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

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[Audio Gap] asset. It's a GLP-1 receptor antagonist. So it's a competitive inhibitor of the GLP-1 receptor. And this is quite important in diseases of hypoglycemia. Despite the GLP-1 agonist now being very famous for obesity, they were initially used for and still are used for diabetes in part because they can cause the secretion of insulin through activation of the GLP-1 receptor and then the reduction of blood sugar. With our compound, we are able to competitively inhibit the GLP-1 response, which can reduce hypoglycemic events and reduce hypoglycemic loads or at least that's what we've seen in our prior trials. So the compound is currently in Phase III -- the Phase III is ongoing. We expect to complete recruitment by the end of the year, with top-line data in the first half of 2026. We're quite excited about that trial, especially coming off of 5 previous positive studies on the compound, which led to FDA breakthrough therapy designation. We do believe that pending positive results from this trial that this trial would be the pivotal trial to support potential registration of the drug as well. And then maybe just touching briefly, as we've learned more and more about post-bariatric hypoglycemia, we've just been very impressed that the unmet need at how much of therapy is really needed to address the symptoms these patients are dealing with. These patients will have recurrent blood sugar drops, which most often happen after meals. But can happen at any time, can happen due to exercise can happen sometimes out of the blue due to psychological stress, caffeine, alcohol. And so, if you can imagine, if at any time your blood sugar could deeply drop you start to have to live a very sheltered life. You are unlikely to be able to drive. You may be very nervous when you go up and down stairs and at high risk for falls. It may be hard to go through your day-to-day life we're in the middle of a meeting or in the middle of a day, all of a sudden, you can't put together a sentence because your blood sugar has dropped so low. So it really limits life quite a bit for people, who have this disease. And we'd be really excited to bring a therapy forward.

Super helpful, Josh. Let's talk about the market opportunity, though, when you think about -- as the -- as the trial is enrolling, is there anything that you had learned about this patient population and a lot of your KOL discussions. Do you think ultimately the incidence rates are going to be higher than you think? Should we look at bariatric surgery procedures as sort of an indicator maybe of the potential of the market? And then related to all this, like what -- I know GLP-1s don't play a direct role in what you're talking about maybe you talk about that. I think in investors' minds like that's kind of -- people view that as competitive, which is not.

Yes, very, very important question. So let me take it a little bit in reverse -- so right now, we estimate there are about 160,000 people in the United States, who have PBH or post-bariatric hypoglycemia. Now that sounds like a really high number, but it's actually quite rare. The reason that there are so many people, who have PBH is there have been so many bariatric procedures over the past couple of decades, particularly in the past 10 years. So the estimate is only about 8% of people, who get bariatric surgery will develop PBH, but 8% of millions of people, you get to very high numbers. And so, it's really a rare complication in the years following bariatric surgery that someone gets PBH, but the unfortunate thing for people with PBH is, it seems to be very persistent. So once someone has PBH once whatever and their body potentiates the GLP-1 response, it stays. So for example, in the prior studies, the average time people had had PBH was about 10 years. So they had had PBH for a decade and that's despite having medical or particularly dietary intervention, they're still having these very frequent hypoglycemic events. So I think in our estimates, the numbers, the population will only grow and it will grow based off of the number of bariatric procedures. So to start, though, 160,000 is already quite a substantial, it's orphan, but it's quite a substantial orphan market with no treatments currently. So far, there have been about the same number of bariatric procedures year-over-year particularly over the past several years. And that does not seem to be impacted by the new weight loss drugs. Now no one can, of course, perfectly predict what's going to happen in the future. But what we've heard from weight management clinics is that these are really not the same population that people are talking about. Someone who gets a bariatric surgery is looking to lose 100 pounds, 150 pounds. These are people who have severe obesity. That's very different than your typical person, who is looking for a weight loss therapy. And in fact, even if you look at the trials, while oftentimes, they've talked about percent weight loss, they're very different populations of people. In the bariatric surgery trials, these are generally people, who are 300 pounds and above. In the weight loss studies, these are people who are generating 200 pounds. So these are very, very different populations. So I think that's why hearing from weight management clinics, these are not sort of the same populations that we're looking at. And then in terms of what we've learned about the PBH market, I think the more we learn, the more the unmet need comes through and the more we're excited about an opportunity to help people. These are people who have really a debilitating condition. If you think if at any time you're afraid that you may lose consciousness, you may become so severely confused that you don't know where you are. Some people have seizures. People are in and out of the ER quite frequently. And these are often typically women in their 40s, often caring for children as well. They're afraid to be alone. They are afraid to leave their homes. So what we hear from endocrinologists is these are -- this is a very -- this is a population who really, really need treatment. And as Josh said, we're excited about the potential to be able to help them.

