Amylyx Pharmaceuticals, Inc. ($AMLX)

Great. Good morning, everyone. Thanks for joining us here at the Goldman Sachs Global Healthcare Conference. Thrilled to be on stage today with Justin Klee, Co-Chief Executive Officer of Amylyx.

And maybe before we get started, it would be great if you could just provide some introduction to the company. And I've been asking a lot of people this week, what do you think of as the core competencies of the Amylyx business?

Sure. Yes. Well, first, thanks so much for having us. We're thrilled to be here. So Justin, Co-CEO, Co-Founder at Amylyx. We have a number of exciting programs under development. Lead program is, I think, where our focus, a lot of investor focus and attention is right now. The asset is called Avexitide. It's a first-in-class GLP-1 receptor antagonist, and that's for the potential treatment of PBH, post-bariatric hypoglycemia. PBH affects about 160,000 people in the U.S. today. We expect that population only to continue to grow over time. It's a very severe condition. People present with persistent symptomatic severe hypoglycemia, meaning neuroglycopenia, meaning their brain doesn't get enough blood glucose. And so people have all manner of complications ranging from severe confusion to loss of consciousness, even seizures. So it's a very severe condition and people are having these events on a very frequent basis. There are no treatments for PBH today, but we have a pretty good [Audio Gap] biology of PBH. These [Audio Gap] low blood sugar are really driven by the body upregulating the GLP-1 response. The body will produce 10x, 15x, sometimes even 20x normal levels of GLP-1. And so that causes insulin to spike, which then causes a severe hypoglycemia. So Avexitide is a GLP-1 receptor antagonist. So it blocks that GLP-1 effect, which then blocks the downstream hypoglycemia. So 5 prior trials of Avexitide in PBH, very substantial reductions in hypoglycemia, which supported FDA breakthrough therapy designation. So we are in a Phase III pivotal study now, top line results expected in Q3 next quarter. So we're really looking forward to that, preparing for the NDA and commercialization alongside it.

Okay. Great. Maybe you can give us some background on kind of how you guys arrived at Avexitide and developing a drug for the PBH market. Like what did you find sort of appealing or attractive about pursuing drug development here, as you mentioned, there's no other approved therapeutic options.

Yes, absolutely. And I think it speaks to your first question on core competencies as well. So I think at Amylyx, we've built a really great expertise in rare disease drug development, particularly on the clinical manufacturing and then on the commercial side. So the first treatment that we worked in for ALS, we did, I think, quite efficient clinical development, ended up commercializing that ourselves and quite successfully. So we were looking for other opportunities where there was a high unmet need, probably a particular focus in either rare neurodegenerative or rare endocrine diseases given that that's where we've done our work historically. And where we thought we could make a really big impact on people's lives. So I think what, really, we found compelling about Avexitide in PBH, I think, first, is the unmet need. It's PBH, as you talk to adult endocrinologists, they very frequently say, this is one of the most severe conditions that I have to manage. And there are many people. I mean 160,000 is still an orphan disease, but it's a large orphan disease. So I think it's quite impactful. And then connected with that is the pharmacology. The primary driver of this hypoglycemia is GLP-1. So if you block that effect, then you have a substantial impact on the hypoglycemia. So that was shown trial to trial to trial. The manufacturing was done well. The toxicology was done well. So we felt like this is an area where, again, the science really makes sense, and we think we can have a really big impact on people's lives.

Okay. You've talked about Phase III data that's coming in the third quarter, and you have disclosed that you completed enrollment back in March. Any clarity you could provide on the specific timing within the quarter?

Well, so we're saying Q3, but to your point, to say what we've said. So we enrolled the last participant in the study at the end of March. So it's a 16-week double-blind placebo-controlled trial. So -- and then a little time for cleaning database lock and analysis. So that puts us nicely in Q3, and we're working hard leading up to those, that exciting milestone.

Great. Maybe we can spend some time on the study parameters. And first, I'd love to talk about dose. You selected the higher 90 mg dose. What were the advantages and any potential trade-offs that you have to consider as you move to the 90 mg versus 60 mg that had been studied previously?

