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

Perfect. So welcome, everybody. I'm Caitlin McGurk. I'm a member of the investment banking team at Morgan Stanley. It is my pleasure, my absolute pleasure, to welcome Josh Cohen and Justin Klee, co-founders of Amylyx, to the stage today. Just a very brief disclaimer before we get started. You've been to many of these before. Please visit the Morgan Stanley Research Disclosure website, www.morganstanley.com/researchdisclosures for important information about this and other presentations. So without further ado, it's fantastic to have you at our conference. It's been a highly eventful and highly successful summer at Amylyx with the amazing data you had on Avexitide and PBH over August. Let's start there because obviously it's the burning question. Let's talk a little bit about the data, you know, firstly in terms of the headline results, what you were expecting, and then obviously a lot of follow-up questions on this topic.

Sure, yes. So first I'd say, we had high expectations given all of the prior trials of the Avexitide, but I'd say this exceeded our expectations. The data, just to kind of highlight, on our pre-specified primary outcome, which was the rate of level 2 and level 3 hyperglycemia in people living with PBH, these are events that are extremely debilitating. Any one of these events is kind of considered a global emergency. We saw a 55% reduction with the active versus placebo with a p-value of 0.000003. We hit all of our secondary outcomes, also with high statistical significance, similar effect sizes as well. And I'll note what's nice about the secondaries too, those include looking at level 2 individually, by finger stick or by CGM, both of which were met, as well as looking at level 3 hypoglycemia which is a clinical event. That's when basically people have become so hypoglycemic that they're incapacitated, basically warranting rescue from another person. Safety profile was also consistent with prior studies with a very favorable safety profile. So overall, we were thrilled and I think maybe most so, we've gotten to know a number of physicians that treat PBH, patients living with PBH, over the last years, and for many people with PBH, this is a completely disabling condition. There was a survey recently where 90% of people with PBH interviewed described themselves as having a disability, you know, due to the condition. So it's just been incredibly gratifying, incredibly exciting. It's really our mission as a company to be able to deliver therapies to diseases that have either nothing or completely inadequate options, and that's certainly the case in PBH. So, you know, coming off this, we're planning to submit our NDA by the end of the year, and then, you know, already prepping to launch in 2027 if approved.

Maybe just a follow-up question. So this was a 78-patient study with a crossover design. You saw very impressive statistical significance on the primary endpoint. What does that, you know, tell you about the targets, the underlying biology in an era where everyone is trying to agonize GLP-1 and you're antagonizing? So how should we sort of see the result relative to the underlying biology in the disease?

Well, I think that I'd start with the prior work that had been done in post-bariatric hypoglycemia. So, post-bariatric hypoglycemia, PBH, doesn't occur in most people. It happens to about, we estimate about 8% of people who get bariatric surgery. In the years following, it takes years to manifest. And what appears to occur is that nutrient transit has been increased because a significant portion of the GI tract has been resected. And in some individuals, this causes very significant increase in their body's own production of GLP-1. So this is a condition that is driven by this excessive exaggerated GLP-1 response. So people have 10 times, 15 times, sometimes 20 times normal levels of GLP-1 in response, often to nutrients, but it can be for other substances, triggers as well. GLP-1 is a very strong potentiator of the insulin response. And so what occurs in people with PBH is that their GLP-1 has this inappropriate production and secretion, which causes this exaggerated insulin response, which causes, of course, blood sugar to drop significantly. In these cases, this sort of drop in low blood sugar is by definition a medical emergency because of course our bodies, particularly our brains, need glucose to function to do all of our sort of daily activities, to fuel all of the cells in our bodies. So when your blood sugar gets to this very significant low, essentially the brain starts shutting down its functioning. So that's why we see these, essentially neurological complications. So people get severe dizziness, confusion, even loss of consciousness, seizures. So this biology had been known for a long time, actually going back to the '80s, some really elegant work showing that in response to various gastric surgeries, people could develop this very debilitating chronic condition. There was a group, particularly at Stanford, who reasoned that, well, then if we have an antagonist of the GLP-1 receptor, then we would block that GLP-1 response, and maybe that would then block the downstream hyperinsulinemic hypoglycemia. That is what they saw in five consistent studies. The LUCIDITY trial, which we just read out, was the longest, largest duration study that had been run to date. And so that was really testing the question of in a real-world setting when people are at home, following their dietary guidance and the sorts of things to control their PBH, if you inhibit this GLP-1 response, can you prevent these hypoglycemic events from occurring? And that's indeed what we saw with the clinical data. So I think this is really exciting because to your point, not only are the results very promising for PBH, but we really feel like we're getting at the heart of what's causing this very debilitating condition. And I think that's why we've seen such strong results of the Avexitide now consistently through six studies.