Great. And maybe as you highlighted the high unmet need in the space, maybe could you help paint the picture of what is currently available as a treatment for patients and why there is such an unmet need for avexitide. And what is the competitive landscape for PBH? And how would avexitide differentiate itself from existing or other pipeline therapies?

Sure. So unfortunately, there really isn't much today for PBH. The mainstay treatment, as Justin mentioned as well, is what's called medical nutrition therapy. But this in and of itself is a very unpleasant thing to have to go through. Basically, it's avoiding all or as many as possible simple carbs never eating a large meal. So that means you're basically never having a full dinner for the rest of your life. You're having very, very small kind of snacks and never eating kind of a full meal for the rest of your life. And even with that, patients still report having frequent events. Again, you can have events both from meals, but also from other triggers, whether exercise stress, caffeine, all the manner of other things can drive these events. There are some off-label therapies that are tried generally kind of hormonal therapies, including somatostatin analogues and alpha-glucosidase inhibitors like Acarbose. These show pretty limited efficacy with quite significant side effects. So they really are not particularly helpful in the treatment of PBH. And I'd say probably won't spend much time commenting on others, but there really is no other drug in the pipeline with a profile like avexitide. So we see ourselves in a very strong position competitively.

Got you. That makes sense. And then maybe speaking of the Phase 3 LUCIDITY study, you mentioned the rarity of PBH, but given the overall number of bariatric surgeries, there are a decent number of patients out there. Could you provide some early color on how patient recruitment and retention for this study is coming along? How is the enrollment timing looking? Is it still year-end '25? I know earlier you said the readout is still targeted for the first half of '26.

Yes. So I'll take it in reverse. So yes, target still year-end to complete enrollment and then data in the first half of next year. So there's been a lot of enthusiasm and excitement from the centers. Again, if you imagine, this is a highly debilitating condition. There are 160,000 people in the country, and there are no treatments available. And I think what we've heard very consistently from endocrinologists is these are some of the most fragile patients they have under their care. So there's a tremendous excitement. And then, of course, given that there were 5 prior trials of avexitide in PBH showing very strong reductions in hypoglycemia and hypoglycemic events, people are very excited that there may be a therapeutic on the horizon for their patients.

Awesome. And then maybe let's talk a bit more about LUCIDITY. Reduction in the composite Level 2, Level 3 hypoglycemic events, obviously, is primary endpoint. What are some other key secondary endpoints that might help influence your data assessment of avexitide?

Yes. I mean maybe I might start with hypoglycemic events are already quite significant. The ADA defines Level 2 and Level 3 hypoglycemic events as a medical emergency. So when you're talking about reducing those types of events, you're talking about reducing something really significant and important for patients. We are also looking at a number of kind of quality of life scales, including scale specific to how hypoglycemia can affect your life. We'll certainly be looking at health care utilization as well, including hospitalizations, things like that. But I think our primary endpoint is already quite a clinically meaningful endpoint. So that's certainly going to be the main driver here, I think, as well.

One of the questions, I guess, we can wrap on this program, I guess, with more of a commercial question. I know you have a rare disease model. This is you guys wheelhouse. You know the rare disease structurally, the market, but maybe not this indication. What work have you guys done in advance, right, to try to maybe prime the pump in terms of what -- how payers may view this, how the cost benefit? Is there sort of a magnitude of effect that you think would be reasonable from a cost benefit and a risk benefit. Questions like that.