Yes, I really appreciate that because it's a really important point. So the first Phase II trial, as you noted, used the 60-milligram dose, and that was very effective. But I think that the investigators noted that in probably the late hours of night, maybe early hours of morning, there might have been some breakthrough events in hypoglycemia. And so they thought -- they went back and looked at the PK and it suggested that maybe they weren't getting quite the coverage that they wanted. And so they increased the dose by 50%. And by doing that, they did get the coverage for sort of the full day night cycle. And sure enough, that's what they saw in the Phase IIb trial as well. So they saw even greater reductions in hypoglycemic events. And as measured by CGM, they saw reductions in both day and night hypoglycemia. So that's why -- and of course, importantly, with a good safety profile. So that's why we took forward the 90-milligram dose.

Okay. How did you go about setting parameters for the treatment and control arm expectations into the Phase III? And just remind us what that study is powered to show with respect to changes in L2 and L3 events?

Sure. So I think a nice part about having 5 prior trials is that we can first learn from those and given the strength of those results, particularly in the Phase IIs, change as little as possible going into the Phase III trial. So I think the first really important thing in the Phase II trials is they required at least an event per week had a run-in period looking for 2 events in 2 weeks. In the Phase III, we had 3 events in 3 weeks. We gave an extra week just to help with training and that sort of thing, but still same event frequency. And that gives you a very robust study design. It also gives you very robust powering. So if you think about the overall study design, assuming no treatment effect, we have an event rate of 1 event or more per week times 16 weeks, times 78 people, you get to over 1,200 events. So you just get to a very robustly powered study. So we did many thousands of simulations as we did our powering analysis. We tried to be as conservative in our assumptions as possible. The kind of headline would be that we're 90% powered to see a 35% relative difference. In the Phase IIb, we saw a 64% treatment effect. So we're 90% powered to see roughly half of the effect that we saw in Phase IIb, and that's even under very conservative assumptions.

Great. I think partly because of the robustness of the Phase II data, clinical trial conduct has been a big topic of conversation and concern for investors, I think for you guys as well. Maybe let's just review some of the areas that we field questions on. One, could you talk about how the events are, like, specifically measured in the course of the clinical trial? And what is required of the patient to appropriately capture those events?

Yes. So again, and I'll probably keep repeating that first is to be consistent with the Phase IIs. So we're measuring the events the same way. We're looking at the same overall outcomes. So first, the primary outcome is a composite of Level 2 and Level 3 hypoglycemic events. That is in FDA guidance as an acceptable outcome. FDA has also reviewed the protocol ahead of time, and we have breakthrough status. So we feel quite confident in that. But the Level 2 is measured by a fingerstick, self-monitored blood glucose. That's still the gold standard for measuring hypoglycemic events. If the blood value is less than 54 milligrams per deciliter of blood glucose, then that counts as a Level 2 event. The Level 3 event means that you need independent rescue. So participants are instructed to fill out a brief drop-down menu diary. That is then sent along with all the other information to an adjudication committee for a group of expert endocrinologists. They also have a charter they follow that was reviewed by FDA that says this was a Level 3 event or not. Level -- these things are very well defined by the American Diabetes Association and other groups. So again, it was nice that we could use the Phase II's guidance as well as just general practice in endocrinology. I think clinical quality is obviously very important and something we pride ourselves in. I think probably the most important thing is, first, selecting good sites, which we have, and then making sure that we have the right participants in the study, which we believe we have. So in that run-in period I mentioned before, we were looking for not just people who meet the strict criteria of the study, but also people we thought were good trial participants. Are they being consistent in their data capture. And so we looked very carefully at that. And so we think we have done that. Of course, at every site visit, we still train and retrain and remind on all these various outcomes. But I think [Audio Gap] start the study right [Audio Gap]

A little bit more about that last point, which was like how do you monitor and manage patient behavior throughout the course of the study?

