Amylyx Pharmaceuticals Aktie

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 hypoglycemia 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 5 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 6 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 extreme 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.

And, 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?

I think, you know, 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 our current population of about 160,000. We work with people who've had PBH for 15 plus years, 20 years. So, it appears that sadly and, 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 that talk to many clinics, weight management clinics, bariatric surgeons, and I'd say generally they're not having trouble filling their OR time. And, you know, I think what we've seen in terms of the dynamic is I think early on there's this sense of, oh, well, now we have these weight loss drugs 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 pounds, 150 pounds. They're not going to achieve that with the current weight loss drugs. That's very different than if somebody needs to lose 20, 30, 40 pounds. And so they're very different parts of the population. If we just look at the U.S. population of the BMI 40 or greater, that's about 30 million people. So that's quite a substantial group still.

And even at this last year's ENDO, you know, I really pressed many of the endocrinologists I met with, you know, do you see a use for bariatric surgery still? And to a physician they said, absolutely. They said if somebody has a serious, severe obesity, I'm thinking about bariatric surgery. If somebody has diabetes, I'm thinking about bariatric surgery because they're 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. And 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 rare side effect as well.

Coming back onto the, just in the approval, the filing time. I think you've stated your intention to file the NDA by the end of this year, which is pretty fast. 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?

I give our team a ton of credit. They've been working hard on the NDA all year. High confidence going into the LUCIDITY trial based on the first 5 trials of the Avexitide. And so we thought, hey, this is an unmet need. We need to be ready. And the team did just that. So I just give them tremendous credit. So the last wood to chop, as you were saying, is everything around the Phase 3 trial, the CSR and the associated work around the Phase 3 trial. But 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 3.

So, sort of walking through the timelines a bit more. So, goal is to submit by year end. We have breakthrough status with Avexitide. So, we would hope for, expect a priority review. And so, with that, we're planning for a potential launch in 2027, so alongside our NDA preparation work, we are also doing all of our launch preparation work as well.

And on the commercial side, as you ramp up there, what are the most important, you know, 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. Really our focus ahead of the data was getting all of the leadership elements in place, beginning to make the key decisions we would have to make or at least getting the work started, whether that's in channels or otherwise. I'd say I think with any launch it comes down to working very hard to have the right and 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 that's as frictionless a process as it possibly can be. So I'd say we're continuing to hire that team, continuing to kind of 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. But I think kind of a reflection from past launches or past launches as well is really, it comes down to great people and great teamwork. And I think that's, 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.

And I'll say something that we did in advance is we built out, started to build out our field medical team. And so for a number of months now, we've 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 the company. And I think now with these very strong Phase 3 results, again, working toward presentation, publication of those results, we're very pleased to have that team out in the field because, again, there's 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'd say we'll continue to build both in terms of people as well as all of the associated operations over time, 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's a huge opportunity just in front of you, which is around PBH. As you think about the biology of Avexitide, you know, the mechanism where receptor antagonism may be appropriate and attractive, how are you thinking about other indications? What's the most interesting or compelling for you?

Um, I think there are a number. So, I'd start with, as one surgeon put it to us, the body doesn't know that the gut is resected for weight loss or for cancer or for whatever indication. It just knows that it's gone, right, and that the nutrient transit has now been increased. 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, 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's certainly something that we're very excited about. We have data from a prior study or a couple investigator studies as well of Avexitide in those other surgery-induced type of glycemias. So it's something we're 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, 1 as a leading cause of death. And so 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.

And so 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. And I think, you know, 1 nice thing about Japan, particularly as a country as well, is, you know, great regulatory agency, you know, great experience with orphan products, and you know of course a single country, single language as well. So I think that's of high interest to us. We get compassionate use requests though from all over the world, from Europe, probably similar prevalence, order of magnitude prevalence of PBH as there is in the U.S., in South America, Middle East. So 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 3 very strong trials supporting that indication. And then we have a long-acting program in IND-enabling studies right now of Avexitide as 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 concern with a daily injection. However, if we could get to a long acting, that may be even better for patients. And so our goal is to have our IND next year in 2027 for the long-acting AMX0318.

So 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. So we see a long road ahead here.

We have just under 5 minutes. Maybe in the last couple of minutes, I don't know if you call it 114 or 01. Yes, that's what I gather. Maybe just talk a little bit about that program, obviously a different indication and sort of what we should expect over the next 12 to 18 months.

Sure. So AMX0114 is an ASO targeting Calpain-2. So 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 preclinically, as well as other groups have seen preclinically, really for decades of 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 sort of exquisitely target just Calpain-2, and we wanted to be targeting 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, you know, primarily target, um, you know, the nervous system, so to speak.

So 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. So 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 kind of disease engagement as well. So we're, you know, quite excited about that program and we should have more biomarker data in the coming months and quarters.

And you've been busy, so 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. Um, you know, what are you looking to do?

Yes, we were so proud, pleased with our first collaboration and so we started a second around another rare endocrine target, as you mentioned. So, you know, we acquired Avexitide in July 2024 and we were looking at the peptide space generally, and I think there's been just tremendous advancements in the chemistry and biological understanding of how do you develop peptides, including how do you develop long-acting peptides. And so we did what we tend to do when we're in a new space, which is try to talk to as many people as possible. And I'll say several people, including some of the academic leaders said, Gubra is the company you want to talk to.

So we met with Gubra, I'll 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 preclinic to clinic. And I also think we just had a really nice, I'll 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 sort of 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. So just a great collaboration from the start.

So at the end of December 2024, so just 6 months or so after we acquired Avexitide, we started our collaboration with Gubra to develop the long-acting GLP-1 receptor antagonist. We were so pleased with the collaboration, you know, in just about a year's time, we came up with molecules that met our, you know, very strict criteria. And so we're 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're starting the collaboration now, so we're very, very excited. And I think that's how we generally want to view innovation at Amylyx. I certainly think we have great ideas. We have exciting things in our pipeline. We're always looking for other people or groups who can bring complementary expertise. So this is another nice such example. And again, with the goal of delivering treatments that are for really areas of high unmet need.

Thank you. We actually are bang on time. So I did have 1 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.

Good morning. My name is Kat, and I will be your conference operator today. At this time, I would like to welcome everyone to the Amylyx Pharmaceuticals Phase III LUCIDITY Topline Data Conference Call. [Operator Instructions] Please be advised that this call is being recorded at the company's request. I would now like to turn the call over to Lindsey Allen, Vice President, Investor Relations and Communications.

Good morning, and thank you all for joining us today to discuss the top line results from the Phase III LUCIDITY trial of Avexitide in Post-Bariatric Hypoglycemia or PBH. The slide deck accompanying our remarks this morning will be available on the Investors section of our website for your reference following the conclusion of the call. With me on the call today are Josh Cohen and Justin Klee, our Co-CEOs; Dr. Camille Bedrosian, our Chief Medical Officer; Dr. Marilyn Tan, Principal Investigator of the LUCIDITY clinical trial and Clinical Professor of Medicine at Stanford University School of Medicine; Jim Frates, our Chief Financial Officer; and Dan Monahan, our Chief Commercial Officer, will join us for the Q&A portion of the call.

Before we begin, I would like to remind everyone that any statements we make or information presented on this call that are not historical facts are forward-looking statements that are based on our current beliefs, plans and expectations and are made pursuant to the safe harbor provisions of the Private Securities Litigation Reform Act of 1995. These statements include, but are not limited to, the therapeutic potential and safety of Avexitide as a treatment for PBH, expectations regarding the timing for NDA submission with the FDA, the potential benefits of regulatory designations held with the FDA, the plan to present data at an upcoming medical meeting and expectations regarding the timing and preparations for potential commercialization of Avexitide if approved.

Actual events and results could differ materially from those expressed or implied by any forward-looking statements as a result of various risks, uncertainties and other factors, including those set forth in our most recent filings with the SEC and any other future filings that we may make with the SEC. You are cautioned not to place any undue reliance on these forward-looking statements, and Amylyx disclaims any obligation to update such statements unless required by law.

Now, I will turn the call over to Camille.

Thank you, Lindsey, and thank you all for joining us this morning. It is with great enthusiasm that we share the positive top line results from the Phase III LUCIDITY trial of our lead asset, Avexitide, an investigational first-in-class GLP-1 receptor antagonist in post-bariatric hypoglycemia or PBH, following Roux-en-Y gastric bypass surgery. LUCIDITY met its FDA agreed upon primary endpoint, demonstrating a 55% reduction in the composite rate of Level 2 and Level 3 hypoglycemic events compared to placebo p-value of 0.000003.

The trial also met all secondary endpoints, demonstrating consistent reductions in both Level 2 by self-monitoring blood glucose, or SMBG, and continuous glucose monitoring, or CGM, and Level 3 hypoglycemic events versus placebo. And importantly, Avexitide was generally well tolerated through the double-blind study period with a favorable safety profile. LUCIDITY is the sixth clinical trial of Avexitide to generate statistically significant results in PBH and the largest and longest study conducted to date. Taken together, these findings support the potential for Avexitide to become the first FDA-approved therapy for PBH, a condition with a profound unmet medical need.

I would like to briefly recap the design of the Phase III LUCIDITY trial. LUCIDITY is a multicenter, randomized, double-blind, placebo-controlled trial evaluating the efficacy and safety of Avexitide in adults with PBH following Roux-en-Y gastric bypass surgery. The prespecified primary endpoint was the composite rate of Level 2 and Level 3 hypoglycemic events compared to placebo through week 16. In addition, we evaluated secondary endpoints of Level 2 hypoglycemic events as measured by SMBG and by blinded CGM and Level 3 hypoglycemic events.

Level 2 events are defined as glucose levels below 54 milligrams per deciliter, an established threshold for clinically significant hypoglycemia and Level 3 events are defined by significant cognitive or physical impairment requiring assistance from another person. These endpoints capture hypoglycemic events that matter to patients and can have meaningful consequences for safety and day-to-day functioning. In a few moments, Dr. Tan will speak about the day-to-day impact of PBH on those living with this condition.

In the trial, 78 participants were randomized 3:2 to receive either Avexitide 90 milligrams once daily or placebo. The treatment groups were generally well balanced. More than 90% of the participants completed the 16-week double-blind treatment period and all eligible participants entered the ongoing open-label extension portion of the trial. Avexitide met the primary endpoint, demonstrating a 55% reduction in the composite rate of Level 2 and Level 3 hypoglycemic events compared to placebo through week 16 with a p-value of 0.000003. It is important to note that these results are on top of current standard of care medical nutrition therapy. We are deeply inspired by these results and the potential to address a long-standing unmet need for people living with Post-Bariatric Hypoglycemia.

In addition, LUCIDITY met all secondary endpoints, demonstrating consistent, highly statistically significant and clinically meaningful reductions in Level 2 hypoglycemic events by SMBG, Level 2 hypoglycemic events by CGM and Level 3 hypoglycemic events compared to placebo. Taken alone, each of the prespecified primary and secondary endpoints yielded highly statistically significant and clinically meaningful results. Taken together, these efficacy findings demonstrate a compelling body of evidence for Avexitide in PBH.

Avexitide was generally well tolerated in the double-blind portion of LUCIDITY with a safety profile consistent with that observed across all PBH clinical trials completed to date. The majority of adverse events were mild to moderate, and there were no serious adverse events deemed related to Avexitide treatment. The most common adverse events were diarrhea, injection site redness or erythema and injection site bruising. Furthermore, there were no changes in body weight observed in either the Avexitide or placebo group over the 16-week double-blind period.

To close, the LUCIDITY results demonstrated highly statistically significant and clinically meaningful reductions in hypoglycemic events together with a favorable safety profile. Based on these positive data, we believe that Avexitide has the potential to be the first ever FDA-approved therapy for PBH. I want to thank the PBH community for their collaboration and participation in the study, including the 21 LUCIDITY sites, investigators, study coordinators and importantly, the participants. I also want to acknowledge our outstanding Amylyx team for their unwavering dedication to running such a robust and high-quality trial.

Now I would like to turn over to Dr. Tan, principal investigator of the LUCIDITY clinical trial to give an overview of PBH and what these trial results mean to the PBH community.

Thank you, Camille. It is my pleasure to be here today to discuss these exciting results and how they can make a difference for this underserved population. PBH is a rare chronic metabolic condition believed to be caused by an exaggerated GLP-1 response primarily after food intake, resulting in recurrent and often debilitating hypoglycemia. These episodes can lead to Neuroglycopenic symptoms, including cognitive impairment, loss of consciousness and in some cases, seizures or even worse.

Patients frequently describe living with PBH as a constant cycle of highs and lows with sudden and unpredictable glucose crashes that can be difficult to anticipate and manage. The impact extends far beyond just physical symptoms. The unpredictability of hypoglycemia can affect a person's ability to work, drive, care for family members, participate in social activities or even remain alone safely. As a result, many patients structure their daily lives around the risk of hypoglycemic events, creating a substantial burden both on the patients and their loved ones. This burden is reflected in patient-reported data.

In one study, more than 90% of individuals with PBH described themselves as living with a disability. This underscores the profound impact the condition can have on quality of life and day-to-day functioning. Based on a growing body of prospective and retrospective published literature, we estimate that PBH impacts approximately 5% of people who have undergone sleeve gastrectomy and 12% of people who have undergone Roux-en-Y gastric bypass, the two most common types of bariatric surgery. This corresponds to an estimate of approximately 160,000 people living with PBH in the U.S. who require medical management but currently have only the option of medical nutrition therapy and off-label medications, which are usually inadequate. And this is also why I'm so excited about the potential for Avexitide in this disease space.

Looking mechanistically, individuals with PBH can present with more than 10x normal physiologic GLP-1 activity. By binding to the GLP-1 receptor on pancreatic islet beta cells, Avexitide is designed to reduce this exaggerated GLP-1 response and restore activity towards more physiologic levels. Today's positive results support the hypothesis that a GLP-1 receptor antagonist targets a central pathway of PBH pathophysiology.

The top line results show that Avexitide significantly reduced both SMBG and CGM Level 2 and Level 3 hypoglycemic events, which can each be medical emergencies. Based on my clinical experience treating people living with PBH, they want more than anything to reduce the number of hypoglycemia events so that they can live independently without the fear of hypoglycemia. This is our hope for the approximately 160,000 people with PBH in the U.S. alone who face a significant unmet need for treatment. Importantly, Avexitide was generally well tolerated with a favorable safety profile. Overall, these results build on positive results from five prior clinical trials of Avexitide in PBH.

Today marks a significant moment for the PBH community who have a high unmet need for an FDA-approved treatment. PBH is a lifelong journey, and I believe that Avexitide has the potential to be a first-in-class treatment for patients that will make a meaningful difference in their lives.

Now I would like to turn it back over to Josh, Co-CEO of Amylyx.

Thank you, Dr. Tan. Our mission at Amylyx is to deliver novel therapies for communities with high unmet needs, and today's results are an important step forward towards achieving this goal. With these results in hand, we are acting with urgency to bring this potential treatment to the PBH community. We have been advancing NDA readiness and regulatory preparations so we can move rapidly now that we have positive top line data. Avexitide has received breakthrough therapy designation from FDA, and we are working expeditiously towards an NDA submission by the end of this year.

Following the top line data readout, we are also focused on presenting the LUCIDITY results through congress presentations and publications and deepening our understanding of PBH via expert engagement. We continue to execute against a comprehensive launch readiness road map to ensure we are fully prepared for commercialization of Avexitide if approved in 2027. As part of our launch readiness efforts, we are continuing to build our understanding of the PBH market and making key hires in our medical affairs and commercial organizations.

Additionally, we recently activated our disease state education campaign, Uncover the Mystery of Post-Bariatric Hypoglycemia to address the educational need among HCPs and the PBH community. As part of this initiative, we launched uncoverpbh.com. This platform provides educational resources for both health care professionals and the PBH community. With over $250 million in cash on hand at the end of Q2, we believe we are well positioned to execute on the next stages of our launch plans. We are excited about today's results and the potential to bring Avexitide to people living with PBH as the first approved therapy of its kind.

I'll now turn the call over to Justin for concluding remarks.

Thank you, Josh. At the start of the year, we outlined three primary objectives for Avexitide to deliver top line data from the LUCIDITY trial, advance NDA readiness to support a potential submission and strengthen our commercial launch preparations. With strong top line data in hand, we have achieved our first objective. We are well on our way to achieving our further objectives as we diligently prepare to advance Avexitide through the regulatory process and ultimately, if approved, deliver this potential treatment to the PBH community. This is a remarkable moment for people living with PBH, their loved ones and for Amylyx, and we are deeply grateful for everyone's support. I would like to once again thank the PBH community, investigators and our team for their collective efforts.

Now I would like to open it up for Q&A.

[Operator Instructions] And your first question comes from the line of Seamus Fernandez with Guggenheim Securities.

Congratulations on the data. Maybe just one confirming question. As I look at the data and the way that it's presented, I think the most simplistic way to look at this without knowing the exact placebo response may be to kind of draw us back to the Phase II results where we saw a 55% to 60% absolute reduction in the events. Is that the right way to think about the data? It's just we haven't seen slides posted yet. And so it's a little bit challenging to draw conclusions there. So if you could tell us the placebo response, that would be very helpful. But if it is the right way to think about it, just go back to the Phase II because you're preserving these results for publication and for a major medical meeting, that would be super helpful, I think, to everybody on the line.

And then separately, we have this outstanding question, and this is a question for the team and for Dr. Tan as well. Is there any reason to think that Roux-en-Y versus all other types of PBH or hypoglycemia brought on by a bariatric surgery or even a gastric surgery would have a meaningfully different result than what we saw in this Roux patient population. I asked that question just because it seems like there is a broader potential opportunity should the agency take a more flexible approach to the results that were just published.

Yes, possibly, I'm happy to maybe take the first one and Dr. Tan, and I'll pass to you right after that if it works. So maybe kind of confirming on your first question about the placebo. Yes, I think you're thinking about it right. And probably overall, our goal in LUCIDITY was to be as consistent with the prior trials as possible. And I think we're quite excited to have seen that the results appear quite consistent with what we've seen in prior trials. So yes, the 55% is relative to placebo, very similar to the 55% reduction we saw in the composite relative to placebo in PREVENT, the Phase II trial. And then yes, on your question about Roux-en-Y versus other surgical types, I'll pass to Dr. Tan.

Thank you. As mentioned, the data from Phase IIb in particular, we had reanalyzed looking at a similar endpoint. And so we're very excited for the results compared to placebo. And as you know, this study was in patients with Roux-en-Y gastric bypass. And increasingly, we are seeing more vertical sleeve gastrectomy. However, there is still a very prevalent population of those with Roux-en-Y gastric bypass. And in my personal practice, I have many patients actually with other subtypes of surgery as well, which you alluded to. Many patients who have had total gastrectomies for gastric cancer, Nissen fundoplication, other upper GI surgeries. And while this study only included patients with Roux-en-Y gastric bypass, the Phase IIb study did include patients with other surgical subtypes.

And when we separated out the VSG and gastrectomy patients, their response to Avexitide was just as robust for reducing Level 2 and Level 3 events. We know that there is an exaggerated GLP-1 response in those patients as well. So I'm excited to have this option available. And I am fairly certain that most health care providers who are treating these patients would use it in PBH patients who have other surgical subtypes.

Yes. And I'll just add -- just to give a little more context from our perspective and a bit on the landscape. So I think the best current prevalence estimates come from the work from the team from Stanford, which found that the current U.S. prevalence of PBH is about 160,000 people. And of that group, the estimate is about 120,000 of the 160,000 had Roux-en-Y gastric bypass leading to their PBH. As Dr. Tan said, though, there are many different surgeries that can lead to this condition.

I'd say from an FDA perspective, obviously, it's early. We have yet to even submit our NDA. Our position is that PBH is PBH, and we have evidence that Avexitide appears to work regardless of the surgical intervention. But FDA can also take the stance that the Phase III population was Roux-en-Y gastric bypass PBH. And so we'll see as we get into the NDA. But again, our belief is that PBH is PBH. However, if we need to run an additional study to show that comparability, we think we can do that in a pretty efficient manner, given that we can see the effect of Avexitide in a single dose.

And your next question comes from the line of Joseph Thome with TD Cowen.

Congratulations on the data. Maybe one for Dr. Tan. Can you talk a little bit, assuming a broad label here, how quickly this would be adopted into your practice? Maybe sort of what proportion of your PBH patients would you recommend the therapy to upon approval? And then one for the company. Is there anything left on the sort of pivotal path to the NDA submission related to CMC? Or is it mostly just kind of getting this data into the NDA now? Anything you can highlight there?

My patients and I are extremely excited. I mean, the patients who have been on prior studies, the patients who are following this on the Facebook group, are asking me -- I literally had two asked me yesterday in clinic, when can I be on this drug. So there is a lot of excitement despite it being a new therapy, people are ready for it. So I don't think that there will be any hesitation. There is robust evidence in the PBH population. And more importantly, there is just no other effective treatment for these patients. And so to actually have a dedicated treatment targeted for this disease that actually targets the underlying pathophysiology is extremely exciting.

Yes. And as far as your second question on the NDA submission. So we've been working on the NDA this entire year, given the confidence in the five prior trials in anticipation of these results, although I'll say these results exceeded even our high expectations, which is really exciting with both the significant primary outcome and also the consistency across the secondary outcomes. But as far as the NDA submission goes, our goal was really to be in a position where the sort of last piece would be the Phase III data and all of the writing associated with that. And so that's the position we're in today. We're in a very strong position with our NDA. The goal is to submit by year-end. We have a breakthrough therapy designation for Avexitide, which makes the product eligible for priority review. And so with that, that's how we are planning for a potential launch of Avexitide if approved next year in 2027.

And your next question comes from the line of Michael DiFiore with Evercore ISI.

Huge congrats on the data, very well deserved. Two questions for me. Would you be able to provide the mean and median absolute composite event rates for Avexitide and placebo as well as for the 3-week run-in? And my second question is, what was the percent of Avexitide patients with 0 Level 2 or Level 3 events over the 16 weeks? I think your Phase IIb showed that they were -- this proportion was greater than 50% who were event-free.

Yes. Thanks, Mike. So yes, here, we're presenting the primary outcome, which to remind, we saw a 55% reduction with a p-value of 0.000003 which we're incredibly excited about. So that's our primary outcome here. I think as Seamus brought up a little bit earlier, we do want to preserve some results for publication. So we haven't given every nitty-gritty detail at this point. But what we have seen is kind of consistent and strong results across, including hitting every single one of our secondary outcomes with high statistical significance. And then yes, I think probably the same answer on the question of percent with 0, but I think you can probably tell from the p-value, the placebo and active groups are quite separated.

And your next question comes from the line of Jeff Meka with Citigroup.

This is Jarwei on for Jeff. Just wanted to add our congratulations on the strength of the data as well. Maybe first for Dr. Tan, just a question on Level 2 versus Level 3 differences given the -- it's very clear that the placebo response and the Avexitide response are quite separated. But at the end of the day, does it really matter the differences between Level 2 and Level 3? Or does the totality of the composite is just so compelling that it would be broadly applicable to patients living with PBH. And then for the Amylyx team, just thinking about the data that you guys generated, can it be utilized to maybe generate some pharmacoeconomic estimates? Just thinking about from a reimbursement perspective.

I can go first. As you noted, the data are just so compelling, and it was statistically significant for both Level 2 and Level 3. And I would say that from a clinical standpoint, I mean, we make this distinction in research, right? We have to have cutoffs. We have to have a number of cutoffs, and we have to have an adjudication committee to verify that it is a Level 3 event. But in the real world and in clinical practice, any hypoglycemia event can lead to a catastrophic accident or some other bad outcome. And so really any reduction in these significant -- clinically significant episodes of hypoglycemia is meaningful to these patients.

Yes. And I'd just add from a pharmacoeconomic perspective, we're continuing to evaluate and continuing to learn there. We did present a poster at ENDO earlier this year where we began to describe the burden of PBH from a pharmacoeconomic perspective, probably unsurprisingly, given how severe these events are, there is quite a large economic burden to the health care system from PBH. So we do believe a drug that's able to impact that can have quite a significant benefit there as well. But that's something we'll continue to research as we go into our payer interactions.

And I'll just add from a payer perspective as well. First of all, there are no treatments for PBH today. So that's the landscape that we go into. However, payers are very aware of the dangers of hypoglycemia given their long-time coverage of insulin and other drugs that may be associated with hypoglycemia. So I think they're very aware of just how dangerous severe hypoglycemia is for individuals. And I think that gives us a great position as we work toward the hopeful approval of what would be the first approved treatment for people with PBH.

And your next question comes from the line of Marc Goodman with Leerink Partners.

Can you talk about the diarrhea adverse event? Was it relatively mild? Did it occur at the beginning of the 16 weeks? Was it lasting throughout the whole period? Maybe Dr. Tan, was it severe enough that anybody complained about it and you think would prevent anyone from using the drug?

Happy to start, and then we can pass to Dr. Tan. So I'd say, again, obviously, these are the top line results, but I'd say, generally, the safety profile was quite good and Avexitide appeared to be quite well tolerated in line with prior studies. And so generally, events such as diarrhea were mild or occasionally moderate. And I would say, just generally, we had very good compliance continuation in the study. All eligible participants went into the open-label extension. So hopefully, that gives you a sort of population view, and I'll pass to Dr. Tan for her comments on the study as well.

So I can't speak to the exact details of all of the participants, but I can tell you that I did not have any participants discontinue and all of them went on to open-label extension. And just looking back at the prior trials that I've done with Avexitide, there have been four that I was the principal investigator -- or three others that I was the principal investigator on. And I have not had any drug discontinuations and even patients who have had any GI events in the past have asked me repeatedly when they can get back on the drug. So it has not been anything to the point where it discourages a patient from actively seeking out the treatment again.

Can I just ask Dr. Tan, how many patients do you have that would be eligible here for this drug?

The vast majority of my patients, over 90%. I have a more severe patient population, which tends to be more moderate to severe, although I do have a couple of mild ones that I've just kind of incidentally diagnosed in my clinic. But I would say anybody who is having any clinically important hypoglycemia would qualify for this medication. And people are waiting. They're excited. They're ready.

So over 90% of what absolute number.

Well over 100. But I don't focus so much on the number because I personally limit my clinic because I have no meaningful treatment for them. And so more importantly, I'd like to highlight that I literally get 1 or 2 new referrals each week, sometimes more, which I expect there will be more after this week from all over the country and from even outside of the country for PBH patients. So have I actually -- had I actually accepted all of those, I would have probably over 1,000 patients. I've literally had that number of referrals over the last couple of years.

And your next question comes from the line of Rami Katkhuda with LifeSci Capital.

Just wanted to pass along my congrats on the data as well. Fantastic results. I guess, can you touch on how consistent the efficacy was across baseline disease severity? Did patients with the highest event burden drive a similar greater, I guess, relative benefit? And could that influence whether the initial commercial focus is concentrated in more severe PBH patients?

Yes. So one, I'll just remind that everybody in the study was required to have at least an event per week during the run-in. So that was one of the key inclusion criteria of the study. I'd say based on the kind of difference you see here and the strength of the p-value, the groups are quite separated. So no individual or no small set of patients is driving this. The groups are really not overlapping once they're on drug. But yes, we'll continue to share more details as we get towards publications and presentations as well.

And Rami, I'll just add a bit to that. So of course, the primary outcome, 55% reduction and a very significant p-value, I think that gives a good picture. But it's also the consistency across all secondary outcomes. Level 2 hypoglycemia self-monitored blood glucose, Level 2 hypoglycemia by CGM and Level 3 events, all consistent with the primary outcome, all highly statistically significant as well. So hopefully, that gives you the results were very robust.

And I guess, has the strength of the LUCIDITY results changed or accelerated your plans for Avexitide outside the U.S.?

So I would say that we went into the study with high confidence given the five prior trials. These results, as I said, really even exceeded our high expectations. And I would say, remind us of the unmet need in PBH including, as you were saying, for other surgeries leading to hypoglycemia. I'd note that it depends on the region you're in the world, what surgery leads to hypoglycemia. We estimate in Europe that there's a similar prevalence as in the United States. In most major Asian countries, for example, Japan, there are very high rates of gastric cancer. And so people get gastrectomy for their gastric cancer and a significant portion of people develop the same chronic hypoglycemia condition. And we have data from the Phase IIb that Avexitide appears to work regardless of the gastric surgery that led to the hypoglycemic condition.

So we're very excited about the opportunity internationally as well. We hear from people around the world, as Dr. Tan does, very consistently asking about Avexitide. But first and foremost, we also have to execute on what we have in front of us in the U.S. And so our first objectives are really submitting the NDA, preparing for U.S. commercialization next year, but we certainly have our eyes internationally as well.

And your next question comes from the line of James Condulis with Stifel.

Congrats on the data. Great to see. Maybe one on efficacy. Curious if you can comment on any quality of life measures you looked at? And what benefit you saw there, if any? And maybe more broadly for Dr. Tan, it would be helpful if you could just help us sort of like characterize how meaningful these hypoglycemic data are in terms of actually translating into like everyday life and improving quality of life.

Yes, I'll comment very briefly and then pass to Dr. Tan. So we're still analyzing data. So here, we have kind of the top line results. We'll expect to kind of have our PROs later on. But I would say part of the goal and the primary outcome of Level 2 and Level 3 hypoglycemia, these are clinical events that have inherent significance, but I'll pass to Dr. Tan to talk more there.

Yes. So clinically, I would actually like to think back to that first slide that was shown with our patient with PBH. I don't know if any of you have seen a video that was her -- in her home talking about how being on Avexitide made her feel like she could take care of her own children, gave her the confidence actually to have another child. And so that is how life-altering just her couple of weeks on Avexitide was for her to show her that she could at some point, have the hope to function independently.

Now that is obviously a very extreme situation, but that is the degree of impact the hypoglycemia has on these patients. And so as mentioned, we will have more data on the quality of life later. But just based on individual patient testament, the patients who just tell me this changed my life, my husband can now go to work during the day. Things like that, it's just life altering not only for the patients, but also for their families.

And your next question comes from the line of Graig Suvannavejh with Mizuho.

Congrats on the data. I've got two. One for Dr. Tan. Dr. Tan, in the future potential of Avexitide being approved for your PBH patients. If we go on an assumption, just an assumption that the label is restricted to Roux-en-Y patients -- who've had Roux-en-Y procedures. Can you talk about what you think it would be like for patients who haven't had Roux-en-Y surgeries to be able to get Avexitide? I guess I'm trying to get your sense of what you think the work would be involved on either your end or others to have the drug used in patients who've had surgeries or procedures done otherwise and then being able to get on treatment?

And then my second question is for the company. Team again, congrats on the data. I was wondering if you could just review kind of where we are in the competitive landscape. I saw a development last week that a Phase II company working in the space went public and just want to get your thoughts on where you think kind of the competitive landscape is right now.

