Good morning and welcome to day two of the Goldman Sachs Global Healthcare Conference. Since this is the first session, before we get started, I'm required to read certain disclosures. We are required to read certain disclosures and public appearances about Goldman Sachs' relationships with companies that we discuss. The disclosures relate to investment banking relationships, compensation received, or 1% or more ownership. We are prepared to read aloud disclosures for any issue or upon request. However, these disclosures are available to you in our most recent reports available to you as clients on our firm portal. All right, with that done, thanks so much to the team from Amylyx Pharmaceuticals that are here joining us this morning. Maybe we'll just kick off. A few months ago, the complexion of the company kind of changed.
Maybe let's characterize where Amylyx is today, both with respect to pipeline and with respect to the focus you see for the company on the forward.
Certainly, thank you. Thanks so much for having us. So the company has always been focused on cell death and degeneration, which we believe is critically important across many diseases, probably particularly neurodegenerative diseases. And that's still our focus today. So we have two programs in the clinic, one in Wolfram syndrome, which is a rare neuroendocrine disease. It starts off looking like diabetes, then turns into a neurodegenerative disease. PSP, which is a really devastating, fairly well-known neurodegenerative disease. And then we have a new drug candidate going into clinic for ALS later this year. So we think cell death and degeneration is critically important. I think the critically important thing is also matching the mechanism of drug to the mechanism of disease and having good biomarkers and clinical outcomes we can measure in those diseases too. So that's where we're focused today.
We had the PHOENIX trial results earlier this year for ALS that obviously led to some reprioritization of the company. So we made some swift changes to refocus our efforts, refocus the organization, and focus on our pipeline.
Perfect. Maybe we'll go in order then. We'll start with Wolfram syndrome. Maybe you kind of touched high level about what it is, but let's dig a little deeper. What exactly is Wolfram syndrome and how does it manifest?
Yeah, thank you, Corinne. Yes, Wolfram syndrome is a rare monogenic disease. The main gene that is impacted is WFS1, which regulates endoplasmic reticulum stress, and mitochondrial dysfunction. It manifests at first in the pediatric setting, age 6-9. Individuals present with type 1 diabetes that progresses, and then other manifestations of neurodegeneration present, such as diabetes insipidus, optic nerve atrophy, which is a very prominent feature of Wolfram syndrome and ultimately leads to blindness because of the progressive nature of the disease. And individuals then have other manifestations, brainstem dysfunction, which includes ataxia, respiratory challenges, bulbar swallowing challenges. And actually, it's those latter two that ultimately lead to premature death, median age around 30, anywhere from 29-40 years of age. So it's a devastating disease and irrevocably progressive.
I might just add to one thing nice about going after a disease like Wolfram is that it is monogenic. So preclinically, clinically, you know the cause, you can diagnose it genetically, et cetera. And I think the other thing that we've shared is that having that genetic test, hopefully in the future, will allow us to continue to find patients as well. We estimate that there's about 3,000 patients. But as Camille has experienced in other rare diseases, as awareness grows, as drugs move along, oftentimes you find additional patients as you're searching in a disease.
Okay. So maybe you could talk about, I mean, I know there's not really anything, but how patients are currently managed when they are diagnosed with Wolfram syndrome and what the aim then is in terms of unmet need to address.
Yeah, there is a profound unmet need. Certainly for the diabetes, there are insulin and other glucose managing drugs. But otherwise, there really isn't anything for the optic atrophy. There can be water balance, diazoxide, et cetera, for the diabetes insipidus. But there really is nothing. And to this date, there haven't been any industry-related drug development programs for Wolfram. So we're very privileged to be able to be seeking a definitive treatment for this disease.
