Hey, everybody. We're going to get started if you could find your seats. Thank you. Perfect. Welcome, everybody. I'm Cailin 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. Without further ado, 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 in PBH over August. Let's start there, because obviously, it's the burning question. Let's talk a little bit about the data.
Firstly, in terms of the headline results, what you saw, what you were expecting, and then obviously, a lot of follow-up questions on this topic.
Sure. Yeah. At first, I'd say we had high expectations given all of the prior trials of avexitide, but I'd say this exceeded our expectations. The data, just to kind of highlight our pre-specified primary outcome, which was the rate of level two and level three hypoglycemia in people living with PBH. These are events that are extremely debilitating. Any one of these events is considered a medical 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. I'll note what's nice about the secondaries, too. Those include looking at level two individually by finger stick or by CGM, both of which were met, as well as looking at level three 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. 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 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.
Coming off this, we're planning to submit our NDA by the end of the year and then already prepping to launch in 2027, if approved.
Maybe just a follow-up question. This was a 78-patient study with a crossover design. You saw very impressive statistical significance on the primary endpoint. What does that tell you about the targets, the underlying biology in an era where everyone is trying to agonize GLP-1 and you're antagonizing? 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. 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. What appears to occur is that nutrient transit has been increased because a significant portion of the GI tract has been resected. In some individuals, this causes a very significant increase in their body's own production of GLP-1. This is a condition that is driven by this excessive exaggerated GLP-1 response. People have 10x , 15x , sometimes 20x normal levels of GLP-1 in response often to nutrients, but it can be for other triggers as well. GLP-1 is a very strong potentiator of the insulin response.
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 the cells in our bodies. When your blood sugar gets to this very significant low, essentially the brain starts shutting down its functioning. That's why we see these essentially neurological complications. People get severe dizziness, confusion, even loss of consciousness, seizures.
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 University, 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. 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?
That's indeed what we saw with the clinical data. 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. I think that's why we've seen such strong results of avexitide now consistently through six studies.
Yeah. Very minor correction, too, also. Parallel group study.
Parallel group study. Yes, correct. Maybe we should just think about 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?
Yeah. One, with avexitide, we start seeing a benefit at a single dose. 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. We do not see any difference over the 16 weeks, and we would not really expect to. This pathway does not really have any feedback loop that would sort of prevent that.
So we would expect kind of a persistent effect. PBH itself is also a chronic disease. Once you have PBH, you have it for life. Once you've had the surgery, the surgery does not 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 what you saw in this study.
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 a GLP-1 antagonist? And the answer is no. There was no avexitide-related weight gain. There is no avexitide-related medical hyperglycemia. The safety tolerability was consistent with the prior studies, even over this longer time period. So we are very pleased with that, but I'd say it was not surprising to us.
Yeah.
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 are trying to dampen that response, and it appears like that's what we are able to do with avexitide for people with PBH.
And obviously, from the disclosure so far, we have seen obviously the hit in terms of 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 data set?
Yeah. So one, I think we tried to share all of the 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 is very important. One of the most important audiences here will be those physicians who are looking to learn more about avexitide and understand it better, and so we do think it is important to publish data in that way. But again, I think we have shared kind of the key data, so I do not think there is 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 had made some sort of interesting observations. One of them being that even presenting a single severe hypoglycemic event, in her mind, was clinically meaningful. Clearly, your results suggest you have achieved far more than that. But I do not know, Josh, Justin, if you want to just dwell a little bit more on that in terms of the feedback that you have had from physicians, patients. What impacts them the most? And as they look at potentially embarking on treatments with avexitide once approved, what aspects of the profile are going to be most compelling from your standpoint?
Sure, happy to. And yeah, 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 is 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 is because, as I mentioned, you get neurological complications when you are not keeping up your blood glucose to these levels.
I think that's why we heard such consistent feedback that in the phase III study, any reduction, even preventing a single event, as you were mentioning, would be clinically meaningful. We kind of interpreted that to mean statistical significance is really the bar for success. I will say when we shared the results with our steering committee, they were over the moon. I think that this was a profound reduction in these hypoglycemic events, clearly very highly statistically significant. Also, I think it was the totality of the results. It was all of the secondary outcomes also showed highly significant results as well. It was kind of like whichever way you looked at it, you get a very clear picture that this is truly impacting PBH. Again, in the backdrop of currently, there are no FDA-approved treatments for PBH.