Yes. Maybe I'll comment very briefly and then pass to Dr. Tan as well. So yes, I mean, I think for any drug, we can only be -- it's only appropriate to be prescribing the drug on label. So that would be our focus depending on whatever label we ultimately are able to receive from the FDA if we're potentially approved in 2027. Maybe I'll just touch the competitive comment, and then I can pass to Dr. Tan if she wants to add anything as well. So yes, I think especially with these results today, there really, in our view, is nothing that has the profile of Avexitide. So our focus is on getting it to patients who can potentially benefit if approved in 2027.

Well, and just adding one other point as well. So I think the -- again, I go back to first the prevalence estimates today of the current people in the United States who have PBH, we estimate that about 120,000 out of the 160,000 had Roux-en-Y gastric bypass leading to their PBH. If we find ourselves in the position where FDA requires additional evidence to show that Avexitide is -- works in other surgeries that led to the same hypoglycemic condition, again, we think we can do that pretty efficiently given the now six studies supporting the effectiveness of Avexitide. The fact that we can see it in a single dose. And I think this all gets the point that we really think we're getting to the heart of PBH with the GLP-1 receptor antagonist.

Okay. And I can follow up on that. So as Josh noted, the target is on-label use with this trial. But as a clinician and health care provider caring for patients with PBH, I can tell you that people with other surgical subtypes will be doing anything possible to get on this therapy, whether it's on-label or off-label. I am not advocating for off-label use per se, but I'm confident that if another trial were needed, I have a list of patients with VSG and gastrectomy and other surgeries who are anxiously waiting and literally asking me every week when they can be in a trial and when they can be on the drug. So I don't think that another trial would be a challenge in any way.

Your next question comes from the line of Jason Gerberry with Bank of America.

One for me, just for Dr. Tan. I guess it would seem like there is a complex referral pattern to get these patients to endocrinology specialists. But, your comment about an expectation for a pretty quick ramp to a larger patient population. Maybe what gives you the confidence and how you see this referral pattern sort of settling out over time? Do you just think it's word of mouth and education more broadly in the community that an option is out there? Because I guess one would wonder, it's a pretty rare population. So how do you see that dynamic playing out?

Yes. When I first started my work with Avexitide over 10 years ago, it was hard to find patients because there wasn't a large community. There was no ICD-10 code, which we're excited to share if you're not aware already, will be coming later this year. But the awareness has really increased significantly over the last 10 years. And you can see that reflected in the fact that there will be a diagnostic code that there are -- there's a large patient Facebook group and actually not just for PBH patients, but also there is a large support group for total gastrectomy patients with gastric cancer where they talk about the hypoglycemia.

Furthermore, as one of the earlier questions were about the competitive landscape, you can see that there is obviously awareness from other companies as well that there is this increasing unmet need. And so my referrals have only increased over the last 10 years as I've done more and more of these studies, and I'm confident that the referrals will continue and will increase after this week. And I have to create space for these patients in my clinic. We do have other providers in our clinic as well. But there's a lot of excitement over this. And even our fellows, for example, are so excited to see these cases because they present these really -- I guess, there's challenges, but in a very satisfying way when you get a good result from these patients.

And Jason, if I just may add. I'll add a couple more comments there. Just from an initial market research that we've done, there is a very high intent to treat amongst the endocrinology community. So with the patients that they have in front of their setting, we've tested this. And again, there is a high intent to treat. That would be the first point. The second is we've launched our disease state educational efforts, and we've received great feedback from both the community as well as from the endocrinology community.

So as these educational efforts take hold, the market will continue to grow over time. So yes, there are patients in these various settings of care that we're aware of. But as we continue to educate the endocrinology community, I think we'll see more and more comfort from community endocrinologists and their willingness to prescribe as well.

And your next question comes from the line of Ananda Ghosh with H.C. Wainwright.

On the fantastic data, guys. Two questions. Given the data, what did the trial teach you in terms of the placebo response, blinded CGM, the fear of unmasking daily injection issues? And probably more importantly, what it taught about the mechanism itself? Is there a window beyond 55% that keeps an option for developing a franchise-based pipeline over the period of time? And also can tolerability be managed like the GLP-1s?

Yes. Great question. So I think first and foremost, we tried to design LUCIDITY based on the prior trials. And the goal was to replicate as closely as possible those very strong results we had seen in the past studies. I think what we were quite excited about was, as I mentioned earlier, PREVENT the Phase II study at a 55% reduction in the composite. Here, we also saw a 55% reduction in the composite. So I think we were able to take the learnings from the past study as we designed and executed the Phase III as well.

I think on your question on tolerability, the drug was very well tolerated. More than 90% of people completed the study and everybody who is eligible for the LOE went into it as well. But I think it does continue even from some of the early work at Stanford and otherwise, there's been a strong link that GLP-1 is one of, if not the main driver of this disease. And I think seeing the strong efficacy just kind of further supports that kind of mechanistic understanding that GLP-1 seems to be sort of at the center of why these patients are experiencing hypoglycemia.

And Ananda, I'll just add with that. That's why we started investing in our next-generation candidate, AMX0318, that our long-acting GLP-1 receptor antagonist. So that's in IND-enabling studies now. Our goal is to get the -- submit the IND next year and to have that in clinical development alongside the potential launch of Avexitide. So we really do think that this exaggerated GLP-1 response is at the center of PVH. And so we really do see many opportunities to continue to innovate and continue to try to help as many people with PBH as we can.

Sorry, I just had a couple of things to add. There were a couple of parts to that question. So hopefully, I address all of it. But there was a question about the CGMs, and I've actually received many questions about the alarms. And we had thought about this and very thoughtfully considered where to set that alarm cutoff. Primarily, our concern is safety for this patient with a high degree of hypoglycemia unawareness. And I think some people had asked me, are we worried that the alarm might make us miss hypoglycemia events. And clearly, from the data with that 55% reduction, we did not have events missed the CGM did not interfere. And as Josh and Justin noted, compared to the prior studies where we did not have alarms, we saw similar results. And tolerability to me is not of concern.

As noted, we haven't had any significant treatment-related adverse events. And in my prior clinical trials, I have not had any patients discontinue due to any tolerability issues. And I think there was a question about the daily injections, and I know that the long-acting version was mentioned. But I can tell you that this population is extremely motivated. And while medication adherence in some other chronic diseases may be variable, I think that's largely driven by the fact that many chronic diseases are asymptomatic.

So for example, if you miss a shot of insulin, maybe your CGM alarms you that you're high, but you don't really feel it unless you're in severe dangerous hyperglycemia. Or if you miss a dose of your statin or your injectable cholesterol medicine, you probably won't have symptoms. However, if you have PBH and you miss a shot of your Avexitide, you will be symptomatic once you eat. And so that in itself is a daily reminder and motivator for these patients. And I would say that the adherence with symptomatic disease and the willingness to continue with therapies with symptomatic disease far exceeds that of other chronic diseases that are less symptomatic.

Your next question comes from the line of Christopher Chen with Baird.

Let me add my congratulations. Great data. First for Dr. Tan, just regarding standard of care for PBH currently, could you just provide a rough estimate of your patients who are on Acarbose? And of those on a Acarbose, how well their symptoms are being managed and whether -- how willing they are to try Avexitide? And then just for the team regarding regulatory, I know you have breakthrough designation. Any thoughts on pursuing priority review or rolling review or both?

Yes. The question of Acarbose, it's off-label therapy, but I agree that it's essentially the standard of care for these patients for a couple of reasons. We have a lot of experience with it from just long-term use as a diabetes drug. It's fairly well tolerated with minimal risk aside from some bloating. And importantly, it is inexpensive. However, the issue is just that it is really not effective. And while some small studies have shown fairly convincing data with oral glucose tolerance testing and mixed meal tolerance testing. The reality in clinical practice is that probably about 5% of my patients actually get some relief from Acarbose. I have more patients where I just keep them on it because in my mind, if it provides any bit of relief when there's really not much else that's effective that if it helps reduce their hypoglycemia by 5%, even we'll take it, right? There's nothing else available currently. But I would say that in my patient population, it's fewer than 5% that are reasonably controlled on Acarbose alone.

And thank you, Chris. On the regulatory front, so we're working hard on the NDA. Our goal is to submit by the end of the year. With breakthrough therapy designation, that does make that medication eligible for priority review. So we will be seeking priority review. We could also be eligible for a rolling NDA submission. However, we've been working on all sections of the NDA all year with the goal of submitting the whole package at once. So we'll be -- so our plan is to submit the full NDA by the end of the year and to seek priority review as well.

Your next question comes from the line of [ Freddy Lee ] with Wolfe Research.

Again on the strong data. I have a question. Can you talk about the plan to continue to build your GLP-1 antagonist franchise? Maybe talk about the time line strategy for Avexitide label expansion, but also importantly for the long-acting play with AMX0318.

Yes. Great question. So I think exactly as you mentioned, we remain incredibly excited about our GLP-1 antagonist franchise opportunity as well. First and foremost, as you've heard from Dr. Tan, this is a really serious condition, and we want to get this therapy to patients who can potentially benefit in the U.S. as quickly as possible. However, as we've continued to learn, PBH does not just occur in the U.S., it occurs worldwide with similar numbers of bariatric surgeries overall occurring in Europe and then also people getting hypoglycemia from other surgeries in the upper GI tract, whether that's gastrectomy for gastric cancer, esophagectomy for esophageal cancer, Nissen fundoplication for severe gastric reflux disease, et cetera. So those are certainly things that we're thinking about.

And then also while Avexitide, as Dr. Tan has said, we don't believe that the once-daily injectable will be a challenge for people living with PBH. We are continuing to invest in additional presentations, including a longer acting with 0318. And just to remind, that came out of a collaboration with Gubra who are a company really focused in peptide drug discovery and development. We worked with them to try to make as optimized the GLP-1 antagonist as we possibly could. So we screened a very large number of peptides, tried to arrive at ones that had great drug-like properties, great potency, great half-life, et cetera.

And the goal with that would be to have an agent that is once weekly or even less frequently administered than that. But we'll see as we get our IND filed, which we expect in 2027 and then as we get clinical data thereafter.

And your next question comes from the line of Seamus Fernandez with Guggenheim Securities.

So just a couple of quick ones. Just hoping you guys could give us a sense of the OLE participation rate, the early access program participation rate. And if you could just help us understand, are there any gating factors to expanding the EAP, whether it's kind of manufactured product or access to manufactured product? And is an expansion of the EAP a possibility?

And then just as it relates to the longer half-life opportunity, I just wanted to understand a little bit are you seeing opportunities in the data itself for Avexitide where a longer half-life drug could provide even better coverage than your 90 milligrams of Avexitide. We have the 4-week Phase II data. We've got the headline results here for your 16-week data. So just trying to kind of square the circle on what you see as the opportunity for a weekly? Is it convenience or perhaps even better efficacy?

Sure. So maybe go one by one. For OLE participation, every eligible patient who could participate in the OLE did. So very strong OLE participation. EAP, it's still early days, but I think as Dr. Tan said, there's quite a lot of excitement about the potential to try Avexitide. So I'd expect continued interest in the EAP as well. And we will be working now that we have the top line data towards that expansion.

We'll provide more details there in the future as well. And then in terms of -- given that the long-acting is not yet in the clinic, I think we don't want to speculate too much on exactly what the profile might be. But I will just remind, as we worked with Gubra, the goal is to make as optimized the GLP-1 antagonist as we possibly could. So at least preclinically, we do believe we've developed a molecule with quite a good profile here.

I'm not showing any further questions in the queue. I would now like to turn it back over to Justin for closing remarks.

Thank you all very much for joining. On behalf of Amylyx, we would like to extend our sincere gratitude to everyone whose dedication and commitment made this research possible, including people living with PBH, the trial participants, their families, the LUCIDITY investigators, the team at Amylyx and our shareholders. Thank you all for joining us today, and we look forward to talking more as we embark on this exciting new chapter.

Ladies and gentlemen, this concludes today's conference call. Thank you all for joining. You may now disconnect.

Good morning. My name is Carrie, and I will be your conference operator today. At this time, I would like to welcome everyone to the Amylyx Pharmaceuticals Second Quarter 2026 Earnings Conference Call. [Operator Instructions] Please be advised that this call is being recorded at the company's request.

I would now like to turn the call over to Lindsey Allen, Vice President, Investor Relations and Communications. Please proceed.

Good morning, and thank you all for joining us today to discuss our second quarter 2026 financial results and business updates. With me on the call today are Josh Cohen and Justin Klee, our Co-CEOs; Dr. Camille Bedrosian, our Chief Medical Officer; Dan Monahan, our Chief Commercial Officer; and Jim Frates, our Chief Financial Officer.

Before we begin, I would like to remind everyone that any statements we make or information presented on this call that are not historical facts are forward-looking statements that are based on our current beliefs, plans, and expectations and are made pursuant to the safe harbor provisions of the Private Securities Litigation Reform Act of 1995. These statements include, but are not limited to, our expectations with respect to avexitide, AMX0035, AMX0114, and AMX0318, statements regarding regulatory and clinical development, the impact thereof and the expected timing thereof, and statements regarding our cash runway.

Actual events and results could differ materially from those expressed or implied by any forward-looking statements. You are cautioned not to place any undue reliance on these forward-looking statements, and Amylyx disclaims any obligation to update such statements unless required by law.

Now, I will turn the call over to Justin.

Good morning, everyone, and thank you for joining us. This is an exciting time for Amylyx and the post-bariatric hypoglycemia community as we approach the pivotal Phase 3 LUCIDITY top-line data readout. At the beginning of the year, we outlined 3 strategic priorities for avexitide, our investigational, first-in-class GLP-1 receptor antagonist with FDA breakthrough therapy designation in post-bariatric hypoglycemia or PBH.

First, advancing the pivotal Phase 3 LUCIDITY trial toward top-line data. The last participant has recently completed their last visit in the trial. We are on track and eagerly anticipating the top-line data readout in late August or early September. The database has yet to be locked at this time, and we remain blinded to the data.

Second, in parallel, advancing NDA readiness and regulatory preparations. We are actively preparing all applicable sections of the NDA to support a potential submission.

And third, strengthening our launch readiness to prepare for the potential commercialization of avexitide in 2027, if approved. We've deployed our field medical affairs team to facilitate on-the-ground HCP scientific exchange, and we've continued to build out our teams across marketing, market access, and commercial operations.

At ENDO 2026 in June, we activated our disease state education campaign, Uncover the Mystery of Post-Bariatric Hypoglycemia, designed to increase awareness, understanding, and action around PBH. Dan will provide more details on our launch readiness efforts later in the call. We're fully focused on execution as we work toward the potential of delivering the first FDA-approved therapy for people living with PBH.

With that, Camille, I'll turn the call over to you.

Thank you, Justin. PBH is characterized by recurrent and often debilitating hypoglycemia thought to be caused by an exaggerated GLP-1 response, primarily after food intake. The American Diabetes Association recognizes hypoglycemia as a potential medical emergency because low blood glucose levels can compromise the body's ability to maintain essential physiologic processes and can result in cognitive dysfunction, seizures, or loss of consciousness.

PBH is a chronic condition with no FDA-approved therapies. Many people with PBH live with the ongoing fear of hypoglycemia. Our pivotal Phase 3 LUCIDITY trial is a randomized, double-blind, placebo-controlled trial evaluating avexitide 90 mg once daily in adults with PBH following Roux-en-Y gastric bypass surgery. The LUCIDITY trial is anchored in the robust data generated to date from the 5 prior avexitide clinical trials in PBH that demonstrated statistically significant reductions in hypoglycemic events.

The primary endpoint is the FDA-agreed-upon outcome of reduction in the composite of Level 2 and Level 3 hypoglycemic events through week 16. At the ENDO 2026 Annual Meeting in June, several case reports describing many aspects of PBH and hypoglycemia were presented, highlighting a growing recognition of PBH and the seriousness of hypoglycemia across the medical community.

Dr. Colleen Craig presented a poster characterizing the clinical, economic, and humanistic burden of PBH in the U.S. and evaluating how Level 2 and Level 3 hypoglycemic events in PBH impact healthcare utilization, productivity, and overall cost. At the patient level, patients face direct medical costs, productivity loss, such as missed work, diminished quality of life, caregiver burden, and out-of-pocket non-medical costs. At the systemic level, societies face resource utilization and downstream clinical consequences in addition to direct healthcare costs, non-medical system costs, and societal productivity loss.

Also at ENDO 2026, we had meaningful scientific dialogue about PBH with endocrinologists that underscored the tremendous unmet need for people living with this condition. We met many endocrinologists with whom we had not previously engaged, and many of them already were aware of PBH. They describe the challenges in managing these individuals, given the limited options for treatment.

They had strong interest in learning more about this condition. This interest is inspiring as our field medical affairs team furthers PBH scientific exchange and engagement with endocrinologists. In addition, in June, CMS and CDC published their 2027 ICD-10 code files, which represent the official code set to be used for patient encounters beginning October 1, 2026. This code set includes an ICD-10 code specific to PBH, also demonstrating the growing recognition of this condition by the medical community.

In closing, we are encouraged by the increasing awareness and understanding of PBH, along with our informative engagements with healthcare professionals. We continue to be focused on strong execution as we approach our anticipated LUCIDITY top-line data readout.

With that, Dan, I'll now turn over the call to you.

Thank you, Camille, and good morning, everyone. We continue to make significant progress in our preparations for the potential commercialization of avexitide next year. We remain encouraged by the growing recognition of PBH among healthcare professionals. Importantly, our understanding of the PBH population continues to strengthen. We estimate that approximately 160,000 people in the U.S. are living with PBH following the 2 most common bariatric procedures, Roux-en-Y gastric bypass and sleeve gastrectomy.

This estimate remains supported by our independent claims analysis, ongoing field insights, and a growing body of published prospective and retrospective literature. Together, these data continue to reinforce both the significant unmet need and the opportunity to identify and reach appropriate patients. Our market research also continues to demonstrate a high intent among endocrinologists to treat PBH with an approved therapy, providing further confidence in the commercial opportunity should avexitide be approved.

We are excited to share that we recently activated our disease state education campaign, Uncover the Mystery of Post-Bariatric Hypoglycemia, to address the educational need among HCPs and the PBH community. As part of this initiative, we launched UncoverPBH.com. This platform provides educational resources for both healthcare professionals and the PBH community.

The HCP website is intended to help clinicians better recognize and understand PBH. The community website empowers people with PBH with information to support discussions with their healthcare teams. As Camille mentioned, engagement at ENDO 2026 was high, where we also introduced an interactive disease state education experience that generated strong engagement and positive feedback. One of our most encouraging early observations was the level of familiarity many healthcare professionals already had with PBH, reinforcing our view that awareness of the condition continues to grow within the endocrinology community.

In parallel, we continue to add key talent across the organization and advance our commercial readiness efforts as we prepare for the potential launch of avexitide in 2027, should it be approved.

And with that, I will now turn the call over to Jim to review our financials.

Thanks, Dan. Good morning, everyone. Our financial results for the second quarter reflect our continued disciplined execution of the Phase 3 LUCIDITY trial and targeted investment in advancing our broader pipeline. We ended the second quarter with $250.8 million in cash and marketable securities, compared to $279.8 million at the end of the first quarter. This capital provides us with an anticipated cash runway into 2028 to fund our operations through expected milestones, including our key focus, top-line readout, potential FDA approval, and potential commercial launch of avexitide in 2027.

Turning now to our results for the quarter, total operating expenses for the quarter were $45.7 million, up 7% for the same period in 2025. Research and development expenses for the quarter were $23.8 million compared to $27.2 million in Q2 2025. The decrease was primarily due to a decrease in spending related to AMX0035 for the treatment of progressive supranuclear palsy, offset primarily by an increase in spending related to the clinical development of avexitide in PBH and other costs related to avexitide.

Selling, general and administrative expenses for the quarter were $21.9 million, compared to $15.6 million in Q2 2025. This increase was primarily due to increased legal expenses, including a 1-time legal charge and investment in commercial strategic initiatives. We recognized $8.3 million of non-cash stock-based compensation expense for the quarter compared to $7.4 million of non-cash stock-based compensation expense in Q2 2025.

With the LUCIDITY top-line data readout later this month or early September, we're entering into an exciting phase. We're investing in a disciplined manner as we prepare for the potential launch of avexitide, and we believe we're well-funded to execute.

With that, I'll turn the call over to Josh.

Thanks, Jim. In addition to avexitide, we continue to advance our broader pipeline and our commitment to the communities we serve with high unmet needs. For AMX0035 and Wolfram syndrome, we presented week 96 data from the Phase 2 open-label HELIOS clinical trial in the spring, which continued to show stabilization or improvement in measures of glycemic control and vision, consistent with week 24 and week 48 data.

Under AMX0114 and ALS, we continue to advance the Phase 1 LUMINA multiple ascending dose clinical trial in people living with ALS. We are progressing through the dose cohorts given the favorable safety profile AMX0114 has exhibited in LUMINA so far. We are currently enrolling cohort 3. And for AMX0318, our long-acting GLP-1 receptor antagonist, IND-enabling studies are underway, and we are targeting a 2027 IND filing.

Additionally, we are pleased to share we entered into a second research collaboration with Gubra in July, following the collaboration that identified AMX0318. This new collaboration will screen and develop peptide candidates for another rare endocrine disease of high unmet need. We're looking forward to sharing additional updates on this program as it advances.

In closing, we are executing against our 3 strategic priorities for avexitide, including delivering top-line data from LUCIDITY, advancing our NDA readiness, and strengthening our commercial launch preparations. Guided by the profound unmet need of the PBH community, we are working with urgency to bring this potential treatment to people living with PBH.

Before we turn it over to the operator for Q&A, I want to reiterate that this is an exciting time for Amylyx as we are eagerly awaiting Phase 3 top-line data. Because we are getting close to locking the LUCIDITY trial database, we will be entering a quiet period after this call.

[Operator Instructions] We'll pause momentarily to assemble our roster. Your first question will come from Seamus Fernandez of Guggenheim.

So I just have a couple here. You know, I believe maybe you guys could just update us on when the last patient visit was. And, you know, what are the kind of key factors to that kind of need to be completed to lock the database? Where are the areas of kind of core focus or is it, you know, the sort of need to get all of the sites kind of fully aligned to be able to lock the database.

And then the second question is, I'm guessing you won't be able to update us on specific numbers, but maybe you can provide us a little bit of color on how the Early Access Program is progressing at this point. Are patients actively being recruited into the EAP? And, you know, how would you kind of characterize the demand for that program at this point? It's obviously an opportunity to really put the company commercially on a very strong footing going forward.

Great. Seamus, hi. Thanks for the questions. So your first question revolved around last patient visit and what efforts need to continue to be ready for the database lock and then top-line data. If we start with when our last patient's first visit was, we announced we completed enrollment late March or mid-March, I would say. And so it's a 16-week double-blind period. So advance toward that. We get to about mid-late July.

And there are, as you point out, rightly so, there are a number of activities that the team is working on, and they're continuing to execute beautifully and the enthusiasm continues very strong by the trial participants as well. There is data cleaning, making sure that everything matches up, dotting all the I's, crossing all the T's, because we only block a database once in this instance for the core study, double-blind period. So the team is being very diligent in that regard. And as we said, we expect, you know, top-line data late August, early September.

With regard to the Early Access Program, yes, we're so excited to have an Early Access Program for people living with PBH. The initial phase, if you will, of the EAP as we abbreviate it, is for those individuals in LUCIDITY who have completed the study, double-blind period, of course, and then the open-label extension. And then they had the opportunity to roll over into the EAP.

And also, at this period of time, it's open for those individuals who have been in prior avexitide trials. Many of those individuals are at other centers, so they have to be activated as well in order to participate in the EAP. It's a separate study, separate protocol. So we're early days yet. The enthusiasm is great about being able to participate in the EAP, and we'll continue to give you updates along the way.

Your next question will come from Joseph Thome, TD Cowen.

I'm not sure if you can answer this, but I guess in terms of the patient population that you did enroll for the Phase 3, I guess, does it overall look similar to the prior Phase 2 experience or any sort of comments can make on that. And then second, can you just remind us what sort of mechanisms were in place during the study to monitor compliance with the injections, just to make sure that, you know, patients were getting all the recommended doses over the...

Sure, sure. Thank you. So just to reiterate, we designed LUCIDITY with the Phase 2 studies in mind, the highly successful statistically significant outcomes for those Phase 2 studies. And we're enrolling participants who are very consistent with the populations that were enrolled in the Phase 2 and Phase 2b.

Furthermore, well, I can't give you specifics. Furthermore, our Amylyx team conducting the study were those who decided at the end of the day whether an individual was eligible or not. We went through a very rigorous assessment of eligibility before patients enrolled. So we're very confident and very pleased with how the study has been executed from day 1, actually.

Your second question is about study drug compliance. Yes, that is monitored throughout as well. And, you know, we're also pleased with those metrics and parameters also.

And I'll just add in terms of the trial conduct and sort of compliance, I'd say first it starts with the right clinical trial sites. So we were very rigorous in finding clinical trial sites who not only could recruit the right participants, but also were good clinical trial sites with good experience.

Second, we paid particularly close attention during the run-in period to see that not only were participants meeting inclusion and exclusion criteria, in particular the 3 events in 3 weeks, including 1 Level 3 event, but also that they were good study participants, that they were consistent, and we thought would be good trial participants for the study.

And then all throughout the study, our team had very close oversight and monitoring in partnership with the clinical trial sites to make sure that people stayed compliant with all study protocol needs as well as drug, as you were mentioning.

Your next question will come from Mike with Evercore ISI.

What evidence package would be required for an initial broad label encompassing all PBH? Like does LUCIDITY have enough sleeve patients to make for a compelling subgroup analysis here? And if the FDA restricts the label, potentially, what study design, enrollment size, and timeline would be needed to add sleeve patients? That's my first question.

And the second's on a commercial question. Hoping you could bridge the 160,000 patient prevalence estimate into the commercial funnel better. What percent of these 160K patients represent a realistic 5-year treated population?

Hi, Mike. Thank you for the question. So, the first in terms of label, I'll start with that, you know, given that we have yet to see the Phase 3 trial results, we have yet to submit the NDA, it's, you know, it's early to know too much about what the label will be. Give you the context as we see it today.

So first and foremost, we believe PBH is PBH, regardless of the surgery that leads to PBH, we believe the pathophysiology is the same and that the primary driver of hypoglycemic events is this exaggerated GLP-1 response. Now, looking through the clinical studies of avexitide, the majority of people with PBH studies with avexitide have had Roux-en-Y gastric bypass surgery leading to PBH, and that includes the Phase 3 LUCIDITY trial. One of the inclusion criteria was Roux-en-Y gastric bypass surgery that led to PBH only.

Now, in the Phase 2b, different surgery that led to PBH were allowed in for inclusion criteria, and avexitide appeared to work just as well regardless of the surgery that led to PBH. So as we submit our NDA and have the discussions with FDA, we think there's sort of 2 paths that could emerge. What we will strongly make the case for is that we believe avexitide should be for people with PBH, regardless of the surgery led to it due to the same pathophysiology and due to the evidence that we've generated to date.

FDA could of course take the stance that the Phase 3 trial was studied only in Roux-en-Y gastric bypass PBH patients. And so could say, you know, that would be the indication in the label. If that's the case, then I think you're right. The question would be what additional evidence would we need in order to show that avexitide should be applicable regardless of the surgery that led to PBH. And so we're working through those, you know, various scenarios right now. I'd say the way we view it, it should be pretty efficient.

You're just trying to show that, you know, that these are not different and that avexitide works regardless. We're able to see the effects of avexitide in a single dose. So we think that that should not be an overly burdensome study. And maybe last piece I'll say on the sort of commercial side of things, if we go back to the Stanford prevalence work, their estimate is that of the current 160,000 people with PBH in the United States, about 120,000 had Roux-en-Y gastric bypass leading to their PBH.

So I'd say at launch, we're already talking, if we were in that narrower label scenario, we're already talking about a very substantial population. And so our goal would be then to run an efficient study to show that avexitide should work regardless of the surgery that led to PBH. And for your second commercial question, I'll pass to Dan.

Thanks, Justin. Mike, thanks for the question on the commercial front. And just to build on what Justin had shared on the 160,000 patient population in the prevalent market. So we are aware through market research and through our claims-based analyses of centers and academic centers or different settings of care that have 50 to 60 patients. Some settings even have informed us that they have potentially 100 patients in their care.

So now that we know where those patients are, we'll certainly focus there at our launch, and then as our educational efforts take shape and we have more and more education with our commercial colleagues and alignment with our medical colleagues, we look to see that launch trajectory continue to grow. But again, the prevalent population is 160,000 and we remain confident in that number.

Your next question will come from Geoff Meacham with Citi.

Just had a couple of quick ones. The first is, when you look at pricing reimbursement sort of guidelines, do you think that, I get it that it's a completely unmet medical need, PBH is, but do you think there'll be differentiation between Level 2 and 3 events that you'll see in the study? So that's the first question.

The second one is just beyond the Phase 3. Are you totally done with other elements of the filing on preclinical, CMC, et cetera, et cetera?

Sure. Yes, I'm happy to maybe take part of that and maybe pass to my colleagues as well. So for Level 2 and Level 3, I think it kind of bears noting that usually these travel pretty closely together. The reason the ADA selected less than 54 mgs per deciliter as a level for a Level 2 event is because once you're less than 54 mgs per deciliter, that's when your brain is really starved of glucose.

So people often begin experiencing below 54, serious glycemic events, whether that's loss of consciousness, seizures, severe confusion, et cetera. So it's not often the case that you have a patient that has Level 2s but not Level 3s or vice versa, these things really do tend to travel together.

I guess in terms of the NDA preparation as well, we have been working throughout the year to be prepared as possible, and we do believe that the 16-week double-blind outcome from the LUCIDITY Phase 3 trial, which we're very excited for, is kind of the last piece of the NDA that we need to kind of put together. Regarding pricing guidelines, I guess I would pass over to Dan.

Sure. Thanks, Josh. And Geoff, thank you for the question. I would just add, PBH, as we all know, is a very dangerous condition without any approved medications for these patients living with post-bariatric hypoglycemia. So, when we go down the pricing journey, we will certainly take a look at and consider various analogs across both rare as well as rare endocrinology. And again, following top-line data and the LUCIDITY results will then initiate our pricing research.

Your next question will come from Marc Goodman with Leerink Partners.

Yes, as you have done this review of where the patients are, can you help us understand just the concentration of patients? You just started to mention there were some sites over 100, some 50 to 60. I mean, if you think about the 160,000 patients, are 50% of them at concentrated sites or is it only 20%? Just give us a sense of that.

And then 1 question that we just keep getting, I just want to make sure we hear it from you guys now, and that is, what should we expect the placebo response to be in this study?

