we hope has really united the ALS community as well. So in very late 2019, we announced positive clinical trial results from our first major clinical trial in people with ALS, the CENTAUR trial. And about nine months later we published the results in the New England Journal of Medicine and the trial for the first time, showed a benefit on both the functional rating scale, so people retained their function longer, and then as we looked out over long term, people lived longer also. And in ALS that's a huge deal considering that it's a rapid, progressive, fatal disease.

Justin Klee:
So the question became what's next. And we met with regulators globally, Health Canada, FDA, and the EMA, and the feedback was very encouraging. I think they recognized the tremendous unmet need in ALS. They recognize that the data should be reviewed as a potential new treatment option for people. And so we then had to set out to actually submit the documentation needed, which is no small task. So I think the first thing we did, which we're really proud of is, as Josh said, we hired many people and really experienced people who believed in the mission at the way that we do.

Chris Garcia:
On the other side of a complex clinical trial. And with encouraging data in hand, AMX0035 had passed several important checkpoints. However, one of the biggest hurdles was still ahead, submitting multiple new drug applications. Fortunately, Josh and Justin had hired a team of regulatory experts led by Amylyx's Head of Global Regulatory Affairs, Tammy Sarnelli, to complete the herculean task of submitting documentation for an NDA in the United States, NDS in Canada, and upcoming MAA in Europe. Each regulatory body has its own distinct requirements for application. Each requiring the submission of over a thousand meticulously formatted pages detailing the company's research to date. We'll leave that light reading to the experts, but let's hear from Josh and Justin with the cliff notes version of how this drug works in the body.

Justin Klee:
Yeah, so the treatment is a combination of two small molecules and each molecule is designed to target something that we think is particularly important in the neurodegenerative pathways. So particularly one small molecule targets endoplasmic reticulum stress in the unfolded protein response. We see in these diseases that there are many unfolded, misfolded, mislocalized proteins, and that's one of the main triggers for the cell to die. Further, in the other small molecule, targets mitochondrial dysfunction. And we see that many of the canonical death pathways in cells and particularly in neurons, originate in the mitochondria. And so, we thought it was important to target both of these organelle stress pathways because they're both key regulators of how neurons degenerate and die.

Justin Klee:
And so the hope with the treatment was that while there are many insults and risk factors that lead to ALS or other neurodegenerative diseases, if we can slow, stop, prevent, the neurodegeneration from occurring, then maybe we can have a meaningful therapy. And so through our pre-clinical development, we tested this combination in different ratios and doses to look at the ability to prevent or slow the degenerative process. And of course, we're tremendously excited to see that the work translated into meaningful clinical differences as well.

Gina Mullane:
Wow. I'm sure it was exciting to see the effects from the lab translating into the clinical benefits for patients. So what did you discover in CENTAUR, your phase two multicenter clinical trial?

Josh Cohen:
Yeah. Great question. So CENTAUR we conducted between 2017 and the end of 2019, which was a large placebo controlled study or large for ALS at least, where we assessed patients over time, looked at their function, looked at their survival ultimately, and what we found, well maybe I'll add to that this whole process of conducting a clinical trial, for Justin and I, was our first time doing this. And so very much so as we were going along, it was made possible by the folks at Mass General, Sabrina Paganoni, and Merit Cudkowicz who basically taught us how to run clinical trials and together with them, we conducted this.

And pretty much late in 2019, we found ourselves late at night in a conference room, anxiously waiting on the results, because I think a lot of people think that pharma companies somehow miraculously know the results in advance, but it really is, kind of one day, one moment, you find out and it's either good or it's bad. And so ultimately what we learned was that the drug was able to extend function, able to extend survival, and on the safety side, we saw more gastrointestinal adverse events in the AMX0035 treated arm, but aside from that, generally the safety events were at similar levels between active and placebo.

Justin Klee:
Yeah. I-

Josh Cohen:
You want to add to that?

