Welcome to the Morgan Stanley Global Healthcare Conference. I'm Jeff Hung, one of the Biotech Analysts. For important disclosures, please see the Morgan Stanley Research Disclosure website at www.morganstanley.com/researchdisclosures. If you have any questions, please reach out to your Morgan Stanley sales representative. For this session, we have Amylyx Pharmaceuticals with co-CEOs Justin Klee and Joshua Cohen. Welcome.
Thank you.
Thank you.
Thanks so much for having us.
For those who may not be as familiar with Amylyx, can you provide a brief introduction?
Yeah, happy to. So, thanks so much for having us. Justin, Josh, are the co-CEOs, co-founders of Amylyx. So Amylyx was founded about 10.5 years ago. We are focused in neurodegenerative diseases, and particularly ALS. The company is especially focused right now on our FDA-approved treatment, RELYVRIO, also brand name ALBRIOZA in Canada, which was approved last year, and we're now commercializing to help people with ALS. So we're really excited with how things are going so far, but we also feel like we're just at the start of the journey, trying to help people who really need it.
Great. Well, you guys have had a strong launch for RELYVRIO, going from 1,300 patients in Q4 to 3,000 patients in Q1 and 3,800 patients in Q2. Do you have a sense for how much of the initial bolus you've gone through?
Yeah, you know, I'd say it's hard to say, and when we talk about... You know, it's actually very hard to define bolus in ALS, in general. You think about this disease, people are constantly being diagnosed, and unfortunately, people are constantly passing away as well. So there's constant, in our view, work to do. Thinking generally, ALS has a prevalence of roughly 30,000 in the United States, probably around 3,000 in Canada, and 40,000 in Europe, and we have 3,800 people on therapy out of 30,000 people that are out there. So we very much believe there's a ton more opportunity for us to address and a ton more people for us to help.
Where do you see growth coming from over the next 1-2 years for the drug, and what initiatives are you planning or implementing to drive further growth?
Yeah. Well, thank you so much for asking. So, you know, as I started with, we feel very much like we're at the start of this journey. We're really proud of what... And I shouldn't say, you know, what we've done, really our team. We have a just tremendous team out there every day trying to help people who really need it. And so, that's meant, as of the end of the second quarter, 3,800 people were on the treatment. That means 3,800 people we're helping and their families, plus more in Canada, and we're awaiting a final decision from CHMP in the fall, so we hope in Europe soon as well. But it really has to be the start.
We have the first treatment that, not just slowed ALS, but also in a longer-term post-hoc analysis, showed an overall survival difference as well. So not just slowed the disease, but kept people alive longer. And we feel a deep responsibility that we need to get that to people as quickly and effectively as possible. So when we have treated 3,800 people, but in the U.S. alone, there's 30,000 people, we have a lot more to do. So how are we going to do that? Well, I think we're trying to transform the disease space. We've started with focusing a lot on specialists, ALS specialists, who see many patients. I think there's still more work to do there.
I think that ALS is a big, rare disease, and so there are a lot of general neurologists who tend to see people with ALS. ALS takes a long time to diagnose. We hope that there's ways that we can shorten the time to diagnosis so that we can help people sooner. We can get people while they still have more function, I think, would presumably lead to better outcomes. So I think there's so much more growth ahead of us. So, you know, we're just three quarters into our launch. We're really proud of what we've done so far, but there's a lot more to do.
Now, you've indicated that prescribing remains fairly concentrated at major ALS centers, and that was a focus at launch. Have you begun shifting focus to other centers, or how much of a shift do you expect over the next 12 months?
Yeah, I think the growth is actually pretty widespread. You know, we said in the last quarter that roughly 80 prescribers accounted for 50% of the prescriptions. The previous quarter, we said the same thing, roughly 80 prescribers accounted for 50% of the prescriptions. So you think, how, how could that have happened when we've gone from 3,000 to 3,800 patients on therapy? Well, we've seen growth in the top prescribers, and we've seen growth outside of the top prescribers as well. So I think we see that there's still opportunity in both areas, and I... Still opportunity, frankly, we think there's still a lot of opportunity in both areas with, you know, roughly 30,000 people out there. And ALS also isn't just a U.S. disease, it's a global disease.
Not only do we think we can grow in the U.S., but we think there's patients worldwide to address.