Very minor correction too also, parallel groups. Parallel groups, sorry, yes, correct. Maybe we should just think about, you know.

Patients have this condition chronically, how should we be thinking about the durability of the benefit beyond 16 weeks, and sort of any thoughts on that?

One, with Avexitide, we start seeing a benefit at a single dose. You know, in our prior studies, there were studies where people basically took a single dose of Avexitide, had a meal test, and you could see a significant difference from placebo with just the single dose. As we've looked out further, that benefit seems to be persistent, any difference over the 16 weeks. And we wouldn't really expect to. This pathway doesn't really have any, it doesn't kind of have any feedback loop that would sort of prevent that. So we would expect kind of persistent effect. PBH itself is also a chronic disease. Once you have PBH, you have it for life. You know, once you've had the surgery, the surgery doesn't go away, you have it for life. So we do expect that to continue deriving the benefit that this would be a kind of chronic treatment, chronic therapy.

And just one last question around the other observations. Obviously, in this population that have been through bariatric surgery, the concern around weight regain with GLP-1 antagonism, you did, Justin, talk about the GLP-1 levels being supraphysiological, but just comment on.

Yeah, I think that was encouraging as well. Given that this is the longest study duration, would we see any sort of adverse effects of the GLP-1 antagonist? And the answer is no. There was no Avexitide-related weight gain. There's no Avexitide-related medical hyperglycemia. You know, the safety tolerability was consistent with the prior studies, even over this longer time period. So we're very pleased with that, but I'd say it was not surprising to us. We are trying to bring back the GLP-1 response to a more physiologic level. These are people who have very exaggerated GLP-1 responses. We're trying to dampen that response, and it appears like that's what we're able to do with Avexitide for people with PBH.

And obviously from the disclosure so far, we've seen obviously the hit in terms of, you know, clearly, clearly meeting the primary endpoint, the consistency. What can you tell the audience, if anything, at this point around publication and presentation of the full dataset?

Sure. Yes, so one, I think we tried to share all of their relevant data, met the pre-specified primary, high statistical significance, met all of the secondaries, good safety profile. We will be looking to publish this in kind of high profile format, also to present it, hopefully in high profile format as well. I think that's very important. One of the most important audiences here will be those physicians who are looking to learn more about Avexitide and understand it, and so we do think it's important to publish data in that way. But again, I think we've shared kind of the key data, so I don't think there's going to be anything new really there, just more details around the edges.

Thank you, Josh. I wanted to come back to the point you made around the sort of the impact on patients, and you had Dr. Marilyn Tan, your PI for the LUCIDITY study, on the call, and she'd made some sort of interesting observations. One of them being that even presenting a single severe hypoglycemic event in her mind was clinically meaningful. You know, clearly your results suggest you've achieved far more than that. But I don't know, just Josh, if you want to just dwell a little bit more on that in terms of the feedback that you've had from physicians, patients, what impacts them the most? And as they look at potentially embarking on treatment with Avexitide once approved, you know, what aspects of the profile are going to be most compelling from your standpoint?

