Amylyx Pharmaceuticals, Inc. (AMLX) Earnings Call Transcript & Summary

Okay. Welcome to the second day of the Bank of America Healthcare Conference. I'm Jeff Meacham. I'm the senior biopharma analyst here. And Charlie Yang from my team is also with me on stage. We're thrilled today to have Amylyx Pharmaceuticals. First time you guys have been here in the conference live. And so we have Josh Cohen, Justin Klee and Camille Bedrosian. So guys, thanks for joining. Thanks so much. Our pleasure. So if you guys want to kick it off with just kind of give us the kind of the high level sort of post- ALS, how investors should think about Amylyx going forward and we get into some of the pipeline as well.

Yes, I'd be very happy to. And great to see you both. Excited to be here as well. So as people know or likely know, we have the PHOENIX result. We moved very quickly to restructure to ensure that we had cash for quite a while. The other thing that is kind of exciting going forward, we had already been developing, I think, a really exciting pipeline. I think most of the focus had been on Amylyx being synonymous with ALS, but I think we had always had these really exciting programs going. For example, our Wolfram program, which started about 7 years ago, Wolfram is a monogenic disease. What's nice about that is know exactly what's causing the disease when you study it preclinically, you're using the exact gene that is the same gene that the people actually have. I think we saw pretty dramatic preclinical data, which then led us into our clinical trial where we just reported some interim data earlier this year. We'll have final results later this year in the fall as well as we're looking to meet with FDA as quickly as we possibly can to discuss what the path forward there is going to be. We also have been studying the drug in PSP. PSP is a tauopathy. And the strongest evidence for that comes from the fact that the genetic association of particular tau mutations with PSP as a p-value less than 10th to the negative 100. So the field is pretty confident that this is a tauopathy. In our Alzheimer study, we saw quite a significant reduction in tau and phospho-tau and the CSF with this drug. So we're excited about that study that should read out mid next year. And then finally, we have an antisense oligonucleotide going into clinic targeting Calpain-2. This is an axonal degeneration target, which of course, is important in ALS and other neurodegenerative diseases. There's been decades of literature supporting this as a target of interest and probably importantly, to Calpain's long been associated with neurofilament biology. We've seen that in our own hands as well when you inhibit Calpain-2, you see a pretty notable drop in neurofilament, which makes for good clinical translation as we move hopefully into clinical trial before the end of the year, kicking off in a multiple ascending dose study in ALS. So it probably went on longer, but the overview of where we stand.

Let's start with the Wolfram syndrome. So maybe give us a bit of the disease ideology, kind of the standard of care today and then maybe when you talk about the clinical studies.

Great. Thank you, Geoff. Yes, we're very excited about our Wolfram program. In particular, given the interim data that we saw where the hypothesis for our Phase II study was slowing down progression or deterioration of the manifestations, and we actually saw improvements in beta cell function and in some -- for some individuals modest improvement in vision. You asked about the disease and how it's treated currently. As Josh mentioned, it's a monogenetic disease, mutations in the WFS1 gene. And it's been known since the 1930s, but there's -- to this day, there's no definitive treatment for it. And it's managed by supportive care for the different manifestations and characteristics of the disease. The insulin requiring diabetes, insulin for vision, not too much there, except corrective lenses until people go blind, hearing, sensory, neural, hearing loss, neurogenic bladder, catheterization. And there are other manifestations, brainstem manifestations in which people forget to breathe, their brainstem doesn't give -- have that autonomic function. And actually, respiratory deterioration and decline is the main cause of death in the early 30s for these individuals.

So similar to ALS on that respect?

Similar to ALS in that respect. Having said that, our studies have -- or study, but the nonclinical study, too, recapitulating with our Phase II has -- we do have biomarkers and pharmacodynamics to be able to tell us whether we're having an impact relatively soon, 12-week and 24-week improvements in C-peptide with a mixed meal challenge has been very helpful in guiding us to realize we're improving beta cell function, not just on the deterioration.