Yes. Well, I would say that, again, the most important thing is first try to enroll the right people in the study and have good site investigators that you're partnering with. But then it's about not only training but monitoring. What's nice in this study is that our team has access to the data in virtually real time because people are checking their fingerstick blood glucose, they're filling out their diaries. Everyone also has a blinded continuous glucose monitor on. So our team can constantly look at as the CGM is going low, do we see people doing fingersticks? Do we see them filling out their diaries? So we can keep a very close handle on all of those things.

You've talked about the similarities between Phase II and Phase III. One of the differences is the duration of the trial. So how do you think about how the Avexitide and then also the placebo arm will perform over a longer time course?

Yes. So the Phase II trials were both 4 weeks in duration. The Phase III is 16 weeks in duration. We have no reason to believe that, that should make any difference. I'd say we've seen no evidence of tachyphylaxis or waning of effect. We certainly don't see that in the GLP-1 receptor agonist space. It seems like you can keep engaging the receptor and continue to have the effects. In terms of the events over time, what characterizes PBH, very sadly for people with PBH, is that it's persistent. People are doing everything they possibly can to try to control these events, and they're still having them. And so our expectation is that people, unfortunately, without a treatment effect, will just continue to have these events over time. And so a 16-week study should only give you greater powering than we saw in the Phase II even though in the Phase II, very statistically significant results.

What do you -- what can you share regarding the risk of diet liberalization in the study, particularly if patients who are maybe on treatment start to feel better?

Yes. So I would say, this is again going back to the Phase II. So in the Phase II trials, people did [Audio Gap] But I would also say in the first Phase II trial, [Audio Gap] that some people did liberalize their diet. So I would say, first, there was still a 55% reduction in hypoglycemic events in the Phase II trial despite that. I would say it's also something we're probably even more careful of in the Phase III trial. We train on the diet. We retrain on the diet. People have to certify at every visit that they're doing this. But I'd go back to the mechanism of Avexitide because I think that's the most important thing here. We believe that what's causing the hypoglycemia in PBH is this GLP-1 bolus. And so if you block that, you really should block the substantial majority of the hypoglycemic events. In the first Phase I study, that's exactly what they tested and showed. So the investigators at Stanford gave everyone Glucola, which is just liquid sugar and gave it to people with PBH. To a person, unsurprisingly, they became hyper and then severely hypoglycemic and they rescued them. And then they gave them Avexitide. It 100% blocked the hypoglycemia. So even with a 75-gram liquid sugar ingestion, they still were able to block the hypoglycemia. So I think it really speaks to the strength of Avexitide in this disease.

I'm familiar with those strengths. So maybe last question on trial conduct, which is just, is there anything else that you guys felt was really important to kind of ensure the quality of the trial that we haven't touched on yet today?

I would say, I'll just reiterate what I said before, which is we're using the Phase II trials as a guide. We have a really talented clinical operations, clinical development team as well, as all of the various parties who help biometrics, biostats, et cetera. So I think you asked about core competencies. I think we're very proud of the team we have. And I think we're very pleased with the quality of the studies we run.

Great. Maybe let's switch gears. Assume that this is successful, you'll be gearing up for a launch next year. Maybe let's start with the framing of the market opportunity, which you talked a little bit at the top. Maybe, what do you think about the direction of travel for the number of patients there are in a post-GLP world?

Yes. Yes, it's a really important point. So we did a lot of work understanding the overall population in the United States, and we feel pretty confident in our estimate of about 160,000 people with PBH in the U.S. today. And that's because there's so many different sources all pointed towards the same overall number, including claims data. And I think so we have visibility to that population in the United States. The -- so I think the question -- the other important point I should mention is that PBH doesn't appear to go away. We work with people who have had PBH for 15, sometimes even 20 years. In fact, if anything, in some people, it appears it can be progressive. So it seems like as the body upregulates this GLP-1 response, it sort of sticks. And that's what makes this such a tough condition. So I think what we're -- the question becomes what's the growth rate of the population over time. And the growth rate of the population is basically how many bariatric surgeries are performed each year. There's been well over 200,000 surgeries annually, including since the introduction of the GLP-1 receptor agonist. Hard to perfectly predict what the numbers will be in the future. But we think bariatric surgery will continue to be a very important treatment, particularly because it's especially indicated in people who have severe obesity. People have BMIs of 40 or greater, for example, which is 30 million people in the United States. Just to give one anecdote of a story to illustrate this, we're talking with a woman with PBH recently, she was very open about things and said that she was willing to share, she lost 190 pounds in 10 months on bariatric surgery. Now she eventually also developed PBH. But I think for her, she said, look, this is probably a life-saving, life-extending surgery for me. So she was very happy to have the surgery despite obviously the consequences of PBH being very debilitating. So I think that's the type of impact bariatric surgery can have, and that's also the type of person who this is indicated for. So that's why we hear from weight management clinics. They're happy to have all these tools. They're happy to have weight loss drugs and they're happy to have surgery. It just depends on the individual.