Now, you received a negative opinion from the CHMP in June and requested a formal reexamination of the MAA in July. Can you just talk about the reexamination procedure and any updates to note?
Yeah, very happy to. Well, so I think, first, the reexamination process in the EMA is a process where, upon a negative opinion, you're given 15 days to file for reexamination, and you are assigned two new rapporteurs or new rapporteur and co-rapporteur. Those are the representatives of the CHMP who do the evaluation of the data and of the product. You are given the potential to have another Scientific Advisory Group meeting, another oral explanation, and then ultimately, it's presented to CHMP, and there's a vote. If you look historically, maybe 25-30% of the time, historically, the CHMP will come to a different opinion than they did the first time around. So we're in that process now.
We estimate October, November, is when we should get the final opinion from the CHMP. You know, I think our viewpoint is that the CHMP and EMA regulations have a conditional marketing authorization, and we feel like this should be tailor-made for that. Conditional marketing authorizations are supposed to be for unmet medical needs. ALS clearly meets that bar, especially in ALS, where the last approved treatment for ALS, and the only approved treatment for ALS in Europe, was 1996, riluzole. So there's tremendous unmet medical need. There has to be clear evidence of benefit. As we mentioned before, this is the first treatment that's shown both a functional and survival benefit in a progressive fatal disease. And there has to be certainty that you'll be able to get the confirmatory data, which clearly we will.
We'll have those results mid-next year. So, you know, we're excited that the EMA has this reexamination process. Ultimately, the approval decision is, of course, up to the regulatory authorities, but we think we have a strong case to make.
Can you talk about the commercial launch strategy for Europe and any differences that you would highlight from the strategy in the U.S.? You know, like, what kinds of launch preparations have you made?
So first I'd say that in Europe, the launch is usually a little more sequential. In many countries, after approval, you still have to go through an HTA process before the drug can be reimbursed. So I'd say our launch focus is first on Germany. We've already hired the German sales force. They're in the field. And, you know, in Germany, you have free pricing, so at the time you're approved, you can already price, commercialize the drug. So that usually leads to it being your first market. Beyond that, France and Italy both have paid early access programs that are, you know, kinda where, you know, where market access kind of happens next frequently. But ultimately, when we take Europe holistically, some of the things that are most exciting.
You know, in the U.S., we look at riluzole prescriptions, and we see that, you know, only approximately 25%-30% of people living with ALS are receiving riluzole. When we look in Europe, that number becomes more like 70%-90% of people receiving riluzole. So we think there's quite an opportunity with a, let's say, seemingly higher propensity to treat in Europe as compared to the U.S.
And I'd just add, too, I think that something that's so important to our mission, as Josh was saying, ALS is a global disease. It doesn't matter where you are in the world, ALS is the same. It's a progressive, fatal disease with very few options for people. It has about the same per capita incidence and prevalence globally. And so I think we feel like we have a really important step forward for ALS, and we feel a deep obligation to deliver that to people.
Let's shift to PHOENIX. Can you talk about the design of the study?
Yeah. So I mean, first of all, we're very excited about PHOENIX, which is our global phase III clinical trial. So going into PHOENIX, similar to as we went into CENTAUR, we worked closely with experts in the ALS field. I think we designed CENTAUR in a way that was state-of-the-art. We met our pre-specified primary outcome in CENTAUR, showing a slowing in functional progression as measured by the ALSFRS-R. That was coupled to an overall survival benefit, as well as, you know, strong trends on all of the secondary outcomes as well. So we were, you know, obviously very excited about CENTAUR, which then led us into PHOENIX. So PHOENIX, in a lot of ways, is very similar to CENTAUR. It's a randomized placebo-controlled study. It's much larger.
It's nearly 5 times the size of CENTAUR, so it's quite a bit larger. We recently presented the baseline characteristics at the ENCALS conference, and what we found was that at baseline, patients were quite similar to CENTAUR. Within a month on the ALSFRS-R, or sorry, within a point on the ALSFRS-R and within a month in the time since symptom onset at baseline, so very, very similar populations between the two studies. We're looking at effectively the same endpoints. We're looking at the ALSFRS-R, we're looking at breathing, we're looking at quality of life. Very, very similar to what we're looking at... Really the same as what, as what we're looking at in CENTAUR. So, I think overall, we're really excited. Much better powered, same endpoints, and similar population.