Justin Klee:
I just had to smile when you were saying one day, one moment, because I think Josh and I will certainly never forget the moment because we didn't know, it was almost midnight, and we had been working for most of our professional lives up until this one moment and fortunately it worked and I think what was particularly exciting too, is the statistics group that we work with has been working in neurodegenerative diseases for decades. And unfortunately nothing's worked. And so for them, this is their first successful trial also. So that was certainly a moment I'll never forget.

Josh Cohen:
It was funny too. Before we actually saw the data, we got a good sense that it was positive because you could hear in the background of the statistician telling us the data, all of the other statisticians cheering.

Gina Mullane:
Oh, wow.

Josh Cohen:
So you kind of knew from this phone call that something good had happened.

Gina Mullane:
That's incredible.

Chris Garcia:
The success experience in this moment was particularly sweet given the series of challenges the team had experienced in getting there. Amylyx began with a kernel of an idea in a Brown University dorm room in 2013, but Josh and Justin knew it wouldn't be an easy road to see that idea to fruition. In an area of research that's had its fair share of failed studies and failed drugs, generating funding would prove to be a significant hurdle. Each year as the program advanced the company required additional backing to maintain momentum for its research. The team took what they described as a door-to-door sales approach until things changed dramatically in 2016. As a part of its Series A funding, the company was fortunate enough to get a grant with the ALS association and A ALS Finding a Cure, partially funded by the viral ice bucket challenge. With $3 million to fuel its clinical trial, Amylyx was able to move forward, gaining credibility and earning additional support from mission focused investors like Morningside, the ALS Investment Fund, and Henri Termeer. Then came the hardest part of living up to the expectations investors and the ALS community.

Josh Cohen:
You know, it's both unbelievably exciting when you get positive data, but it also puts a pretty heavy responsibility and suddenly we're the company holding this positive data that has to deliver for patients and that if we make a misstep, then it's not just us who get hurt by that misstep, but it's tens of thousands of people. And so I think the other challenge really has been the kind of pressure that ads in terms of figuring out. You really want everything to be perfect at every step, at every juncture, and that's hard. Especially doing it rapidly as well. So I think that's been the other main theme of the last couple years is how do we maintain and pursue perfection while also recognizing that people are... This is a really rapidly progressing disease and every day, hour, minute counts and we can't waste weeks or waste months in getting this drug to people as quickly as we can.

Justin Klee:
Yeah. I couldn't agree more with that.

Gina Mullane:
I imagine these circumstances make scaling quickly a top prior for the company. How have you managed to balance this pursuit of perfection as you described it, with your motivation to keep the tightest timeline possible?

Josh Cohen:
I guess I'd say that we've kind of approached most problems in a similar way of asking a lot of questions and finding some really good people. So I'd say really for all of those challenges, we've sought people in the industry and outside of the industry who have built, whether it's manufacturing processes, whether it's regulatory processes, or experiments or otherwise, and just asked them a ton of questions. Justin and I have been accused of having meetings crossed the prescribed hour or otherwise because we just kind of keep asking questions and try to keep learning. One of the things we've learned through this process frankly, is even nine years in, is just how much we don't know. We've learned a lot in nine years, but this industry is big and wide, and there's always more to know and always more nuance to know. And so I think the biggest recipe for success really is just to stay curious, keep asking questions, keep talking to people, and surrounding ourselves and surrounding the company with really, thoughtful, curious people as well.

Justin Klee:
It's why "be curious" is one of Amylyx's core values.

Gina Mullane:
Oh. Oh.

Justin Klee:
That said Josh and I wouldn't be here if we didn't ask 10 million questions. And just one other thing to highlight is I think Josh's points extend to the groups we work with as well. And I'd certainly put Charles River Labs right up there as one of the partners who's been with us through thick and thin and through many different stages of development. And I think for a small company like us, it's so essential that those groups are really an extension of our company. They have capabilities that we don't, people that are experts in the field that we're looking at, so I think that Amylyx could not exist if there weren't groups like Charles River Labs who can support us all along the way.