To underscore a bit of what Camille was saying too on the progression of the disease, so it presents as early-onset diabetes. So people immediately get on diabetic interventions. What characterizes Wolfram syndrome is that the disease continues to progress. And it's because it's caused by this genetic mutation that causes loss of beta-cells in the pancreas. And then that same pathophysiology is what causes the optic nerve atrophy, hearing loss, ataxia, et cetera. So despite all of the interventions that we have in medicine today for diabetes or for these other complications, the disease continues to progress because nothing's actually getting at the root cause.
Yeah. That's a great segue to my next question, which is, could you just dig a little deeper on the mechanistic rationale for RELYVRIO in this patient population?
Yeah, we'd be very happy to. So this is a program we've been working on for seven years. And what got us into the space was our lead candidate, AMX0035, targets endoplasmic reticulum stress and mitochondrial dysfunction, which we believe are critical cell pathways in cell degeneration and death. Well, as Camille was explaining, Wolfram syndrome is caused by mutations in WFS1. Those loss of function mutations cause stress, mitochondrial dysfunction, and then cell dysfunction and death. And basically what we see is that from cell type to cell type, the same thing happens. So we studied it first preclinically. We looked in beta-cells. We looked in a variety of neuron types. And we saw the same thing: stress, mitochondrial dysfunction, dysfunction, death. And then when we treated with AMX0035, we saw a recovery across all of the different cell types.
We then went to a mouse model of the disease, saw the same thing. Now we're seeing early encouraging results from our first clinical study. Again, we think it's because we're targeting the root pathophysiology of the disease. While we're not correcting the gene per se, we're just one step down in correcting the root pathophysiology that's actually causing this progressive disease.
I'd say too, one other thing nice in Wolfram is that it's a nice translation story. Because it's a monogenic disease, all of our preclinical models are monogenically based. The cell lines that we used are patient-derived and have actual patient mutations in the Wolfram protein. The mouse model we did was a double knockout. So they basically have no functional Wolframin protein. Across those preclinical experiments, we saw pretty striking results. So I think that really, along with the kind of mechanistic rationale, led us to believe that there's a very high chance of success or that there was good rationale going into clinic.
Perfect. So you alluded to the data that you've recently reported in patients. Maybe you can outline what that study was designed to show and what's considered clinically meaningful on those endpoints?
Sure. Yes. And actually, the study was designed to show whether AMX0035 could slow progression of the disease. As you've been hearing from all of us, the disease is relentlessly progressive. So that was the premise. And we started by looking at a measure of beta-cell degeneration and death, namely the release of insulin from the beta-cell. And that's measured by C-peptide, which one-to-one correspondence. So we are studying adults first in this disease. And it's a 12-patient single-arm study, single-center of individuals with relatively advanced Wolfram insulin-dependent diabetes. Yes, a little bit of residual insulin by measuring the C-peptide. But otherwise, two of the individuals are blind, legally blind, and severe optic atrophy and vision loss. So that was the premise for going into it.
What I would say is that the data from the clinic is recapitulating the results that we saw from the preclinical work and much more dramatically than we had anticipated. Again, we were hoping to slow the progression. So when one measures C-peptide response to a mixed meal, it's a mixed meal tolerance test, we expected, well, maybe over time the C-peptide levels would be less, but not as low and not decreasing as much as we would have thought. And what we saw in these individuals, we presented on the first 8 of the 12 patients at 24 weeks, we saw an improvement in the C-peptide response, which is quite dramatic and tells us that this drug is really acting as it seemed to do in the preclinical work as well.
You mentioned obviously the C-peptide result. I know that was the primary, but in terms of other secondary endpoints that you reported on.
Yeah. We also measured other parameters of glycemic control, which were consistent in the same direction as the C-peptide. Another key parameter we measured is visual acuity using the LogMAR Snellen test, the eye chart that one goes to the ophthalmologist to experience. We saw that 5 of the 8 individuals had improvement in their visual acuity, which we were not expecting. Although we cannot anticipate that every individual is going to respond in this way, one of the individuals who is legally blind recovered vision in one of the eyes. That, again, where we were hoping that maybe visual acuity would decrease less than the natural history, we actually saw improvement.