Why is the inclusion/exclusion criteria broader than CENTAUR, and why analyze a subset of patients who meet CENTAUR criteria as well as the broader population?
Yeah, so, that was really from feedback, particularly from EMA, where they wanted to see a slightly broader population, and their guidelines say that they want to see 48-week duration trials, so that's what we did. That being said, you know, I think now with the baseline characteristics and that really is the most important aspect here, because with the inclusion criteria, it's: Well, here are the guardrails. Here's who we want to enroll. The baseline characteristics are: Here's who we enrolled. And, I think as Josh was saying, and we have on our website, the baseline characteristics of the studies are virtually the same. So in fact, it looks like the population we studied in CENTAUR is the same population that we're studying in PHOENIX.
Now, it's always a good idea to look at subgroups and to pre-specify subgroups if you can, so I think the identical CENTAUR population, sub- subpopulation in the PHOENIX study, you know, makes sense to look at that. But I think the reason that we're very encouraged about the baseline characteristics is, as Josh said, we're looking at the same outcomes, and we had a successful study. So the only thing that, you know, you might get worried about, are you looking at the same population? Looks like we are.
So you completed enrollment earlier this year and expect to report data in mid-2024, as you said earlier. What do you need to see to consider this study a success?
You know, I think coming out of CENTAUR, we're super excited about this study. You know, with a successful study here, we would be the only drug ever to have two positive randomized placebo-controlled studies in ALS, which I think kind of sets it up to be the de facto standard of care in the space. You know, in terms of the study itself, you know, our primary endpoint's the ALSFRS-R. Certainly, that's our target, to hit the ALSFRS-R. But, you know, it's a big study with a lot of data, so of course, you know, we'll analyze fully as well. But, coming out of CENTAUR, where we hit our pre-specified primary outcome, I think we're running a very similar study, similar population, same endpoints.
That's what we're trying to hit.
Well, one thing we're going to be excited about, too. So in mid-2024, we'll get the top-line results, especially the ALSFRS-R. It will take more time to accrue enough survival events, though, to be able to ascertain if we see the same survival benefit that we saw in CENTAUR. So we likely won't accrue enough events until mid-2025, but I think that'll be a really exciting point for us, too, because I think what one wants to see in ALS, as we saw in CENTAUR, is that you can slow the disease down, you can keep people alive longer. So we're excited to look at both of those in the PHOENIX study, too.
Great. Let's move to PSP, for which you're starting a phase III study this year. Can you just talk about PSP and the potential opportunity in that indication?
Yeah, PSP, we're so excited. We were sharing earlier with some folks that when we had an advisory board with some of the leaders in the PSP community, the general feedback was, "Why have you not started the study yet?" You know, I think the reason is, we have a drug that worked in ALS, safe and well-tolerated. In our Alzheimer's study at the same dose, we showed a very significant lowering of Tau, which is the key biomarker in PSP. PSP is considered a very pure Tauopathy. It's shown by both a particular pattern of brain degeneration as well as Tau deposition. So we've hit the key biomarker at that same dose.
So I think people are very excited to see, hey, this maybe could just be a meaningful treatment for people with PSP. Progressive supranuclear palsy is one of those rare diseases that it's really not all that rare. In the U.S., there's at least 20,000 people with PSP. It's probably underdiagnosed. In fact, there's pretty good publications that it's underdiagnosed. But when you don't have meaningful treatments for people, you're going to have a disease that's underdiagnosed. When you talk to people who specialize in it, they'll say, "Yeah, it's called an atypical Parkinson's disease," but it's pretty clear it's not Parkinson's. People don't respond to dopamine therapy.
They have a very clear neurological pattern, including the progress- the supranuclear palsy point, as people can't look up, and they have a very clear what's called a gunslinger's gait, as well as other neurological signs. The disease ends up being fatal, on average, in about 6-8 years. So it's a really tough disease and, again, no treatments for people with PSP. It's also, like I said, a very large disease. There's probably 20,000+ in the U.S. and probably many more than that globally. So I think it's another one of these rare neurodegenerative diseases that, frankly, isn't all that rare and, sadly, is a tremendous unmet medical need. We're really excited, both from an opportunity to help people as well as a value creation opportunity.
You mentioned PSP tau. What is your current thinking for how AMX0035 influences PSP tau pathology?