Chris Garcia:
Another benefit of collaborating in the greater scientific community is the synergies that can occur as a result. As we discussed in earlier episodes of Vital Science, groundbreaking discoveries do not occur in a vacuum. New therapies build on those that have come before, be it through direct repurposing of an existing drug, or by learning from the studies conducted by fellow researchers. In the case of AMX0035, the CENTAUR trial has proven to be a springboard, not only for the treatment of ALS, but also other neurodegenerative diseases, such as Alzheimer's.

Gina Mullane:
And from what I understand, some of the preclinical trials we conducted together found that AMX0035 may also have some value for other neurodegenerative diseases. Can you tell us a bit more about the PEGASUS study and what you hope to accomplish there?

Justin Klee:
As I was saying before, the mechanism of AMX0035 is to target neuronal death and degeneration pathways. And that's not specific to ALS, that's as you said, Gina, true for so many other diseases as well. Each of which is a tremendous unmet need and has unfortunately touched the lives of just about everyone. So one of the first other diseases that we're looking into is Alzheimer's and it actually goes back. We ran some of our very first experiments with our friends in Kuopio, Charles River Labs Finland, and showed potential benefit in mouse models of Alzheimer's disease. And so in the PEGASUS study, which was our nickname for our Alzheimer's study, the challenge is how do you run an Alzheimer's study that doesn't cost hundreds of millions of dollars, but can help us understand the drug's potential in the population.

And so we ran a small study, about a hundred people, and six months treatment, funded almost completely by the Alzheimer's Association, the Alzheimer's Drug Discovery Foundation, and the Cure Alzheimer's Fund, which we were very, very grateful for. And we looked at all manner of different outcomes. But I think what we were hoping is that we could learn about the drug's effects in the brain, because while in a short period of time in a small study, it may be hard to look at things like cognition, what we can look at is what's happening in the brain.

And so I think what we were really excited about is we did indeed show that the drug hit some key biomarkers in Alzheimer's, including amyloid and tau, the two canonical markers. So now we're working with key opinion leaders to this discuss what the next steps might be in Alzheimer's as well as how we think about clinical development and other diseases too. Because again, some of these markers like tau are shared across many different unmet needs. And so we want to try to efficiently get to people where this drug might be able to benefit.

Josh Cohen:
I'd just maybe add from a kind of high level, our goal is pretty clear. You know, we want to help as many people as we can as quickly as we can. And so, along those lines, we really do want to advance AMX0035 in additional indications as quickly as we possibly can. And I'd also add that I think we're very committed to the ALS community and are kind of here to stay as well. So all stuff that's still kind of in early work and early discussions, but also very much want to continue improving on what we're able to offer in ALS also.

Gina Mullane:
It's amazing to think how together these two small molecules could be useful in treating multiple neurodegenerative diseases. How did this idea originate? What made you think to combine these therapies?

Josh Cohen:
I mean, basically it was mechanistic initially. So we had kind of mapped out in our view, how we thought that, what pathways were involved in neuronal death. And what we found was that it wasn't just one pathway. It was multiple. And so we looked and said, well, these are probably the two most critical pathways. And the only way we could see to target them was with two drugs. Now, I think there was maybe an advantage to naivety too, because I think most experienced developers would say, well, developing two combo at the same time is going to introduce all sorts of challenges, which it did, but we had no idea that that would introduce any sort of challenges. It just seemed like the logical thing to do.

Gina Mullane:
So I think back to our discussion last year and we focused a lot on two guys in a dorm room, where you were eight or nine years ago. How have the values for Amylyx evolved since then? Since those early days or have they pretty much stayed the same?

Justin Klee:
I love that question. Well, I'd say, I think we got wonderful advice from some of our advisors, which is that the values should be true to who we are. At the time, we wrote them down, Josh and I and our colleague Kent were the only people in the company so we sort of looked around and I think Josh and I really tried to think about how did we... Any success we had, how did we get here, and what did we want to build, and what did we want to have hopefully speak to future colleagues.