Right. With kind of that data now available for a couple of months now, I guess, could you share any of the feedback you've gotten from the Wolfram syndrome community around it?
Yes, yes. They're very excited, very hopeful about the possibilities of AMX0035 for individuals with Wolfram. And they are eager to do whatever they can and sharing their stories and sharing their experience, which is very helpful for us to understand what is most important for these individuals, how can AMX0035 help them the most?
And I'd add too, as you might expect for some of, particularly, the mothers who are, as you may not be surprised, amazing advocates, some of their kids are in the study. And so for them, this is very personal. And I think anytime in a progressive disease, you're seeing stabilization or even improvement, I think it's just really meaningful. And for them, I think it's, again, for them like us, I think it's probably much more encouraging than I think we would have hoped for from the first study.
Sure. So in terms of next steps, particularly for the ongoing study, and then we'll talk about a registrational path, but for this ongoing trial, what should we anticipate in terms of next data?
Yeah, absolutely. So we do plan to present the full 12-patient experience through 24 weeks in the fall. And we very much look forward to sharing those data. And the individuals are continuing in this study for another year, 48 weeks, and then 96 weeks. So we will continue to share data as they become available over time because that also will be very meaningful to see slowing progression or even improvement and sustained improvement. So that's the first step. The other key aspect for the program now is meeting promptly with the FDA. Given these data, we have to move with all good speed to see next steps so that individuals can ultimately, if possible, have access to AMX0035.
I definitely want to talk about the regulatory side. As you think about the 24-week update in the back half of the year, what would you like to see from that study or from those results to confirm the clinical activity you've seen thus far?
Sure. So all 12 patients at 24 weeks, we hope to see that the additional four individuals have the same directional response as the first eight. And those eight individuals will now be well beyond 24 weeks. And we'll share those data as well. And we hope to see that the results are sustained or maybe further improved.
Okay. Okay. So let's talk on the regulatory side. You plan to meet with the FDA. I guess, how quickly can you get in to see them and talk to us about your wish list or kind of your goals as you think about what a trial could look like?
Uh-oh. It's like Christmas, right? Yeah. So yeah, we are working with the FDA to schedule a meeting with them so that we can discuss. We will present to them the original 8-patient data. We didn't want to wait for the 12 patients at 24 weeks because of the urgency that these patients have. And given that C-peptide is a well-established marker of beta-cell function or dysfunction, as the case may be, and it's very objective, we do plan to present that as a key endpoint and likely the primary endpoint. And beyond that, whether that serves sufficiently as an accelerated approval, we don't know. But we'll have discussions with them about that aspect as well as what a follow-on study would be.
Okay.
And I think, yeah, sorry. Yeah, just to maybe underscore, I mean, so Wolfram syndrome from a sort of industry-sponsored interventional study is new. But the outcomes we're looking at are not. They're very well validated, as Camille was saying. So C-peptide, Hemoglobin A1c, time in target glucose range, visual acuity, et cetera. So I think our hope is that we can, in our development program, make a clear case that what we're seeing in a very short time period on something like C-peptide is predicting long-term outcomes. So I think that would be a nice way to set up for a surrogate outcome for sort of accelerated approval path.
Remind me, C-peptide in the past has been used as a surrogate or as a confirmed endpoint for full approval? It's been used in other places.
Primarily, it's been in cases where there's also probably the most notable is the Provention case where their primary was actually preventing kind of the onset of diabetes. But it was the kind of key additional data. And in the New England Journal of Medicine, when they published teplizumab, the primary endpoint was the C-peptide response. So I think the field, you look at most of the type 1 diabetes studies and otherwise, the field has been moving quite strongly towards C-peptide as either the primary or key secondary outcome.
I would.
No. I'm sorry. I just wanted to add that Hemoglobin A1c is a well-established endpoint for full or regular approval in the diabetes world. That measures the last two or three months of experience that an individual has where C-peptide is immediate and it measures the beta-cell function in that moment, which, dare I say, probably is as meaningful, if not more so. But if the two tracking together is helpful.