Yeah, I mean, in our, in our Alzheimer's study, we showed a reduction in total tau, so we think overall, we're showing a reduction in tau. That was a randomized placebo-controlled study over 24 weeks. We looked in the cerebrospinal fluid, and tau was reduced in active versus placebo. As it relates to PSP, a lot of the evidence is that the tau deposition we're seeing there may also be very influenced by endoplasmic reticulum stress. One of the genes that's popped out of the GWAS in progressive supranuclear palsy is an ER stress gene. There's a good amount of evidence that where there is ER stress, there was a kind of single-cell study in postmortem brains that showed where there is ER stress, that's also where the tau shows up.
And we have a combination drug here that we believe targets endoplasmic reticulum stress and mitochondrial dysfunction. On the mitochondrial side, it PSP is also a disease of significant apoptosis, and the mitochondria is the general regulator for where apoptosis ultimately occurs. So we're quite excited about that. I'll add the other thing is, in our Alzheimer's study, we also did an exploratory analysis with the CSF, where we did unbiased proteomics to look at which proteins were most changed in CSF. And what we found was that out of 288 proteins that we measured, the most changed one was tau. So there does seem to be a very distinct tau effect with AMX0035.
So what biomarker analyses, and you kind of touched upon this, but can you just talk about the biomarker analyses you've conducted that gives you confidence... for AMX0035 and PSP?
Yeah, absolutely. Well, I think it's especially what Josh said from a biomarker perspective, and I think what, you know, if I step back, why is the PSP community so excited about this? I think first, we've had very few drugs that work in neurodegenerative diseases, period. If a drug works in a disease like ALS, which in probably any case is the fastest, most profound neurodegenerative disease there is, then I think that alone makes people excited. I think secondly, ER stress and mitochondrial dysfunction are very clearly implicated in PSP. Whether you look at the mouse models or you look at postmortem brain, that's very clear. I think then on top of all of it, out of all of the different neurodegenerative diseases we see, there's a very clear tau signature.
In fact, you know, particular mutations in tau are virtually causative of PSP. So we're very certain that tau deposition is part of the degenerative cascade in PSP. So I think when you combine the mechanistic data that we have working in ALS, plus the tau biomarker, it's why I think the community is very excited about the opportunity in PSP. Maybe the last thing I'll say about PSP is that, it's quite reliably progressive as well. So when we were looking at what diseases to look into next, PSP, if you look at the PSP Rating Scale, and if you look at survival, it's sad, but people tend to progress very reliably on the PSP Rating Scale.
If you look at past clinical trials, the progression rate's about the same from trial to trial, and again, people die at about the same time frame from trial to trial or, and in different natural history studies. So it's quite a sadly reliable disease as well, but that's why we hope to help.
Can you talk about the design of the ORION study and what kind of difference in PSPRS score on a placebo-adjusted basis do you need to see to be clinically meaningful?
Yeah. So, one, we had a webinar maybe a month and a half ago on PSP. I definitely encourage everybody to watch as well. We had Professor Dr. Günter Höglinger, who's one of the top PSP researchers in the world, present on, you know, all things PSP. So there's a lot to dig into there. He was asked the question by one of the... During the question and answer on that call: What's clinically meaningful in PSP? And his answer was, "Any slowing is clinically meaningful." Looking at the literature, there isn't much data, frankly, in PSP about what is or what isn't clinically meaningful. As it relates to our study, there have been past studies that have looked at the PSP Rating Scale over a year, multiple of them, in fact.
Generally, the PSP Rating Scale progresses about 10 points in a year. We powered the study to be able to see, you know, frankly, even small changes in the PSPRS. Of course, we hope we'll see larger changes, but we do believe with 600 patients, we should be more than well-powered to see, you know, effects, let's say, well below even 30% slowing.
Great. Maybe moving to Wolfram Syndrome. You're also studying AMX0035 in Wolfram Syndrome. What is the rationale for treating this indication?
Yeah, well, it's something we're very proud of, and I think for those of us who've worked in rare disease, it's a sort of wonderful, classic rare disease story. So, we had been studying the treatment for ALS and neurodegenerative diseases when one day we were contacted by a mother who happens to be a physician, but her daughter has Wolfram Syndrome. And so, she said, "You know, I've been reading up on your mechanisms. I think there's a lot of potential application here for Wolfram Syndrome." And so she sort of invited us into the community and actually helped fund some of our early preclinical studies at WashU, St. Louis, with one of the world experts in Wolfram Syndrome, Dr. Fumihiko Urano.