And that's how we came up with our values. So just sort of listing them quickly to be audacious, curious, engaged, accountable, and authentic. And I think if I look at those words, I think it really speaks to who we are and some of them can contrast, but in ways that I hope are true to us. So for example, to be audacious but authentic, I think Josh and I like to dream big. That's how we started, but Josh and I are also, I don't know how else to say it, probably allergic to bureaucracy. I don't think we'd last too long in a big company with sort of a very classic corporate hierarchy.

Josh Cohen:
Yeah. And I just add to, they very much come out of that dorm room experience as well. You know, particularly ones like be curious, I think comes very much from the fact that we had to learn everything. We had started knowing absolutely nothing and there's still a time to learn. And I think we want to encourage people that it's okay not to know everything. It's okay to stop and say I really don't understand that or otherwise, because that's how we get better. That's how we learn.

And similarly I'd say being accountable, being engaged, for a time in the company it was just Justin and I, eventually Justin and I and Kent. And so no task was too small. Whether it was buying stamps for mailing various things, to figuring out the strategy for our upcoming experiments or otherwise. And I think that's part of how we think of being accountable and being engaged in terms of everybody pitching in, everybody rolling up their sleeves, nobody's saying, "I have this big title. I can't." I'm not going to stoop and buy the stamps or something. Everybody's in it together. We're all fighting for the same thing and it's all trying to help out.

Justin Klee:
I have to add that I think stamps are probably particularly both near and dear Josh, to your heart, but also maybe some PTSD because for many, many of the early years of the company, Josh, among other things, would hand write every check and hand write and mail every letter. And so Josh developed-

Chris Garcia:
Wow.

Justin Klee:
This amazing system of how many stamps we needed for what packages and bills and probably a skillset, Josh, that you knew you were... Are happy now that you don't have to use anymore. But if anybody needs any advice on mailing stuff, Josh became an expert just because who else was going to do it?

Gina Mullane:
I love your humility. You both are just such a pleasure to speak to. You're very down to earth and real. And a lot of the times when I hear you speak, it's about patience. What motivates you? What motivates your team to push for the solutions of people living with neurogenerative diseases like ALS?

Josh Cohen:
We have a lot of calls that it's hard to, or used to be in person meetings, but at this point, mostly calls and Zoom where it's hard to walk to end the call and not want to let's say, work till midnight or 2:00 AM or whatever it might take to keep pushing ahead. Just to give an example, we were talking about the data release.

Shortly after the data release, the Mass General folks threw us kind of a small party to celebrate. And one of the nurses came up to Justin and I and said, "You know, typically in the ALS clinic, one of my main jobs is to talk to people about the fact that they might only have a few years left, and what they might do, how they might best preserve function, and maintain what they have. These are usually really tough, really difficult conversations." And the nurse said, "When you guys announced positive data, for one day in the clinic, all my conversations were about how ALS is changing and how it might be different than it is today." It's little things like that that you... It's hard to then go home and say, "You know what? It's been a hard week. I'm going to close the computer for some hours." You quickly, at least for us, I think when things like that happen, it just makes you want to kind of redouble efforts and push a little harder and keep fighting.

Justin Klee:
Yeah. Well, that's certainly one of those moments that again, will stick with us, I think our whole lives. And one other thing Josh highlighted is not only do we meet and get to work with just the most amazing patient advocates, but it's also the people who have dedicated their lives to helping people with these diseases. And for us, we often say waking up in the morning and feeling motivated is so easy because we get to work with people who have dedicated their lives to trying to help. And for us to get to partner with those people is just wonderful. And I think one other thing we found with ALS and neurodegenerative diseases is that in the face of these really tough diagnoses, you just see the most amazing strength in community and just the really best in people. And while it's so hard that people have been given this diagnosis, the people who then become the warriors for those who maybe have harder time, knowing what to do or speaking, are just extraordinary people.

Josh Cohen:
Maybe the only other thing I'd add is we also get inspired a lot by our team.

Justin Klee:
Oh yeah.

Josh Cohen:
I mean, I think we're really lucky to have just a great team and there is something really quite neat as the company's gotten bigger that just to see what everybody's accomplishing, the passion everybody's bringing, things like the NDA, where everybody just completely gave it their all to make it happen. That's quite inspiring too. And so I think we've also just been really lucky that the team that's come together behind this.