Sure, I'll start with the first question just on where patients are, and we continue to do more and more research using really the claims-based analyses from multiple databases that continue to point us in the direction as to where these patients are. So yes, I've mentioned earlier that there's some settings of care where there's 50 to 60. Some have 70, some have 100, and the more research we do, the more confident we get in those conversations.

This is something our medical affairs colleagues have also begun to validate as our MSL team has engaged with various customers to understand and validate some of our claims-based analysis. And again, as we get closer to a potential launch, we will share what our go-to-market plans are in terms of how we'll engage these various centers.

Great, and thanks for the question regarding placebo. I'll start by reiterating that we've had 5 highly successful trials of avexitide in PBH to date, with the Phase 2 trials showing statistically significant and clinically meaningful reductions in both Level 2 and Level 3. And at ENDO 2025, we shared an endpoint and ad hoc analysis of the composite as well, which was also highly statistically significant.

LUCIDITY is designed to replicate those Phase 2 studies and we have powered the study very conservatively even in the face of those very highly significant studies. So even with, we're powering at least at 90% with a very modest effect size and with a placebo rate as well. We don't know specifically what the placebo effect is going to be. This is the first Phase 3 pivotal study of people living with PBH. You know, so that's an important consideration.

And finally, as we've been discussing this morning, PBH is a devastating condition. And people already are doing whatever they can to control or mitigate their events. Clearly those who are enrolling in our study continue to have events, but they end, they continue to do whatever they can to minimize it, given that there is, you know, much fear of hypoglycemia that these patients experience. And I'll say...

Sorry, go ahead, Marc. No, I was just going to say, should we be thinking, you know, placebo has a 20% response and the drug does 55%, you know, and we have that 35% delta, like, is that a realistic, you know, and a good scenario?

Well, I think there are 2 different ways, I think, to look at it. I think the first is, you know, what does the prior data tell us? And so the best placebo-based data we have comes from the first Phase 2 PREVENT study. If you look at the crossover design, so if you look at the run-in to placebo to active on the means, there's a difference of about 30%. If you look at the median though there's no difference.

So I would say then looking at the Phase 3 study, our goal was to be conservative in our assumptions. We believe avexitide should work for PBH. That's what the prior studies tell us. And so conservatively powering the study, we thought was the right thing to do. So, we powered the study to be 90% powered to detect a 35% treatment effect with even an up to 50% placebo effect.

We have not seen any evidence of such a placebo effect in prior trials, but again, we thought that the right thing to do is to power conservatively. And going back to the Phase 2 trial, if you look at those very statistically significant results, including for example, 55% reduction in Level 2, Level 3 composite hypoglycemic events, that's against the placebo. So again, if we're powering to 35% difference versus placebo, you can see why we're saying we're using conservative assumptions.

Your next question will come from [ Rami Kakuta ] with [ LifeSci Capital ].

I guess for LUCIDITY, what secondary endpoints will be included in the top-line release and which do KOLs view as the most important? And maybe more broadly, can you provide any additional color on the second research collaboration with Gubra and the type of endocrine indication or target that you're ultimately going after?

Sure. So, we're very excited and eager to see the top-line data, as I expect all of you are as well. And we plan to share the data that is consistent with other rare diseases that, to present Phase 3 top-line data. So stay tuned. We're very eager as well.

Absolutely. And maybe I just add on the second collaboration with Gubra as well. So yes, we really quite enjoyed working with Gubra. I think they have a particular peptide expertise that we certainly saw with AMX0318, where we tried to develop as optimized a GLP-1 receptor antagonist as we possibly could.

We are looking at another rare endocrine disease here of significant unmet need. I think it's, you know, it kind of fits with kind of our focus, focusing in rare diseases of really serious unmet need, where there are either no or really inadequate treatments as well. But we'll share more details there as maybe again, that's further along as well.

And I think just to Camille's earlier point as well, we are quite excited for the top line. I think you can expect us to share kind of typical data that you'd expect for a top-line data release. And I'd say in talking with KOLs as well, our primary endpoint really is quite a meaningful endpoint here. Level 2 and Level 3 hypoglycemia are viewed as very significant clinically meaningful events. Physicians describe that they have nothing for these patients and any impact on what they basically describe as medical emergencies, these Level 2 and Level 3 hypoglycemia events would be quite significant.

So I really think that's where people are mostly focused. But we are evaluating in our secondaries, you know, things like the, you know, individual Level 2 and Level 3 rates, as well as, you know, kind of other patient-reported outcomes and otherwise, you know, in the study as well.

Our next question will come from James Connolly with [ Sequel ].

You know, on the commercial front, as you've done more work here, curious if you have any more thoughts on sort of, you know, what the right analogs are here, specifically as it relates to what a launch trajectory may look like and, you know, essentially do you worry at all about a bolus in the sense of getting a lot of traction at those centers that have 50, 60, or 100 patients, but it's taking longer to kind of get to the next level or next rung of patients? Or, you know, do you think it'll be more steady because there's so many patients here? Just like curious how you're starting to think about that as you've done more work.

Sure. Thanks for the question, James. And on the launch trajectory, the first thing I'd say and just reiterate is, again, that there's, for these patients with post-bariatric hypoglycemia, there are no approved therapies. And we continue to stand behind the 160,000 prevalent population. We're very confident in the market size there. This is a market we continue to see building over time.

A point that we haven't emphasized yet is just the research that we've done with our endocrinologists. They have a very high intent to treat these PBH patients. So, on the trajectory, again, we will be focused on these centers at launch because that's where we know there are existing patients from the KOLs and endocrinologists who have already communicated to us that they've raised their hands and identified patients.

So we'll focus there. But then again, as that educational effort takes shape, as we continue to engage with the marketplace, we do see this building over time. So we'll start with those key centers, educate the centers, and then expand broader into the endocrinology community. And we're certainly looking forward to this educational opportunity with the endocrinology community.

Your next question will come from Graig Suvannavejh with Mizuho.

Just trying to anticipate that in the case that you do get positive data and then you do end up getting the drug approved, could you just remind us how you're thinking about the competitive landscape? There aren't all that many companies that are focused on PBH, but I think it would be good as we think about our uptake curves over whether it's a 5, 10-year period, how we should be thinking about the competitive landscape.

Yes, great question Graig. I'd say, you know, maybe first our view of the kind of pathophysiology of the disease is that this is really driven by an exaggerated GLP-1 response and that's why we believe that avexitide is sort of on target and, you know, a really appropriate way to, you know, to try to you know, ameliorate or, you know, significantly impact the disease.

So I think, you know, based on the, I mean, obviously we got to get the top-line data and we're quite excited for that. But, you know, we don't really see, you know, much else that, you know, has shown, you know, close to the profile of avexitide to date. So we really do believe this will sort of be the first and only, you know, if, you know, pending an approval would be the first and only therapy, and we don't really see other things that, you know, have shown the same profile.

And I would just add and underscore the point that, you know, because we really believe in this mechanism of, you know, exaggerated GLP-1 driving hypoglycemic events in PBH, that's why we started development on our long-acting AMX0318 early as well. That's still in IND-enabling studies. Our focus right now is on avexitide, but we really do intend to continue to innovate. And we think AMX0318 may be a very nice way to do so.

Can I just quickly follow up just on 318? I know it's still early days, but what are the different types of formulations that are being considered for 318?

Yes, great question. So maybe first just to say on 318, you know, kind of came out of the collaboration with Gubra where our goal was to, and you know what we did was screened a large number of peptides to try to find as optimal a GLP-1 antagonist as we possibly could. And this is really sort of Gubra's bread and butter. It's, you know, their kind of main focus is on peptide drug development.

And we do believe, you know, based on our preclinical data that we were able to arrive at a, you know, very strong GLP-1 receptor antagonist. I'd say from a formulation perspective, you know, I think all the options, you know, for injectables are certainly available to us, whether that's a, you know, vial and syringe or, you know, more advanced formulation such as autoinjectors or pens or otherwise. Luckily, I think both with avexitide and with how we've been designing AMX0318, at this time, we don't really see technical hurdles, you know, to being able to do that.

Your next question will come from Jason Gerberry with Bank of America.

Hi, good morning. This is Dina on for Jason. Thanks so much for taking our question. In your filings, I believe you disclosed a total of $35 million in CMO payment commitments throughout 2028 for avexitide and in the event of a positive Phase 3 readout is your current manufacturing scale sufficient for a commercial launch? Or would a positive readout trigger additional CMO capacity obligations?

And then just a quick question on AMX0035 for Wolfram. Any guidance on when we can maybe expect the update on regulatory interactions regarding the Phase 3 trial design and just maybe open this to that accelerated approval pathway.

Yes, I'd say great question. So I'd say we're certainly kind of proceeding with our manufacturing, you know, in line with, you know, prepping for commercial launch as well. And so we, you know, do, you know, from time to time make commitments to secure supply and capacity. And I think we expect to continue doing so, you know, as we get towards our launch.

And then I guess on your question on Wolfram as well. Yes, so I mean, we are quite excited about our week 96 data, which continued to show stabilization or improvement across glycemic measures as well as visual measures. You know, this would be the first Phase 3 trial conducted in Wolfram syndrome, and it is a multifactorial disease. People have not only diabetic symptoms, but also visual symptoms, sensory motor symptoms, kind of vestibular symptoms of kind of balance and otherwise.

And patients ultimately usually pass away from respiratory or swallowing difficulties in their early 30s. So there is thought about what is kind of the best design that kind of most efficiently you know, can show, you know, efficacy in the Wolfram population. So that's what we're continuing to work on, but we remain quite excited, including from our week 96 results.

Your next question will come from Ananda Ghosh with H.C. Wainwright.

A couple of questions from me. Can you tell me, like from our KOL discussions, use of avexitide has been always highlighted in certain surgeries, especially the gastric cancer or upper GI surgeries. So I just wanted to get your thoughts on what you are hearing from the KOLs on that.

Now, the second question is, what is the development plan for the long-acting avexitide vis-a-vis the avexitide when you are thinking from a commercial point of view? The third is, does a dedicated ICD-10 code change the payer conversation and given the diagnosis is a barrier to penetration of avexitide, what are the efforts from the company on that end?

Excellent. So, I'm happy to start with the first. So, yes, I appreciate your mentioning the potential use of avexitide in other surgery-induced type of glycemias. That's certainly something we hear a lot about from key opinion leaders. There are many gastric surgeries, as you mentioned, for example, gastrectomy for gastric cancer, that can lead to this same hypoglycemic condition.

And in fact, in the Phase 2b trial, there were people who had a gastrectomy or esophagectomy due to cancer-induced hypoglycemia who responded very well to avexitide as well. So we do believe that the mechanism there is very similar, that it's this exaggerated GLP-1 response that is primarily driving the hypoglycemic events so that is certainly something we're interested in studying in the future.

And I'll add that while this is certainly an unmet need in the United States, it's a very substantial unmet need in most countries in Asia due to their very high rates of gastric cancer and esophageal cancer, and 1 of the risks is that people develop this hypoglycemic condition.

As far as the 318 development plan, I'd say, you know, please stay tuned. We're in IND-enabling studies now. I'd say the, as Josh was mentioning, we really screened for molecules that would meet all of our criteria, including good drug-like properties and good sort of manufacturing qualities. So we, as we go through the IND-enabling studies, we'll outline our development plan.

But we really do believe that the primary driver events in PBH, in surgery-induced hypoglycemia, is this exaggerated GLP-1 response. And so that's why we're investing in 318 as well as investing in avexitide because we really believe that there's a substantial unmet need and opportunity here. For the ICD-10 code, maybe I'll pass to Dan to share more on that.

Sure. Thanks, Justin. And as Camille mentioned earlier, in June, CMS and the CDC, they did publish their 2027 ICD-10 code files. So beginning October 1st, this is when we will have a specific code for post-bariatric hypoglycemia. First thing I would say is this new code really recognizes PBH within the broader medical community.

ICD-10 codes, they are certainly helpful for tracking and diagnosing patients. And oftentimes the coding, the ICD-10 codes are used for epidemiology. From a payer perspective, an ICD-10 code is not necessary for reimbursement. And this is again, just back to the claims analysis. Patients can still be identified today through the claims analysis. You don't need an ICD-10 code to identify them. But again, this is really a recognition of PBH in the broader community, and we're excited that a code is going to be effective October 1st.

And on your last question, in terms of diagnosis, so I think the first thing I'll say is I think, you know, PBH awareness and diagnosis is high. We've certainly seen that in all of our market research. But as Dan was saying as well, you know, this is also a condition where there had not been FDA-approved treatments. There are many education gaps. And so I think starting on the education front is why we were so excited to launch our disease state education campaign. We've been very pleased with the feedback on that so far. So those efforts will continue.

Your final question will come from Christopher Chin with Baird.

Two for me. Can you characterize just the nature of recent interactions, if any, with FDA surrounding the NDA? And do you plan on having any additional interactions before submission?

And then just 1 for Dan. I know it's still somewhat early days, but assuming positive data and approval, how soon do you think you can launch following approval? And what would you say are the primary factors dating a launch?

Great. So, thank you, Chris. With regard to our FDA interactions, as you know, we don't really discuss the details of the interactions. We have had, as part of avexitide's breakthrough therapy designation, we have had consistent interactions with the agency throughout this period of time. You know, not starting with but 1 of course was, you know, reviewing the LUCIDITY protocol and throughout this time.

So we're very excited about, you know, the potential to submit an NDA. We have a tremendously experienced team working on the NDA elements and they're making great progress. Obviously, when we have the core 16-week data set, those will be included in the NDA and we'll go from there. And we continue to plan for a launch in 2027.

Chris, I'll just jump in on the launch date and the launch timing. We're certainly excited about the Phase 3 LUCIDITY results. At this point in time, we've guided towards a launch in 2027. From a launch preparation perspective, as we've mentioned, we've made key hires across the organization within medical affairs and across the commercial side in market access, marketing, as commercial operations. So our launch plans are on track and certainly underway as we prepare for a successful launch.

There are no further questions at this time. I'll turn the call back over to Mr. Klee for any closing remarks.

Thank you, operator, and thank you all for your time. We're looking forward to connecting when we report the top-line data after final database cleaning and lock. We're excited about what these results could mean for people with PBH. We hope you have a great rest of your day.

Thank you for your participation.

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

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

Sure. Yes. Well, first, thanks so much for having us. We're thrilled to be here. So Justin, Co-CEO, Co-Founder at Amylyx. We have a number of exciting programs under development. Lead program is, I think, where our focus, a lot of investor focus and attention is right now. The asset is called Avexitide. It's a first-in-class GLP-1 receptor antagonist, and that's for the potential treatment of PBH, post-bariatric hypoglycemia. PBH affects about 160,000 people in the U.S. today. We expect that population only to continue to grow over time. It's a very severe condition.

People present with persistent symptomatic severe hypoglycemia, meaning neuroglycopenia, meaning their brain doesn't get enough blood glucose. And so people have all manner of complications ranging from severe confusion to loss of consciousness, even seizures. So it's a very severe condition and people are having these events on a very frequent basis. There are no treatments for PBH today, but we have a pretty good

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biology of PBH. These

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low blood sugar are really driven by the body upregulating the GLP-1 response. The body will produce 10x, 15x, sometimes even 20x normal levels of GLP-1. And so that causes insulin to spike, which then causes a severe hypoglycemia.

So Avexitide is a GLP-1 receptor antagonist. So it blocks that GLP-1 effect, which then blocks the downstream hypoglycemia. So 5 prior trials of Avexitide in PBH, very substantial reductions in hypoglycemia, which supported FDA breakthrough therapy designation. So we are in a Phase III pivotal study now, top line results expected in Q3 next quarter. So we're really looking forward to that, preparing for the NDA and commercialization alongside it.

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

Yes, absolutely. And I think it speaks to your first question on core competencies as well. So I think at Amylyx, we've built a really great expertise in rare disease drug development, particularly on the clinical manufacturing and then on the commercial side. So the first treatment that we worked in for ALS, we did, I think, quite efficient clinical development, ended up commercializing that ourselves and quite successfully. So we were looking for other opportunities where there was a high unmet need, probably a particular focus in either rare neurodegenerative or rare endocrine diseases given that that's where we've done our work historically. And where we thought we could make a really big impact on people's lives.

So I think what, really, we found compelling about Avexitide in PBH, I think, first, is the unmet need. It's PBH, as you talk to adult endocrinologists, they very frequently say, this is one of the most severe conditions that I have to manage. And there are many people. I mean 160,000 is still an orphan disease, but it's a large orphan disease. So I think it's quite impactful.

And then connected with that is the pharmacology. The primary driver of this hypoglycemia is GLP-1. So if you block that effect, then you have a substantial impact on the hypoglycemia. So that was shown trial to trial to trial. The manufacturing was done well. The toxicology was done well. So we felt like this is an area where, again, the science really makes sense, and we think we can have a really big impact on people's lives.

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

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

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

Yes, I really appreciate that because it's a really important point. So the first Phase II trial, as you noted, used the 60-milligram dose, and that was very effective. But I think that the investigators noted that in probably the late hours of night, maybe early hours of morning, there might have been some breakthrough events in hypoglycemia. And so they thought -- they went back and looked at the PK and it suggested that maybe they weren't getting quite the coverage that they wanted. And so they increased the dose by 50%.

And by doing that, they did get the coverage for sort of the full day night cycle. And sure enough, that's what they saw in the Phase IIb trial as well. So they saw even greater reductions in hypoglycemic events. And as measured by CGM, they saw reductions in both day and night hypoglycemia. So that's why -- and of course, importantly, with a good safety profile. So that's why we took forward the 90-milligram dose.

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

Sure. So I think a nice part about having 5 prior trials is that we can first learn from those and given the strength of those results, particularly in the Phase IIs, change as little as possible going into the Phase III trial. So I think the first really important thing in the Phase II trials is they required at least an event per week had a run-in period looking for 2 events in 2 weeks. In the Phase III, we had 3 events in 3 weeks. We gave an extra week just to help with training and that sort of thing, but still same event frequency. And that gives you a very robust study design. It also gives you very robust powering.

So if you think about the overall study design, assuming no treatment effect, we have an event rate of 1 event or more per week times 16 weeks, times 78 people, you get to over 1,200 events. So you just get to a very robustly powered study. So we did many thousands of simulations as we did our powering analysis. We tried to be as conservative in our assumptions as possible. The kind of headline would be that we're 90% powered to see a 35% relative difference. In the Phase IIb, we saw a 64% treatment effect. So we're 90% powered to see roughly half of the effect that we saw in Phase IIb, and that's even under very conservative assumptions.

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

Yes. So again, and I'll probably keep repeating that first is to be consistent with the Phase IIs. So we're measuring the events the same way. We're looking at the same overall outcomes. So first, the primary outcome is a composite of Level 2 and Level 3 hypoglycemic events. That is in FDA guidance as an acceptable outcome. FDA has also reviewed the protocol ahead of time, and we have breakthrough status. So we feel quite confident in that.

But the Level 2 is measured by a fingerstick, self-monitored blood glucose. That's still the gold standard for measuring hypoglycemic events. If the blood value is less than 54 milligrams per deciliter of blood glucose, then that counts as a Level 2 event. The Level 3 event means that you need independent rescue. So participants are instructed to fill out a brief drop-down menu diary. That is then sent along with all the other information to an adjudication committee for a group of expert endocrinologists. They also have a charter they follow that was reviewed by FDA that says this was a Level 3 event or not.

Level -- these things are very well defined by the American Diabetes Association and other groups. So again, it was nice that we could use the Phase II's guidance as well as just general practice in endocrinology. I think clinical quality is obviously very important and something we pride ourselves in. I think probably the most important thing is, first, selecting good sites, which we have, and then making sure that we have the right participants in the study, which we believe we have.

So in that run-in period I mentioned before, we were looking for not just people who meet the strict criteria of the study, but also people we thought were good trial participants. Are they being consistent in their data capture. And so we looked very carefully at that. And so we think we have done that. Of course, at every site visit, we still train and retrain and remind on all these various outcomes. But I think

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start the study right

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

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

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

Yes. So the Phase II trials were both 4 weeks in duration. The Phase III is 16 weeks in duration. We have no reason to believe that, that should make any difference. I'd say we've seen no evidence of tachyphylaxis or waning of effect. We certainly don't see that in the GLP-1 receptor agonist space. It seems like you can keep engaging the receptor and continue to have the effects.

In terms of the events over time, what characterizes PBH, very sadly for people with PBH, is that it's persistent. People are doing everything they possibly can to try to control these events, and they're still having them. And so our expectation is that people, unfortunately, without a treatment effect, will just continue to have these events over time. And so a 16-week study should only give you greater powering than we saw in the Phase II even though in the Phase II, very statistically significant results.

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

Yes. So I would say, this is again going back to the Phase II. So in the Phase II trials, people did

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But I would also say in the first Phase II trial,

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that some people did liberalize their diet. So I would say, first, there was still a 55% reduction in hypoglycemic events in the Phase II trial despite that. I would say it's also something we're probably even more careful of in the Phase III trial. We train on the diet. We retrain on the diet. People have to certify at every visit that they're doing this.

But I'd go back to the mechanism of Avexitide because I think that's the most important thing here. We believe that what's causing the hypoglycemia in PBH is this GLP-1 bolus. And so if you block that, you really should block the substantial majority of the hypoglycemic events. In the first Phase I study, that's exactly what they tested and showed. So the investigators at Stanford gave everyone Glucola, which is just liquid sugar and gave it to people with PBH. To a person, unsurprisingly, they became hyper and then severely hypoglycemic and they rescued them. And then they gave them Avexitide. It 100% blocked the hypoglycemia. So even with a 75-gram liquid sugar ingestion, they still were able to block the hypoglycemia. So I think it really speaks to the strength of Avexitide in this disease.

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

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

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

Yes. Yes, it's a really important point. So we did a lot of work understanding the overall population in the United States, and we feel pretty confident in our estimate of about 160,000 people with PBH in the U.S. today. And that's because there's so many different sources all pointed towards the same overall number, including claims data. And I think so we have visibility to that population in the United States.

The -- so I think the question -- the other important point I should mention is that PBH doesn't appear to go away. We work with people who have had PBH for 15, sometimes even 20 years. In fact, if anything, in some people, it appears it can be progressive. So it seems like as the body upregulates this GLP-1 response, it sort of sticks. And that's what makes this such a tough condition. So I think what we're -- the question becomes what's the growth rate of the population over time. And the growth rate of the population is basically how many bariatric surgeries are performed each year. There's been well over 200,000 surgeries annually, including since the introduction of the GLP-1 receptor agonist. Hard to perfectly predict what the numbers will be in the future.

But we think bariatric surgery will continue to be a very important treatment, particularly because it's especially indicated in people who have severe obesity. People have BMIs of 40 or greater, for example, which is 30 million people in the United States. Just to give one anecdote of a story to illustrate this, we're talking with a woman with PBH recently, she was very open about things and said that she was willing to share, she lost 190 pounds in 10 months on bariatric surgery. Now she eventually also developed PBH.

But I think for her, she said, look, this is probably a life-saving, life-extending surgery for me. So she was very happy to have the surgery despite obviously the consequences of PBH being very debilitating. So I think that's the type of impact bariatric surgery can have, and that's also the type of person who this is indicated for. So that's why we hear from weight management clinics. They're happy to have all these tools. They're happy to have weight loss drugs and they're happy to have surgery. It just depends on the individual.

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

Yes. So this is where the claims data have been very helpful. We have visibility to the group of people with PBH in the United States. We've been reaching out to many adult endocrinologists and endocrinology centers. And there are centers who care for many people with PBH, as you might expect, given a population of 160,000 people. I think what's nice, too, is that as we're just starting our disease state education work now, including at the upcoming ENDO meeting, we'll look forward to seeing you there.

The -- there's already, I think, growing awareness of PBH. So we learned last year that PBH is now on the endocrinology board exams. We learned, actually, even just yesterday, that there will be an ICD-10 code adopted in October of this year for PBH. There are many more posters and presentations on PBH at ENDO and other meetings like that. So I think there's already growing awareness. And now we can work on our own education efforts alongside that.

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

So I think we see PBH as, I'd say, very typical of rare disease and unmet needs. So right now, the mainstay is diet. People are told to do what's called medical nutrition therapy, which is a very draconian lifestyle, basically eat frequently, small meals, no carbs, at least no simple carbs, try to keep your glucose as controlled as possible. People are still having events despite that. And it speaks to the physiology. Your body is producing 10x normal GLP-1 levels. You're going to have hypoglycemia no matter what you do.

Physicians right now try kind of a hodgepodge of different medications, all off-label. None of them really work because none of them get at the heart of the matter, which is this GLP-1 bolus. So what we've heard very consistently in our market research is that physicians really want a treatment. They understand the mechanism. And if they -- if we see data, anything like what we've seen so far with Avexitide, they're very excited about that.

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

I would say I would not draw that conclusion. I'd say, first, we really had no trouble finding participants. It was important to also enroll the right participants in the study. I would also say, ultimately, again, we recruited the study in a pretty efficient manner. I would also say all of our market research, if anything, has been even more positive than what our expectations were. There's a very high intention to treat here.

As I mentioned, estimating population sizes in rare disease is always difficult. This is the best, I think, estimates, at least that I've worked on before, given that everything has come to about this very similar population, and it's quite a substantial population. So I would say we don't feel nervous about that at all.

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

Yes, it's a great question. So I would say we're refining our go-to-market strategies now. I would say it's interesting in the market research, talking or interviewing adult endocrinologists. One thought was, well, if people are having, let's say, people are going to the hospital very frequently versus people who aren't, maybe that's the way to differentiate. Can you differentiate on so-called severity of the condition or how frequent people may be having events. It didn't differentiate that much.

Physicians, I'll say it's kind of the more, like, the kind of quotes and stuff would be that just because somebody is not yet going to the hospital, by definition, every one of these severe hypoglycemic events is a medical emergency. And so the next event might send them to the hospital. So physicians are very, very concerned and anything they can do to prevent these events from happening, they're interested in. So that hasn't -- basically, it just sort of came back like physicians are very interested in a treatment that can help for PBH.

I think as we've started to think on it more, I would imagine that one of the key pieces will be, there are centers that support very large populations of people with PBH, 100-plus people. I think we're really, at launch, going to want to make sure that we are partnering with that kind of whole organization. Some of them are academic centers, some of them are large endocrinology centers. They might care for tens of thousands of patients, which also means that they have very strong back office, people who help with insurance, nurse educators, all these different folks. So I think my guess is that's going to be a really key piece as we first launch, is making sure we're being really good partners to those centers as we do our more broader marketing efforts to reach the rest of the population.

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

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

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

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

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

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

What analogs are you pointing payers to consider?

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

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

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

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

Yes. Well, I'd say we really feel strong that this is a high unmet need, an exciting market opportunity and that the pharmacology here just really makes sense. And that's why there's been such great effects of Avexitide in the prior trial. All that being said, let's learn from what's been done, for example, in the GLP-1 receptor agonist space, the first-generation products are once daily and then the chemistry evolves to be able to do once weekly.

So we established a really nice collaboration with a company called Gubra. They're one of the world experts in peptide drug development. They have a really nice peptide discovery platform. So all last year, we worked on a collaboration with them to develop potential long-acting GLP-1 receptor antagonist. We came up with a few that met those criteria and had good drug-like properties, and now we're taking the leads into IND-enabling studies. Goal is to be in clinic next year. So I think overall, our goal would be to launch Avexitide in 2027, while we have the long-acting in development as well.

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

Yes, yes, great question. And I think in terms of core competencies, it's another good reminder of that. I think our core competencies in this regard are really around PBH, drug development in the space, clinical development, commercialization. But peptide drug discovery is core competencies in and of itself. So that's why the partnership with Gubra made a lot of sense. They spent decades building this really robust platform. They had all the GLP-1 receptor assays already up and running. They've had multiple molecules that have sort of gone the distance from concepts into clinical trials across multiple incretins. They're sort of part of that Danish brain trust who have been working on these incretins for some time.

So the -- we track thousands of molecules for all sorts of different properties. Obviously, things like potency and half-life, but also solubility and fibrilization, and stability, impurities, all sorts of different profiles simultaneously. In fact, they've built machine learning into their platform, maybe now called AI so that they can track multiple endpoints with their peptide simultaneously. And that allowed us to get candidates that met quite strict criteria. So we're really excited about that program.

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

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

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

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

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

Certainly. Yes, we're very excited about our calpain-2 ASO 114. So that's something we developed in-house. Calpain-2 has been a well-recognized target in neurodegeneration for decades. It's just been hard to target. Calpain-2 is one of the key effectors in axon degeneration. So what happens, particularly in neuromuscular diseases, but other neurodegenerative diseases as well, are these long processes of the neurons in the case of ALS that connect to the muscle. Those start to degenerate and then the muscle goes but it doesn't have that connection anymore.

So that process of degeneration has been well studied. And one of the key actors in it is calpain-2. The challenge has been that there are many calpains. And so you want to very particularly target calpain-2. You also want to get enough exposure into the central nervous system. So that's where an intrathecally administered antisense oligonucleotide is a really nice approach. We know we're targeting calpain-2, not the other calpains, and we know that we're getting adequate exposure.

So that molecule is now in a multiple ascending dose study in people with ALS right now. We are through the first two cohorts of dosing. The first cohort biomarkers, the lowest dose, we'll be presenting those biomarker results at an ALS conference this month. We're through Cohort 2. So we'll start to plan out when we'll have the biomarkers for that cohort and another medical meeting to target, and we're on to Cohort 3. So we're very excited about that program. It's moving really quickly. And I think calpain-2 being a protease, there are a number of biomarkers that we can look at to see if we're seeing the target engagement we hope to.

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

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

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

Excellent. Thanks so much, Corinne.

Perfect.

Company presenter at the BofA Annual Healthcare Conference. My name is Jason Gerberry. I cover pharma and biotech, and I'm pleased to be introducing Amylyx Pharmaceuticals and Joshua Cohen, Co-Chief Executive Officer; This is an interesting time for Amylyx on the cusp of pivotal Phase III data expected in the third quarter, a transformational event. So I imagine a lot of our discussion is going to be focused on the lead program for PBH. So Josh, thanks for joining us.

Yes. Thank you so much for having us.

So fresh off of 3Q and I guess, ahead of the pivotal LUCIDITY trial. Maybe if you could just talk a little bit about the trial design, some of the questions that it's designed to answer. And if successful, how this could be an advancement for patients with PBH, this sort of frame and then we'll go from there.

Sure. So we're very excited about the Phase III readout expected next quarter. Avexitide, our lead asset has been through 5 prior trials, all of which showed highly statistically significant effects on glucose and insulin. And then in the Phase II and Phase IIb, we studied the rate of Level 2 and Level 3 hypoglycemia, which showed quite a strong effect as well.

So under that backdrop for the Phase III, our goal is to try to keep as much consistent as we possibly could. So very similar inclusion/exclusion criteria, looking at the endpoints in the same way, you try to replicate that success we saw previously. To your point about meaningfulness as well, this is a patient population that's completely underserved. There are no approved therapies for PBH. The disease consists of having these frequent recurrent dramatic blood sugar drops, sometimes following a meal, but sometimes more out of the blue, maybe after exercise or stress or otherwise.