The last thing I'd say too is I think our plan, again, going into the trial was, can we slow progression? We're seeing an increase. And the reason that's so important, not just for patients, but if you come from a regulatory perspective, if you're saying, "I'm slowing progression versus a natural history," well, you can understand how, well, how certain are you that the natural history would have gone that way instead of a different way. When you're seeing an improvement, it changes the discussion.
Okay. In terms of number of patients that you think would be reasonable for this kind of trial?
Yeah. In the rare disease world, 30, 50 patients is a large study, is considered a large study. In some studies, 12 patients, 17 patients. So that would be a very robust study. More to come.
Okay. We'll be anxiously waiting for that. And then in the market opportunity, you alluded to something like 3,000 patients or so. But maybe talk to us a little bit more about how you think through the kind of commercial opportunity for this product.
Sure. Yeah. So I'd say, first of all, it's a genetic disease, which is nice insofar as there is a genetic test. There are commercially available monogenic diabetes panels. Wolfram is not the only genetic diabetes. There are other genetic diabetes. But the utilization of those is not incredibly high, which makes sense given that there's not treatments or actions that you can necessarily take upon these diagnoses. So we believe that there's roughly 3,000 people living with Wolfram in the United States. When we think about where those people may be, one is in the pool of type 1 diabetics. In theory, any type 1 diabetic may have some chance of having Wolfram. And if you think of the clinical course, first they present as type 1 diabetes. It takes several years for them to start presenting the optic atrophy.
You can imagine when they first start going from 20/20 to 20/40, people get glasses. It's not until it's severe that people say, "Okay, this is not just some normal vision loss. This is something different." But if you could up that index of suspicion, that would presumably change quite significantly in terms of how quickly people found patients and ultimately how quickly, if there's an approved therapy, how quickly they're able to get on it.
I think to Josh's point too, one of the challenges often in a rare disease is trying to find the needle in the haystack. In this case, I hate to say it this way, but we know where to look, right? People have early-onset diabetes, and then you do a genetic test, and the test is already on the diabetes genetic panels. I think it's a nice opportunity to build awareness, build the case for diagnosis, and then the reason for diagnosis is because you have a treatment.
I know the study thus far has been in adults, but obviously this is a disease that onsets in childhood. So how are you thinking about expanding towards the pediatric population?
That very much is our plan as well. We'll discuss that also with the agency and come back with our plans.
Yeah. And I think, as Camille can attest to, I think if we're seeing, we feel like if we're seeing these sorts of results in adults who've had the disease for many years, we think, and I think all experience would say that the earlier you go, the more profound impact you can have on the disease. So I think we're really excited to continue in adults or even more excited to go earlier.
Yeah, of course. The trajectory of the disease will certainly change as we treat the younger individuals.
Of course. Maybe we'll switch gears to PSP. So maybe start with the same question. What is PSP? How and when does the disease manifest?
So progressive supranuclear palsy, PSP, is a neurodegenerative disease that is considered a tauopathy because one sees tau bundles in various neural structures in the brain. It presents in adults. I don't know if I dare say older adults, but in the 40s, 50s, and above. Sadly, it's a very rapidly progressive deterioration. Within 6-8 years, these individuals succumb to the disease. It's quite debilitating as well. During that time, individuals, their eye movement is disrupted, upward gaze, et cetera. So they can't even use machines to help them to communicate or to type or do anything because their eyes, they cannot control their eyes. There are other movement issues. They suffer from falls quite frequently, which can be quite serious in terms of the injuries. There is nothing for this disease either. It's really quite devastating.