Maybe just to follow up on that. Just given GLP-1, I guess, are kind of used in this population. Just talk about -- I think those are some of the things you mentioned in terms of the rate of called background therapy with GLP-1 and how you think how the additive benefit with the AMX0035.

Well, maybe I'd first start with Camille's point, which is that there's nothing approved for Wolfram syndrome. And GLP-1, I think people are hopeful that it may help with some of the diabetic complications. But Wolfram syndrome is not diabetes, Wolfram syndrome is a disease that WFS1 mutations cause ER stress, which causes mitochondrial dysfunction and then cell dysfunction and death. And I think what's nice from a translation perspective is you can see that in basically any cell type you study preclinically. So we studied beta cells, we study different neuron populations. And no matter how you look, it's the same thing, WFS1 mutations cause ER stress, mitochondrial dysfunction, cell dysfunction and death. So then the question is, well, how do you target a disease like that? Well, we have a treatment that targets ER stress in mitochondrial dysfunction. So what you see in the disease etiology is the dysfunction in beta cells because I think they're probably a little less resistant to that pathophysiology and then different neuron populations, and that's basically why you see the disease manifests as it does, starting with what looks like type 1 diabetes at age 6, 7, 8, 9, then progressive vision loss, progressive hearing loss, ataxia, et cetera. So going back to your question, I think the real question is, can you target the root pathophysiology of the disease, I think based on our preclinical studies, we were hopeful that we could because it's a great match of the mechanism of the drug to the mechanism of disease. And now what we're seeing clinically is as Camille was saying not even just slowing progression, but stabilization or even improvement over a relatively short period of time. So I think what we're hopeful is that we're indeed getting at the root cause of disease and that's why we're seeing efficacy across different organ systems rather than even just the diabetic complications, which are critical, but not the whole disease.

And one other thing just to add that I think is important -- in this study, we allowed diabetic medications people are on insulin, people are on metformin, people are on all sorts of diabetic medications. GLPs have also been around for diabetes for a long time. They've been used in Wolfram for a long time, and Wolfram is still Wolfram, so it's not that -- I don't think we should expect that GLPs are going to dramatically change. I think they'll help in the management of diabetes as they have elsewhere. In our particular trial, we did exclude the GLP-1s. The reason we did that was looking at the population, there was a mix of people who are on them or not on them if we had just enrolled. And we didn't really want people to start the mid-study from a kind of statistics and otherwise perspective. But we don't think that, that presents any particular challenge, some of these people have been on GLPs before, their diabetes was being managed as best as it possibly could by their endocrinologist. And I feel pretty strongly that the clinician would not have taken them off therapies that they thought were working.

Got it. So let me just to -- so these patients -- the patients are not on GLP-1 as part of the treatment with ...

Correct.

Got it. Okay. And then -- so then maybe just to think about kind of the upcoming data in the fall with 12 patients, 24 weeks? Like kind of what's your expectation there and maybe even a step further Phase III design, right, are you planning to include people with GLP-1 or are the GLP-1s on background therapy or not?

Well, maybe I'll start with right now and then pass it to Camille on some of the development plan. So I think the first thing is for us to meet with FDA, I think, as Camille was saying, our original hypothesis going into the study is a progressive disease, can we slow progression. We're seeing stabilization or even improvement. So that's exciting but very different than what we went into the study thinking. So I think that's why with our current data, we're going to meet with the FDA to talk about the development plan and I think what's nice too, is that while Wolfram syndrome, there's nothing approved for Wolfram syndrome, everything we're measuring are very, very well-known outcomes. So I think in rare disease, you often get into this challenge of, well, how do you measure it? And if you measure this biomarker, does it matter? In this case, we're measuring C-peptide, we're measuring hemoglobin A1c, we're measuring visual acuity, CGIC and PGIC, these are all very, very well-known and things that FDA is very familiar with too. Then maybe on the development plan, I'll pass it to Camille a little bit.