And when these occur, people can become very dizzy, they can lose consciousness. And most patients end up describing themselves as disabled because they can't drive. They may want somebody with them at all times in case they lose consciousness or otherwise. So to have potentially the first and only therapy that can impact that disease would be transformational for these patients.

Okay. And I think you framed on your recent earnings call that a stat sig result would be a win on the primary endpoint. What does that mean relative to treatment options like acarbose that are used by doctors when you talk to them and they cite this as something that they're giving patients. Is there any ability to kind of tease out what sort of benefit patients get from existing modalities even if they're not FDA approved?

Yes. So there have been some small trials of acarbose. And I'd say what happens in PBH is sort of what happens in a number of rare diseases where there's no available options. People try what they can, even if it's not particularly effective. So acarbose is an alpha-glucosidase inhibitor. It basically makes it harder for your body to break down complex carbs. That doesn't really treat the underlying disease. People continue to have events.

And the other thing is when you cannot break down complex carbs, they end up getting broken down by the bacteria very late in your gut. So you get severe gas and kind of gastrointestinal side effects, not uncommon that people have trouble being on acarbose for more than a couple of weeks. But -- so we don't see -- as we've talked to KOLs and otherwise, we really don't see much eagerness, excitement. It's sort of what they have, but it doesn't really prevent the events and very hard drug to take. This would really be the first drug targeting what we see as the underlying mechanism.

In PBH, people have faster nutrient transit, which leads to a dramatically increased GLP-1 response. So after meals, patients with PBH may see 10x normal, sometimes 20x or 30x normal GLP-1 responses. So with Avexitide, we have a GLP-1 antagonist. We're going at what we believe is kind of the core of the condition, which is unique. There's nothing else like that.

Yes. So to maybe summarize, it sounds like, hey, we're the first with the positive RCT with the drug where mechanistically, there's a lot of sensible rationale in the eyes of HCPs, and that's going to be enough to be kind of enough for physicians to want to use this most of their patients. Is that a fair summary?

I think it is. And maybe I'd just add, just characterizing the burden that these patients go through, they're having frequent severe hypoglycemic events. The ADA defines a single Level 2 or Level 3 hypoglycemic event as a medical emergency. And it's true. I mean we've spoken to endocrinologists who have described patients passing away in their sleep due to severe hypoglycemia. Patients can have falls, car accidents, all manner of things.

And it also is just dramatic and scary when you suddenly lose consciousness, you may need somebody to rescue, you wake up, you don't quite know where you are. These are really, really severe things for patients. And there's nothing available today that's been proven to do anything to these hypoglycemic events. So to potentially have a therapeutic that could impact that, as we've done market research, the intent to treat does seem high. They're really looking for an option for their patients.

Okay. Can you talk a little bit about Phase II to Phase III, I imagine you try to keep as many things consistent as possible, but what are some of the -- maybe the risks of a Phase II to Phase III effect size compression? Is it more heterogeneous population, which is oftentimes the case in a lot of studies? Is it the slightly longer endpoint? What are some of the key variables from a Phase II to Phase III translatability?

Yes. I mean maybe highlighting your first point, we are trying to keep as much consistent as we possibly can. Probably the key inclusion criteria in these studies is the event rate of people coming into the study. So we do have a run-in period during the Phase II and Phase IIb, people were required to have at least 2 severe hypoglycemic events in 2 weeks. In the Phase III, we're requiring at least 3 severe hypoglycemic events in 3 weeks. So it's an event a week to get into the study, you have to be having at least an event a week. So we kept that consistent.

In terms of the elements that are different, the Phase II and Phase IIb were 4 weeks, the Phase III is 16 weeks. We don't really expect that to change treatment effect or otherwise. We haven't seen on the reverse side with the agonist, a real attenuation over time. So we don't think with the antagonist, you'll see an attenuation. We don't see ADAs of any particular nature with this drug either.

So nothing that would really lead us to believe that the effect changes there. And then in terms of sites and otherwise, too, we've tried to keep the sites quite consistent. So the Phase II was 5 centers. The Phase IIb was a single center trial. The Phase III includes just about all of those sites, and it is a U.S.-only trial at kind of expert endocrinology centers and expert clinical trial centers. So it's all groups that we think were kind of handpicked and we believe can run a quality study.

Okay. Correct me if my details are wrong. I think LUCIDITY, 90% powered to detect 35% effect size placebo response, 50% is sort of the statistical assumptions here.

I'd say that -- we are powered to that. I'd say we don't -- we try to be conservative in our statistical assumptions. So I'd say we don't think there'll be a 50% placebo effect. Patients with PBH are already doing everything they possibly can not to have these events. So we don't think, for example, they enter a trial and they suddenly become much more successful at not having events. So I'd say we don't anticipate too much in terms of placebo effect.

And similarly, with effect size, we powered to see a 35% relative rate reduction. But in Phase II, we saw 55% and in Phase IIb is 64%. So I'd say we were conservative in all the statistical assumptions in part because this is the first Phase III we've conducted with the compound. And we believe we have an active compound. So we want to make sure we have more than enough power to detect that effect.

Okay. Yes, because I think the 2 things that come up most commonly with the Amylyx story is placebo rate risk and market size. So maybe if we just dig in a little bit more on placebo. I agree when we talk to physicians, they all tell us that they wouldn't expect much placebo response in this population. So echoing what you said. I do wonder what you learned from like the run-in period of the -- when you assess that how much can be gleaned from natural history with this population as you think about that?

Some people talk about Rezolute's CHI study and the placebo response there as maybe an analog population where there was a higher-than-expected placebo response. So how do you kind of -- what's the rebuttal on some of those points? Or just how would you contextualize that?

Yes. Maybe I'd first underscore your first point from the KOLs. This is really a condition where people do everything they possibly can not to have these events. If you think about it, if having one of these events meant that you're going to become unconscious, is going to feel incredibly bad, be incredibly confused, you really try actively not to have them.

So patients are already really doing everything they possibly can. We don't expect that, that's going to change all that much when they enter a trial setting. Additionally, there have been other trials in the space, including a trial of dasiglucagon in PBH. There wasn't a placebo effect observed there either. So I'd say, again, we don't -- we were conservative in our powering. We have enough power even if there is a placebo effect, but I think we don't expect too much medically.

You also mentioned Rezolute and CHI. I maybe remark that they're very different conditions. CHI is primarily a fasting hypoglycemia. So you're basically -- people with CHI basically bleed out insulin somewhat constantly. So if they don't eat very frequently, their blood sugar will drop, particularly a problem nocturnally, their blood sugar can drop because, of course, you're not eating during the course of the night.

But you can prevent most of the hypoglycemia in CHI if you just eat frequently and eat very slow burning carbs like cornstarch or otherwise. That's very different than PBH. PBH is a triggered hypoglycemia. So it occurs following a meal, it gets triggered. And sometimes it's triggered out of the blue, such as from exercise stress or otherwise. So there's not really -- you can't just eat more and not have this hypoglycemia like you may be able to in CHI.

Yes. Okay. And if data are positive, what are the outstanding work streams, operational work streams that are most critical just to enable a rapid NDA submission?

Yes. I mean we have the benefit of having a very experienced team on this. It won't be the first NDA that Amylyx has submitted. So we took the action of trying to get as much done as we possibly can ahead of the data so that it's really a process of sort of dropping in the data once the trial reads out compared to starting the NDA after the trial reads out. Everything is kind of proceeding in lockstep with that, too. So there's not like a big CMC or otherwise thing that we have to wait on after the trial reads out to be able to submit. It is still a big document. NDAs are not infrequently hundreds of thousands or even millions of pages. So it's a big document and you want to do it right.

But our intention will be to submit as fast as possible following data to enable a 2027 launch. And we do have breakthrough therapy designation. So we'd expect the kind of 2-month filing period and the 6-month review, that priority review that you get with a breakthrough.

Yes. Can you speak to regulatory interactions that you've had so far? You're dealing with the endocrinology division, right? And some investors do flag that division and specifically maybe some more unexpected review outcomes of late. So I don't know, is there anything that you can say to the division and your regulatory interactions?

So the division we're in is actually sort of a subdivision. It's DDLO that we interact with. Our interactions have been pretty business as usual. And I'd say, one, we have breakthrough therapy, which I think helps in any FDA interactions. And I think we're also just very down the fairway, whereas I think some of the cases where there have been maybe more contention with FDA have been open-label trials or external controls or novel endpoints. Here, we have a placebo-controlled study with a very well-established endpoint. Hypoglycemia is something that's been known for quite some time. And we did have -- we did submit our protocol and it was reviewed prior to initiating our study. So we do believe we're running the study in a way that could support registration.

Okay. Maybe let's talk about commercial and market size here. There's not a lot of great predicates out there, right? Can you look to things like acarbose utilization or anything in claims data to substantiate. I think you talked about a U.S. 160,000 for epi and then some segmentation factors to that. But anything that we can anchor to get a little higher degree of comfort around who's in the treatment system, who will be accessible? I mean, ultimately, I understand that this is kind of a market build.

Yes, sure. So maybe first starting, we do believe there are about 160,000 people in the U.S. today with PBH. That's based both on a lot of literature. There have been large prospective studies looking at cohorts of people who got bariatric surgery, following them over multiple years. And those cohorts do find about 8% of people in general with bariatric surgery going on to get PBH, and there's been over 2 million procedures in the last decade, which gets you to 160,000.

In addition, we've done quite a lot of claims work and recently, we do expect that the ICD-10 code will become available for PBH October this year. But what we've done so far in absence of an official ICD-10 code is looked at those people who had bariatric surgery who went on to have claims for hypoglycemia that couldn't be explained otherwise. That couldn't be explained by diabetes or drugs they're taking or otherwise. And that similarly came out to about 160,000 as well.

We went to sort of further validate that claims work by doing kind of blinded market research with a number of sites. We're unaided. We ask them how many patients do you see with PBH? And then we compared that to our claims data to say, is our claims data accurately estimating what these sites actually have. And that came back quite concordant. So we do believe that we're successful in our claims data identifying the patients. But there's one other element of your question.

Yes. I mean just maybe around segmentation, like what proportion do you think are kind of at the bottom of the funnel and...

Yes. I mean we're trying to target the 160,000. Certainly, as with any rare disease launch, our initial focus is going to be on those centers of highest expertise as well as the centers that are most densely serving the patient population. But severe hypoglycemia is really, really bad. One, you have the kind of the acute complications of possibly losing consciousness, seizures, car crashes, falls. You also have long-term complications. You look in the type 1 diabetes literature, people who have regular hypoglycemia are at much increased risk for heart challenges, for cognitive challenges, et cetera. So these are things that should be treated if they can be treated. And so our goal is to -- for every eligible patient to try to get them on therapy if our drug is successful.

Yes. Is there an aspect of this when you launch where could there be a leakage or loss of patients in the funnel at the referral stage? I imagine not all these patients are in these higher volume centers, so to speak. And so there's going to be an education. And then how do you envision that kind of playing out?

Yes. I think it goes to your point, there will be a build here as well. We think there's both a number of patients that are already under very active care who we think will be able to get on therapy quickly, but there will also be some time where we have to educate, continue building the index of suspicion. Not for all physicians right now, if somebody has had bariatric surgery and they lose consciousness, do they instantly go to, okay, this is probably a blood sugar problem or this very well might be a blood sugar problem. There's education we can do to kind of keep building this market and expand out from those more expert centers.

So I think it leads to a dynamic where we can keep growing this market year-over-year, which I think is a nice thing to be able to grow into. And I'd add with that, too, we also want to keep investing in this market. First and foremost, we have Avexitide for PBH in the U.S. That's what we want to launch in 2027. But beyond that, one, there are a number of other surgical types that can cause hypoglycemia, other surgeries that sort of alter the gut and speed nutrient transit.

For example, people who get gastric cancer will sometimes have gastrectomy, which can lead to a very similar set of symptoms as what you get in PBH. People with esophageal cancer can get esophagectomy, people with various gastric reflux disorders can get various surgeries. So there are quite a lot of ways you can find yourself towards having hypoglycemia. So we see that as sort of an expansion opportunity as well as looking at ex-U.S. geographies. We're working on a long-acting version. So I'd say, first and foremost, we want to serve those -- the patients with PBH in the U.S. that we can get to immediately, but we also see this as kind of a multiyear expansion beyond that.

Okay. Is that education both on the patient side and the doctor side, i.e., do you feel like a lot of patients might be out there and they need to kind of elevate what they're at risk of or dealing with or just not aware of what they're dealing with and need a physician interaction? Or how does that dynamic look to you?

Yes. I think it is education on both the patient and the physician side. On the patient side, right now, physicians really don't have much to offer their patients. So there are some patients who have maybe gone to the endocrinologist several times, sort of heard the same advice every time and may be less prone to go back to the endocrinologist at this point because they've -- they don't have something new to be told. So there may be some patients we sort of have to reactivate the now that there may be a new treatment available for them. But there are also those patients who are very actively under care today. So I think we'll see both in the market.

Okay. So your expanded access protocol, if I understand right, is larger than the LUCIDITY enrollment. What are the criteria to get into the EAP? And I just wonder, is this at all an indicator at all of the market overall, right, of faster enrollment?

Yes. I wouldn't say it's an indicator of the market. We do expanded access programs mainly to provide free early access to drug, particularly in diseases that are very severe. If we're able to, we like to get drug to people sooner. Initially, we're enrolling people who are -- who have completed LUCIDITY or who are in some of the past Avexitide trials. Those patients have -- many of them have reached out to Amylyx are very eager to get back on therapy. So that's kind of the initial cohort. And then we do envision kind of expanding beyond that as we get kind of up to the 250. But I think as expanded accesses go, I think it's actually a fairly large one. There's only so large you want to go prior to launch as well.

Okay. So Avexitide is a daily subcu. Can you talk about, I don't know, any observations with past trials that have been done, how you think patients are going to adhere to a daily injection?

Yes. I think we -- well, when we look at the past trials to start, adherence was very good. In the Phase II and Phase IIb, we didn't have dropouts. Treatment compliance was very strong. And I think it starts from how severe this disease is. Patients are really looking for treatment. In the II and IIb, there were structured interviews of a number of the patients. And you could hear in the interviews, they described feeling a difference as well. When you get severe hypoglycemia, you feel terrible. And patients know that. And so when you have a treatment that potentially is reducing the rate of that or helping that, you hope patients can feel that as well. Say this is also not a particularly needle phobic population. Just to manage their disease, they're doing regular fingersticks for blood glucose.

So when we've done market research and asked about what do you think about a daily subcu, particularly with a super thin needle and all of that, patients really don't describe that much anxiety or fear about that. So we don't think that's going to have a significant impact in this market.

Okay. So I'm going to preface by saying I'm not asking you what you're going to price the drug at because I know you won't answer that question. But do you at least know in your mind where you'll price it if you produce stat sig benefit? Or do you think that based on the strength of the data that, that could have an impact on pricing power here?

Yes. So we do a lot of research as we kind of approach the pricing. And included in that research, we bring our data in front of sometimes retired payers, sometimes different KOLs, patients, et cetera, to try to get kind of a multi-stakeholder view and to learn as much as we can.

So yes, a little early on the price. What I will say has been encouraging for us is looking at various other launches in the rare endocrine space, some with healthy price points as well. We've seen generally good coverage. I think there's general recognition among payers and really among the medical community more broadly that hypoglycemia is a severe and very -- can be a very bad thing can even lead to death. And so I think there's an appreciation, I think, that if you have a drug that impacts that, that's really bringing value.

What do you think one of these patients cost the system, right, in terms of these attacks? Like how many hospitalizations or ER visits are we talking about that could be money saved? I'm just trying to think through the pharmacoeconomic arguments.

Yes. I'd say stay tuned. We'll probably have more of that data as time goes on. Certainly, our kind of HEOR team is working hard on kind of getting more exact numbers. But I do believe these are high health care utilizers. Even as we've gone through our claims data, you see a much higher-than-normal hospitalization rate in these patients. You see a lot of complications. You see a lot of drug use to treat various comorbidities in this population. So I do think that this is a pharmacoeconomically expensive population as well.

Okay. On the competitive front, some data from Recordati, I believe, recently. Your thoughts on that?

Yes. So we probably don't comment too much on competitors, but I'll say, unfortunately, the trial from Recordati did not see differences on Level 2 or Level 3 hypoglycemia. This is with Pasireotide, which is an approved drug, has an approved label. So I think overall, I think we see ourselves as very well positioned, breakthrough status, Phase III. I think there's nothing else out there that has a profile like Avexitide.

Yes. Okay. And you framed cash runway into 2028, right? So that's getting you through early launch. So it is fair to say you won't be resource constrained in 2027 go-to-market?

Yes. So we tried to put ourselves in a very strong financial position. We raised last September. So as you said, cash into 2028. We also did not include revenue in our cash modeling just to be conservative. So when you add revenue in and cash might even go longer than that as well. So yes, I think we'll -- in Q3, when we have our data, we'll be in a very strong financial position.

Yes. Okay. And what does the time line look like for your follow-on once weekly. I don't want to call it once weekly Avexitide, but it's effectively the same API just in different delivery technology?

So it is a novel molecule. We did work with Gubra who are excellent to develop basically as optimized or long-acting GLP-1 antagonist as we possibly could. So basically, Gubra's sort of secret sauce is they can screen quite a large number of peptides very quickly. So they screened all manner of different variants peptides to try to find ones with a long-acting profile, but also good potency, manufacturability, lack of immunogenicity, good in vitro and in vivo data.

So we designed it to be at least once weekly, if not better. We'll know the profile more accurately once we're in clinic. We don't want to promise the exact PK curve in humans until we have a PK curve in humans. But right now, we're going through IND-enabling studies. We'll expect to submit an IND in 2027. And I do believe this disease sort of lends itself throughout the development as well. We haven't outlined the exact clinical studies we might do. But I think the main questions to answer will be optimal dose and then confirming that we're having the effect that we want in a larger group.

Okay. Maybe we'll just a few on the earlier-stage pipeline, the Phase II Wolfram syndrome program. What in the Phase II is sort of the bar for advancing into Phase III from your perspective? What are you focusing in on here?

Yes. So we've presented week 48 data from the Phase II. We'll be presenting week 96 data. This is for AMX0035 in Wolfram syndrome. Wolfram syndrome is a monogenic disease of a protein called wolframin coded for the gene WFS1. It's an autosomal recessive disease. So it's basically complete loss of function of this wolframin gene. And it's considered a prototypical disease of ER stress, which AMX0035 is thought to address.

In our trial thus far, up to 48 weeks, we've generally seen stabilization or improvement across the outcomes we've measured. So we've been quite excited. And Wolfram syndrome is a disease where people pass away on average in the early 30s. It starts by looking like juvenile diabetes, but it becomes clear, it's not just juvenile diabetes when people start getting vision loss, hearing loss, eventually kind of walking difficulties, speech and swallowing difficulties, breathing difficulties. These are what eventually lead to death for people with Wolfram.

So our trial was really focused on the diabetic outcomes as well as the visual outcomes because those move a little quicker as well as kind of a global outcome of global impression of change, both from the patient and the clinician. All of those moved in the direction of stabilization or improvement in a disease where you'd expect them to progress. That was for the 1-year data, that had 48-week data. We'll be excited to have the 96-week data. I think we see that data as good to kind of progress to the next study. What we're still working on with FDA is what exactly does a Phase III look like in Wolfram syndrome. It is a disease that has multiple systems involved. So the exact primary endpoint and the exact design takes a little time to kind of work through.

Yes. And does this asset if developed through Amylyx makes sense to keep in-house? Is this a partnership candidate?

Yes, I'd say we always consider our options. But we don't see that this will be an overwhelmingly we would -- it's quite a rare disease, about 3,000 people. We estimate have Wolfram in the U.S. We don't estimate we're running an unduly large or long trial here. So we don't think that this will be much of a financial strain, if you want to put it that way.

Yes. I guess do you see strategically some rare orphan focused companies, there's a core competency in patient finding commercially in the organization? And does it fit from that perspective with an asset like Avexitide and your ALS pipeline that you have as well?

Yes. I mean I think it does. I mean, Wolfram has components of both an endocrine disease and components of a neurodegenerative disease, generally treated by pediatric endocrinologists who are often in a similar center as adult endocrinologists and otherwise. So I do think there's an overlap in competency. We look at similar outcomes as well on the kind of glycemic side for Wolfram.

But overall, first and foremost, our focus is on Avexitide. I think we see if we're successful with LUCIDITY and hopefully a very strong launch that enables us to do more things. But from a kind of capital and human resources perspective, our main focus is make sure we keep our eyes on the prize with Avexitide and try to get it as best as we possibly can.

All right. Great. Well, we're out of time. So thank you for joining us at the conference.

Thank you so much. Really appreciate you having us.

All right. Have a good one.

Good morning. My name is Kate, and I will be your conference operator today. At this time, I would like to welcome everyone to the Amylyx Pharmaceuticals First Quarter 2026 Earnings Conference Call. [Operator Instructions] Please be advised that this call is being recorded at the company's request.

I would now like to turn the call over to Lindsey Allen, Vice President, Investor Relations and Communications. Please proceed.

Good morning, and thank you all for joining us today to discuss our first quarter 2026 financial results and business update. With me on the call today are Josh Cohen and Justin Klee, our Co-CEOs; Dr. Camille Bedrosian, our Chief Medical Officer; Jim Frates, our Chief Financial Officer; and Dan Monahan, our Chief Commercial Officer.

Before we begin, I would like to remind everyone that any statements we make or information presented on this call that are not historical facts are forward-looking statements that are based on our current beliefs, plans and expectations and are made pursuant to the safe harbor provisions of the Private Securities Litigation Reform Act of 1995.

These statements include, but are not limited to, our expectations with respect to avexitide, AMX0035, AMX0114 and AMX0318, statements regarding regulatory and clinical developments and the impact thereof and the expected timing thereof and statements regarding our cash runway. Actual events and results could differ materially from those expressed or implied by any forward-looking statements. You are cautioned not to place any undue reliance on these forward-looking statements, and Amylyx disclaims any obligation to update such statements unless required by law.

Now I will turn the call over to Justin.

Good morning, everyone, and thank you for joining us. The first quarter of 2026 was marked by execution across our pipeline. Most notably, we continue to progress the pivotal Phase III LUCIDITY trial of avexitide, our investigational first-in-class GLP-1 receptor antagonist with FDA breakthrough therapy designation in post-bariatric hypoglycemia or PBH. We are executing on the 3 strategic imperatives for avexitide that we outlined earlier this year.

First, we are advancing the pivotal Phase III LUCIDITY trial toward top line data. Randomizing and dosing the last participant in late March was a significant milestone. We have a clear line of sight toward the completion of the 16-week trial, and we remain on track for a top line readout next quarter.

Second, we are advancing NDA readiness and regulatory preparations. We are already drafting NDA sections to support a potential submission.

And third, we continue to strengthen our launch readiness. We are executing against a comprehensive commercial readiness road map to help ensure we are fully prepared for commercialization of avexitide, if approved, in 2027.

In addition to avexitide, we continue to make progress across our broader pipeline. For AMX0318, our long-acting GLP-1 receptor antagonist, IND-enabling studies are underway. We are targeting a 2027 IND filing.

For AMX0035 in Wolfram syndrome, we anticipate presenting longer-term week 96 data from the Phase II open-label HELIOS clinical trial at an upcoming scientific meeting.

And for AMX0114 in ALS, we fully enrolled Cohort 2 of the Phase I LUMINA trial in March. At the ENCALS Annual Meeting this June, we expect to present early biomarker data from Cohort 1, the first and lowest of 4 doses being evaluated in the trial. We expect these data will provide initial information about the levels of the ALS biomarkers being assessed in the LUMINA trial from the first cohort.

As we continue to advance our pipeline, we are simultaneously preparing for the potential commercial launch of avexitide. To discuss our launch readiness efforts, Dan Monahan, our Chief Commercial Officer, is with us on the call today.

Dan joined Amylyx in January 2024, bringing more than 2 decades of experience. He was instrumental in the commercialization of Otsuka's Rexulti, Novartis' Cosentyx and Sanofi's Lantus and Actonel, among others.

With that, Dan, I'll turn the call over to you.

Thank you, Justin, and good morning, everyone. I'm pleased to be on the call today to discuss how we have been refining our launch strategies as we prepare for the potential commercialization of avexitide next year. The more we engage with the PBH community, the more we understand the profound unmet need that exists. We are operating with a deep sense of urgency.

To date, our commercial efforts have been focused on gaining key insights into the PBH market. This includes gathering direct insights from people living with PBH and the health care professionals who are managing their condition. In addition, we are developing a deep understanding of the patient journey and continuing ongoing claims work to help us determine where patients are being treated. To enable our commercial preparations, we've made key hires across marketing, market access and commercial operations.

Ahead of the potential approval and commercial launch of avexitide, our immediate focus is on disease state education. This includes raising stakeholder awareness of PBH with an emphasis on the pathophysiology, the importance of accurate and timely diagnosis and the profound unmet need and burden of the condition. We plan to launch this disease state education campaign this summer.

Looking at the market opportunity, our independent claims analysis and ongoing field engagements continue to support our estimate of approximately 160,000 people living with PBH in the U.S. who have undergone the 2 most common types of bariatric surgery: sleeve gastrectomy and Roux-en-Y gastric bypass.

Our estimates are firmly rooted in the growing body of prospective and retrospective published literature, including large long-term cohort studies evaluating hypoglycemia in people who have undergone bariatric surgery. Importantly, our ongoing market research indicates that endocrinologists have a high intent to treat PBH if there were to be an approved medicine.

To reach appropriate patients, we have initiated our marketplace sizing efforts and continue to identify key centers and endocrinologists that manage this condition. Building up to the potential launch, we will refine these efforts as more insights are generated.

Our commercial preparations are advancing in lockstep with our clinical progress, and we look forward to sharing additional details as we move closer to the commercialization of avexitide, if approved.

With that, I'll turn the call over to Camille to provide an update on our clinical and medical affairs progress this quarter.

Thank you, Dan. To start, PBH is a chronic metabolic condition driven by an exaggerated GLP-1 response, primarily after food intake, resulting in persistent recurrent and often debilitating hypoglycemia. These events cause an inadequate supply of glucose to the brain known as neuroglycopenia with potential clinical consequences such as cognitive dysfunction, seizures and loss of consciousness.

For people living with PBH, this can create a life of perpetual vigilance where a meal with friends or a drive to work carries the risk of debilitating hypoglycemia and its ramification. This fear can disrupt independence and compromise safety, nutrition and overall quality of life. Currently, there are no FDA-approved therapies.

Our pivotal Phase III LUCIDITY trial is evaluating avexitide, 90 milligrams once daily, in individuals with PBH following Roux-en-Y gastric bypass surgery using the FDA agreed-upon primary outcome of reduction in the composite of Level 2 and Level 3 hypoglycemic events through week 16.

LUCIDITY was designed with the goal of replication. Five prior avexitide trials in PBH, which demonstrated statistically significant results, including reductions in hypoglycemic events directly informed the dose, the primary endpoint, inclusion criteria and surgical subtype for LUCIDITY.

Echoing Justin's earlier remarks, our clinical team remains deeply focused on the execution of the LUCIDITY trial, and we continue to work closely with our investigators as we approach our anticipated data readout next quarter. In parallel with our clinical trial execution, we are actively ramping up our field medical affairs team to facilitate on-the-ground engagement with KOLs.

I also am pleased to share that we recently launched a U.S. expanded access program to provide avexitide for up to 250 adults with PBH following Roux-en-Y gastric bypass. This program is a direct response to the urgent need we are hearing from individuals who are struggling with the devastating daily realities of PBH and the physicians who treat them.

Initial eligible patients include individuals who have either completed LUCIDITY or participated in previous clinical trials of avexitide in PBH. As a reminder, avexitide is an investigational drug and has not been approved by the FDA for any indication.

Working directly with the PBH community and seeing the everyday impact of this devastating condition drives our continued commitment to our clinical and medical efforts.

And with that, I will now turn over the call to Jim to review our financials. Jim?

Thanks, Camille. Our financial results for the first quarter were in line with our plans and reflect our focus on the Phase III LUCIDITY trial and targeted investments in advancing our broader pipeline.

We ended the fourth quarter with $279.8 million in cash and marketable securities compared to $317 million at the end of the fourth quarter of last year. This capital funds our anticipated cash runway into 2028, including our key expected milestones: the LUCIDITY top line readout expected in Q3 2026, potential FDA approval and potential commercial launch of avexitide in 2027.

Turning now to our results for the quarter. Total operating expenses for the quarter were $43.8 million, up 16% from the same period in 2025. Research and development expenses were $27.6 million compared to $22.1 million in Q1 2025. The increase was primarily due to an increase in spending related to the clinical development of avexitide in PBH.

This quarter, we also recognized a milestone payment of $4 million to Gubra following the identification of AMX0318 as a development candidate for PBH and other rare diseases. The increase was offset by decreased spending related to the clinical development of AMX0035 for progressive supranuclear palsy.

Selling, general and administrative expenses were $16.2 million compared to $15.7 million in Q1 2025. This increase was primarily due to an increase in consulting and professional services as we prepare for the potential commercial launch of avexitide.

We recognized $6.1 million of noncash stock-based compensation expense for the quarter compared to $6.8 million of noncash stock-based compensation expense in Q1 2025.

Turning to our balance sheet. Our cash usage was slightly higher in Q1 compared to Q4 because of our Gubra milestone payments and the payment of our annual corporate bonus during the quarter.

We're in the midst of a pivotal year for Amylyx with the top line data readout for LUCIDITY expected in Q3. The team will continue to focus on scaling our business with discipline, and we're actively laying the groundwork for a potential commercial launch. This focus positions us well, particularly for our work with avexitide. We continue to believe Avexitide has the potential to be a breakthrough treatment for PBH.

With that, I'll turn the call over to Josh.

Thanks, Jim. To close, we are focused on the execution of the LUCIDITY trial as we track toward our anticipated top line readout next quarter.

PBH is a chronic lifelong condition with symptoms that often emerge 1 to 3 years following bariatric surgery. Many people who receive bariatric surgery are in their 40s, suggesting that if they develop PBH, they may have decades of life impacted by this condition. The broader medical community continues to recognize this critical need in PBH.

In March, Dr. Colleen Craig and her colleagues at Stanford published the first U.S. prevalence model for PBH in surgery for obesity and related diseases, the official peer-reviewed journal of the ASMBS. And in April, CMS published their annual list of ICD-10 codes to be potentially effective October 1, 2026, which includes an ICD-10 code specific to PBH. The planned adoption of an ICD-10 code shows the growing recognition of this condition by the medical community.