I think just the feedback we have heard so far is people are very excited, and it is part of the reason we are so excited to both get the results out, but then submit our NDA and start our launch preparations for next year.
Yeah, I would not add too much to that, but maybe I would just share maybe a couple of the stories or the types of stories we hear from physicians that really probably define why Marilyn, Dr. Tan, is sharing that as well. We have heard stories about people getting into car accidents. We have heard stories of people falling down the stairs, having fractures, going to the hospital, potentially even broken hips, things like that. Most extreme story I have heard as well is somebody dying in their sleep from hypoglycemia. I think these are the reasons why the physicians say, "I want to prevent as many of these as I possibly can," because they have all seen how bad it can get if hypoglycemia gets deep enough. They really want to do what they can to try to prevent that.
Perfect. Maybe just coming back to the population and the market opportunity for avexitide following the filing and launch. I think you have said in the U.S., there is approximately 160,000 patients, which is actually pretty sizable. How have you defined that patient population? Are these patients easy to find? The obvious questions when you are the first in an area around patient identification and building a new franchise.
Yeah, happy to start, and if you want to add. 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 unacceptable chronic symptoms following bariatric surgery. We followed up that work with claims-based analysis. 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, if our claims data predicts that a site has 73 patients, our survey results will often come back very concordant with that they have that number of patients as well, which I think all comes to using kind of the claims-based analysis, which is down to the level of individual sites, individual doctors.
It does allow us to 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 were 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.
Yeah, 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 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 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 our research and even research that wasn't done by us, for example, by the team at Stanford University, has come back to this about 160,000 current population of people with PBH. Of course, as a percentage of the bariatric surgery annual numbers, we expect that that number will only continue to grow over time. At what growth rate, we of course, don't know yet, but even 160,000 is just sort of the foundation, as you were saying, quite a sizable unmet need.
Justin, maybe just on that, in light of obviously newer, higher efficacy weight loss options, the propensity or the sort of funnel in terms of bariatric surgery going forward, what have you seen in recent years, and is that slowing down in any meaningful way, or what are your views there?
Yeah, I think first I'd say in terms of the overall population, because I think sometimes the math can get a little confusing. So we're starting from a current population of about 160,000. We work with people who've had PBH for 15+ years, 20 years. So it appears that sadly, once someone has PBH, it doesn't go away. So I think the question is then, what's the growth rate of the population over time, and is that 15,000 new people per year? Is it 12,000? Is it 17,000? Of course, we don't totally know, but it's some percentage of the bariatric surgery volume. We've talked to many clinics, weight management clinics, bariatric surgeons, and I'd say generally, they're not having trouble filling their OR time.
I think what we've seen in terms of the dynamic is, I think early on there was this sense of, oh, well, now we have these weight loss drugs, and maybe there won't be a need for bariatric surgery anymore. I think what we've seen now happen is actually because weight management is more in the public discourse, that more people are having conversations about bariatric surgery, and they're very different populations. Bariatric surgery is often for someone who might have a BMI 40 or greater. So that's somebody who may need to lose 100 lbs, 150 lbs. They're not going to achieve that with the current weight loss drugs. That's very different than if somebody needs to lose 20 lbs, 30 lbs, 40 lbs. So they're very different parts of the population.
Now, if we just look at the U.S. population with a BMI 40 or greater, that's about 30 million people. So that's quite a substantial group still. Even at this last year's ENDO, I really pressed many of the endocrinologists I met with, do you see a use for bariatric surgery still? To a physician, they said, "Absolutely." They said, "If somebody has severe obesity, I'm thinking about bariatric surgery. If somebody has diabetes, I'm thinking about bariatric surgery," because there are very, very good diabetes remission rates. "If somebody just doesn't want to take something chronically, I'm thinking about bariatric surgery." So I think the physicians absolutely still see it as a mainstay of weight management. Of course, this is a rare side effect.
Hopefully now, though, as we do our work and look for hopeful approval next year, they'll have an answer to this rare side effect as well.
Coming back onto the, Justin, the approval, the filing timeline, I think you've stated your intention to file the NDA by the end of this year.
That's right.
Which is pretty fast.
Yep.
What sort of wood do you need to chop between now and then? What is important that you need to do in order to get that filing, that submission in on time?