Could you speak to where these patients are currently being seen and their current level of interaction with the health care system?

Yes. So this is where the claims data have been very helpful. We have visibility to the group of people with PBH in the United States. We've been reaching out to many adult endocrinologists and endocrinology centers. And there are centers who care for many people with PBH, as you might expect, given a population of 160,000 people. I think what's nice, too, is that as we're just starting our disease state education work now, including at the upcoming ENDO meeting, we'll look forward to seeing you there. The -- there's already, I think, growing awareness of PBH. So we learned last year that PBH is now on the endocrinology board exams. We learned, actually, even just yesterday, that there will be an ICD-10 code adopted in October of this year for PBH. There are many more posters and presentations on PBH at ENDO and other meetings like that. So I think there's already growing awareness. And now we can work on our own education efforts alongside that.

Could you talk a little bit about the current standard of care for these patients? And what percentage of them are trying some sort of therapeutic intervention?

So I think we see PBH as, I'd say, very typical of rare disease and unmet needs. So right now, the mainstay is diet. People are told to do what's called medical nutrition therapy, which is a very draconian lifestyle, basically eat frequently, small meals, no carbs, at least no simple carbs, try to keep your glucose as controlled as possible. People are still having events despite that. And it speaks to the physiology. Your body is producing 10x normal GLP-1 levels. You're going to have hypoglycemia no matter what you do. Physicians right now try kind of a hodgepodge of different medications, all off-label. None of them really work because none of them get at the heart of the matter, which is this GLP-1 bolus. So what we've heard very consistently in our market research is that physicians really want a treatment. They understand the mechanism. And if they -- if we see data, anything like what we've seen so far with Avexitide, they're very excited about that.

Great. One of the questions we've had was that you did have some delay in the Phase III enrollment. Some people would suggest that might imply, like, less enthusiasm for a new product. What do you say to those people?

I would say I would not draw that conclusion. I'd say, first, we really had no trouble finding participants. It was important to also enroll the right participants in the study. I would also say, ultimately, again, we recruited the study in a pretty efficient manner. I would also say all of our market research, if anything, has been even more positive than what our expectations were. There's a very high intention to treat here. As I mentioned, estimating population sizes in rare disease is always difficult. This is the best, I think, estimates, at least that I've worked on before, given that everything has come to about this very similar population, and it's quite a substantial population. So I would say we don't feel nervous about that at all.

Yes. How are you thinking about patient stratification or like what the best candidates will be maybe at the time of launch, but then also over time?

Yes, it's a great question. So I would say we're refining our go-to-market strategies now. I would say it's interesting in the market research, talking or interviewing adult endocrinologists. One thought was, well, if people are having, let's say, people are going to the hospital very frequently versus people who aren't, maybe that's the way to differentiate. Can you differentiate on so-called severity of the condition or how frequent people may be having events. It didn't differentiate that much. Physicians, I'll say it's kind of the more, like, the kind of quotes and stuff would be that just because somebody is not yet going to the hospital, by definition, every one of these severe hypoglycemic events is a medical emergency. And so the next event might send them to the hospital. So physicians are very, very concerned and anything they can do to prevent these events from happening, they're interested in. So that hasn't -- basically, it just sort of came back like physicians are very interested in a treatment that can help for PBH. I think as we've started to think on it more, I would imagine that one of the key pieces will be, there are centers that support very large populations of people with PBH, 100-plus people. I think we're really, at launch, going to want to make sure that we are partnering with that kind of whole organization. Some of them are academic centers, some of them are large endocrinology centers. They might care for tens of thousands of patients, which also means that they have very strong back office, people who help with insurance, nurse educators, all these different folks. So I think my guess is that's going to be a really key piece as we first launch, is making sure we're being really good partners to those centers as we do our more broader marketing efforts to reach the rest of the population.