We believe that avexitide, if approved, could play a meaningful role in addressing this highly underserved patient population. In parallel with LUCIDITY, we are actively preparing for a regulatory submission following top line results while simultaneously scaling our commercial and medical teams to support a strong commercial launch of avexitide in 2027, if approved.

With that, I would like to now open the call up for questions.

[Operator Instructions] Your first question comes from the line of Seamus Fernandez with Guggenheim.

I hope you'll bear 2 for me quickly. The first question is really on the initiation of the EAP. Typically, we see companies sort of waiting for the completion of their Phase III and then the announcement of an EAP in the wake of a positive Phase III. Just wanted to get a better sense of, obviously, how you were able to execute this and get it approved, and then also how you are really responding to the community with the implementation and announcement of the EAP.

And then just a quick follow-up question. I wanted to get a sense of just sort of that relative impact that working on the NDA now could actually have from a filing perspective. Typically, when we see biotech companies with positive Phase III data, it will take as much as 6 to 9 months to see that file. So just wanted to get a sense of how working on the NDA now might advance that ahead of those types of time lines.

Thank you very much, Seamus. This is Camille. So for the EAP, indeed, we are responding to the community where there is currently no approved therapies for PBH, and we recognize and have received several requests and demands. Importantly, we're starting the EAP now because we want to be sure there's continuity of treatment for people in the LUCIDITY study who are completing the OLED portion of the LUCIDITY trial. So that drives the timing for the EAP.

Now with regard to your question about NDA preparation, Yes, we're sort of not typical for sure. And we are working, as noted, on NDA preparations. And we do hope that, that will allow us to be most efficient as we reach top line data next quarter. And because there is a great sense of urgency, there are no treatments for people with PBH. And if positive, we want to be sure that we're providing the opportunity for access as promptly as possible.

Yes. And maybe just -- maybe underscore from Camille as well. I think both of these activities both underscore too, the unmet need in PBH. We know that patients urgently need a new therapy and also our excitement about avexitide. We've had 5 prior trials of avexitide, all which showed very strong results. We have breakthrough therapy from FDA. So we want both to get patients access as quickly as possible, which, of course, is reflected with the EAP, but also, pending positive results, to be able to submit as soon as we possibly can, which is reflected by our ongoing work on the NDA.

And just one more thing to add, thank you, Seamus, is we also have a very experienced team here. Our team has experience with global regulatory approval, certainly a lot of experience with FDA as well. And so that allows us to start working on the NDA documents now. Again, everything is driven by the urgent unmet need for people with PBH, but I think coupled with the strong experience we have here, both for regulatory submissions and process as well as commercialization.

Your next question comes from the line of Joseph Thome with TD Cowen.

This is Jacob on for Joe. We were wondering how the baseline for the enrolled Phase III population compare to the patients in the Phase II studies, and then what the expected placebo response in Phase III might be versus what we know about the patients in Phase II and the differences in the run-in periods.

Sure. So the study is ongoing and blinded. And so we will not really comment on the details of this ongoing study. Having said that, we are very much looking forward to top line data next quarter where we'll share the top line data with you and hope you're sharing our excitement as well for this possibility.

With regard to the placebo, remind as well, we've had 5 prior highly successful trials. The Phase II trial showed statistical significance and clinically meaningful reductions in the composite as we presented at ENDO. In the PREVENT study, 55% reduction with a highly statistically significant value, and with -- in the Phase IIb with a 90-milligram dose, the dose in LUCIDITY, 64% reduction with a p-value of 0.0031. Those p-values do take into account all aspects of the trial, including the possibility of any placebo effect.

We designed LUCIDITY with the goal of replicating these prior successful trials. So -- and we powered -- we're highly powered, 90%, to detect a clinically meaningful reduction in events even under the most conservative circumstances.

Your next question comes from the line of Corinne Johnson with Goldman Sachs.

This is Kevin on for Corinne. Could you just talk about the steps that you've taken beyond the event rate quota to ensure patient quality in the study for LUCIDITY and then also to ensure, sort of as much as possible, adherence to study protocols for the full 16-week treatment period?

Sure. So we -- again, we're replicating as much as possible the way LUCIDITY is being conducted, mirroring what was done in the successful Phase II and Phase IIb studies. We have training -- extensive training at the clinical sites at the onset of the clinical trial. That training is reinforced throughout the conduct. And we also have materials for the participants to guide them on the study procedures throughout the study as well. And we also do have quality checks on the data overall to be sure that things are moving along well.

Yes. And I'd just add too, we have a very experienced team at Amylyx and quality starts from selecting great sites, having strong oversight. And I think throughout the whole course of the study, I've been quite proud of the team's efforts, just kind of continually keeping close and making sure that quality is kind of built in from the start and continues through the whole study.

Your next question comes from the line of Michael DiFiore with Evercore ISI.

Congrats on all the continued progress. First one for me is, now that LUCIDITY is fully enrolled, can you help us think through what the top line disclosure will actually look like, what it will contain, beyond whether the primary endpoint is met? What do you think will be the most important aspect of the data for people to understand, again, beyond the primary endpoint in that initial release? And secondly, since you're already preparing for NDA, since the last update, can you share more light on what work remains to be done between top line and potential submission, maybe in terms of QC, any additional studies, et cetera?

Yes. Thank you, Mike. So I think first, in terms of top line disclosure, you know us well. We're a transparent company. So our goal is always to present things as they are. I think what's important in this study is probably 2 things to remind.

The first is that the primary outcome, which is Level 2, Level 3 hypoglycemic events, not only is it the primary outcome, it's in FDA guidance, but it's also very well known by endocrinologists and it's inherently clinically meaningful. Level 2 events being less than 54 milligrams per deciliter blood glucose, which is the blood value at which neuroglycopenia occurs. Level 3, of course, means that the clinical manifestations of hypoglycemia have already occurred. So those are inherently clinically meaningful.

And then I think a second important point is that there are currently no treatments for PBH. And so what we have heard consistently, not just from people with PBH, but from physicians as well is that any reduction in hypoglycemic events is meaningful. Each one of these events is a medical emergency. And so what we hear from physicians often is that they are worried for their patients, and they have really very few tools to help prevent these medical emergencies. So any reduction in these hypoglycemic events is meaningful.

In terms of the NDA, we're working hard on everything we can now. I think the goal would be that the last really substantial piece of work would be everything associated with the Phase III trial. So we're trying to write everything in advance that we can. As I said, we have a very experienced team who's been through many regulatory submissions before. So they're hard at work as we speak.

Your next question comes from the line of Marc Goodman with Leerink Partners.

This process of adjudicating the claims data, can you give us an example or 2 of just some of these efforts and just so we understand what you have done so far and how confident you are that you're finding these patients in the places that you think they are based on the claims data? And are you only counting, like, the moderate to severe ones, you're not counting the benign ones, right?

Thanks, Marc. Appreciate the question. Just to talk a little bit about the claims analysis, so within the claims databases, we start with identifying patients that have a presence of bariatric surgery. And then, we look at patients who also have documented hypoglycemia, so nondiabetic hypoglycemia. And then, after that, we'll then apply and we have applied additional signs and symptoms associated with PBH such as fatigue, dizziness, seizures, even blood glucose tests or even ER visits. And then, to add to that, we can look at it from how many of those type of events they've also had within the claims databases. So that's really how we've continued to look at the databases. I'll say we've done it several times. And each time we do it, we are confident in the 160,000 patient population that we've mentioned a few times.

Yes. And I might just add, too, some added work the team has done, too, is both speaking to many of the sites and doing kind of market research with many of the sites to validate what we're finding in claims. For example, if the claims are saying a site has 50 patients, actually checking with the site and seeing if they do have 50 patients. And so far, those have been quite confirmatory as well. And I'll also just add from the call today, we also received notification kind of through the CMS manual list that there's likely to be an ICD-10 code for PBH going live in October, which will provide an additional tool kind of to track the claims data as well.

Yes. And directly to your point, too, on excluding benign, based on the coding, both on hypoglycemia, as well as the signs and symptoms, these are people who have severe hypoglycemia.

Your next question comes from the line of Geoff Meacham with Citibank.

I have 2 quick ones. So ahead of LUCIDITY top line, I know the primary outcome measure is Level 2 or 3 events as a composite. But is there a thought of looking at each one of those separately, in particular, Level 3, just to have a cleaner look at the profile from maybe a more commercial context?

And then, the second question. As you guys begin to focus on commercial and further evaluate the PBH prescriber base, how has your thinking evolved in terms of size and scope of sales force and MSL teams?

Geoff, I'll take your first question and then pass to Dan for your second. So, as you say, our primary endpoint, which is FDA agreed upon, we were looking at the reduction in the composite of Level 2 and Level 3 events, and that is well established in the ADA, Diabetes Association, literature and community as well. We do intend as well -- our secondary endpoints are looking separately at Level 2, which is by fingerstick blood glucose level of less than 54 grams per deciliter, and separately Level 3, which is independent of glucose level, signs and symptoms that require individuals to have another individual help or signs and symptoms that would have required someone else to help them if no one else is around. And that is adjudicated by an independent group of experienced endocrinologists who are blinded to the data as well, and they do that adjudication on an ongoing basis.

And I'll just add, too, from the sort of commercial point of view, so you're right, absolutely, Level 3 means the person has had the manifestation of hypoglycemia. And so, of course, that's important. But Level 2 being less than 54 is very well established, too. So I think endocrinologists will be interested in both. And if you think about the outcome, it's really a nice mix. You have a blood value which indicates severe hypoglycemia, so you kind of know what's happening in the body. And then, you have a clinical outcome in Level 3, where you know the person has had the impact of severe hypoglycemia.

And then, for your question on prescriber base, I'll turn it to Dan.

Geoff, thanks for the commercial question. So, on the sales force sizing, we are initiating the go-to-market efforts at this moment. I would say, this is a rare endocrine launch. So from an expectation -- you can expect that the sales force would reflect this particular size of the sales force. I'd also add that on Camille's team and the medical affairs function, we have initiated hiring our regional Scientific Director team, also known as an MSL team, but those hires are in place.

Your next question comes from the line of Rami Katkhuda with LifeSci Capital.

I guess, can you touch on the degree of natural variability there is in Level 2 and Level 3 hypoglycemic events for PBH patients? Do you expect a massive difference from one week to another? And then, secondly, from a commercial perspective, are these PBH patients generally managed at centers of excellence? Or would you need to target endocrinologists more broadly?

Sure. Maybe starting with the variability. So all of that's taken into account in our powering analysis, and I think we were quite conservative in our powering, both on the effect size and on the placebo effect, whereas we saw a 50% and 64% effect size at the 60 and 90 mg doses, we powered to a 35% effect, and then, of course, retaining power up to a 50% placebo effect, even though I don't think we expect that in this condition. You can certainly look at the variability kind of from previous studies. But again, that's all kind of accounted for in our powering analysis. And generally, it's a chronic condition. Generally, people are not able to prevent these events from occurring. So often, if people are having events, that will be a continuous thing. They don't kind of come in fits and starts, so to speak, all that often.

In terms of the question of how we'll target centers of excellence versus the broader endo community, I'll pass it over to Dan.

Sure. Thanks, Josh. And I appreciate the question on the potential [indiscernible]. On the -- where the patients are potentially treated, so we have initiated that work, and we are aware, and Josh mentioned this earlier, but there are centers of excellence. There are also key opinion leaders, and that's likely where we'll start from a launch perspective. We know that there's potentially 50 to 60 patients at certain centers, and some centers have even mentioned even more. But we'll start there. We know there's a concentration. And then, as our disease state education efforts take a foothold, we'll expand into the broader endocrinology community.

Your next question comes from the line of James Condulis with Stifel.

This is Mark on for James. One for me on Recordati. I believe we should be getting some data this quarter. And just curious your thoughts here as it relates to potential placebo effect and what the implications are for LUCIDITY and whether really this is something that can actually be sort of read through on your trial.

Yes. Thank you, Mark. So I would say, no, I wouldn't think there should be any read-through. They're very different studies. And of course, we're conducting our study and Recordati is conducting their study. As I understand it, I think their study is a Phase II, looking at mixed meal tolerance test. And ours is based on the prior Phase IIs, which is a much more real-world type approach, looking at Level 2, Level 3 hypoglycemic events, which, of course, is within FDA guidance, to support a potential registration. So, no, I don't think there should be any read-through between the studies.

Plus the mechanisms of the drugs are very different as well.

Your next question comes from the line of Graig Suvannavejh with Mizuho.

This is Sam on for Graig. Maybe switching over to 0114 with the ALS data coming up shortly, can you just remind us of the specific biomarkers potential [indiscernible]? I know there was some prior analysis done by you guys highlighting certain biomarkers. But maybe just a reminder, and then also some of the expectations you guys have or we should be thinking about going ahead into the data.

Sure. Thanks very much. So just to remind, our ALS study with AMX0114, which is an ASO against calpain-2, is ongoing. We announced that we completed enrollment of Cohort 1 in March and that we are recruiting Cohort 2 at the moment. And earlier this year, we reported on the safety data for Cohort 1. And we do anticipate, as you point out, reporting on the biomarker data. Actually, it will be this June at ENCALS in Madrid, Spain. So the biomarkers that we're studying are related to the mechanism of the calpain-2 ASO, blocking this protease, as well as biomarkers that are related also to the ALS disease process. And we look forward very much to sharing those data with you.

And just to add as well, as Camille said, the study is proceeding incredibly well. So I think as Camille was mentioning, we've completed enrollment in Cohort 2, and we're now recruiting for Cohort 3 as well.

Your next question comes from the line of Jason Gerberry with Bank of America.

This is [indiscernible] on for Jason. Maybe just a couple of commercial questions on avexitide. I think you've mentioned before that the ICD-10 code was not necessary for successful commercialization. But just curious how ultimately having an ICD-10 code kind of alters your confidence in identifying and capturing patients at scale. I know you've outlined the centers you're targeting and what your commercial strategy is, but just curious if it impacts how you're approaching your commercial plan.

And then, just a second quick follow-up. I believe you plan to position avexitide as a chronic therapy. I'm just curious what your -- what assumptions you're making around expectations for persistence and adherence in the real world.

Great. Thanks, [ Tina ]. So, on the ICD-10 question, so in April, CMS, they published a list of ICD-10 codes to be effective October 1. These codes demonstrate a recognition of PBH in the broader medical community. The ICD-10 code, yes, it is helpful for diagnosis and tracking of patients. However, it's not necessarily -- it's not a necessity. ICD-10 codes are often used for epidemiology. So, in implementation of the code, this will enable patients to be tracked across the various electronic medical record systems. It's also important to note that patients, today, they still can be identified via the claims analysis, and that's how we validated the 160,000 patient population.

And then, to your other question, too, about kind of chronic therapy and persistence, it's probably early to comment there. We're quite excited about avexitide. And PBH is a chronic condition where the needs do not go away over time. So certainly, we do think that patients will have an ongoing need for therapy.

Your next question comes from the line of Chris Chen with Baird.

Congrats on the progress. Just a quick one on the OLE. Can you just remind us what the setup is specifically for that? And are you able to kind of share high level how enrollment in that is going?

Sure. So, are you speaking of the OLE or the EAP, just so I'm clear, please?

The OLE for LUCIDITY, the...

Open-label extension?

Open-label extension, yes.

Yes. So while I will not comment on details of our ongoing blinded trial, I am pleased to share that LUCIDITY is proceeding well, including participants transitioning from the double-blind period to the OLE portion of the study. We're confident that we're running the right study, and we're very pleased on how the team has been executing on the trial. We have such an experienced team, and they're overseeing the trial with great focus and care.

Yes. And you asked the OLE setup. So just to add there as well, so we expect the randomized double-blind study is the study that will -- we expect to use in our NDA to support potential commercialization. The OLE itself, though, also has a Part A and a Part B. During the Part A, we keep the study very similar to how it's conducted during the double blind. That allows to look at kind of data in a similar way to we look at as the double blind. And then later, they enroll in the [ OLE B ] after 8 weeks in the OLE, at which point, it's a little more -- there's less -- it's a less burdensome kind of trial participation at that point. But overall, just to kind of reiterate what Camille said as well, we're very pleased with the conduct of the study. There's a lot of excitement from sites and otherwise as well, and we'll look forward to reporting our data in Q3.

And I think it's obvious, but just to say also, for the open-label extension, I think it's very important when you work in rare debilitating conditions like post-bariatric hypoglycemia that you always try to think about the people we are trying to help. And so, for an open-label extension, if you're on treatment and you believe that you're benefiting in open-label extension, allows you to continue. And if you are randomized to placebo, then allows you to take active medication. So that's something that we always really try to think about in our programs.

Your next question comes from the line of Ananda Ghosh with H.C. Wainwright.

Maybe one question. People have been focusing on U.S. opportunities. So one question would be, have you done work with respect to avexitide on ex-U.S. opportunities? What are you hearing from the KOLs or stakeholders? And then, I have one follow-up question on LUMINA.

Absolutely. Thank you, Ananda. So there's a tremendous unmet need globally for post-bariatric hypoglycemia. Now, our focus is very much on the U.S. right now with 160,000 people in the U.S. with PBH today. That's a substantial unmet need and people to help and address. But our -- first of all, bariatric surgeries occur globally. And also, as we mentioned before, virtually any gastric surgery has the potential to cause the same debilitating hypoglycemia.

So, for example, in major Asian countries, gastric cancer rates, esophageal cancer rates are very high. And so, gastrectomy or esophagectomy is often indicated. And so, for people with those surgeries, they also have the potential of developing the same debilitating hypoglycemia, and we have data from the Phase IIb study of avexitide that avexitide may be beneficial for people who had those surgeries leading to this debilitating hypoglycemia as well. The pathophysiology is the same regardless of the surgical intervention. So, our focus is really on the U.S., really on the U.S. population of post-bariatric hypoglycemia. But absolutely, there's a huge unmet need internationally. We get compassionate use requests from people around the world constantly.

Got it. One question on LUMINA. I know there was a question on biomarkers. So given that it's the lowest dose, do we -- are we -- can we expect the preliminary NfL data or target engagement data with respect to calpain-2 levels or other downstream markers like SBDP-145 in the data readout, or that is for later...

Yes. I mean, it's hard to know -- sorry to interrupt. It's hard to know until we have the data. I'd say, we do preclinically believe we have a potent ASO. As you look at past ASOs that have been in clinic, usually, they've been studied between the range of generally about 10 mgs to 100 mgs for CSF injection. And we're at the very low end of that range. So we may see signals, but it also may require us to go to a higher dose before we start significantly moving the biomarkers.

But I'll add, too, Ananda, to your point, we really are -- our goal is to have a picture of, first, are we replicating the biology that we saw in the preclinic to the clinic? Are we seeing the implications of calpain-2 knockdown? And then, are we seeing effects on biomarkers that we believe to be prognostic for ALS as well? So that is indeed the goal of the biomarkers in all of these cohorts is to try to get a picture of are we seeing the impacts of calpain-2 and are we seeing potential impacts on ALS as well?

Thank you. There are no further questions at this time. I'll turn the call back to Mr. Klee.

Thank you, operator, and thank you all for your time. If you have any follow-up questions, please reach out to Lindsey. And we hope you have a great rest of your day.

Thank you, everyone.

Good morning, everyone. My name is Jim, and I will be your conference operator today. At this time, I would like to welcome everyone to the Amylyx Pharmaceuticals Fourth Quarter and Full Year 2025 Earnings Conference Call. [Operator Instructions] Please be advised that this call is being recorded at the company's request, and it is now my pleasure to turn the floor over to Lindsey Allen, Vice President, Investor Relations and Communications. Welcome, Lindsey.

Good morning, and thank you all for joining us today to discuss our fourth quarter and full year 2025 financial results and business update. With me on the call today are Josh Cohen and Justin Klee, our Co-CEOs; Dr. Camille Bedrosian, our Chief Medical Officer; and Jim Frates, our Chief Financial Officer. Before we begin, I would like to remind everyone that any statements we make or information presented on this call that are not historical facts are forward-looking statements that are based on our current beliefs plans and expectations and are made pursuant to the safe harbor provisions of the Private Securities Litigation Reform Act of 1995.

These statements include, but are not limited to, our expectations with respect to avexitide, AMX0035,-AMX0114 and AMX0318, statements regarding regulatory and clinical development the impact thereof and the expected timing thereof and statements regarding our cash runway. Actual events and results could differ materially from those expressed or implied by any forward-looking statements -- you are cautioned not to place any undue reliance on these forward-looking statements, and Amylyx disclaims any obligation to update such statements unless required by law. Now I will turn the call over to Justin.

Good morning, everyone, and thank you for joining us. In 2025, we meaningfully advanced our pipeline, made important progress on our regulatory and commercial preparations for avexitide strengthened our financial position, which extended our cash runway into 2028 and position the company for what will be a transformative year in 2026. We Importantly, in 2025, we initiated the pivotal Phase III LUcIDITY trial of our lead program, avexitide, a GLP-1 receptor antagonist in post-bariatric hypoglycemia, or PBH. In addition, our collaboration with Gubra progressed significantly. In January of this year, we announced the nomination of AMX0318, a novel, long-acting GLP-1 receptor antagonist, as a development candidate for PBH and other rare diseases. We also made strides in ALS. AMX0114 received fast track designation and demonstrated a favorable safety and tolerability profile in cohort 1 of the Phase I LUMINA trial in people with ALS, allowing us to advance into the next cohort.

As we look ahead, our top priority is our work toward potentially delivering the first approved therapy for PBH. We are focused on 3 objectives to avexitide in 2026. One, deliver top line data from the pivotal Phase III LUCIDITY trial expected in Q3 2026. We are excited to share that the recruitment phase of LUCIDITY is complete, and we are on track to fully complete enrollment this quarter. With the final potential patients currently in screening, we continue to expect to randomize and dose the last eligible participants this month. Two, advance NDA readiness and regulatory preparations so we can move rapidly following top line data. We are already hard at work drafting NDA sections to support a potential submission. And three, strength and launch readiness to support a potential 2027 commercialization of avexitide, if approved.

We are actively building our commercial infrastructure and fine-tuning our launch strategies. Drawing on our experience of successfully establishing a commercial organization in the past. As we prepare the organization and continue to understand the market, we are making key hires conducting market research, including gathering insight from clinicians and people living with PBH and building our disease education initiatives and market access strategies. We are acting with urgency driven by the significant unmet need in PBH and our conviction in the opportunity we believe is ahead of us. When we assess the epidemiology of PBH, we benefit from a growing body of prospective and retrospective published literature including large long-term cohort studies evaluating hypoglycemia in people who have undergone bariatric surgery.

From these studies, we estimate that there are approximately 160,000 people living with PBH in the U.S. Out of the more than 2 million people over the last decade, who have undergone the 2 most common types of bariatric surgery sleeve gastrectomy and Roux-en-Y gastric bypass. Our independent claims analysis across multiple databases continues to help validate our view of the market opportunity and further our understanding of where people with PBH are being cared for. Additionally, we continue to hear from clinics and families about the difficulty in managing PBH and how the lives of patients are upended by this condition. With that, I'd like to now turn the call over to Camille to further discuss the unmet need in PVH, the LUCIDITY trial and some of the launch preparation underway in her organization.

Thank you, Justin. PBH is a chronic metabolic condition driven by an exaggerated GLP-1 response, primarily after food intake, resulting in persistent, recurrent and often debilitating hypoglycemia. These events cause an inadequate supply of glucose to the brain known as neuroglycopenia with potential clinical consequences such as cognitive dysfunction, seizures and loss of consciousness. For people living with PBH, this creates a life of perpetual vigilance, where a meal with friends or a drive to work carries the risk of debilitating hypoglycemia and its consequences. This fear disrupts independence and compromises safety, nutrition and overall quality of life. Currently, there are no approved therapies by the FDA.

Our pivotal Phase III LUCIDITY trial is evaluating avexitide 90 milligrams once daily in individuals with PBH following Roux-en-Y gastric bypass surgery. Using the FDA agreed upon primary outcome, a reduction in the composite of Level 2 and Level 3 hypoglycemic events through week 16. The LUCIDITY trial is anchored in the robust data generated to date from 5 prior avexitide clinical trials in PDH that demonstrated statistically significant reductions in hypoglycemic events. Most notably, avexitide 90 milligrams once daily led to a 64% lease squares mean reduction versus baseline in the composite rate of Level 2 and Level 3 hypoglycemic events with a p-value of 0.0031.

Also of note, the Phase II trial showed no placebo response. However, to be conservative, we modeled up to 50% placebo effect and 35% effect sales relative to placebo for lucidity and under these assumptions, we believe LUCIDITY remains well powered to detect clinically meaningful benefit. LUCIDITY was designed with the goal of replication. The 5 prior avexitide clinical trials in PBH directly inform the dose, the primary endpoint, inclusion criteria and surgical subtype. We focused on enrolling a similar patient population, collecting the data in a similar manner and executing lucidity with high quality. As Justin shared, the recruitment phase of LUCIDITY is complete, and we continue to expect to randomize and dose the last eligible participants Visma.

We are pleased by the ongoing high participant interest and broad engagement we have seen across all clinical trial sites. The open-label extension or OLE portion of the trial is also already underway. Participants become eligible to enter the OLE immediately upon completion of the double-blind phase. In addition to NDA preparation activities ahead of the potential approval of avexitide, we are actively ramping up our medical insights capabilities, disease education activities, and community engagement and evidence generation. These efforts will facilitate understanding of the avexitide data, PBH burden and the potential value of a new treatment for PBH by key stakeholders, including the broader medical community, payers and people living with PBH.

We established core medical leadership functions and have already hired leaders for our medical field force, health economics, outcomes and real-world evidence research and patient and professional advocacy. 2026 is a busy and exciting year for our medical team as we prepare to potentially deliver the first treatment for people living with PBH. With that, I'll turn over the call to Jim to review our financials. Jim?

Thanks, Camille. We entered this pivotal year in a strong financial position. We ended the fourth quarter with $317 million in cash and marketable securities compared to $344 million at the end of the third quarter. This capital provides us with an anticipated cash runway into 2028 to fund our operations through our expected milestones, including our key focus, the LUCIDITY top line readout expected in Q3 2026, potential FDA approval and the potential commercial launch of avexitide in 2027. Turning now to our results for the quarter. Total operating expenses for the quarter were $36.6 million, down 8% from the same period in 2024. Research and development expenses were $21.2 million compared to $22.9 million in Q4 2024. This decrease was primarily due to decreases in spending on AMX0035 for the treatment of ALS and PSP.

The decrease was offset by increased spending related to the clinical development of avexitide in PBH. Selling, general and administrative expenses were $15.4 million compared to $17.1 million in Q4 2024. This decrease was primarily due to a decrease in consulting and professional services. We recognized $6.4 million of noncash stock-based compensation expense for the quarter compared to $6.8 million of noncash stock-based compensation expense in Q4 2024. Of note to be aware of for our Q1 2026 results. As Justin stated earlier, in January, we announced the nomination of AMX0318 as a development candidate for PBH and other rare diseases. The selection and handover of the development candidate resulted in a milestone payment of $4 million to Guba, which we will reflect within research and development expense in our Q1 2026 income statement.

Before I turn the call over to Josh, I'd like to just take a step back from the financials for a moment. The more we learn about the PBH landscape and speak with those living with or treating the condition, the more we recognize the importance of our work, given the magnitude of this unmet medical need. We believe avexitide is a potentially -- excuse me, a breakthrough treatment for PBH and are working hard to prepare to launch the treatment, if approved, for people living with this difficult condition. With that, I'll turn the call over to Josh.

Thanks, Jim. While our immediate focus is on exide our broader pipeline strategy is designed to leverage our expertise in endocrine conditions and neurodegenerative diseases to build a diverse portfolio of potential medicines. This strategy is exemplified by AMX0318 and which, as Justin mentioned, is our investigational long-acting GLP-1 receptor antagonist. We selected AMX0318 following a rigorous evaluation of a large number of peptides against key criteria. AMX0318 demonstrated a robust chemical stability profile, strong in vitro potency, evidence of in vivo activity and tolerability, high solubility and a favorable pharmacokinetic profile consistent with a long-acting peptide. IND enabling studies for 0318 are underway with an IND filing targeted for 2027. For AMX0114, we plan to present biomarker data from cohort 1 of our Phase I LUMINA trial in ALS in the first half of this year.

LUMINA is a randomized, double-blind, placebo-controlled multiple ascending dose clinical trial in people living with ALS, with Cohort 1 investigating the first and lowest of 4 doses being evaluated. We presented initial safety and tolerability data from Cohort 1 at the International Symposium on ALS and MND last December, and we're pleased to observe that AM114 was generally well tolerated with no treatment-related serious adverse events. Based on these data, we proceeded with the next cohort of participants, and we expect to complete enrollment of cohort 2 of the LUMINA trial this month. We look forward to sharing our progress in this dose escalation study.

For AMX0035, we continue to work with the FDA on a Phase III trial in Wolfram syndrome, following the long-term data from the Phase II HELIOS trial that we presented last year. To close, Amylyx has an exciting path ahead. First and foremost, we are focused on LUCIDITY. In parallel, we are working on the NDA to be prepared for a strong submission following top line results. Additionally, we are expanding our commercial and medical teams efforts as they work towards a potential launch in 2027. Now I would like to open the call up for questions.

[Operator Instructions] Our first question today will come from the line of Seamus Fernandez at Guggenheim.

Great. So wanted to just ask the learnings that you've gained from the execution of the clinical trial so far, specifically the recruitment is now complete. We're going to see a lot going forward. But in terms of the run-in, I was hoping you might be able to give us a little bit of color in terms of the quality of the sort of events that are occurring during the run-in, the severity. I know there were very specific requirements around that. But in terms of the powering dynamics, just I'll have a follow-up question in that regard. But what have you learned during the run-in period about these patients and the patient population along the way that gives -- that can basically maybe give us a little bit more color and certainly enthusiasm to match what we've heard from thought leaders in the space.

Yes. Thank you very much for the question. And I'll start with the inclusion criteria, the whole design of the study was really informed by the prior trials, particularly the prior Phase II trial. So those were very successful, showed very statistically significant, clinically meaningful reductions in hypoglycemic events. And so we carried all of that forward into the Phase III. We do believe that we're recruiting the right participants. We believe that we're conducting the right study. And what I can say probably more anecdotally from the sites is what's really come through is the unmet need here. Each one of these hypoglycemic events is a medical emergency. If you look at the materials from the American Diabetes Association, for example, very clearly on their website, they say severe hypoglycemia, which means Level 2, Level 3 events is a medical emergency.

And so you really hear that from the sites that these are really challenging events, and that's what makes PBH so challenging as a disease. We've also been very encouraged by the broad participation across the sites. And I think, again, it just underscores that all of our market research as well, which is that this is a substantial unmet medical need. It's a large orphan condition. There are many people who are struggling with PBH and there are no treatments approved for PBH right now, really the mainstay is just the medical nutrition therapy, and that's really just to try to control excursions as best as possible, but people continue to have these events regardless. So really, just our conduct of the study has underscored the opportunity we have ahead of us.