Sure. Thank you very much. Yes. We're very excited to meet with the agency to move the program forward. Before I do that, I do want to respond to your question about what do we expect in the fall. So as you said, all 12 individuals in the study, 24 weeks, we'll look at C-peptide and the other measures of glycemic control as well as visual acuity. And some of the individuals, as you can imagine, some of those 8 individuals have now gone beyond 24 weeks, and we'll look at the totality of the data and also share what we know about those as well. And what we intend to do in meeting with the FDA is share the interim data that we have now. We're not -- we don't want to wait to meet with them because this is a disease that leads to premature mortality, has tremendous unmet need, and we do believe that AMX0035 has a great role. Now as Justin was saying, we're seeing tremendous responses with C-peptide and that is a well-established objective measure. So that's something that we certainly will be discussing with the agency in terms of how we can proceed in that regard. In addition to the visual acuity and the global impression of change, which get to the clinical benefit and measures of clinical benefit.

And maybe not to belabor this question, but the one other aspect I'd add to is one of the things that gives us particular confidence as we're moving forward in Wolfram is the translation story here. It's a monogenetic disease. And so the advantage is the preclinical models were WFS1 mutations in cells and then a double knockout WFS1 mutation in mice where the groups were completely separated. Our p-value in the mice was less than 001, it was pretty unquestionable, which mice were on drug and which mice were on placebo. And what's nice in a disease like Wolfram, for example, as compared to a disease like ALS, is you know that this gene is what's causing it. And so when you're studying that preclinically, you're studying the same gene, then you're studying the same gene in humans. So it's a nice trend -- of course, there's no guarantee, but it's a nice translation story to be following that same gene throughout.

Got it. And just given that, is there a way -- is there a way to build in some novelty to the Phase III design, looking at biomarkers and predictive of efficacy that way, obviously, even in the real world commercially, it could be able to maybe easily more easily identified patients and how the drug is working.

Yes, absolutely. I think that's exactly why we want to meet with FDA and talk about things. I mean, for example, in our current study, where we enrolled people 17 years of age and up in any disease like this, the earlier you treat, the better. So I think one of the things we're most excited about is we're seeing stabilization or improvement in adults. I mean you treat earlier, we can -- we hope really fundamentally change the trajectory of the disease. Then in terms of biomarkers and then longer-term clinical outcomes, that's why I think it's so nice using well-known, well-validated outcomes because I think there's potential for accelerated approval following up with long-term well-known clinical outcomes. And then in terms of identifying patients commercially, so we think that there haven't been great estimates of population size in Wolfram syndrome. I think our best estimate is there's roughly 3,000 people with Wolfram in the U.S. But I think what's -- we definitely think it's under-diagnosed which I think tends to happen when you have a rare disease with limited or no treatment available. But I think what's nice is often in rare diseases, especially sometimes things called syndromes, you're saying, well, how do we actually find these people? How do we actually identify them? In this case, well, they present with what looks like type 1 diabetes, so that's already a population to look in, and it's caused by a single gene. And so there's already an ICD-10 code for Wolfram syndrome. There's already genetic tests available. So it's really about, okay, look in this population, test for WFS1 mutations and we think it should be relatively straightforward to identify people with Wolfram. And the last thing I'd say is probably unsurprisingly, there are people with Wolfram globally. And you tend to find different sort of founder effects in different places. But everywhere you look, whether it's Japan or Sicily or Brazil, the U.S. or U.K. there are indeed people with Wolfram syndrome. So I think our hunch is that it's quite significantly under-diagnosed, but I think it's pretty easy, we hope, I'm pretty straightforward to get good estimates to the population.

And post type one diabetes, post that diagnosis, vision is the next thing to kind of breakdown, is that -- obviously, you guys could incorporate that in the Phase III design as well.

Yes, absolutely. And I'd say it was a surprise, but a nice surprise that in just 6 months treatment, we're seeing stabilization or even improvement in visual acuity, including -- I don't think we want to set this expectation, but one participant went from legally blind to not, which is really exciting, so I think there's many different outcomes we think we can look at in the Phase III that we think will be really meaningful.

Yes. Okay. Can we move to PSP trial?

Yes.

Okay. Yes. So talk a little bit about PSP with 035 and just give us maybe some context for your development plans.