So, that began a wonderful collaboration over four or five years, where we studied our drug in fibroblasts, in iPSCs, and in a mouse model of Wolfram syndrome. In short, the studies looked very promising. So we've now gone into a clinical study of Wolfram syndrome, and this is really the first industry-led trial and one of the very first interventional studies in Wolfram syndrome. But I think as you learn more about the disease, as you hear from people with it, it's definitely one of those areas you sure hope you can help. Wolfram syndrome typically presents as type 1. It's a genetic disease that's caused by mutations in the WFS1 gene.
It presents typically as type 1 diabetes, usually when people are maybe 6-9 in that sort of range, but then people start to lose vision, then hearing loss, then gait, then they're wheelchair-bound, and then people pass away early. So it's a really, really hard disease, both for the people who have it and their families. So we're so excited to at least advance the program into clinical development, and we hope it may be a treatment for people, too. The preclinical results we published in JCI Insight. So if people are more interested in the preclinical rationale, we're definitely proud of that publication.
I'd just add, too, trial is currently enrolling. We expect data next year.
This is the HELIOS study?
The HELIOS.
Yes.
Correct.
So you mentioned-
Sticking with our Greek theme.
Yep. And you mentioned that you're expecting data next year, so you know, what do you need to see on the C-peptide response?
Yeah, so our primary endpoint's the C-peptide in the HELIOS study. Typically, people with Wolfram syndrome... We use that somewhat as a canary in the coal mine endpoint. You know, Wolfram syndrome is very much a multi-system disease. People go deaf, they go blind, et cetera. But when you look at the natural history that's been done, by far, the most powered outcome is the C-peptide. And so that led it to be, you know, likely the first place you will see efficacy, you know, when you're treating Wolfram syndrome. So C-peptide, classically, when the disease declines, as people progress eventually to effectively zero, suggesting no more insulin production or very, very low insulin production. We've powered the study to hopefully see a slowing compared to what you might expect for this population.
We enrolled people in the inclusion criteria for to have people who had some residual C-peptide as well, so that there is something to preserve. I think in the dream scenario, you'd see an increase. You'd see it go in the other direction. But of course, you know, that's, that's historically challenging in diseases like this.
Great. Maybe, a couple housekeeping questions. Can you just talk about your IP and when do your method of use patents expire?
Yeah, and, and I'd say, composition of matter, too. So, despite that these are existing compounds, we have, composition patents and claims as well. So the, patent family, we filed originally in 2013, so they go out through 2033, although with patent term extension, we expect probably at least 2035. We've continued to file since then, so we have some, patent families that go out into the early 2040s. And I'd say that, it's, it's something that we, certainly get asked about a lot, but I think we have a very strong patent position. And what was, in fact, nice was our, our patents were, formally challenged, in Europe, and, all claims were upheld.
So I think in many ways, the best evidence of how strong a patent is, is, you know, when it gets battle tested. And so not only for the patents to be upheld, but to be upheld on all claims, I think speaks to the strength of our position.
How much cash do you have, and how far does that get you?
So good question. So we have, roughly, $357 million in cash. We have no debt, and we're profitable. So in fact, the, the curve is not going in the direction towards zero, it's going in the, opposite direction. So I'd say we have no immediate... You know, we have no financing needs at this, at this time.
Maybe one last question is, what, if anything, do you think that the Street misunderstands about the Amylyx story?
Well, I think that we're really trying to transform the disease space here, and it's a major disease. If you look at ALS from lifetime risk, what's the chance that someone develops ALS and therefore dies from ALS? It's about one in 350 or so people, which is the same as multiple sclerosis. So ALS, from that perspective, is as big of a disease as if MS were just one large disease. So it's an enormous unmet need. It also just seems to have the same incidence and prevalence globally, so it just scales with the population. So everywhere in the world, ALS is the same. It's a relentlessly progressive fatal disease. So we believe, in many ways, we have the first meaningful treatment for a major unmet medical need.
I think that we are very proud of what we've done so far in our launch. There is so much more to do. When we say we're trying to transform a disease space, it's a big undertaking, but we feel very strongly that we have the treatment to do it. We have the team that is partnering with the community, and we really feel like we're just at the start of the journey.
Great. Looks like we'll leave it there. Thanks so much for your time.
Thank you very much.
Thank you so much.