Great. Maybe just as a quick follow-up. The powering of the study and the sort of statistical design, you've got 16 weeks of treatment versus a much shorter treatment period from the Phase II. Also -- and unusually low placebo rate. But obviously, the powering assumptions that were discussed as much as a 50% placebo rate, just trying to get a better understanding of why that level of placebo would be even possible in this case when we go from 0 in the Phase II. Just trying to get a better understanding of some of those characteristics what could actually impact the placebo response relative to what we've seen in the Phase II.

Yes, great question. So maybe I'd start by saying scientifically and based on prior data, we really don't expect much of a placebo response. When you look at the past Phase II trials, there really wasn't much of a placebo response at all. And actually, some prior work from Zealand Pharma with asaglucigon also didn't see much of a placebo response in PBH. So we really don't expect one. But what I'd say is we do believe that avexitide is an active drug, going through the 5 prior trials, we see consistent effect, so I think strategically, as we were designing the Phase III, we wanted to make sure we were very well powered.

So I'd say not just on placebo effect, but across all the assumptions that went into our powering analysis, we tried to be conservative to make sure that we would have more than adequate quick power in the study. We'll take our next question.

We'll take our next question this morning from Karen Jenkins at Goldman Sachs.

This is Kevin on for Karen. Just a follow-up basically on the commercial prep that you all are doing, including market research. Could you just put the learnings so far from LUCIDITY into the context of the commercial prep you're doing now, how that has helped you? And sort of, I guess, where are you in terms of commercial prep? And then just a quick follow-up on the OLE. Can you just tell us give us some color on how many patients are currently having been enrolled into the OLE?

Thank you. So I would differentiate 2 things. So priority 1 is our execution in the LUCIDITY trial I do think, again, it underscores the unmet need and opportunity here. But in addition to that, we are also doing substantial commercial preparations, particularly across our medical affairs and commercial organization. And I can share what's really come through there. I think in 2025, we tried to get a real handle on the market. We spent a lot of times, a lot of time first in the literature assessments, talking with key opinion leaders, going to conferences and then after that, we spent a lot of time with various claims databases and other sort of medical information systems so that we got a real sense of how many people with PBH there are where they're being treated, what's the patient journey, those sorts of elements. And I'll say that first, all of our research really triangulated to this about 160,000 prevalence number.

And that's today, we expect that the population will only continue to grow from there, given that this is a rare occurrence that happens to some people in the years following bariatric surgery. But once PBH occurs, it seems that does not go away. We work with people who've had PBH for 15 or 20 years. What we've done subsequently then is to reach out to many of those centers from the claims work and try to corroborate our numbers. For example, we see you have 100 patients, 120 patients under your car. Is that right, who are the primary healthcare professionals who care for them, what's the frequency of visits, those sorts of things. and everything has come back really corroborating our claims work. And I think, again, it just underscores that this is a large orphan condition. This is a substantial unmet need. We hear that again and again from all of our market research there are really no treatments available for people with PBH today. There's a growing awareness of PBH as well. PBH is now on endocrinology Ford exams. There -- we expect to hear on a potential ICD-10 code this year as well.

So I think everything is pointing towards that this is a large unmet need, it's a growing unmet need and underscores the importance of a potential treatment in the future. For a question on the OLE, I'll pass to my colleague, Camille.

Sure. Thank you. So we really do not report on details of an ongoing study. Having said that, we are pleased with the participation in the LUCIDITY study, having now completed recruitment and participants are rolling over into the OLE. We are very much looking forward to top line data Q3 of this year.

Our next question will come from the line of Marc Goodman at Leerink Partners.

Yes. Can we go back to this checking out the claims database data and figuring out whether these sites actually have the patients and whether they match up. Can you just elaborate a little bit more on how many of these sites that you actually checked out? Are you checking out large ones, medium-sized like small ones, just give us a sense of what it looks like out there as far as numbers of patients in these sites, like how many have over 100, how many are in the 50 to 100, just so we understand like the concentration.

Yes. good question, Marc. So maybe we'll probably get more into that as we kind of get closer to our kind of commercial -- hopeful commercial launch in 2027. But what I'd say is we did try to pressure test our claims data pretty well, looking at a variety of different natures of center, as you suggest, trying to make sure that what our claims are identifying are real, that there's not some issue on how the claims data is finding patients. And I'd say one thing that's helpful for us, too, is not just in validating the epidemiology, working to continue corroborating the 160,000 number, but also in determining where these patients are seen, which helps us as we start thinking forward into deployment and then to the best way to reach these centers.

I will say that our data continues to suggest that this is organized like you might expect for an orphan disease. There certainly are a number of centers that see quite a concentrated pool of patients, and then there are some centers that see less as well. But I think that all lends itself well to some of the kind of orphan disease strategies that you might typically see in a commercial launch.

And I'll just add as well, I think the -- again, it's -- I just -- I really want to underscore the unmet need that we hear, again, is we've talked to a substantial number of clinics now -- and the story is the same again and again, which is that PVH is a really difficult condition for patients is a really difficult condition to manage as a physician because people are hyper reactive. They sometimes have triggered events, but sometimes it's for no seeming trigger at all. And as a physician, I think they feel a little helpless because they really don't have tools to either prevent or really treat these hypoglycemic events. And going back, each 1 of these events is a medical emergency. So you think from the physician's point of view, you have a patient who is very frequently having medical emergencies. I think it just underscores the opportunity we have.

Our next question this morning will come from Michael DiFiore at Evercore ISI.

Just want to examine the avexitide Phase IIb trial for a bit. I noticed that the -- in Phase IIb, the standard deviation for hypoglycemia were very large, especially in the 90-milligram arm, which would suggest that there could have been nonresponders or at least some sub responders to therapy. So were there nonresponders or suboptimal responders. And if so, to what extent might they have played a role in driving the hypoglycemic event rates?

Yes. Good question. So going to the Phase IIb and the 90 mg arm, so maybe just to start with, we saw a very strong effect there. Roughly 66% effect with a very strong p-value, less than 0.001 as well. And the median effect, the median patient actually had their event rate go to 0, which gives you a sense of just how strong the results we saw. Yes, there is some variability. Some people have more events, some people have less events, which I think does account for that staired deviation. But by and large, we were seeing the response across the cohort that was studied. And I think that shows up also frankly, in the p-value, which is showing that the effect is much larger than the noise that was observed in the trial.

And I would add, that's 1 of 5 trials, right? That showed the same thing. So avexitide in all 5 trials showed substantial reductions in hypoglycemia -- hypoglycemic events. And that's what ultimately supported FDA breakthrough therapy designation as well.

We'll hear next from James Condos at Stifel.

Congrats on the progress. I wanted to ask another commercial one. And I think 1 of the more interesting data points that we've seen coming out of some of the work that Stanford did in terms of this market is that there's critical PBH patients? And I guess the question is, as you've continued to do work on this market and look at things like claims, do you think they're there's really this many very, very severe PBH patients that are going to the ER being admitted to the hospital, et cetera. And I guess as you think about it, are those patients kind of fair to think about as maybe lower hanging fruit relative to the rest of the patient population.

Yes. Thank you, James. It's an important question. And I'll say again, this is something we started to look into in our market research and our interactions with clinics. And this -- and I'll say what's really come through is, I think generally, physicians have said, yes, certainly, people who are in and out of the ER are high on our list of people we really want to help, but there hasn't been that much differentiation between someone who's very frequently in and out of the ER and somebody who maybe is having hypoglycemic events on a less frequent basis, and I think the reason is that physicians believe that any one of these events could land somebody in the ER, right? Each one of these events as a medical emergency has the potential to be a catastrophe.

And so while, yes, they are certainly particularly interested in helping the people who are really critically impaired, they really believe that PBH by itself is a very dangerous condition. And so again, that's why I keep underscoring the unmet need here. That's just come through again and again and again. So I think for us, I think all of this is informing our sort of go-to-market strategies and the type of commercial opportunity we have ahead of us.

Yes. may just add to anecdotally too, as we've talked to sites, and I think this bears out and the claims based work that we've been doing, severe falls that result in people having fractures, cases where people have maybe had seizures or hypoglycemic coma. So I'd add that it's not just the direct consequences of hypoglycemia, the kind of failures of the brain to function due to low glucose. It's also all the indirect effects, falls, accidents, things like that as well. And pretty much every clinician we've spoken to has their stories about seeing those really severe outcomes come to manifest.

Yes. And I'll also add here. for individuals, not every individual may go to the ER or be hospitalized because their lives have changed completely. Their lives are very, very constrained and narrow staying in the home. People with PBH learn to understand what they can and can't do and try and avoid the accidents or the profound hypoglycemia that leads to unconsciousness or seizures. So even though someone doesn't go to the ER, it doesn't mean they're not severely, severely constrained, living at home, needing a companion, et cetera.

Our next question today, we'll move forward to the line of Rami Katkhuda at LifeSci Capital.

I guess, based on your conversations with physicians and payers, is there a magnitude of reduction in these hypoglycemic episodes that is considered meaningful? Or is statistical significance and lucidity enough to see broad uptake?

Right. So the -- what we've heard from physicians certainly is ultimately what they'd like to see as an approved drug for people living with PBH. Leading up to that, as we've been articulating today as the American Diabetes Association clearly states on their website, hypoglycemia of the Level 2, Level 3. Each one is a medical emergency. So the physicians also say, and the patients too that they would like a reduction in just 1 event will be absolutely meaningful. Having said that, of course, we're conducting LUCIDITY and we would say that a statistically significant reduction will be obviously very important and take us to our next steps with avexitide.

Got it. And I guess, do you plan to share baseline characteristics from Lucidity before the Q3 readout?

So I think as we're still considering, but I think as we look at the study it's a pretty quick turnaround, given that it's only a 16-week study. So we'll continue considering that, but I think mostly, we're excited about data coming out in Q3. .

We'll hear next from Jeff Meacham at Citibank.

I know you guys called out 0318. I know you're thinking life cycle management and PBH, but maybe help us with the timing. Is there a fast path to a pivotal once you finish the initial Phase I and with LUCIDITY experience in hand? And then related to 0318, are there other endocrine indications, rare or otherwise that at this point look interesting to you or still too early to tell?

Yes. So maybe starting with 0318, maybe I'd just start to reiterate, we're very excited about the compound, especially given the work that we did with Gubra where we screened a very large number of peptides and really try to find the best possible GLP-1 antagonist that we could trying to optimize across many parameters, including the PK profile as well as the potency of the in vivo activity, manufacturability, things like that as well. So certainly, we're moving that compound ahead as quickly as we can. But I think going to your other point, we really do see this as part of our kind of broader excitement about GLP-1 antagonism. We've heard from clinics, and we've seen the literature as well, that it's not just bariatric surgery that can result in these dangerous hypoglycemic events. But people get these events after surgery for gastric cancer, gastrectomies, esophageal cancer, esophagectomies, people may have surgeries for peptic ulcer disease, gastrointestinal reflex disorder, et cetera., all of which can lead to these recurrent hypoglycemic events.

And I'd also add that's not just in the U.S., people are having these, including due to the high rates of gastric cancer in Asian countries. Certainly, there are both bariatric surgeries and cancer-related surgeries in Europe as well. So I'd say we kind of look at the efforts to make a long-acting kind of in that context that we think that this is a really exciting approach, GLP-1 antagonism, and we want to keep investing in it and moving the science forward.

Our next question this morning will come from Graig Suvannavejh at Mizuho.

If I can just go to the market opportunity for avexitide and PBH. Can you just remind us of the current patient and physician experience with cabo -- and on the assumption that avexitide gets to the market whether existing use of acarbose by PBH treaters might represent in any way a potential hurdle to uptake of avexitide?

Thanks, Greg. SP1 Yes, very important. So I would start with a CARBOs is not FDA approved for the treatment of PBH. And right now, I think PBH is probably pretty typical of a rare disease with no available treatments. And what I mean by that is that physicians are kind of willing to try whatever they can to help their patients. ACARBOs helps with potentially 1 small aspect of what causes the hypoglycemia, which is the general digestion of carbs. However, one, that's only a limited part of what can trigger these hypoglycemic events. Two, acarbose is really not well tolerated in our -- as we look through, for example, the prior trials and experience of people with -- on acarbose, it was not uncommon for people to come off a carbs in a matter of weeks because it just has -- is really not well tolerated, very significant GI discomfort and symptoms.

And probably the most important thing I would say is that we really don't think it's targeting the root cause of PBH. We think what characterizes PBH is this very hyperreactive state. And people are hyper reactive because the body has substantially increased its GLP-1 response. GLP-1, the GLP-1 response is often up to 10x normal. And so with the up to 10x normal response, that's what causes the insulins like and therefore, the hypoglycemic events. And so I think if you're not targeting the root cause of what's causing this hyperreactivity, then people are going to continue to have events. And again, this is what we've heard again and again from physicians. So probably the short answer to your question is no, we do not believe that acarbose in any way is holding the challenges of PBH nor do we think that, that will impact the uptake of avexitide.

Our next question today will come from Christopher Chen at Baird.

Congrats on the progress. Just regarding potentially getting an ICD-10 code for PBH this year that you mentioned, Justin, can you talk a bit more about -- just for those unfamiliar, what an ICD-10 code specifically is? And what would your curing per PBH for avexitide in your view? And then can you just put a finer point on the nature of those discussions currently -- and are you able to actively engage in those discussions?

Yes. Thank you very much. So an ICD-10 code is a medical code that designates particular conditions. And there's a sort of government process to determine whether ICD-10 codes are necessary. And generally, it's that there's a particular medical condition and it's a substantial enough importance and at times population as well that there should be a new code introduced and so the fact that they are considering an ICD-10 code for PBH, we think just speaks to the growing awareness of this condition, of its importance of the substantial population. And I'll say that these efforts were -- have been really led by the medical community. And as I also mentioned, PBH is now on the endocrinology board exam.

So I think really the awareness of PBH as an unmet medical need and that's a very difficult condition and a growing prevalence has really become front and center. So we're -- we'll hear more in April. I think it's important to mention as well, we don't need an ICD-10 code for future reimbursement if the product is approved, because this would be through pharmacy benefit, it's a take-home product, but an ICD-10 code certainly helps with, for example, as we're looking in claims databases, as big health systems are looking for people with PBH and making sure they're cared for appropriately. That's where this designation really helps. And again, we just think it speaks to the overall growing awareness of this condition.

Our next question will come from Jason Gerberry at Bank of America.

This is Dina on for Jason. We just had a quick maybe follow-up to a prior discussion point on the events in the LUCIDITY trial. Curious in your market research, you similarly hear that clinicians are more focused on a reduction in Level 3 hypoglycemic events as opposed to the regulatory composite end point? And can you just remind us what is your expectations for how events should skew at baseline between percentage Level 2 versus Level 3?

Yes. Great question. So maybe just to kind of give context to why the different levels were selected. So Level 2 was really defined by a number of research studies in the diabetes space as well, where they looked at what level of blood sugar do you start to have severe symptoms. And they found that, that level was often when you get below 54 mg per deciliter. So that's why Level 2 is defined. It's the level where symptoms start to get -- frequently start to get severe for individuals. Level 3 is when the symptoms have become so severe that you're incapacitated and that rescue becomes warranted, for people who did that deep into hypoglycemia. So as we speak to clinicians, I don't think they -- I think they view a Level 2 as both a symptomatic and very risky event, people who are having Level 2, maybe right around the corner from having a Level 3.

And I think that's also why there's the value in the composite endpoint as well because these events often travel together. Often Level 2 is turning into Level 3 fairly quickly. So I think -- and then I guess the other part of your question was how did that actually look in previous studies as well. There was maybe slightly more Level 2 than Level 3 in the previous studies. But generally, the events were occurring with similar frequency. And I'd add too, it was not uncommon in previous studies, too, that they occurred together that you would quickly have a patient going from Level 2 to Level 3 or logging the blood sugar below 54 in the time where they're becoming capacitated.

Moving forward, Ananda Gosh at H.C. Wainwright.

So one of the common questions we have been getting is the assumption of extended LUCIDITY trial compared to prior trials. -- and the impact on the Tactivaation. So I was wondering how during the design of Phase III, these factors were incorporated.

So with regard to diet, we provide diligent training to sites and detailed information to the participants the focus on maintaining consistency in diet, the medical nutrition therapy throughout the study, each phase of the study. This point is reinforced as well at various points throughout the study and participants actually are asked to reaffirm that they are adhering to the dietary guidelines that we've set out for LUCIDITY. Important to note also and reiterate that we are doing -- conducting LUCIDITY was replicating many of the features of the prior successful Phase II studies and dietary consistency is one of them, in fact. Also, I'll point out that the participants are very highly motivated in the study to follow all aspects of it because they are eager as well as their investigators to have a treatment for PBH.

I'll finally conclude with that we are really pleased with how LUCIDITY is being executed. So thank you for the question.

Yes. And I'll just add as well, from a drug perspective, we have no reason to believe that there should be any sort of waning effect or tachyphylaxis or anything of that nature. On the safety profile of avexitide, both from the nonclinical and clinical studies has been very good. And so as we look forward to the results in the third quarter, as Camille said, we designed the study. We're conducting the study, obviously, to support regulatory approval, but really with the Phase 2 elements in mind.

Great. Maybe a quick follow-up question. Is there any like mechanistic rationale, which shows that whether GLP-1 receptor blockade remains effective even if patients kind of increase their carbohydrate intake?

So I think it might cut off a little bit, but I think if I heard the question, it was about -- will this affect their carbohydrate intake. We really haven't seen that in -- sorry.

Sorry, no. So the question was whether GLP-1 receptor blockade remains effective as any patients kind of increase their carbohydrate intake?

Well, great question. Yes. So -- so we do believe that the effect of avexitide is quite strong. And maybe as 1 example of that, in the Phase I studies that kind of paradigm of those studies was that they gave people with PBH, a large bolus of glucose, either with or without avexitide. And what they saw in people who are receiving placebo was after the large bolus of glucose, the people with PBH blood sugar would go up and that it would drop precipitously into the hypoglycemic range and patients would need to be rescued for people who are on avexitide, particularly in the first Phase I, but also in the other Phase Is that were conducted, nearly all participants did not go into that hypoglycemic range. And those studies evaluated levels of glucose such as a 75-gram bolus of glucose. So we do believe that the effects of avexitide are robust to a pretty significant carbohydrate load.

Of course, though, in PBH, the recommendation and really what patients have been doing for years to avoid these really dramatic events is to avoid any foods that can cause that type of glucose excursion. So people with PBH are usually very well trained, and we continue training them over the study as well. to avoid meals that will result in big glucose extrusions.

And ladies and gentlemen, we'd like to thank everyone that did signal for a question today. And at this time, we'll take a follow-up from Seamus Fernandez at Guggenheim.

Great. Just wanted to ask about the tolerability profile of avexitide, in particular? And then what you would hope to learn in the early phases of the Guber asset development particularly as it relates to things like antidrug antibodies, injection site reactions, the factors that you think are most important to advancing the Guber asset and ensuring that it provides a profile consistent with the market expansion opportunities beyond avexitide.

Yes, great question. So maybe starting with the tolerability of avexitide, it's been quite excellent through our studies to date. When you look at the 5 prior trials, there really were not dropouts. People were able to stay on the drug quite successfully. And to your question on ISRs, those were generally mild when they occurred and generally at a pretty similar rate to placebo. So really not all that much seen there. And then also ADAs were very, very rare and not really associated with much when they occurred. As it relates to the Guber molecule, 1 of the things we did look for was in the animals that we studied, we did try to make sure we selected a molecule that was not immunogenic, at least in animals. Of course, as we translate to humans, that will be something we continue to evaluate, but our goal is definitely to select a molecule that does not have significant ADAs or ISRs and yes, I think it also comes down to doing -- to lean in a little bit on Guber's experience as well as we try to select peptides that avoid those types of liabilities.

And to our phone audience joining today, this does conclude the Amylyx Fourth Quarter Full Year 2025 Earnings Conference Call. We thank you all for your participation. You may now disconnect your lines. Have a great day.

All right. Okay, welcome to the Citi Global Healthcare Conference. I'm Geoff Meacham. I'm the Global Head of Healthcare and Senior Analyst, and Smid-Cap biotech and pharma. Obviously, Jarwei Fang is up here with me from my team. We're thrilled to have Amylyx. So Justin Klee is with us, Co-CEO. We won't trash the other Co-CEO. You got to look to Miami.

Yes. Yes, exactly. Yes.

We also have Jim Frates, CFO, in the crowd here. Yes, Justin, do you want to just give a bit of a kind of a 2-minute drill, and we get into some questions. How about that?

Sure. Yes, very happy to. And yes, my fellow Co-CEO, Co-Founder, Josh, is out at the ALS conference in San Diego, so we have some data, planning to present there.

So yes, so we -- we've had an exciting year, and we're especially excited about 2026. So our lead asset, Avexitide, it's a pivotal study for post-bariatric hypoglycemia, that's following 5 prior trials that supported FDA breakthrough therapy designation.

PBH has about 160,000 people in the country, no treatments approved for it, a very high unmet need. So we anticipate completion of enrollment in the first quarter and top line results in the third quarter, which then would mean commercialization in 2027. So we're very excited about that program.

We're also working on a potential long-acting. So it's a daily subcutaneous treatment. We think that's very appropriate for the market. But if we can make a long-acting even better. So we're working on that now and that research has come along really nicely. So we expect to reach a decision point on a candidate to take into IND-enabling studies in the next few months. And then we have 2 other candidates, AMX0035 in Wolfram syndrome and AMX0114 in ALS. So a very exciting next 12 months for us.

Exciting. Yes. No, thanks, Justin. So let's talk about Avexitide. So in PBH. I guess, give us some context for this as an opportunity when you first brought it into Amylyx. I know you were looking for in-licensing deals, and this is a home-run. Put the context or put the -- maybe the background of it, like help us with that first.

Sure. Yes. Thanks so much. I'd say we've had an ongoing process for some years now looking for opportunities to in-license exciting assets, particularly, I think, in the sort of rare disease space. And while I think historically, we've done quite a bit of work in neurodegenerative disease. We've done some work in rare endocrine as well.

We've been working on Wolfram syndrome for about 8 years now. And so we're on the -- always kind of on the lookout there as well. So we came across Avexitide, which is a competitive inhibitor of the GLP-1 receptor, and it turns out that there are a whole series of conditions or diseases characterized by excess GLP-1 that drives hyperinsulinemic hypoglycemia and hypoglycemia is super dangerous.

The ADA says a single event of severe hypoglycemia is a medical emergency. And so we started doing diligence on the asset. We, at that point, we had done deep diligence on well over 300 assets. And it's -- drug development is tough. And there's -- you really want something that checks all the boxes, and Avexitide really checked all the boxes. I mean, beautiful pharmacology, 5 prior trials, all of which were very strong in PBH breakthrough therapy designation, actually another 3 trials in congenital hyperinsulinism, separate breakthrough therapy designation, good CMC work, good toxicology, really ready for a Phase III.

And then as you learn about the unmet need in PBH, you almost can't believe it. I mean it's really significantly debilitating. We estimate about 160,000 people in the country have it today, and we expect that number only to increase. And as you talk with endocrinologists, you hear again in the end, these are some of the most severe people I have under my care and I don't have anything for them. So to your point, it was really like, assets like this don't come along all that often. So we're very excited, frankly, honored to get to develop it further now into the Phase III.

And I guess the market awareness, typically in metabolic disease, there's a huge DTC component. This is obviously orphan to the point where -- but it's urgent unmet need. It doesn't seem like it's going to require a lot of activation energy from endocrinologists, right, just given the state of some of these patients. Is that fair characterization?

Yes, I think so. I think there's a bit of both components of the market is probably -- is typical for rare disease. There are a lot of patients who are actively under management today. There are a whole lot of clinics that have 100-plus people under care, under active management. But there's also -- I think, historically, there hasn't been that much you can do for PBH. It's mostly dietary intervention, do everything you can to prevent these events, but people still have them.

So I think there's a big educational component as well. I think what's been nice to see, though, is that even before we've started any disease state education, marketing and those sorts of things, organically, there's been kind of a groundswell of increasing awareness of PBH. PBH is now on the endocrinology board exams. There is a large group of physicians who have submitted a petition to CMS to get CGM coverage for PBH.

There was -- just this past September, there was a presentation to the CDC saying there should be an ICD-10 code for PBH. So there's just a whole lot going on, and that's even before we start any of our pre-commercial efforts. So it's all the things that you'd hope to see. And again, as we go into the pivotal readout, we hope that we can help people with it as well.

And so that's second half of next year, 3Q. Maybe at a high level, give us kind of what you would view like success looks like? It doesn't seem like you would be stat sig, but not clinically meaningful. It's like they're the one and the same and underserved population like this.

Yes, I think that's a good way to characterize it. What we consistently hear from physicians is a single hypoglycemic event, severe hypoglycemic event is a medical emergency. And so if you think about it from their perspective, they're getting calls from their patients all the time. I've had this event. I've had this event, and I fell, I hurt myself, I ended up in the hospital. And as a physician, they feel like they can't really do much about it.

So they really want to keep their patients safe. So they really tell us any reduction in these hypoglycemic events would be meaningful. As the same thing we hear from people with PBH also is that this is really debilitating. I mean they're afraid often to leave their homes because they don't know when they're going to have an event.

They're afraid to be alone because they don't know when they're going to have an event. So any sort of return to normalcy in their lives would be just really appreciated. So I think you're exactly right, high unmet need. And so the clinical meaningfulness, the bar is very low.

So maybe Justin, maybe just remind investors kind of the bar that you guys already set with Phase II data and then also just the powering that you have with the Phase III LUCIDITY and what that means and your probability of success and your views on encouraging physicians to identify this disease more now that they may have a potential treatment on market?

Yes, yes. Those are great points. So Phase II trial, so I'll particularly go to the Phase IIb, where they tested the 90-milligram dose, that's what we've taken forward to the Phase III. There is a 64% reduction in the Level 2, Level 3 hypoglycemic events, highly statistically significant, and that is what supported the FDA breakthrough therapy designation.

Now as we've gone into the Phase III, we're powered to see a much smaller effect size than that. So we have greater than 90% power to see a 35% treatment effect, and that's even using conservative assumptions. If you kind of think about the trial design and again, the goal of the trial design was really to be as consistent with the Phase IIs as possible because strong Phase II trials try to get to as close to replication in the design and conduct as you can.

And if you just sort of add up the events, not assuming a treatment effect, one event per week because that's what we're looking for in the screening period, and we expect to continue into the study time 16 weeks, time 75 participants is 1,200 events. So it's just the design, it's very robust. It leads itself to a very strong statistical powering.

And then I think all of this is, we think, a really nice foundation as then we go into the market. And I think for people, for endocrinologists who already have many patients under their care, this is the type of data that I think they'd be excited to see for people who need more education on PBH I think there's very strong literature on the unmet need. But then to your point, hopefully, strong data as well that now we can actually do something about it.

And given the frequency of administration, I know you said, Justin, you're working on the longer acting, but what -- in a general sense, what's your persistent rates? What are you modeling when people in the Phase II have dropped off? Is it because of just like the dosing issues? Or has it been breakthrough or what's been the characteristics of...

Yes, yes. So actually, in the Phase IIs, there was basically a perfect compliance -- completion in the studies. I think it speaks to the unmet need and there are exit interviews in the Phase IIs as well. And to a person, they said like, my gosh, I felt so much better. So I think people can really feel the difference, which makes sense, right?

When you're severely hypoglycemic like you feel terrible. And so I think if you can help return to that more normal glycemic range, I think people just feel a lot better. So I'd say then as we go into the market, sadly for people with PBH, the condition does not appear to go away. It seems like once the body has sort of upregulated this GLP-1 response, it stays. And so we, therefore, expect that this would be chronic treatment.

So -- but I think what's also nice is that we really do think that what's driving the PBH, what's driving these hypoglycemic events, is this sort of GLP-1 bolus. So if you block that from happening, then you prevent those downstream events from happening.

Yes. So maybe give us a sense of your prioritization for other life cycle options beyond LUCIDITY, right? You have the long-acting in play as well. But then right now, LUCIDITY is also only concentrated on ROSA Knee patients, right? So how do you think about moving on to sleeve gastrectomy and maybe other indications that may be amenable to GLP-1 antagonism?

Yes. We think there's a whole heck of a lot to do here, which is it's really exciting and powerful biology. We've certainly seen that on the GLP-1 receptor agonist side. We kind of view it as that 50% of the equation, the other 50% of equation is hypoglycemia is not enough, but glucose and too much GLP-1.

So I'd say, first, starting with Avexitide. So we think indeed other surgeries, it's been known actually since the discovery of GLP-1 that it seems like virtually any upper GI surgery can cause the same persistent hypoglycemia. We've studied in the bariatric surgery population, predominantly, to your point, in the Phase III trial.

We're studying people with Roux-en-Y gastric bypass PBH which we believe is the majority of the population in the United States who have PBH, but there's also sleeve gastrectomy. We have studied in some sleeve gastrectomy patients Avexitide appeared to be just as effective there. So I think we'll make the case to FDA that we think it should be appropriate for people with post-bariatric hypoglycemia.

But if they say, well, this is the Phase III population that you studied and we need to generate additional data, I think we can do that. And I think to your point, then there's even other surgeries, for example, gastrectomy, which is often used for gastric cancer, one of the leading causes of death in Japan, in China, in Korea and other countries, same with esophagectomy.

Sure enough, when you have the significant upper GI surgery, you get the same persistent hypoglycemia. And we think that's also driven by this -- the body upregulating the GLP-1 response. So we think there's a whole lot to do there. And then there's even other areas like congenital hyperinsulinism or other reasons that people develop hyperinsulinemic hypoglycemia.

I think if you can get the efficacy and safety profile equivalent, then actually a long-acting would be even more convenient. All of our market research suggests that with such an unmet need, a daily subcutaneous injection is perfectly appropriate. But certainly, a long-acting would be more convenient, so we started a research partnership with a company called Gubra at the start of the year.

They're one of the world experts, both in peptide drug development as well as GLP-1 receptor biology. That's been a really nice partnership. We've been very impressed with their platform. And we expect in the next few months to come to a decision point on a candidate to take into IND-enabling studies. We've seen in vivo potency and PK and those sorts of things that we'd want to see to support a long-acting GLP-1 receptor inhibitor. So yes, long story short, we think there's a lot more to do here. It's a really powerful area of biology that could have major impact on human health.

How far from a PK/PD perspective, Justin, can you can you push a long-acting? I know you can't antagonize GLP-1 receptor for that long, right? So I mean, is it weekly? Is it longer?