To that end, what portion of patients are seen at these kinds of, like, specialty centers or centers with high volume? And do you perceive any difference in physician awareness or, like, intention to treat?

Great questions. I'd say stay tuned for that. I think we're doing that work now. But I would say at a high level, it does feel like there's both centers that are expert at PBH that have high numbers of patients under their care that are well educated, often who know about Avexitide already. And there's a good part of the market that still doesn't have the same level of education on PBH, unsurprising, given there haven't been treatment. So I think it's going to be important we address both.

Right. And how are you thinking about sizing the commercial infrastructure to support that kind of launch?

So I think we're thinking about this as rare disease. I think in terms of our field size, and our general corporate infrastructure, and probably using more digital tools and those sorts of things to build broader awareness. But again, we're still refining these strategies.

What about pricing? How are you thinking about pricing for an agent in the setting with the features you anticipate?

Yes. I would say that even since we started working on Avexitide, the -- it's been nice because there's been -- while there's nothing for PBH, there's been a number of rare endocrine drugs launched with quite premium orphan pricing. And so I think payers typically look for analogs. And while there's no perfect analog here, there's a number of rare endocrine drugs to look at as analogs. I think that, combined with the unmet need in PBH, and given that these are individuals who are pretty high health care utilizers, I think we can be in a pretty nice pricing range. And I think we'll try to work with payers to have good access as well.

What analogs are you pointing payers to consider?

I'd probably hesitate to say specifics right now. But if you look, I'd say, over the past 18 months at any of the rare endocrine drugs launched, there's no perfect analog, but I'd say each one has different attributes that are similar. I'd argue PBH is probably more severe than most. And I would say they all have, I'd say, premium orphan pricing and seem to have good coverage.

Maybe you could just talk about the intellectual property surrounding the asset and anything you're doing to bolster that IP estate?

Yes. So we're starting from a good position. The composition claims go to 2037. That's before patent term extension. So we might expect another 2, 3 years past 2037 for Avexitide. We continue to work on other claims as we learn more, as we find more things that are novel and nonobvious. And then something that we haven't talked about yet is we're also working on a potential long-acting new molecule, AMX0318. It's a GLP-1 receptor antagonist, but it's a totally new molecule, and the goal would be to have once-weekly dosing. And so that's in IND-enabling studies now. Goal is to be in clinic next year. So we think there's a lot more to do. And with that innovation can come additional intellectual property.

Yes. That's a good segue because it was my next question. So tell me about the weekly program and how that partnership kind of fits into your long-term strategy for the indication.

Yes. Well, I'd say we really feel strong that this is a high unmet need, an exciting market opportunity and that the pharmacology here just really makes sense. And that's why there's been such great effects of Avexitide in the prior trial. All that being said, let's learn from what's been done, for example, in the GLP-1 receptor agonist space, the first-generation products are once daily and then the chemistry evolves to be able to do once weekly. So we established a really nice collaboration with a company called Gubra. They're one of the world experts in peptide drug development. They have a really nice peptide discovery platform. So all last year, we worked on a collaboration with them to develop potential long-acting GLP-1 receptor antagonist. We came up with a few that met those criteria and had good drug-like properties, and now we're taking the leads into IND-enabling studies. Goal is to be in clinic next year. So I think overall, our goal would be to launch Avexitide in 2027, while we have the long-acting in development as well.

Could you talk a little bit more about the technical hurdles developing a drug with the drug-like properties that would translate to a target product profile here?

