Amylyx Pharmaceuticals, Inc. (AMLX) June 10, 2026 Conference Transcript

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

Sure. Yeah. Well, first, thanks so much for having us. We're thrilled to be here. So, So Justin, co-CEO, co-founder at Amlex, 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 quality of PBH. These low blood sugar are really driven by the body upregulating the GLP-1 response. The body will produce 10 times, 15, sometimes even 20 times normal levels of GLP-1, and so that causes insulin to spike, which then causes a severe hypoglycemia. So, Avexatide is a GLP-1 receptor antagonist, so it blocks that GLP-1 effect, which then blocks the downstream hypoglycemia. So, five prior trials of Avexatide and 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 think of some background on kind of how you guys arrived at Avexatide 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 yeah absolutely and I think it speaks to your first question on core competencies as well so I think at Amlex we've built a really great expertise in rare disease drug development particularly you know 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 Avexatide and 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, you know, quite impactful. And then connected with that is the pharmacology. You know, 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, you know, 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. It'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, you know, 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 control trial, 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 that exciting milestone.

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

Yeah, I really appreciate that because it's a really important point. So the first Phase II trial, as you noted, used a 60 mg dose, and that was very effective. But I think that the investigators noted that, you know, 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, you know, for sort of the full day-night cycle. And sure enough, that's what they saw in the Phase 2B trial as well. So they saw, you know, 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.

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 has powered to show with respect to changes in L2 and L3 events.

Sure. So I think the nice part about having five prior trials is that, you know, So 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. They had a run-in period looking for two events in two weeks. In the Phase III, we had three events in three 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 and 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 one 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, you know, 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 2B, we saw a 64% treatment effect. So we're 90% powered to see roughly half of the effect that we saw in phase 2B, and that's even under very conservative assumptions.

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?

Yeah, so, you know, 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, you know, we feel quite confident in that. but the level 2 is measured by a finger stick, self-monitored blood glucose. That's still the gold standard for measuring a hypoglycemic event. If the blood value is less than 54 milligrams per deciliter of blood glucose, then that counts as a level 2 event. A 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. 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 guidance as well as just general practice in endocrinology. I think, you know, clinical quality is obviously very important and, you know, 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, you know, we have done that. Of course, at every site visit, we still, you know, train and retrain and remind on all these various outcomes, but I think start the study right.

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?

Yeah, well, I would say, again, the most important thing is first, you know, 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 finger-stick blood glucose, they're filling out their diaries. Everyone also has a blinded continuous glucose monitor on. So our team can constantly look at, you know, as the CGM is going low, do we see people doing finger sticks? Do we see them filling out their diaries? So, you know, 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 Avexatide and then also the placebo arm will perform over a longer time course?

Yeah, so the Phase II trials were both four 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, you know, we've seen no evidence of taxylaxis or waning of effect. We certainly don't see that in the GLP-1 receptor agonist space. It seems like you can, you know, keep engaging the receptor and continue to have the effects. In terms of, you know, the events over time, what characterizes PBH, very sadly for people with PBH, is that is persistent. People, you know, are doing everything they possibly can to try to control these events, and they're still having them. And so, you know, 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 2s, even though in the Phase 2s, you know, very statistically significant results.

What can you share regarding the risk of diet liberalization in the study, particularly of patients who are maybe on treatments or to feel better?

Yeah, so I would say, you know, this is, again, going back to the Phase IIs. So in the Phase II trials, people did, but I would also say in the first Phase II trial 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, you know, it's also something we're probably even more careful of in the phase 3 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 a vexatide, 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 1 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 CBH. To a person, unsurprisingly, they became hyper and then severely hypoglycemic, and they rescued them. And then they gave them avexatide. 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 the vexatide 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, you know, we're using the phase two trials as the guide. We have a really talented clinical operations, clinical development team as well as all of the various parties who help, you know, biometrics, biostats, et cetera. So I think you asked about core competencies. I think, you know, we're very proud of the team we have, and I think we're very pleased with the quality of the studies we run.

Maybe let's switch gears. Let's assume that this is successful. You'll be gearing up for our 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?

Yeah, yeah, 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 just so many different sources all pointed towards the same overall number, including claims data. And, you know, I think that we have visibility to that population in the United States. 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, you know, it sort of sticks. And that's what makes this such a tough condition. So I think 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, you know, 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. You know, just to give one anecdote of a story to illustrate this, we were 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 or 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, you know, 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?

Yeah, so this is where the claims data have been very helpful. the we we have you know visibility to the you know 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, you know, including at the upcoming endo meeting. We'll look forward to seeing you there. 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. If your body's producing 10 times 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, you know, 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 we see data, anything like what we've seen so far with the Vexitide, they're very excited about that.

One of the questions we've had was that you did have some delay in the Phase 3 enrollment. Some people would suggest that might imply 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, you know, first, we really had no trouble finding participants. You know, it was important to also enroll the right participants. the study. I would also say, you know, 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 It's a very similar population, and it's quite a substantial population. So I would say we don't feel nervous about that at all.