Well, I give our team a ton of credit. They've been working hard on the NDA all year. We had high confidence going into the LUCIDITY trial based on the first five trials of avexitide. We thought, hey, this is an unmet need. We need to be ready. The team did just that, so I just give them tremendous credit. The last wood to chop, as you were saying, is everything around the phase III trial, the CSR and the associated work around the phase III trial. That's why we've set quite a tight timeline for the NDA submission, is because our team has really done such great preparatory work, and now the bulk of what's left is around the phase III. Sort of walking through the timelines a bit more, goal is to submit by year-end.
We have breakthrough status with avexitide, so we would hope for or expect a priority review. With that, we're planning for a potential launch in 2027. Alongside our NDA preparation work, we are also doing all of our launch preparation work as well.
On the commercial side, as you ramp up there, what are the most important elements to have in place? What do you have now? What do you need to build between now and the launch?
Yeah. We had already started building ahead of the data.
Yeah.
Really, our focus ahead of the data was getting all of kind of the leadership elements in place, beginning to make kind of the key decisions we'd have to make or at least getting the work started, whether that's in channel or otherwise. I'd say I think with any launch, it comes down to working very hard to have the right and kind of most important messages for the physicians and the community, and making sure they're able to get those messages and get them in the appropriate fashion. As well as making sure that they can access the drug and that's as frictionless a process as it possibly can be. I'd say we're continuing to hire that team, continuing to build out towards that, making decisions such as what is our channel strategy going to look like, what are our patient services going to look like?
I think a reflection from past launches as well is really, it comes down to great people and great teamwork, and I think with a great leader in Dan as well, I think that's one of the main things we're focused on as we're getting towards launching again.
I will say something that we did in advance is we started to build out our field medical team. For a number of months now, we have had a really great team out in the field who had prior endocrinology experience and have been meeting with physicians in different offices to understand their practices, to introduce Amylyx as a company. I think now with these very strong phase III results, again, working toward presentation, publication of those results, we are very pleased to have that team out in the field because, again, there is a really high unmet need here. We really want to meet the community where they are, and I think the best way to do that is, of course, to have people out in the field.
But I would say we will continue the build, both in terms of people, as well as all of the associated operations, over the course of this year and next.
We could easily spend the last 10 minutes or so talking about LUCIDITY and obviously the opportunity in PBH, but maybe whilst we have you, obviously, and rightly so, there is a huge opportunity just in front of you, which is around PBH. As you think about the biology of avexitide, the mechanism where receptor antagonism may be appropriate and attractive, how are you thinking about other indications? What is the most interesting or compelling for you?
I think there are a number. So I would start with, as one surgeon put it to us, the body does not know that the gut was resected for weight loss or for cancer or for whatever indication. It just knows that it is gone, right? And that the nutrient transit has now been increased. So, what that means is that there are any number of upper gastric surgeries that can cause the same condition. Commonly used ones include gastrectomy for gastric cancer or esophagectomy for esophageal cancer.
There are a number of other reasons people get gastric surgery as well. Each of these has the potential to cause the same condition. So we think that that is certainly something that we are very excited about. We have data from a prior study or a couple investigator studies as well of avexitide in those other surgery-induced hypoglycemias. So it is something we are very eager for.
I think that's particularly important when we look at most major countries in Asia, including Japan, China, South Korea, and others, they have very high rates of gastric cancer, one of the leading causes of death. In reaction to that, countries have had very, very strong gastrectomy initiatives. In fact, probably foremost in Japan, where they have nationwide screening efforts and even do prophylactic gastrectomies to prevent people from having gastric cancer. Japan alone does on the order of about 100,000 gastrectomies each year. People with those surgeries end up with this condition at, if anything, higher rates than what we see with bariatric surgery. So very significant unmet need there. I think one nice thing about Japan particularly as a country as well is great regulatory agency, great experience with orphan products, and of course, a single country, single language as well.
I think that's of high interest to us. We get compassionate use requests, though, from all over the world, from Europe. There's probably similar prevalence, order of magnitude prevalence of PBH as there is in the U.S., in South America, Middle East. I think there's a lot more to do and many, many more people to help in that regard. There are other causes of hyperinsulinemic hypoglycemia. For example, there are genetic causes, congenital hyperinsulinism. Avexitide actually has a separate breakthrough status for congenital hyperinsulinism based on three very strong trials supporting in that indication. Then we have a long-acting program in IND-enabling studies right now. Avexitide is a once-daily subcutaneous injection. We see no barriers to entry for that in PBH.