Justin Klee:
Oh yeah, could not agree more with that.

Gina Mullane:
You're also very open and generous in talking about all the partnerships and collaborations and the ecosystem around you that has enabled the progress to happen. And I just think that says a lot about your approach and the core of the company. It's really wonderful to hear. Thinking back and if you could talk to the you of eight years ago, what would you say about where you and the company are today?

Justin Klee:
The first thing that comes to mind, first of all, I don't think Josh and I in a million years could have guessed that we'd be where we are today. I'm not sure we knew enough to know that we could be in this place, but I mean, I think that the first thing I'd say is just to do it.

I think that we feel so lucky that we get to do something every day where it's really interesting. We've worked with amazing people and at the end of the day, if we're successful, we help a lot of people who need it. And I think that in a way I almost wouldn't want to talk to myself or ourselves almost nine years ago now, because I think it was part of that curiosity and learning that helped us develop into who we are today and who Amylyx is today. So I guess I'd say that the journey itself has been amazing and I just feel so blessed to be in the position we are. And with that being said, we also hope it's just the start. There's a lot of work to do, the treatment, we're really proud of the data, but it's not a cure. There are many other issues that I think we want to solve beyond just delivering new treatments for people. So hopefully eight or nine years from now, we'll be having this conversation with you again and sharing all the updates from that.

Josh Cohen:
It's a tough one. A lot's changed, a lot's also the same in the sense that the challenges we faced while starting the company were quite challenging. The challenges we still face are always all consuming and there's always more to do and kind of everything like that. I've often said in this, biotech, you do kind of have to be a bit of an optimist. Unfortunately, most drugs fail. And so you kind of have to take a view of taking it step by step, bite by bite, and rolling with the punches a little bit. So I don't... To Justin's point, I don't know that I would want to give too many hints of what's ahead to my eight or nine year old self, but maybe rather just provide advice on the next two months of-

Gina Mullane:
That's hilarious.

Josh Cohen:
What's to come because when you think about it as a whole, it can be pretty scary. But when you think about it as a few months and a few key work streams, key goals, I think that's how you get... Those key goals start stringing together into, as you said, nine years later, what's been accomplished.

Chris Garcia:
One of the silver linings of having worked through the challenges of AMX0035 is that Josh and Justin are now intimately familiar with the unmet needs of the greater ALS community, and ever the optimists this has not daunted them. It has instead inspired them to see their work in a larger context. Their research began with the goal of introducing a novel ALS therapy in the US, then Canada, and Europe. But now they see that their treatment has the potential to benefit countless patients around the globe, including the Middle East, Asia, Latin America and beyond, but their aspirations don't stop there. They hope that AMX0035 will be a platform that allows Amylyx to go beyond delivering this one treatment, to improve the timeliness of ALS diagnosis, bolster funding for clinical research, and build out a pipeline of therapies that will eventually lead to a definitive cure for ALS and other neurodegenerative diseases.

Josh Cohen:
We were asked at one point, what really is the overall goal? What's the point? And at the end of the day, the goal is to cure these diseases. Having meaningful treatments is critical and that's the first step. And really can't be overstated how important it is that treatments come around that make people retain function longer, live longer, things like that. But at the end of the day, the goal is to take care of these diseases and that's going to take a ton more effort. It's a tough nut to crack and one that we want to be pushing full speed ahead on.

Gina Mullane:
Well, your optimism has served you well so far, and I have no doubt that you'll have much more to report on when we sit down next. Thanks so much for bringing us up to speed on the new and exciting things happening at Amylyx.

Justin Klee:
Thank you so much. Thanks so much for having us back. And as I said, I hope we get to keep doing this and we'll keep pushing.

Josh Cohen:
Thank you so much.

Chris Garcia:
Josh Cohen and Justin Klee are the co-founders and co-CEOs of Amylyx Pharmaceuticals. Wishing our listeners a great 2022. Until next time, thanks for listening.