Yeah. And I'd add just pathophysiologically too, PSP is characterized. One of the reasons we were so interested in it is it's characterized as kind of the prototypical tauopathy. And some of the evidence that comes behind that is in kind of genetic GWAS-type studies, the association between certain variants in tau and the disease as a p-value less than 10 to the negative 100. So it's very clear that tau is linked to this disease. And as Camille said, when you look at autopsies and otherwise of people who live with the disease or at that point are no longer living with the disease, you find kind of flagrant tau pathology. In fact, people have even found in PSP, the tau pathology is so spread, you see it in peripheral nerves, you see it in skin samples. It's a pretty dramatic tauopathy.
That actually contrasts to some other neurodegenerative diseases.
Yeah. And I'll just add one more point, which is that from a prevalence perspective, I'd say right now there's at least 20,000 people in the U.S. alone with PSP. And the reason I say at least is PSP is so underdiagnosed. I mean, if you look at autopsies of people who presumably had variants of Parkinson's disease, a huge number, in fact, had PSP. When you talk to movement disorder specialists, they'll say often, "Oh yeah, I have many, many PSP patients." But as Camille was saying, sadly, there's very little for PSP. And so it's a really, really tough unmet need. And I think the CurePSP Foundation is doing some great work at building further awareness of PSP. But it's really tough, and it's a lot more prevalent than the numbers would suggest.
Okay. You began enrolling in a phase 3 study in the indication last year. I guess, talk to us about the decision to move straight into phase 3 in this setting.
Yeah. Go ahead.
I'm happy to pass over to you as well. So I think we had run a small randomized placebo-controlled study in Alzheimer's disease. That was very biomarker-focused, really looking at CSF biomarkers. In that study, the most significantly changed biomarker was tau and phosphotau, showing a highly statistically significant reduction as compared to placebo. We also did some proteomics, and we found that of 288 proteins we measured, tau was the most changed in that Alzheimer's study. And that led us to the question of, do we want to go further in Alzheimer's? Do we want to follow this biological insight? And so we started looking for what is the disease most associated with tau that might be of particular interest. And I'll also add that one thing that's nice with AMX0035 is, unlike an antibody or otherwise, it gets intracellular.
So we don't think we're clearing some tau that happens to be excreted or somehow out of the cell, but actually targeting it where it's made and where the pathology is starting. So I think PSP is not unique in this. I think in many neurodegenerative diseases, if you're going to go for the functional outcome and you want to hit it with high significance, you need fairly large studies. We had always planned for an interim analysis though in the study as well to ensure that we didn't get all the way down the road and have a surprise or otherwise. And yeah, maybe I'll pass to Camille to comment further on it.
Sure. Thank you. Thanks. Yes. So if you think about the value of a phase 2 study, confirming dose, confirming measures of outcomes, we already know that there are several PSP studies that use the PSP-RS or PSP rating scale. And we know how reproducible that rating scale is across a number of different studies. So with all due speed, given that there's nothing for this disease, we elected to move directly into a phase 3 study. Now, as Josh said also, we are going to take the opportunity to evaluate the outcomes in an interim basis. And we anticipate those data mid-2025. And we will do sort of a seamless study where we have the first tranche of patients. We'll look at those data, and we'll do it so in an unblinded fashion. So we'll be able to share the data.
And then we'll continue in part two, if you will, depending on the results.
Great. Maybe briefly on AMX0114, which is your next generation candidate for the treatment of ALS. I guess, talk to us about that technology, the mechanistic rationale, and where you got that asset.
So yeah, so that was developed entirely in-house. So as I said at the start, we have been interested in cell death and degeneration pathways because they underlie so many diseases, especially so many neurodegenerative diseases. So there are, I'd say, a series of very well-researched targets in cell death and degeneration that we think haven't been therapeutically targeted the right way. One of those is calpain-2. So calpain-2 has been studied for decades. It is a key effector of axonal degeneration as well as neurodegeneration generally. The challenge, I think, has always been, first, there are many different calpains. So mutations in calpain-1 can cause certain forms of spastic paraplegia. Mutations in calpain-3 can cause a form of limb girdle. And there's 4, 5, 6. There's many different calpains. So I think you want to very specifically target calpain-2.