People with PBH are very used to, for example, pricking their fingers multiple times a day and have expressed generally no concerns with a daily injection. However, if we could get to a long-acting, that may be even better for patients. Our goal is to have our IND next year in 2027 for the long-acting AMX0318. I'd say with this whole opportunity around a GLP-1 receptor antagonist, we see so much to do. Obviously, first and foremost, we have to focus on our NDA and our launch preparations in the U.S., but there's really a lot more to do here. We think the biology is so exciting. We get academic requests for all manner of things. We see a long road ahead here.
We have just under five minutes. Maybe in the last couple of minutes, I don't know if you call it 114 or 01.
Yeah.
Yeah, that's what I gathered. Maybe just talk a little bit about that program. Obviously, a different indication and what we should expect over the next 12- 18 months.
Sure. AMX0114 is an ASO targeting Calpain-2. Calpain-2 is a protease that's involved in basically breaking down the cytoskeleton when a nerve's axon degenerates and dies. It's been shown to be associated and activated in multiple neurodegenerative diseases. There's genetic data linking it to ALS. And we've seen pre-clinically, as well as other groups have seen pre-clinically, really for decades, evidence of this being a very important protein in the axonal degeneration process. Our idea with an ASO, there are multiple calpains, and we wanted to exquisitely target just Calpain-2, and we want it to be targeted in the CNS as much as possible. That's nice about an ASO that you can target that particular genetic sequence, and with intrathecal dosing, you can primarily target the nervous system, so to speak.
Trial ongoing, a multiple ascending dose, placebo-controlled study in people living with ALS. Because it's a protease, there are known things that Calpain-2 cleaves, some of which can be measured in the CSF. We'll be measuring those and tracking biomarkers both to look at biologic target engagement, but there are also some biomarkers such as neurofilament light we will look at for disease engagement as well. We're quite excited about that program, and we should have more biomarker data in the coming months and quarters.
And you've been busy. You struck a second collaboration with Gubra out of Denmark. I will be hosting their fireside at around the same time tomorrow for anyone in the audience. What attracted you to the company, the partnership? You've obviously worked together before. What are you looking to do?
Yeah. We were so pleased with our first collaboration, and so that is why we started a second around another rare endocrine target, as you mentioned. We acquired avexitide in July of 2024. We are looking at the peptide space generally, and I think there has been just tremendous advancements in the chemistry and biological understanding of how you develop peptides, including how you develop long-acting peptides. We did what we tend to do when we are in a new space, which is try to talk to as many people as possible.
I will say several people, including some of the academic leaders, said, "Gubra is the company you want to talk to." We met with Gubra, I will say in particular, their scientific founder, and we were just so impressed by the depth and breadth of knowledge that they have around peptide drug development, their experience on multiple programs translating from pre-clinic to clinic. I also think we just had a really nice, I will say, collaboration from the start, both in terms of expertise, I think we brought different expertise to the table, which is always a great place to start, as well as just cultural values. I think we and they have a genuine curiosity about the science and also an interest in trying to develop meaningful treatments for people. Just a great collaboration from the start.
At the end of December in 2024, just six months or so after we acquired avexitide, we started our collaboration with Gubra to develop a long-acting GLP-1 receptor antagonist. We were so pleased with the collaboration. In just about a year's time, we came up with molecules that met our very strict criteria. We were looking for opportunities to partner again and to leverage their great experience with peptide drug development and our own with rare endocrine clinical, and now soon to be commercial development as well. We identified a target and we are starting the collaboration now. We are very excited, and I think that is how we generally want to view innovation at Amylyx. We certainly think we have great ideas. We have exciting things in our pipeline. But we are always looking for other people or groups who can bring complementary expertise.
This is another nice such example. Again, with the goal of delivering treatments that are for really areas of high unmet need.
Thank you. We actually are bang on time. I did have one more, but I think you actually addressed it in the last response, Justin. Again, congratulations to all of you, the broader company as well. Super exciting time. Great to have you here. And obviously, thank you everybody for attending today.
Excellent. Thanks so much for having us.
Thank you so much.