Yes, yes, great question. And I think in terms of core competencies, it's another good reminder of that. I think our core competencies in this regard are really around PBH, drug development in the space, clinical development, commercialization. But peptide drug discovery is core competencies in and of itself. So that's why the partnership with Gubra made a lot of sense. They spent decades building this really robust platform. They had all the GLP-1 receptor assays already up and running. They've had multiple molecules that have sort of gone the distance from concepts into clinical trials across multiple incretins. They're sort of part of that Danish brain trust who have been working on these incretins for some time. So the -- we track thousands of molecules for all sorts of different properties. Obviously, things like potency and half-life, but also solubility and fibrilization, and stability, impurities, all sorts of different profiles simultaneously. In fact, they've built machine learning into their platform, maybe now called AI so that they can track multiple endpoints with their peptide simultaneously. And that allowed us to get candidates that met quite strict criteria. So we're really excited about that program.

As you move into clinical development, are there any key learnings you'll take away from the Avexitide program, recognizing much of that was done away from you? And are there aspects of that, that you can accelerate?

Yes, you're totally right. I think we're thinking really hard about that. We haven't defined the exact development time lines for AMX0318 yet, but we think it can be a fairly efficient program. If you think back, Avexitide, you can see the effects in a single dose. I think the obvious thing to look for with a long-acting is are you seeing a similar or better profile than what we saw with Avexitide and once-weekly dosing. So I think that's what you want to look at. And then I think these Level 2, Level 3 hypoglycemic events are clearly meaningful and objective endpoints. If you look, we're running a pivotal study in roughly 1.5 years or so. So I think it can be a pretty efficient development program.

Maybe last one on this. Just can you refresh us on the competitive landscape in PBH? Obviously, you guys have two programs advancing. Anyone else that you're monitoring?

I'd say not anymore. And I think that's a good update. We knew we were well ahead, but I think that's just been reinforced recently. A couple of programs that were discontinued or didn't meet their endpoints. So we think we're pretty far ahead.

Great. Briefly on pipeline, you have AMX0114, next-generation treatment for ALS. I'm sure that's close to your heart. Maybe just talk about quickly the mechanistic rationale for that agent and time line updates over the next couple of years.

Certainly. Yes, we're very excited about our calpain-2 ASO 114. So that's something we developed in-house. Calpain-2 has been a well-recognized target in neurodegeneration for decades. It's just been hard to target. Calpain-2 is one of the key effectors in axon degeneration. So what happens, particularly in neuromuscular diseases, but other neurodegenerative diseases as well, are these long processes of the neurons in the case of ALS that connect to the muscle. Those start to degenerate and then the muscle goes but it doesn't have that connection anymore. So that process of degeneration has been well studied. And one of the key actors in it is calpain-2. The challenge has been that there are many calpains. And so you want to very particularly target calpain-2. You also want to get enough exposure into the central nervous system. So that's where an intrathecally administered antisense oligonucleotide is a really nice approach. We know we're targeting calpain-2, not the other calpains, and we know that we're getting adequate exposure. So that molecule is now in a multiple ascending dose study in people with ALS right now. We are through the first two cohorts of dosing. The first cohort biomarkers, the lowest dose, we'll be presenting those biomarker results at an ALS conference this month. We're through Cohort 2. So we'll start to plan out when we'll have the biomarkers for that cohort and another medical meeting to target, and we're on to Cohort 3. So we're very excited about that program. It's moving really quickly. And I think calpain-2 being a protease, there are a number of biomarkers that we can look at to see if we're seeing the target engagement we hope to.

Right. Maybe in our final minute here, you could just provide an update on cash runway, balance sheet, et cetera, and what events and activities are embedded within that guidance?

Yes, yes. So I'd say that the most important highlight is that we have cash into 2028. We expect to commercialize in 2027. So in our cash guidance is included all of the work leading up to and through commercialization, including building out our field teams, our inventory, all the things that we'll need to launch and get access for people with PBH. So we're excited. We think we have a really big opportunity here. We're already working on the NDA and pre-commercial preparations right now.

Perfect. So I think that brings us to about time, and I appreciate that, Justin. Thanks again to everyone who joined us here and online.

Excellent. Thanks so much, Corinne.

Perfect.