And of course, as with CNS diseases, you want to make sure that you're getting adequate exposure in the brain. So that's where we thought an intrathecally delivered ASO, antisense oligonucleotide, would be a great way to selectively target calpain-2 and to make sure that we're getting adequate exposure. So calpain-2 is a protease. So it cleaves a number of things. One of the well-known things it cleaves is neurofilament. So as we look in ALS and other neurodegenerative diseases, the neurofilament that we're seeing is actually, we believe, is calpain-2-cleaved neurofilament fragments, as well as it cleaves a number of other things, which makes it nice from a measuring pharmacodynamic effect as well. So it's a very potent antisense. It uses sort of the well-known 5-10-5 GAPMER structure. So we have a pretty good sense of dose toxicity, et cetera.
And then we're excited to have it in clinic later this year.
Yeah. I was going to say, so when could the drug enter the clinic? And how should we think about the development path there?
Yeah. So as Justin just mentioned, later this year, we expect to be in the clinic. Our plan is to do a multiple ascending dose study in individuals with ALS so that we can understand, learn about the dosing, learn about the safety, of course, as well as understand the biomarker profile.
I'd add we expect as cohort by cohort, we'll kind of go through. Texture as well.
Okay. One of the other questions I'm sure you guys get frequently is like, how do you have cash? How are you thinking about where you spend it? Business development, is that on the table? And what would you be focused on?
Yeah. So first, I think we're happy to be in a strong cash position. We reported at the end of last quarter, roughly USD 373 million in cash. We also moved very swiftly after the Phoenix result to restructure and to bring the down. So we expect with the cash we have on hand to get well into 2026. So that takes us through all of the milestones I think we've discussed today. So I'm sorry, I'm spacing out.
Yeah. Business development.
Business development. So yeah, I mean, I think our main focus is on the programs we have right now. I mean, I think we have a lot of excitement with what we're seeing in Wolfram. I think we're the first really kind of intracellular tau approach that's going forward in PSP and to hopefully have data mid-next year. And we're super excited about the antisense. But really for at this point, at least a few years, we've been evaluating opportunities. And if there's something that's nice to bring in and that adds value, we'll certainly do that. But the main focus is on the programs we have right now.
Go ahead.
Go ahead.
I was going to say, on that point, what are the criteria you'd use to evaluate things that are of interest?
I think for us, it's the same as what I'd say our existing programs, mechanistic rationale, diseases where we have clear outcomes and hopefully clear biomarkers as well, and I think high unmet medical need. So those are probably the key ones for us. And just the other thing I was going to underscore to Josh's point, sort of cash runway and milestones. So this year, we'll have feedback from FDA and Wolfram syndrome. We'll have the full data in the fall from the full first study in Wolfram syndrome. We'll have interim results from the PSP study mid-next year. And then with the first cohort dosing in the AMX0114 ALS study, we'll have data from those first cohorts later next year. So we should have many different milestones through the cash runway we have.
Great. Maybe another miscellaneous question. I know you guys so in particular, as you think about a pediatric study in Wolfram syndrome, where are you on the formulation side?
Yeah. So certainly something we're still working on. I think we've shared before. We've been working on a microencapsulated formulation where you basically don't allow the drug to release until it hits the stomach to prevent it from hitting the taste buds and causing the bitter taste that the drug has. So far in Wolfram, as we reported in the interim data, any dropout. So we're certainly evaluating how that's going to be in this space. But it's definitely a program that's still ongoing and that we're certainly thinking about as we consider the pediatric population, especially.
Okay. I think those are all of my questions. I really appreciate the time, guys. Lovely to see you. Thanks to the team from Amylyx. Thanks for all of you who joined us here and on the webcast.
Excellent. Thank you.
Thank you so much.
Thank you so much.
Thank you all.
I guess.