Yes. I think we'll find out as we have the sort of tool compounds to test. Now I'll say what's interesting preclinically, actually, you can knock out the GLP-1 receptor and mice seem to be just fine. And certainly, on the agonism side, it seems like you can dose these pretty chronically and people continue to benefit. So we'll find out on the antagonist side.

I think the way I view it is that the GLP-1 receptor is kind of a potentiator of the response, right? We're not directly targeting insulin, that sort of insulin glucose system. We're targeting a potentiator of the system. And I think that's why it seems to be pretty robust to continued intervention. But we'll see. We'll find that out as we now have the compounds to study that.

And is there a faster -- do you have to go to the traditional IND route or is there maybe a bridge that with the newer compound that you can kind of deploy?

Yes, it's a great question. I'd say we haven't defined that yet, but high in our minds because you're right, like we have a lot we can leverage from Avexitide. And so we don't think we should have to just reinvent the wheel. Now it is a new drug, so I would still expect we need the requisite IND-enabling studies. But then as we chart the clinical path, I certainly think there are a lot of learnings from the Avexitide experience that we should be able to leverage, so hopefully have a more expedited clinical path.

Actually in today's FDA, right, that they're willing to be flexible.

Yes, certainly, in areas of high unmet need like this.

Yes. And I'd imagine that played out also potentially with the labeling that you had talked about with -- beyond just the currently studied type of bariatric surgery to...

Yes, absolutely. And I think that's what's so nice about we have such, I think, clear pharmacology here. We're talking about conditions of hypoglycemia, and we're measuring the outcomes by measuring blood glucose, right? It's a very straightforward development path. And I think that helps a lot as we're making the case about label expansion and other populations where this can be beneficial.

The other piece, Justin, I want to ask you about, if you look at the metabolic companies, so a Lilly or Novo, they have -- their market model has evolved to be more consumer-centric portals, et cetera, but that's set up for high-volume kind of cash pay. This is the opposite. It's more rare disease, labor-intensive.

But you still have to have some supply chain, patient connectivity, care pathways, so talk about your efforts to today to maybe in advance of the pivotal data, how you're thinking about maybe doing continuity of care?

Yes, I really appreciate you asking. So I think we have the benefit of having launched a rare disease product successfully in the past. And that -- our leadership team is still the same. So that's exactly the sorts of things that we're mapping out now. So I think the first thing is really understanding the patient journey. I think that's the most important thing to start with.

I think what we can say pretty confidently is that we do think that the adult endocrinologists, especially their particular experts, will be the first primary call points. There are a number of expert surgeons as well who also, though, follow their patients over longer periods of time. And I think there will be some focus there as well.

Then in terms of the continuity of care, we do think that this would be chronic treatment. And so we're working through our sort of pharmacy model, our patient services models in order to support people in chronic treatment as well.

You're exactly right though, this is rare disease in rare endocrine, and I think what's also good is that there's been a number of recent rare endocrine launches that have both supported premium orphan drug pricing with good market access as well as helped with all of these various models and stuff. So I think we have a nice set of analogs to look at and to take learnings from as we plan our go-to-market strategies.

So maybe we can touch a little bit about commercialization sequence that maybe you guys are thinking about, whether it be across bariatric centers, endocrinology, specialty channels and whatnot. So maybe talk a little bit about that. And also just you previously highlighted that about there's about 160,000 patients in the U.S. with medically important PBH.

There is growing awareness, but diagnosis, we could argue, it's still underdiagnosed by a long shot. And so what can be done to continue raising awareness about PBH beyond just educating doctors? And what type of centers, what type of networks do you think would be best to penetrate as many patients as possible?

Yes, yes, totally. And those are -- again, those are all the things we're working on now with our medical affairs and commercial team. So I'd say starting -- the nice thing is that we're starting from a place where there's a very straightforward diagnosis. I think oftentimes in rare disease, you get the case where it's like, well, if we could just get the right test and then you find the proverbial needle in the haystack, that's not this case, right?

It's -- the diagnosis is if someone gets particularly to an adult endocrinologist, clear signs of hypoglycemia, you measure blood glucose, you see if they react or if they improve with glucose and then they had a bariatric surgery, right? So I think it's a pretty straightforward diagnosis, which helps a lot.

And so even before there are -- there's an ICD-10 code or something like that, having that medical support, I think, is really, really helpful because then as we go to educate other physicians on what to look for or try to make sure that people are getting to the right centers, it's a lot easier. You kind of know what to flag.

I'd say as well, looking in the claims databases, we've done quite a bit of work in major claims databases now. First, I'd say, again, it's been a reasonably easy kind of algorithm to find people with PBH. Again, while there's not yet an ICD-10 code and I'll go into that in a second, there are codes for hypoglycemia. We know that everyone's had a bariatric surgery, and we also know that people are having signs and symptoms of hypoglycemia.

So all of our claims work has just supported kind of roughly 160,000 population that exists today, and it has helped us understand the patient journey as well. Now actually, just as of yesterday, there was now what's called a SNOMED code, which helps with electronic health records.

In September, there was a presentation to the CDC on the need for an ICD-10 code for PBH, and they'll make a determination on that in April. Now this would go via the pharmacy benefit route to payers, so payers in health systems don't need an ICD-10 code for this -- for reimbursement of the product, but it is helpful. And so -- but I think it all really goes back to having a clear understanding of what PBH is and that medical support that then helps as we branch out into the broader medical community and develop our own materials for disease state awareness and those sorts of things.

Justin, just on the patient journey, is there a theme or a common path that someone develops PBH, post surgery? I wasn't sure if you could maybe go one click earlier and identify maybe people at risk that would kind of help you with maybe assessing better, I think, the opportunity?

Yes. Yes. Great point. And I would say, as we think about kind of commercialization, I think first, while it's orphan disease, it's large orphan disease. And so I think the first thing is there are 160,000 people today. And so I think really making sure we get to the centers and address that first is probably the most important. But I also think as our team has started to talk with the American Society of Metabolic and Bariatric Surgery, for example, they have expressed strong interest to work with us on educational materials, to raise awareness of this, especially, of course, if there's something you can do about it.

And so I think that's more kind of as you were saying, to the front end of the funnel, so to speak. And I think what often one finds in rare disease is that sadly, if there isn't something you can intervene or do, then the kind of urgency to diagnose isn't there.

I think we -- while there's already a substantial population, I do anticipate that if there really is a meaningful treatment intervention, then that really kind of boosts up the desire to find people to diagnose even earlier in the stage of the condition. Today, the general sort of patient journey is, on average, it takes about 1 to 3 years for someone to both develop PBH symptoms and then also get a diagnosis, but it can be even longer than that. And I'll say what's interesting biologically this doesn't seem to happen right after the surgery. It seems like it takes time that the body really upregulates this GLP-1 response. And so that's why it seems to take years after the surgery. But then also, of course, there's less of an urgency to diagnose today. And hopefully, we can start to change that in the future.

I just wonder if over utilization of GLP-1s in the broader obesity diabetic communities in the next 3 years, I mean, there's going to be 50 million, 70 million people, those drugs -- that have access to them at least. If that somehow is going to front-end load the -- front part of the funnel?

Yes. I mean it certainly could. And I'd say I think one of the -- on the warnings and precautions on the GLP-1 receptor agonist is indeed that they can cause hypoglycemia. So it's -- as I was saying, it really is the other side of the equation, and we think it's a really important one.

And so maybe just going back to the ICD-10 code and based on what Jeff was saying about the continuity of the patient treatment journey. Maybe just help us better understand whether or not the ICD-10 code, if that were to come in April, would that be viewed as an inflection point for identifying the patients that are out there? And also what implication does that mean for Avexitide and whether or not if there is no connection whatsoever?

Yes. Important question. So I would characterize in this case, an ICD-10 code is kind of a nice to have, but not a need to have. And the reason I say that is because I think it really starts with the diagnosis. PBH is already on the endocrinology board exams. So all endocrinologists are trained to recognize PBH. So I think from that perspective, if someone is presenting sign, symptoms of PBH and has the medical history to suggest so, I think given endocrinologists can diagnose the patient and indeed, in our -- both our market research as well as directly talking with clinics, I think your given adult endocrinology clinic is quite familiar often has quite some patients under their care with PBH.

That all being said, where an ICD-10 code can be very helpful I think is first in sort of claims databases. I think it helps you even more strongly kind of triangulate where people are, even better understand the patient journey. I think in large health systems, it can help as well. Sometimes, unfortunately, in large health systems, people can get kind of lost in the systems, in the funnel, and so I think the ICD-10 code can help their as well.

And I also think over time, it just helps building awareness as well. So I do think it's a very nice thing to have. But as I said, I don't think we need to have it. But we'll look forward to next year to see if they indeed adopt the code.

Yes, absolutely. And to your point about helping the health system as much as you can. One of the aspects of rare diseases that sometimes we see a bolus at launch and then the uptake kind of just peters out. So I mean, how do you think about that helping with consistent identification of patients as even well into Avexitide's future?

Yes. I think there's going to be -- again, we're just doing our sort of market insights work now. But I do think there's going to be both aspects to the market. And we're already seeing this in the claims data. And again, to your point, I think with an ICD-10 code, we may see it even further. There are already many patients, many thousands of patients are very actively under management.

And so I think my hope is that with a pretty targeted team, a pretty targeted field force, we can address those centers and people with PBH. But then I think you get into the broader market, and that's indeed where I think all of these tools are very helpful to make sure that they're at the right physicians, that the right physicians are educated on the product, et cetera.

So again, I think what's nice about having a team that's done this in rare disease before is that these are all the things we're laying the groundwork for now and our first focus, of course, is make sure LUCIDITY is executed really well, and we look forward to those results, but we're planning very actively for commercialization because we think that there's really strong potential here. But it's rare disease, you really need to lay the groundwork the right way. Makes sense?

Should we move on to ALS. So Josh, was at the meeting?

Yes.

So the 114 data. So maybe talk a little bit about the Phase I data, we're going to see. And I know you guys have a long history in this indication. So talk about maybe the conviction here and kind of the potential investment dollars behind 114.

Totally, yes. So I'll say -- maybe I'll start from the last point. So the vast majority of our capital is going towards Avexitide precommercialization efforts, et cetera, as you might expect, supply chain, as you were saying, to prepare for potential commercialization. We're also very excited about 114, but just earlier in development. I think one investor put it to me not too long ago, they said, yes, Calpain-2, that's been hiding in plain sight for decades.

And I think that's certainly what we found. The Calpain-2 is one of the key effectors in axon degeneration and one of the first hallmarks of ALS and what continues to happen is that the long processes of the nurse and the neuromuscular junction retract and then degenerate and one of the key actors in that is Calpain-2.

The question then is, okay, well, this has been hiding in plain sight, why has nobody targeted it? And the challenge, I think, has been twofold. One is there are like 15 Calpains, and we think you very particularly want to target Calpain-2. And the second is that you want to get enough CNS exposure.

And so that's where we thought, well, an intrathecal ASO would be perfect, right? Because you can be very clear you're targeting just Calpain-2 and not the other Calpains, and you know that you're getting enough CNS exposure because you're directly injecting into the CNS. So we've been working on this for a few years. We now have our first cohort that's 12 people with ALS in the first dose group, 9 on active, 3 on placebo.

And at the international ALS/MND meeting this week, we'll be presenting on the safety and tolerability data and that data will also go to the dose escalation committee to determine if we can now go to cohort 2 to the next dose group as well.

Now that being said, we do think it's quite a potent ASO, so we do think there's a potential to see activity even at this dose level. Now that we're through the clinic visits, we can collect all the CSF, send it out to the lab and analyze the biomarker results as well. I'd say the last thing is on the biomarker side, we're starting our sort of method development work on evidence of Calpain activity and very early days, but I think it's exciting. There are particular markers of Calpain activity like spectrin breakdown product 145 or like a particular neurofilament fragments that we may see evidence of upregulation in ALS/CSF.

And so one of our collaborators will be presenting some of that very early data as well. But again, we'll plan to -- as we get the CSF biomarker data from this first cohort, we'll plan on presenting that in the first half of next year.

And are there -- obviously, you guys have a history here in ALS and you probably have novel and the typical biomarkers like if you put Calpain-2 in kind of that in that context, have you looked at it before? And are there other predictive biomarkers that you found in prior research that you would be kind of excited about, not excited about in terms of direction of how this -- the 114 data is going to play out?

Yes. Yes. Great point. I think -- so yes, there are novel Calpain biomarkers, and we think we may see evidence that those are upregulated in ALS/CSF. Again, early days, but we're encouraged by what we're seeing. And then what's very interesting as well is I think there's been this finding that maybe hasn't been talked about enough in ALS, which is probably the most well-known biomarker right now is neurofilament light chain, NfL.

We see this in a number of neurodegenerative diseases. But what's actually measured in the CSF is not full length NfL, it's NfL fragments. And there's a particular fragment that is most prevalent that we may -- we think may be an indication of Calpain protease activity.

So we're starting to do more work looking at these NfL fragments because we think that perhaps what we're seeing in this NfL signal might actually be evidence of excess Calpain activity. And it would make sense mechanistically being one of the key drivers of axon degeneration that, that may be what we're seeing in ALS.

So again, early days, we're doing all of this discovery work now, but we're very excited about the path because we think there's a rich history from the literature going back several decades now. And I think -- but I think it's nicely jiving with what we found more recently in ALS, which is these NfL signatures would seem to be indicative of progression rate in ALS.

So the -- on the topic of ALS. I mean the treatment landscape is just evolving. It seems like with breakneck speed, I mean there's monotherapy combinations. And so with 114 and it's Calpain-2 inhibition, how do you envision that whether it's a planting or adding on to existing treatment paradigms? I'd love to get your thoughts on that?

Yes. Well, I think research in ALS is I totally agree, it's going at breakneck speed, which is great. And we have treatments now, which we certainly didn't always have, which is very exciting. I would say, though, we've said, ALS is still a rapidly progressive fatal disease. And so I think we're strong believers that the future what -- ultimately where we're going to get to real cures, I think is combination therapy. We've certainly seen that in oncology. It's rare to have just a single perfect drug. It's almost always things in combination with one another.

I think the way that we view a drug like 114, we're targeting axon degeneration, which is one of the disease of neurodegeneration. And the first part of that neurodegeneration is the axon degeneration. I'd sort of liking it to like chemo in cancer, right?

In cancer, one of the fundamental theories is we have these cells that are highly proliferative and growing and metastasizing. And so you very often have chemo in combination with something else because you want to -- no matter what, you want to stop that growth and you want to kill these rapidly dividing cells.

Neurodegeneration is kind of the opposite side. we have these rapidly degenerating cells. And so I think our feeling is, no matter what, you want to stop that process and perhaps there are other genetically-targeted treatments or other things like that, that you do in combination, but we really do think a mainstay has to be how do you stop this degeneration from occurring.

And just in the few minutes we have, so a thought on 35 Wolfram?

Yes, yes, yes, certainly.

Status update.

Yes. Yes. So we've been working on this for about 8 years now. And so Wolfram is caused by mutations in WFS1. That's an ER transmembrane protein that causes ER stress in downstream mitochondrial dysfunction. It's a neuroendocrine disease that is very challenging and unfortunately causes an early mortality as well. Very strong data presented this year from our first trial, 12-patient open-label study.

All the outcomes went in the right direction, which is very exciting. We're now working on the Phase III design. Pending FDA alignment, we're working to initiate the Phase III trial in the second half of next year.

So potential for a faster path sort of a streamlined trial just given the unmet need, obviously?

Certainly. And given how rare it is as well.

Okay. Justin, thank you very much.

Yes. Thanks so much for having me.

Good morning. My name is Carly, and I will be your conference operator today. At this time, I would like to welcome everyone to the Amylyx Pharmaceuticals third quarter earnings conference call. [Operator Instructions] Please be advised that this call is being recorded at the company's request.

I would now like to turn the call over to Lindsey Allen, Vice President, Investor Relations and Communications. Please proceed.

Good morning, and thank you all for joining us today to discuss our third quarter 2025 financial results and business update. With me on the call today are Josh Cohen and Justin Klee, our Co-CEOs; Dr. Camille Bedrosian, our Chief Medical Officer; and Jim Frates, our Chief Financial Officer.

Before we begin, I would like to remind everyone that any statements we make or information presented on this call that are not historical facts are forward-looking statements that are based on our current beliefs, plans and expectations, and are made pursuant to the safe harbor provisions of the Private Securities Litigation Reform Act of 1995. These statements include, but are not limited to, our expectations with respect to avexitide, AMX0035 and AMX0114, statements regarding other development candidates, statements regarding regulatory and clinical developments, the impact thereof and the expected timing thereof and statements regarding our cash runway. Actual events and results could differ materially from those expressed or implied by any forward-looking statements. You are cautioned not to place any undue reliance on these forward-looking statements, and Amylyx disclaims any obligation to update such statements, unless required by law.

Now I will turn the call over to Justin.

Good morning, everyone, and thank you for joining us. Q3 was a quarter of progress as we continue to focus on our lead program, avexitide, in post-bariatric hypoglycemia or PBH. Avexitide is our investigational first-in-class inhibitor of GLP-1 receptor activity with FDA breakthrough therapy designation. PBH is a condition characterized by recurrent hypoglycemic events, which can impose a significant and lasting burden on a person's quality of life.

There is a robust body of data generated to date for avexitide, which includes 5 clinical trials, demonstrating statistically significant and clinically meaningful reductions in hypoglycemic events. Based on those results, we designed our pivotal Phase III LUCIDITY trial with the goal of replication. We remain focused on enrolling a similar patient population, collecting the data in a similar way and executing LUCIDITY with high quality. We continue to see high participant interest and broad engagement across clinical trial sites, which we believe supports the urgent need for an FDA-approved treatment. Our previous guidance for completion of recruitment was by the end of 2025, with top line data in the first half of next year. Based on our most recent projections, we now expect to complete recruitment in Q1 2026, with top line data expected in Q3 2026.

We anticipated more of a ramp in the enrollment rate at this stage, but we have seen more of a steady enrollment rate in the last few weeks. Timing for potential launch remains unchanged. With early NDA preparation efforts underway, we continue to expect to be in a position to launch avexitide in 2027, pending FDA approval. Having launched a commercial product in the past, we're focused on key areas required for a successful launch. We are already laying the groundwork to be ready in 2027, if approved.

We've been taking the initial steps towards building the medical affairs and commercial organizations with targeted investments in market research, insights, disease education, market access strategy, and commercial infrastructure. Our continued market research, claims analysis and engagement in the field support our confidence in our estimate of 160,000 people with PBH in the U.S., and bolsters our understanding of the unmet need.

Turning to our broader pipeline. In Wolfram syndrome, we are advancing the clinical development of AMX0035, and pending alignment with FDA, we plan to initiate a focused pivotal Phase III trial in the second half of 2026. For AMX0114, our investigational antisense oligonucleotide targeting Calpain-2 in ALS, we are pleased to share that in September, we fully enrolled Cohort 1 in the Phase I LUMINA trial. We anticipate early cohort data later this year and plan to share the safety data at the 36th International Symposium on ALS and MMD, which is being held from December 5 to December 7. Based on biomarker collection and analysis time lines, we anticipate biomarker data will be available in the coming months and expect to present these at a medical meeting in the first half of 2026.

We are excited by the potential of this novel mechanism and the fast track designation from the FDA. Across all of our programs, our team is focused on execution as we head toward a pivotal year in 2026 with top line data from LUCIDITY anticipated next year.

Now I'll turn the call over to Camille.

Thank you, Justin. As a reminder, PBH is a serious, persistent and life-altering condition with no FDA-approved therapy. People living with PBH often experience frequent unpredictable hypoglycemic events, driven by an exaggerated GLP-1 response that can severely limit their independence and quality of life.

Many people with PBH live with a constant anxiety around meals, social interactions, and basic daily activities. Individuals with these experiences are not outliers. They reflect a broader underserved population that motivate our work. Avexitide is an inhibitor of GLP-1 receptor activity that reduces insulin secretion and stabilizes blood glucose levels. Based on the data and consistency from our 5 previous trials in PBH, we designed the pivotal Phase III LUCIDITY trial to optimize the potential for success by being as consistent as possible with the previous Phase II trials. Specifically, these studies directly informed the dose, endpoints, inclusion criteria, and surgical subtypes. LUCIDITY is evaluating avexitide 90 milligrams once daily in individuals with PBH following Roux-en-Y gastric bypass surgery. The FDA agreed upon primary endpoint, it's reduction in the composite rate of Level 2 and Level 3 hypoglycemic events through week 16. Based on prior Phase II data, we believe the trial is well powered to detect clinically meaningful benefit.

We continue to be encouraged by the execution of the trial that prioritizes scientific rigor and operational excellence. All clinical trial sites are now activated and screening participants. There is high participant interest and engagement across our sites. In addition, investigators continue to report that participants are highly motivated to contribute to the study. Furthermore, participants have begun to move into the open-label extension portion of the trial.

As awareness of PBH continues to grow, we are seeing increased recognition of the burden and the urgent need for a treatment option. We believe avexitide, which has been granted FDA breakthrough therapy designation, has the potential to be the first approved therapy for PBH and to meaningfully improve the lives of those affected.

With that, I'll turn over the call to Jim, to review our financials. Jim?

Thanks, Camille. Our financial position is strong as we focus on careful execution of LUCIDITY and preparing the company for a launch in 2027, should avexitide be approved by the FDA.

We ended the third quarter with a strong cash position of $344 million compared to $181 million at the end of the second quarter. This reflects the recent completion of our public offering in early September. This financing provided approximately $191 million of net proceeds; and together with our existing cash, positions us to support the potential launch of avexitide in 2027, and provides us with an anticipated cash runway into 2028.

Turning now to our results for the quarter. Total operating expenses for the quarter were $36 million, down 53% from the same period in 2024. The decrease is primarily due to the onetime expenses related to the acquisition of avexitide that we incurred in the third quarter of last year.

Research and development expenses were $19.9 million compared to $21.2 million in Q3 2024. This decrease was primarily due to decreases in spending on AMX0035, for the treatment of PSP and ALS. The decrease was offset by increased spending related to the clinical development of avexitide in PBH.

Selling, general and administrative expenses were $16.2 million compared to $17.8 million in Q3 2024. This decrease was primarily due to a decrease in consulting, professional services and other expenses. We recognized $7.1 million of noncash stock-based compensation expense for the quarter compared to $6.8 million of noncash stock-based compensation expense in Q3 2024.

In summary, the more work we do, the more we learn about the patients and providers, the more we believe that there is a major unmet need for people living with PBH. The key for us operationally is to execute the LUCIDITY study well and prepare for a positive outcome. We believe we have the scientific, operational, and financial resources we need to execute on our goals.

With that, I'll turn the call over to Josh.

Thanks, Jim. Our conviction in inhibiting the GLP-1 receptor as a therapeutic approach remains strong. While LUCIDITY remains our primary focus, we also view it as a starting point, both for avexitide and for advancing research into GLP-1 receptor antagonism more broadly. For instance, our research collaboration with Gubra continues to show encouraging proof-of-concept data with new molecules demonstrating strong potency in vitro and in vivo, along with extended half-lives. We are very pleased with how the partnership is progressing to develop a novel long-acting GLP-1 receptor antagonist. We expect to make a decision on a potential development candidate in the next few months, and pending a candidate nomination, we are preparing to initiate our IND-enabling studies.

Before we open the call up for Q&A, I would like to reflect on the urgent opportunity driving our work in post-bariatric hypoglycemia. PBH affects an estimated 8% of people in the U.S., who have undergone the two most common types of bariatric surgery: sleeve gastrectomy, and Roux-en-Y gastric bypass. That translates to approximately 160,000 individuals living with PBH, many of whom experience frequent unpredictable hypoglycemic events that disrupt daily life and limit independence. Multiple lines of evidence support our belief in the significant unmet need in this market, including several robust published prospective and retrospective studies, and our ongoing claims-based work. Most compelling is what we are hearing directly from the field, which has continued to corroborate the substantial burden in PBH. We continue to be excited by the data generated to date in the 5 clinical trials of avexitide in PBH. These findings, together with new analyses we shared last quarter at ENDO 2025, reinforce the robust body of evidence and give us confidence as we advance LUCIDITY towards top line results next year.

We are committed to executing LUCIDITY and preparing to be launch-ready, following FDA approval, and we look forward to keeping you updated.

Now I would like to open the call up for questions.

[Operator Instructions] Your first question comes from Seamus Fernandez with Guggenheim.

I wanted to just get a quick sense of the enrollment update. With regard to a couple of things, as we've been speaking with physicians, there were a couple of dynamics in play here. One, was the very careful decisions on the part of the company to ensure that there is a broad enough participation from a wide enough array of sites that it would take some time to basically, start up those sites. So just trying to get a better sense of the impact here. Is it site start-up that has resulted in the estimated modest delay of a quarter? Is it the run-in period that is potentially impacting the enrollment? Because, again, a 3-week with the requirements for Level 3 events, I could envision having an impact on enrollment just given the careful design there. And then another factor would be just ensuring that the patients that are enrolled are actually fully dedicated and committed to limiting any potential changes in diet over the 16-week period that could negatively impact the study. So just wanted to get a better sense of some of the operational dynamics that could be coming into play as it relates to the study.

Then just a very quick follow-up on the Gubra comments. The DC development candidate selection to IND, can you just give us a sense of the time line that might come into play there?

Great. Thank you so much, Seamus. Great, great questions and important points on operations. So I think first, just to say at a high level, I think we're pleased with how the study is being executed, how it's progressing. The first participants are going into the open-label extension. And you raised really important points as well, which is our real focus -- is on quality, enrolling the right participants, ensuring the right data collection, especially in view of the 5 prior trials of avexitide in PBH, which demonstrated a very statistically significant and clinically meaningful reduction in hypoglycemic events.

So the update is on the time line based on our most recent enrollment projections and estimates. And I would say that certainly, in every trial I've been a part of -- as you have all of the sites up and running -- recruiting participants, you tend to see a ramp in the enrollment rate. Now that could still happen. But so far, it's been a steady enrollment rate. And so that's why we're updating the projections to now estimated completion of recruitment in the first quarter. So I hope that helps, but I really appreciate your points on the quality of the operations. That's definitely where our team is focused as well, and we're pleased with our team's focus.

Maybe just touching on your other questions, too. Included in that quality, certainly, is maintaining the dietary guidance throughout the whole trial. So just as a reminder, at every clinic visit, patients do receive dietary guidance. And the goal of that is to keep everybody following closely with the recommended PBH diet. And we have heard that patients are quite engaged, quite excited to participate in the study and wanting to follow the protocol as best as they possibly can.

You also asked about the drug candidate nomination from Gubra, and a sense of the time line. So first, I'll say we've been quite excited about the data from Gubra. We've seen really encouraging data both in vitro and in vivo, both on kind of efficacy outcomes as well as outcomes related to half-life and kind of the duration of the drug. We'll probably give more granularity on time line as we do nominate or as we get to the point of making the decision to nominate a drug candidate. But certainly, our goal will be to move as expeditiously as we possibly can.

Your next question comes from Joseph Thome with TD Cowen.

Maybe the first one, just on the Phase III study. Do you have a general idea of how long patients have trialed dietary therapy and still are not able to respond to that before entering the study? And maybe related to that, what's your kind of current screen failure rate for patients maybe not meeting the necessary events in the observation period?

A follow-up if I can, on the ALS program. Can you just clarify a little bit what you're going to present later this year? Will you have early biomarker data from that first cohort already in this presentation? Or are you going to present all the biomarker data next year when you have a larger set?

Sure. So probably within an ongoing trial, we don't necessarily kind of give interim data or interim updates. But what I can share is when you look at past studies with avexitide, it was often the case that people have had PBH 6, 7, 8 years. And the usual standard in PBH is certainly the dietary therapy. So most of these patients will -- we do expect that most of the patients, if not all of the patients, will have been on dietary therapy many years prior to entering. And we do require that the bariatric surgery was at least a year prior to entering the study. So everybody has had the bariatric surgery well in their past as well.

In terms of screen fail rates, similarly, we don't kind of report interim data as we're going through a study. But certainly, our goal, as Justin suggested, is to enroll the right patients in the study and to focus on quality throughout getting patients who have the appropriate level of severity and who hopefully will be able to complete the study also.

In terms of the AMX0114 presentation in early December, that will focus on safety at this time. We will have biomarker data. We expect to report on that in the first half of the coming year at a medical conference. The biomarker work just takes a little bit longer, hence that coming in the first half.

Your next question comes from Geoff Meacham with Citi.

It's Ross on for Jeff. We are curious about your sense of PBH and kind of the addressable market; and how has that continued to evolve?

Thank you. And I would say -- as we've done more and more commercial preparations looking forward, I'd say it only increases our confidence in both the unmet need in the market. So we've looked at multiple claims-based analyses now, as well as there's been independent work out of Stanford looking at the total population. And our estimates continue to be that there are about 160,000 people today who have PBH. And we expect more to come as well. Bariatric surgery rates continue to be quite significant. And with that, we would expect the population to only continue to grow from already quite a substantial unmet need.

The other thing that I think has really come out from being out in the field is the unmet need. It's severe hypoglycemia as defined by Level 2, Level 3 events. These are frequent occurrences for people with PBH. To put it in context, severe hypoglycemia according to the American Diabetes Association, a single event is a medical emergency. And these are people who are having frequent hypoglycemic events. So it's highly, highly debilitating. And what we hear from clinics is that they're very worried for their patients because, one, they really have very limited options to help them; and two, that these hypoglycemic events can occur often without warning and, again, so frequently. So I think all of our research just continues to bolster our confidence in the unmet need and the opportunity here that we have with avexitide.

Your next question comes from Corinne Johnson with Goldman Sachs.

This is Kevin on for Corinne. Just wanted to follow up on the addressable market question in terms of the 160,000 PBH patients. As you do more work on that, what percentage of those patients do you think would be uncontrolled on diet? And what percentage of those patients do you think would be eligible for your Phase III?

Good question. So maybe starting with kind of uncontrolled on diet. So in coming up with the 160,000 estimate -- which, as a reminder, is based on published prospective and retrospective data, as well as claims-based work and direct work with physicians treating PBH -- we tried to eliminate upfront those who were controlled on diet. So the 160,000 is intended to be those who are not controlled on diet, and who are continuing to experience unacceptable and clinically problematic hypoglycemic events.

In terms of direct eligibility for the Phase III, that's not an analysis we've done directly through the 160,000. But again, we do view the 160,000 as people who are having, as Dr. Colleen Craig calls it -- from Stanford, medically important PBH, PBH, which is significantly impacting their daily life. And as Justin said, even a single significant hypoglycemic event is considered a medical emergency. So these are patients who, in effect, are having frequent medical emergencies.