Sure, happy to, and yes, Josh, please add in as well. So going back to your question on sort of what were the expectations for the study, what we heard very consistently from, excuse me, from adult endocrinologists is that right now, PBH is among the most severe conditions they see in their practice. They have no treatments for people right now. The mainstay is medical nutrition therapy. And even with medical nutrition therapy, people continue to have these events. And these are potentially traumatic events. It's not uncommon for people to go to the hospital because of one of these hypoglycemic events. If you look at the American Diabetes Association and other endocrinology resources, they say very clearly severe hypoglycemia is a medical emergency. And it's because, as I mentioned, you get neurological complications when you're not keeping up your blood glucose to these levels. So I think that's why we heard such consistent feedback that in the Phase 3 study, any reduction, even preventing a single event as you were mentioning, would be clinically meaningful. And so we kind of interpreted that to mean statistical significance is really the bar for success. When we shared the results with our steering committee, they were over the moon. I think that, you know, this was a profound reduction in these hypoglycemic events, clearly very highly statistical, statistically significant. But also, I think it was the totality of the results. It was all of the secondary outcomes also showed highly significant results as well. So it was kind of like whichever way you looked at it, it's very, you get a very clear picture that this is truly impacting PBH. And again, in the backdrop of currently there are no FDA-approved treatments for PBH. So I think just the feedback we've heard so far is people are very, very excited. And it's part of the reason we're so excited to both get the results out but then submit our NDA and start our launch preparations for next year.

And I wouldn't add too much to that, but maybe I'd just share maybe a couple of the stories or the types of stories we hear from physicians that list really probably define sort of why Marilyn, or Dr. Tan, is sort of sharing that as well. We've heard stories about people getting into car accidents. We've heard stories of people falling down the stairs, having fractures, going to the hospital, potentially even broken hips, things like that. Most exchanges, story I've heard as well is somebody dying in their sleep from hypoglycemia. So I think these are the reasons why the physicians say, I want to prevent as many of these as they possibly can, because they've all seen how bad it can get if hypoglycemia gets deep enough. And so they really want to do what they can to try to prevent that.

Okay. Maybe just coming back to, you know, the population and the market opportunity for Avexitide following the filing and launch. I think you've said in the U.S. there's approximately 160,000 patients, which is actually pretty sizable, you know, how have you defined that patient population? Are these patients easy to find? You know, the sort of obvious questions when you're the first in an area around, you know, patient identification and, you know, building a new franchise.

Yes. Yes, maybe after the starting, if you want to add. So I'd start with, there are great literature to start in this disease. There have been large prospective studies following the outcomes of people who have had bariatric surgery. And it's really from those that we derive this approximately 8% who continue to have, you know, unacceptable chronic symptoms following bariatric surgery. We followed up that work with claims-based analysis. So we've looked in the claims to try to find those patients who have had bariatric surgery, who go on to have hypoglycemic events that can't be explained by any other cause. And we similarly get to the approximately 160,000 that the literature would support as well. Subsequent to that as well, we've done kind of both survey-based work and now work with our MSL team in the field as well to talk to the sites individually and, for example, survey them and ask about their patient populations. Who do you see? What is the nature of these patients? What are their symptoms? Et cetera. And that's been quite consistent with the claims data as well. For example, for our claims data, data predicts that a site has 73 patients, our survey results will often come back, you know, very concordant with that, that they, you know, have that number of patients as well. Which I think all comes to, using kind of the claims-based analysis, which, you know, is down to the level of individual sites, individual doctors. It does allow us to, you know, be very strategic in our kind of deployment model to know which are the most important sites to talk to, how should we sort of divide this market. But I'll say, anecdotally, even maybe to describe Endo earlier this year, we're at a disease state education booth. It was full the whole time, really overfilling the whole time with endocrinologists who were coming to ask about Avexitide. It really is not hard to find physicians with sizable numbers of these patients that they would be quite interested in treating if there was a therapy available.

Yes, and I would say too that we've tried to encourage people to do their own doctor calls, and I think that's what first encouraged us so much. It did not take long to find adult endocrinologists who have quite a few patients under their care and pretty consistently said, these are some of the most fragile patients that I have under my care. And I think doctors feel a bit helpless right now that they don't have better options for their patients. And so that's just been very, very consistent for us. And so I think, and again, in any rare disease, triangulating exactly how large is the population and how many people are diagnosed and who are they cared for is a bit art and a bit science. I'd say in this case, every single piece of art we and even research that wasn't done by us, for example, by the team at Stanford has come back to this about 160,000 current population of people with PBH. And of course, as a percentage of the bariatric surgery, you know, annual numbers, we expect that that number will only continue to grow over time. Now, at what growth rate, we of course don't know yet, but even 160,000 is just sort of the foundation, as you're saying, quite a sizable unmet need.