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?

Yeah, it's a great question. So I would say we're refining our go-to-market strategies now. I would say, you know, it's interesting. In the market research talking or, you know, 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 a way to differentiate. Can you differentiate on so-called severity of the condition or how frequent people may be having events? You know, it didn't differentiate that much. Physicians, I'll say, you know, 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, you know, basically, it just sort of came back like physicians are very interested in a treatment that can help for PPH. 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, you know, 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. You know, they might care for tens of thousands of patients, which also means that, you know, they have a very strong back office, people who help with insurance, you know, nurse educators, you know, 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. You know, 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 Avexatide 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.

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, you know, 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 do you think about pricing for an agent in the setting with the features you anticipate?

Yeah, I would say that even since we started working on Avexatide, 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, you know, quite, you know, premium morphine pricing. And so I think payers typically look for analogs. 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 appointing payers to consider?

I'd probably hesitate to say specifics right now, but if you look, I'd say, over the past 18 months that any of the, you know, rare endocrine drugs launched, there's no perfect analog, but I'd say, you know, each one has different attributes that are similar. I'd argue PBH is probably more severe than most, and I would say, you know, 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.

Yeah, so we're starting from a good position. The composition claims go to 2037. That's before patent term extension. So, you know, we might expect another two, three years, you know, past 2037 for Vexitide. We continue to work on, you know, other claims as we, you know, as we learn more, as we find more things that are novel and non-obvious. And then something that, you know, we haven't talked about yet is we're also working on a potential long-acting new molecule, AMX318. 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. The goal is to be in clinic next year. So, you know, we think there's a lot more to do, and with that innovation, you know, can come additional intellectual property, too.

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

Yeah, well, I'd say, you know, we really feel strong that this is a high-unit need, an exciting market opportunity, and that the pharmacology here just really makes sense. And, you know, that's why there's been such great effects of Exitide in the prior trial. All that being said, let's learn from, you know, what's been done, for example, in the GLP-1 receptor agonist space. The first-generation products were once daily, and then the chemistry evolved 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 antagonists We came up with a few that met those criteria and had good drug-like properties, and now we're, you know, 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 a vexatide in 2027 while we have the long-acting in development as well.

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

Yeah, yeah, great question. And, you know, I think in terms of core competencies, it's another good reminder of that. You know, I think our core competencies in this regard are really around, you know, PBH, you know, drug development in the space, clinical development, commercialization. But, you know, peptide drug discovery is, you know, core competencies, you know, 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 of the GLP-1 receptor assays already up and running. They've had multiple molecules that have sort of, you know, gone the distance from concepts, you know, into clinical trials across multiple incretins. You know, they're sort of part of that Danish brain trust who have been working on these incretins for some time. So we tracked, you know, thousands of molecules for all sorts of different properties. You know, obviously things like, you know, potency and half-life, but also, you know, solubility and stabilization and, you know, stability, impurities, you know, all sorts of different profiles simultaneously. In fact, they've built machine learning into their platform, you know, maybe now called AI, so that they can track multiple endpoints with their peptides simultaneously. and, you know, that allowed us to get candidates that met, you know, 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 Avexatide program recognizing much of that was done away from you, and are there aspects of that that you can accelerate?

Yeah, you're totally right. I think we're thinking really hard about that. We haven't defined the exact development timelines for AMX 318 yet, but we think it can be a fairly efficient program. if you think back, a vexatide, you can see the effects in a single dose. You know, if, you know, I think that the obvious thing to look for with a long-acting is, are you seeing a similar or better profile than what we saw with the vexatide? And, you know, once weekly, you know, dosing. So I think that's what you want to look at. And then, you know, I think these level 2, level 3 hypoglycemic events are clearly meaningful and objective endpoints. If you look, we're running, you know, a pivotal study in, you know, roughly a year and a half 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 the two programs advancing. Anyone else that you're monitoring?

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

Briefly on pipeline, you have AMX-0114, next-generation treatment for ALS. I'm sure that's close to your heart. Maybe just talk about it quickly, the mechanistic rationale for that agent and timeline updates over the next, you know, couple years.

Certainly, yeah. 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, is 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 when 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 intrasequally administered antisyntholigonucleotide as a really nice approach. We know we're targeting Calpain 2 and not the other Calpain and we know that we're getting adequate exposure. So that molecule is now in a multiple sending dose study in people with ALS right now. We are through the first two cohorts of dosing. The first cohort, biomarkers, you know, the lowest dose, will be presenting those biomarker results at an ALS conference. this month. We're through cohort two, 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 three. 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.

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

Yeah, yeah. So I'd say the most important highlight is that we've cached into 2028. We expect to commercialize in 2027. So in our cache 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. You know, we think we have a really big opportunity here. We're already working on the NDA and pre-commercial preparations right now.

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

Thanks so much, Grant.