Yes, very important and work that we're doing now and of course, will continue next year as well. And I'll talk a little bit and invite Josh and Jim to join in, too. So I think the first thing that we've heard is that considering that endocrinologists consider a single hypoglycemic event as a medical emergency, really, doctors are fear for their patients having these events because, gosh, the number of doctors who tell us a story about a patient who had an event and crashed a car or they were shopping and fell and hit their head and ended up with a concussion, it's really frightening. So I think the first thing that's really come out in the research is doctors want to keep their patients safe. And even just a single one of these events is very dangerous. So while there are people who have more frequent events and people have less frequent events, I think generally, what we've heard is like we don't want our patients having any events regardless, if they're -- how frequent they are currently. So I think that's the first thing that's really come out. The second, I think, is the sort of burden of disease, and we're going to work to present and publish on this more. But the amount of hospitalizations and ER visits and just what people with PBH go through is really challenging. Then on the sort of population level, we have looked at a number of different claims databases now, all of which corroborate the numbers that we saw based on the literature estimates. So about 160,000 people actively have PBH in the U.S. Now I think as we continue to do our research, we'll think about segmentation based on how many patients a doctor may have under their care. There are some doctors who have hundreds of patients under their care. There are some who have 10 patients under their care. So we'll continue to do that work. But I think in terms of the rare disease model, we very much think that this has the same sort of characteristics as one would look at in other rare diseases. Now it's a big population of 160,000 is a kind of big rare disease, if I can say that. But it's got the same hallmarks as one would see in these other areas. And I think to your point, with our first launch in ALS, I think we were quite successful at understanding how do you target centers in the right way? How do you educate people in the right way? How do you educate payers in the right way. And at the end of the day, I think we view it as education. One, this is a significant unmet need. So I think it's telling that story, what does it mean to have PDH? Why is it important? And second is that the data supporting the treatment. I think we're fortunate that hypoglycemic events are very well recognized, particularly from the diabetes world. These have been defined for some time. So I think it's really just about education again and again, whether that's in a physician's office or at payers as well.

Yes. And maybe the only thing I'll add that maybe goes back to your question as well about endpoints in the trial. One thing we're also doing in the trial is structured patient interviews where we kind of interviewed the patient post trial. This was also done for a number of the patients in the previous trials. And 1 thing that was striking is that patients described feeling quite a bit different while on drug. And this makes sense given that hypoglycemia -- you feel terrible when you're hypoglycemic, -- it's not just that your blood sugar is a little, but it also causes a huge stress hormone release. Quite often, you become quite nauseous. You can be quite dizzy. You're not thinking clearly. So it's just a very, very unpleasant thing. I think 1 other thing we're excited about potentially commercially is with many drugs, you take a Lipitor or otherwise, maybe you can get a blood test and you can see the difference, but you can't feel the difference. And I think it's something we're quite hopeful for that we continue to see that as we kind of get through our structured interviews. And otherwise, that this is a drug, hopefully that makes people feel better when they're on it. And then yes, I'd say overall commercially as well, echoing what Justin said, physicians describe that any reduction in significant hypoglycemic events is meaningful. And so we're quite excited about that. Again, in the Phase IIb, we saw a 64% reduction, which is obviously quite meaningful for people living with this disease. And yes, I think we do view this as a rare disease launch. There's quite a number of physicians we've spoken to who have over 100 patients those are certainly going to be some of the main stays as we start to launch, hopefully, pending good data as well.

I'm happy to add maybe just 1 last piece, too. I think certainly, when you're buying your home, the advice is that you want to be in a great neighborhood. And I think we're fortunate to have a great house in a great neighborhood. What I mean by that is I think there have been a number of rare endocrine launches recently that support premium pricing that support access and show that in these areas where there's high unmet need, I think physicians are willing to prescribe and payers are willing to pay. Because they recognize the challenges and treatments that are needed here.