Just to give a picture of what we believe is going on from a pathophysiology perspective, the -- we believe that PBH is caused by the body dramatically upregulating the production and secretion of GLP-1. So people will have up to 10x normal levels of GLP-1. And so the reason that we think -- we hear from both clinics and patients that kind of no matter what they do, they continue to have these drops in blood glucose is because of this GLP-1 effect. So if you think no matter what they do, their body is producing up to 10x normal levels of GLP-1, their blood glucose is going to plummet. And that's also why we think avexitide has such potential because really to get to the heart of PBH, we believe that you need to blunt that GLP-1 bolus, which is ultimately what's causing the hypoglycemia.

Your next question comes from Marc Goodman with Leerink Partners.

Just to kind of come back to this delay in the time line. Can you help us understand like -- someone asked the question, but I wasn't sure if the answer was given about. -- I mean, we're talking about 75 patients and 20 sites, right? And this is 3:2 random. I mean, what -- help us understand what's going on here. Like do we need to add more sites? Do we have the right sites? Like what -- help us just understand what that issue is.

You talked about these patients moving into the open-label extension trial. Talk about the side effects that you've seen? Is everything generally the same as what we've seen in the Phase II studies? Anything unusual?

Sure. Thanks, Marc. So first, I wouldn't characterize this as an issue. I'd say that as we continue to go along the study, we've updated our time line to expect to complete recruitment in the first quarter of next year, with data coming out in Q3 of next year. We have seen a lot of excitement across the trial. I'd remind that that time line would still be recruiting a Phase III study in under a year. And Phase III studies entail not just finding the patients, but also all the work that goes into activating sites, everything else. So we actually do see that as a very good time line for a Phase III as well.

We probably won't report, at this point on, side effects or otherwise. We don't report interim data from a trial. But I think as we mentioned, we are excited to see quite a lot of participant engagement and patients moving into the OLE as well. So excited overall about the execution of the study and our team's great efforts in this space.

Your next question comes from Rami Katkhuda with LifeSci Capital.

I guess in LUCIDITY, are you measuring diet adherence via the blinded CGM? And can you intervene based on blood glucose levels if the patient is kind of liberalizing their diet as they start to feel better?

Rami, great question. So I would say that our team as well as the monitors are looking at all of the available blinded data, including CGM, as you mentioned, which we get in virtually real time. And the goal there is really to make sure that, one, yes, people are adhering to diet; and two, that people are collecting events as we would expect in the study. So yes, our teams are continuing to do that. And if we see significant deviations that we think need addressing, then our team will indeed reach out to the site and retrain as necessary.

Got it. Makes sense. And then I know I'm jumping the gun a little, but a number of KOLs are excited to use avexitide for hypoglycemia associated with other GI surgeries as well. I guess have you talked to the FDA on the regulatory path forward there. Would you have to run a study in each population? Or is there a potential for kind of a basket study across a number of these surgery types?

Sure. So the Phase III study is in people with Roux-en-Y gastric bypass. It's early to -- label discussions happen later in the process, so it's early to say what an FDA label would or wouldn't be. But given that the study is in Roux-en-Y, that is a potential risk that we -- that element finds its way into a label or otherwise. That being said, we do believe both physiologically based on the biology of these different surgeries that the pathophysiology is similar or the same for why people are getting PBH across them. And in addition, our Phase IIb study included people with multiple surgical types and the effects look similar across those surgical types as well. So it's certainly something that we want to pursue.

We do exactly, as you suggested, get a lot of interest from academics and otherwise with surgeries beyond Roux-en-Y, including people who have had gastrectomy for gastric cancer, Nissen fundoplication for gastroesophageal reflux disorder and otherwise. So it's definitely an area we're quite excited to pursue. And yes, I'd say stay tuned in that regard.

Your next question comes from Graig Suvannavejh with Mizuho Securities.

This is Sam on for Greg. Can you just remind us of the manufacturing and CMC processes for avexitide in terms of the commercial doses and the process there, and if you anticipate any stags moving forward?

Yes, important question. So I would say we're doing all of the expected work as we move toward commercialization, hopefully with commercialization on the CMC side. So I'd probably touch on a number of points.

So first, as you may expect, we have manufactured our registration batches and they're up on stability. I'd say, second, the suppliers that we're working with, both on the drug substance being the peptide and the drug products being the final finished product are manufacturers that have multiple commercial products and have very good inspection histories as well. And I would say then on the internal side, we're focused on all of the quality parameters, inspection readiness activities, as you might expect, with the anticipated approval in 2027. So I'd say our team is laser-focused on all of the things that would be required for both NDA submission and then eventual approval.

Your next question comes from Chris Chen with R.W. Baird.

Just going back to the LUCIDITY and the clinical sites. Have you noticed any differences in the ramp between sites? And are you kind of maybe learning from those sites that maybe are enrolling faster to kind of overall just make the ramp increase across those sites?

Thanks, Chris. And I would say in a clinical trial, you always have differences across sites, and that's why we have 21 sites. All sites are activated. And I would say, again, in my experience, as you have all of the sites activated and you go into the latter part of the study, that's when you tend to see an increase in the enrollment rate. So that could still come. But so far, in the last few weeks, we've seen more of a steady enrollment rate. Again, our goal is to conclude enrollment as expeditiously as possible. But of course, making sure that we're enrolling the right participants, we have the right clinical oversight as well.

I'd say on the sort of site engagement level, the main message, I would say, is that the unmet need here is very real. I think we have high engagement from the sites. They're very eager to have a potential treatment option for their patients. So that's really come through in all of our engagements.

Your next question comes from Tim Anderson with Bank of America Securities.

This is Susan on for Tim. I have a couple of questions. First question, given that you now have a time line estimate for the pivotal Wolfram syndrome trial, what can you tell us about the potential trial parameters? And just how have your discussions with the FDA gone? And I'll follow up with my second question.

Thanks very much. This is Camille. As we have indicated, based actually on the HELIOS data in AMX0035 for Wolfram syndrome and the very encouraging results out to 48 weeks, we are advancing the clinical development of AMX0035 for Wolfram and plan to initiate our focused pivotal trial second half of 2026.

We are pending, of course, FDA alignment, and we're actively seeking that alignment now, not only with the FDA, but also we are engaging a number of additional stakeholders, clinicians who treat people with Wolfram syndrome, researchers who study the disease as well as the Wolfram community itself, and we're seeking alignment across all those stakeholders.

Sorry to keep coming back to this -- but you've mentioned a couple of times already that you typically see a ramp in enrollment, when all trial sites are activated, but rates have been studied. Why do you think this is? Would you characterize this more as a system-wide issue or specific to the LUCIDITY trial?

I don't think I would characterize this as a system-wide issue or an issue really. I think just as we're updating our projections, we're trying to be as accurate as you possibly can and given the current rate we expect Q1 of the coming year. But remind that's still enrolling a Phase III trial in less than a year, which I think is a good time line for a Phase III, overall.

Your final question comes from Ananda Ghosh with H.C. Wainwright.

I have two; one for LUCIDITY, and the other from the ALS program. So maybe the first question, how is the Level 2 or 3 weighed in for the composite scale? And is there a way to kind of like the nocturnal and the diurnal rates differ? Or how is that kind of taken care of?

The other question you might have discussed beforehand, but just to reiterate, how are prior therapies handled like GLP-1 agonist?

Thank you, Ananda. So two important questions. So first, coming off of 5 prior trials of avexitide in people with PBH, that showed statistically significant and clinically meaningful reductions in hypoglycemic events, the goal really here is replication. So to try to enroll a similar patient population, collect the events in the same way, et cetera.

So for the primary outcome, Level 2 events are done by fingerstick blood glucose and Level 3 is an eDiary that's adjudicated by an expert committee. So that's how the data are collected. People can collect those during the day or during the night.

Now people also have CGMs on, which have continuous monitoring. And so obviously, we will be looking at both. In the Phase IIb trial, where they use the 90-milligram dose that we're using in the Phase III, there were significant reductions, both as measured by the fingerstick as well as by the CGM day and night. But again, our goal really here is with replication. So we're trying to keep things as consistent as possible.

In terms of use of GLP-1 receptor agonist or really any therapeutic that could alter blood glucose, we have a washout period before people can be randomized into the study, so that we don't have things that could affect people's blood glucose levels -- given that, of course, that is a key part of the study.

Great. Maybe just one question on this is that how are those Level 2 or 3 weighed in the composite scale? Like how are they weighted? Are they weighted like equally?

Yes, they're weighted equally.

The next question on the ALS program, if you can -- like how are you measuring the calpain and NfL levels in terms of -- and also given the short trial, what magnitude of NfL change might be practically feasible?

So the calpain, I'd say we're measuring kind of different points in the pathway. So we're certainly working to measure mRNA in the CSF. We are also looking at measures of calpain activity, including things like spectrum breakdown product 145 or SBDP-145, which is a specific protein cleavage fragment that calpain makes and is an element of calpain activity. And then as you mentioned, downstream, looking at markers of axonal degeneration like neurofilament to kind of see that downstream effect of potential calpain inhibition.

I'd say in initial study, we don't quite know yet what the kinetics of changes in those markers might be. In our preclinical work, we have seen changes on multiple of those markers, which certainly makes us encouraged, but we'll have to see clinically how that bears out.

There are no further questions at this time. If you have any follow-up questions, please reach out to the company. This concludes today's conference call. Thank you for joining. Have a great rest of your day.

Good afternoon. I'm just going to read this disclosure. For important disclosures, please see the Morgan Stanley research disclosure website at www.morganstanley.com/researchdisclosures. If you have any questions, please reach out to your Morgan Stanley sales rep. I forgot to do that last time. So I had to do that.

So good afternoon. Welcome, Josh and Justin. What a year?

Yes. Thanks a lot.

It was just -- it was almost a year ago that you were sitting here today, and it's been incredible. Maybe you can just give a couple of highlights, and we're going to dive right into avexitide.

Sure. Yes. Well, first of all, thank you so much for having us here. It's really a pleasure. And yes, it was just a little over a year ago that we had the fortunate opportunity to acquire avexitide. And then this was our first chance to start to share more about why we're so excited about the opportunity. So avexitide is a competitive inhibitor of the GLP-1 receptor. So in some ways, the opposite of the GLP-1 receptor agonist.

And the GLP-1 receptor controls or is one of the key controllers of insulin and glucose. And so a competitive inhibitor lowers insulin secretion and therefore, raises glucose. And it turns out that's very important in conditions of hyperinsulinemic hypoglycemia. And so where we are particularly studying it right now in -- is in what's called post-bariatric hypoglycemia or PBH, which is -- so millions of people have had bariatric surgery. It's a very effective treatment for weight loss, but a small percentage of people develop this very persistent symptomatic hypoglycemia.

I'm sure we'll get into that a bit, but it's highly, highly debilitating. And this is not sort of your run-of-the-mill hypoglycemia. This is your brain starves of glucose, and you have all sorts of clinical manifestations ranging from bout of severe confusion to even loss of consciousness to even seizures. And people have these events very frequently, sometimes once or even more than that per week. So it's highly, highly debilitating. There are no treatments for people. And although it's a rare complication because there have been so many people who have had bariatric surgery, we estimate there are about 160,000 people in the United States today who have PBH.

And unfortunately, once someone has PBH, it does not appear to go away. It's persistent, it can even be progressive. So avexitide has been studied in 5 prior trials of PBH, very strong data, very strong reductions in hypoglycemic events that supported FDA breakthrough therapy designation. And now we are running the Phase III pivotal study of avexitide in PBH and we are targeting completion of enrollment by the end of this year, data first half of next year, which would then support commercialization in 2027. So we're really excited about the opportunity.

We've made a lot of progress, as you said, in the year since we were last at the conference. And we have two other assets in our pipeline as well, AMX 35 for Wolfram syndrome and then AMX 114 our Calpain-2 ASO for ALS. But I would imagine we'll probably spend the bulk of our time on avexitide given that it's in a pivotal study right now.

Yes. Great. Well, maybe we'll drill down a little bit on PBH in terms of -- you mentioned really the symptoms, but I think it's best to describe actually how this is unfortunately impacting people's lives and maybe go through some of the patient numbers. You did say some of the percentages, but I think, again, these are very large numbers and what the standard of care is today.

Yes, sure. I'm just making sure, it's working. So in terms of symptoms so people with PBH will experience sudden blood sugar drops, most often in reaction to a meal. So they'll have a meal and they'll see a spike in GLP-1, corresponding spike in insulin and then a big drop in glucose, which will make them get all of a sudden very -- in the extreme, lose consciousness, have seizures, but even can be things like trembling, confusion, being unable to complete a sentence, maybe not knowing where they are, feel weakness, things like that.

And it's not just after meals. They can also have these during exercise. We had one patient who described to us that she can't walk a full lap around the track without having herself kind of go into hypoglycemia. It can happen during stress. It can happen from caffeine or alcohol. And sometimes it happens without any clear proceeding cause. And I think that's what really makes this disease tough for people. This could happen to them at any point. And so they're always at risk for falls.

They're very -- they may not be able to drive. They're certainly not recommended to drive. They may have trouble in the workplace where all of a sudden, their sentences aren't making sense or they can't think clearly all of a sudden. So it makes their life very limited. Many patients want to have a caregiver around them at most of the time because if they do have a significant event, they want somebody there to be able to help them. So it really constrains the lives of the people who get it.

In terms of the patient number, I'd say we've continued kind of hammering, drilling down on that and trying to learn as best we can. I think we kind of started from going through literature. And this disease are actually quite good literature studies. There have been large prospective studies that follow outcomes in people who have bariatric surgery. Those are some of the studies that have detected rates such as the 8% estimate that we're estimating for patient prevalence.

And I'd say those have been consistent with some of the bottoms-up work we've done too and claims work. But probably most striking to me is when talking to endocrinologists, we've talked to quite a number who will say they have over 100 patients with this condition under their care. And that starts to have face validity too, that when you talk to physician after physician who have a large population, you start getting kind of comfortable around the 160,000 number as well.

And I'll say there's 2 anecdotes that I think have really cemented that I think PBH is starting to be a medical concern that many people are aware of. So recently, the endocrinology board exams are updated and included a question on post-bariatric hypoglycemia, which makes sense that this is a significant population and high unmet need. Recently, there's a group of physicians petitioning CMS for CGM coverage for PBH.

And I'd say at the recent ENDO meeting, there was quite a lot of research going on in PBH. So I think it's really being recognized as a major unmet need independent even of the work that we've been doing.

Great. And you mentioned there's 5 existing clinical trials. And what did you learn from those clinical trials? And how did they help you design your current pivotal LUCIDITY trial?

Sure. So the initial 3 trials were kind of challenged trials, if you want to put it that way. Patients were given either active or placebo and challenged with a meal test, either a glucose meal test or a kind of mixed meal test, which would then cause their body because they have PBH to secrete excess GLP-1, excess insulin and then have a significant blood sugar drop.

And what we're seeing in those first 3 studies was with avexitide in the majority of patients, you could completely prevent that low blood sugar drop. You attenuated the insulin spike that came after the meal. We saw that even with the single dose. In the initial studies even with a single dose, you're seeing statistically significant differences on glucose and insulin. Then the Phase II and Phase IIb follow people in a more ambulatory setting to look at how many hypoglycemic events are people having over the course of their daily life.

And what we're seeing there is quite a significant reduction in so-called Level 2 and Level 3, Level 1, but I'd say we're most interested in Level 2 and Level 3 hypoglycemia, in particular, at the dose we're studying in the Phase III.

I'm sorry, can you explain what Level 1 and 2 and 3 means?

Yes, happy to. So I think these were first defined by the American Diabetes Association and a few other endocrinology groups and they got together to really define what does hypoglycemia mean. So Level 1 is defined by blood glucose less than 70 milligrams per deciliter, typically done by a fingerstick blood glucose measurement could be by CGM these days as well. And that's really where the people are advised to first start sort of taking notice. That's where your body will start to try to do things to boost up your blood glucose.

Level 2 is where your blood glucose is less than 54 milligrams per deciliter. And so that's the first major event that we're talking about. That's where you start to enter into severe hypoglycemia. And the ADA defines a single severe episode of hypoglycemia is a medical emergency. And the reason is because the medical term of what happens is neuroglycopenic, which is kind of a fancy way of saying the brain is starved for glucose. Our brains are the highest glucose utilizers in the body. So when the brain is not getting enough glucose, it basically starts to shut down.

So that's where people start to have real risk of those bouts of very severe confusion or even loss of consciousness as we were mentioning and can have really significant injuries, not to mention the fact that chronic severe hypoglycemia has really deleterious consequences as well.

And then Level 3 is the person has had the events, the clinical events. So someone, for example, has lost consciousness. Basically, they're so significantly impaired that they need someone to help them. They need someone to rescue them. And so when looking at the types of hypoglycemia that we're talking about, the FDA outcome that's really looked at is the composite of Level 2 and Level 3 hypoglycemic events. And that's because that's what's really clinically meaningful. Those are medical emergencies.

And as mentioned, again, to put it in context, whereas in the diabetes world, a single Level 2, Level 3 event is a medical emergency. People with PBH may be having one or more of these events every week. And that's because they're -- as opposed to taking exogenous insulin and trying to titrate your dose and that being the challenge. Here, because of these excess GLP-1 in the body, it's the patient's own insulin that's causing their blood glucose to plummet. And that's why this is such a hard disease for people to live with.

Yes. And just closing on that, too. So what we observed, particularly -- I won't maybe go through all the data, but particularly at the dose we're using in the Phase III, 90 mgs once a day. We saw a 53% reduction in Level 2 with a p-value of 0.004. We saw a 66% reduction in Level 3 with a p-value of 0.003. And when you look at the composite when you kind of combine those together, which is what we're doing in the Phase III as well, we saw a 64% reduction with a p-value of 0.003.

So as we kind of go into the Phase III study, I'd say one of our biggest goals has been to try to keep as much the same as possible, given that we've seen strong results in the Phase II, in the Phase IIb, including on Level 2 and Level 3 hypoglycemia. We want to keep as much as we can the same to hopefully see that again in Phase III.

Right. So the actual trial design for LUCIDITY?

Yes. So I'd say, probably main thing we're trying to do is stay as consistent with the Phase II as possible. As you heard from Josh, very strong results, very significant reductions in hypoglycemic events. So I think we're trying to keep as much similar as possible while making sure, of course, that the trial would support an approval.

So inclusion criteria, we've really tried to keep the same. We want to enroll a very substantially similar population. Level 2, Level 3 hypoglycemic events are what we're looking at, again, like we looked at in the Phase IIs on how we're measuring those, we're doing the same way. The probably key differences are that those were 4-week trials. This is a 16-week trial. And then those were crossover design studies, and this is a parallel group study. So those are the 2 key differences. But besides that, we really tried to keep substantially similar to the Phase IIs.

Right. So from your perspective, what is your target product profile ideally?

Yes, it's a good question. Maybe it starts with what's clinically meaningful. And as we've spoken to physicians, they really do look at Level 2 and Level 3, it's kind of the consensus within the ADA as well as medical emergencies. And so often what we hear is, if you're telling me that there can be less severe hypoglycemia, that is clinically meaningful. So I think we're really -- I think any significant reduction would be viewed as clinically meaningful.

In our Phase IIb, we saw a 64% reduction. I think that is a phenomenal result. I mean I think that is a very substantial reduction in the amount of hypoglycemia that people would be experiencing. But I do think physicians would, I believe, be excited for any significant reduction in hypoglycemia.

Right. You made quite a splash at ENDO 2025. And I believe you've indicated that the clinical trial results will be available at some point next year. Should we anticipate any additional clinical -- like scientific conferences or data before the actual Phase III readout?

So I would say that the main will be the Phase III readout to your point. I think the really key milestones are target completion of enrollment by the end of this year, data first half of next year. But I'd say, given that this is a pretty fast study, we randomized our first study participant at the end of April. We're targeting data -- top line results first half of next year. So that's why I think we're going to stick to our execution for now, and then those will be really the key data readout next.

Right. And Justin, you mentioned earlier, you have breakthrough designation. What does that actually mean?

Yes. Yes, it's a really important point. It's one of these things that gets batted around, but I'd say breakthrough therapy designation, the sort of technical meaning is it's a treatment that as substantial benefit over existing treatment for a high unmet medical need. And what it means sort of more in practice, though, is FDA kind of has designated these as the most promising clinical candidates in development because what it means from an FDA perspective is that they're sort of committing their resources to this program or to these programs.

So you get a number of things. First, companies get much more frequent interactions with FDA. Second is you expect to get a priority review. So it would be 2 months from filing and then 6 months for review instead of 8 to 10 months for review and a number of other benefits as well. But I think the main thing is it really highlights the strength of the data and the unmet need. And I'll say it's been very exciting for us. We've never had the opportunity to work on a breakthrough therapy designation drug before, and it's a privilege.

Great. And you mentioned the rapidity in terms of time line to actual product approval. So we might as well talk about commercial readiness, which is just around the corner.

Yes, happy to. Yes. So I would say the -- what we're really taking our time this year and into next year, building our market insights. I think that's the most important thing, especially in a new market like PBH, there are no treatments for PBH right now. And so our team really will be pioneering in terms of how do you address this unmet medical need.

I think what we're finding so far is, as you might expect from the numbers, 160,000 people, it's an orphan disease, but it's a large orphan disease. And so I think what we're finding is that there are quite significant numbers of people who are diagnosed at key centers, seeking treatment, well educated. And so there's quite a significant population there. But there's also a substantial population of people who maybe have all of these symptoms, but they're not quite sure that they have PBH yet or maybe they are, but they're not sure what to do about it.

So I think really for us, it's going to be about how do you do the right education in both sort of parts of the market. But it's very, I'd say, sort of classic rare orphan disease type commercialization is how we're thinking about this. So really targeted strategies. And I hope it builds nicely on our prior experience launching successfully in rare disease.

I'd say the last piece that's really been a nice sort of wind in our sales is that there have been a number of recent rare endocrine drugs that have been approved and are having quite successful launches and quite successful market access as well. And so I think that's very nice for us as well, particularly as you go into that market access segment that there are a number of analogs to look to point to that have been recently successful in these types of spaces.

No, that's great. And earlier you mentioned the known mechanism of action. So I think beyond PBH, there could be some other indications that you might be able to apply avexitide to.

Yes, we certainly think so. And maybe I'd start surgically. So gastric surgeries are done for weight loss, bariatric surgeries. These can be Roux-en-Y. They can be vertical sleeve gastrectomy. There are other surgeries as well. But gastric surgeries are also done for a number of other causes. They can be done for gastric cancer to try to resect the cancer.

They can be done for peptic ulcer disease, less common today, but there certainly are a number of people who have had gastric resections due to peptic ulcer disease. They can be done due to esophagectomy or they can be done due to esophageal cancer where somebody has an esophagectomy. Sometimes they're even done for other cancers in the gut to kind of cut out the margins and everything like that. [Audio Gap] So there are -- one, I'd say there are quite a number of other gastric surgeries that have been shown in the literature to have the big GLP-1 elevation to have the hypoglycemia, to have what seems to be a very similar set of pathophysiology as what we see in bariatric surgery.

I'd also say when we look at other disease of hypoglycemia, such as congenital hyperinsulinism and some other conditions as well, there also seems to be an opportunity there. You asked about breakthrough. This drug actually has 2 breakthrough therapy designations. It has one in post-bariatric hypoglycemia and one in congenital hyperinsulinism. I would say we're focused on PBH for the time being, but there was also quite strong data with this drug and mechanism in [ CHI ].

Right. Good. And I guess lastly, with respect to avexitide, you solidified a partnership with Gubra in terms of developing a longer acting. Maybe you want to comment on that?

Yes, we'd be very happy to. We've been very pleased with that partnership. So sort of backing up, so avexitide, we think has a great profile in terms of the efficacy we've seen so far, the safety that we've seen so far. It's a once-daily subcutaneous injection, and we think that's perfectly appropriate to bring to market. There are other analogs to look at as well, especially for such a significant unmet medical need.

That being said, if you can have the same efficacy, the same safety profile, longer acting would be nice. And so we were introduced to Gubra, who are a Danish company, who are really some of the world's true experts in peptide drug development as well as incretin. And it was a really nice match from the start because I think we bring our expertise in a post-bariatric hypoglycemia. We were seeking to try to make a potential longer-acting competitive inhibitor of the GLP-1 receptor.

They had already been studying the GLP-1 receptor. Unsurprisingly, they have those assays up and running, and they bring their very robust peptide and long-acting peptide expertise to the table as well. So we signed that research agreement at the end of last year. We just recently announced that we have both in vitro and in vivo data on candidates that show the potency that we're looking for as well as would support half-lives that would support longer acting and less frequent dosing.

So we haven't given exact time lines to clinic yet, but the partnership is going really well, and we're very excited about that. So I think long-term our goal would be to bring avexitide to market, very significant unmet need, continue to look at these additional opportunities, as Josh was just mentioning, and then hopefully come with a longer-acting version in the future as well.

Great. Before we move on to the rest of the portfolio, any other questions on avexitide? Okay. Great. So maybe we'll touch on a few other things that are going on, lots going on here. So I think you -- with respect to AMX0035, you recently announced the termination of the PSP program. But obviously, you've got an ongoing a very successful program in Wolfram. Maybe you can comment on 0035.

Sure. So AMX0035 is a combination of sodium phenylbutyrate and tauroursodeoxycholic acid. These are compounds that have been studied quite a lot by a number of labs, have shown very frequently reductions in ER stress, reduction in various mitochondrial pathways, leading to reduced cell death and benefit in a number of disease models. We conducted a study in PSP based on some prior data we had seen on tau and PSP as a tauopathy. So we believe there was good scientific rationale.

Unfortunately, that study didn't bear out. So we ultimately discontinued the work in PSP. As it relates to Wolfram, with our mechanism, I guess, at this point, probably about 8 years ago, we got contacted by a researcher who said, I'd really like to work with you in Wolfram syndrome. Wolfram syndrome is the prototypical disease of ER stress. And here we are with taurursodiol and phenylbutyrate, which have shown kind of repeated and clear effects on ER stress.

So over multiple years, we ran preclinical models. It's a monogenic disease. So the preclinical models are generally models of not having that gene and what that does to both beta cells and neurons and then eventually in mice. Those results were quite strong in the preclinic and ultimately led us to go into a pilot study in Wolfram, which we conducted a 12-patient open-label study. Maybe it takes -- is worth kind of just saying quickly what is Wolfram syndrome.

This is a monogenic form of diabetes where it initially starts by looking like type 1 diabetes. So people are typically diagnosed with type 1 diabetes. But then as they go on, they start to become fully blind in both eyes. They become death. They get speech swallowing and breathing difficulties and they can have some movement difficulties as well, usually passing away in the early 30s. So it starts by looking like diabetes, but progresses into a much more kind of multisystemic very severe disease.

So in running our trial, we tried to track those symptoms. So we looked at the diabetic symptoms, we looked at visual symptoms. We had kind of global assessments of their symptomology as well. And what we saw initial open-label study, 12 patients, but what we saw across the outcomes we measured was stabilization or improvement, which was exciting in a disease that what you'd expect is progression and worsening instead seeing stabilization or improvement.

So right now, we're working with -- and I probably should also mention, we estimate there about 3,000 people with Wolfram syndrome in the United States. So right now, we're working with FDA on a potential Phase III design. This would be the first pivotal study in Wolfram, and it is multisystemic. So there is stuff to work through in terms of exactly what that optimal design is. But our goal, given the severity of disease is to find a path that is -- gets us to the finish line as quickly and efficiently as possible.

Great. So you would expect to commence this registration trial next year?

We haven't given an exact time line to start the study. But I think given the patient need here, as we align with FDA, we definitely want to move as quickly as we can.

Great. Excellent. You also have another candidate 0114 in terms of an antisense oligonucleotide. Perhaps you can comment on that.

Yes, I would be very happy to. Thank you. So it is an antisense oligonucleotide targeting Calpain-2. And as one person put it to us recently, Calpain-2 has been a target hiding in plain sight for many years. And the reason is because while I think there's been a lot of research in the neurodegenerative disease space, one area that's been reasonably well characterized is how do neurons and axons actually degenerate, which is what underlies all of these neurodegenerative diseases.

And Calpain-2 is one of the key proteases in that process. So as you might guess from the name, the cal is calcium, so it's a calcium-activated protease. So when the calcium levels get to a certain degree, then Calpain-2 is activated and essentially cleaves many things, including the cytoskeleton. So Calpain-2 activity or amount has been implicated in a number of neurodegenerative diseases, but particularly in ALS.

So the challenge though has been there are multiple calpains. And so you want to, in our opinion, pretty exquisitely target Calpain-2 and not the other calpain and you want to be able to get enough CNS exposure. And so that's where we thought an intrathecally administered antisense oligonucleotide would be a really nice approach. So we didn't mess around the sort of any of the chemistry in terms of the backbone or some of those sorts of dynamics with antisense oligo because I think then you can have more predictability in terms of your dose, in terms of your tox, but then have the sequence specific for Calpain-2 and not for the other calpain.

And so what we've seen preclinically is very strong knockdown of Calpain-2 as well as reductions in key biomarkers of Calpain-2 activity, including neurofilament light chain. So Calpain-2 is one of the key proteases that clears neurofilament. So we're now in a multiple ascending placebo-controlled trial in people with ALS. We are enrolling the first cohort now, and we're targeting by roughly the end of the year to first -- have our first cohort data. So that would be safety as well as biomarkers.

So we get lumbar punctures on people at every visit, given that it's an intrathecally administered drug. And then because calpain cleaves so many things, there are a number of sort of calpain signatures, as I mentioned, including neurofilament light chain that we'll be looking at as well. So we're very excited at the potential of that program. Obviously, it's early days, but I think a really well-researched target and really being targeted in the right way for the first time.

Great. And I'm sorry, how many cohorts -- like so you said the initial cohort data at the end of the year. So with that information in hand, what do you envision the next steps there?

Yes. It's a multiple ascending dose study, 4 dose cohorts envisioned ultimately.

Right. So to your point, this first cohort, the safety will determine then going into the next cohort as well as the target engagement from the biomarkers that we'll be looking at.

Great. Okay. Well, good. Well, look, I think we've talked about a lot. And if I can say what's been accomplished over this last year is amazing. And obviously, the prospects. I mean, maybe we should review the milestones that are coming up over the next 12 to 18 months, a lot is coming up in 12 months in terms of the full portfolio, your current cash, your ability to deliver on those milestones, et cetera.

Sure. So maybe unsurprisingly, I think a lot of our focus -- vast majority of our focus, frankly, is on avexitide given that it is nearing its Phase III readout. So we expect to complete enrollment by the end of the year, data in the first half of next year. And then, of course, we will try to move towards potential approval as quickly as we possibly can following that. So that's certainly where the vast majority of our focus is.

We also are interacting with regulators, expect to have an update on the Wolfram Phase III by the end of the year as well as early cohort data from 114 by the end of the year as well. But we are quite excited. Thank you for the kind words as well. I'll say as we've learned more and more about avexitide, we just kind of get more excited. The more physicians we talk to, the more diligence we do.

We've had the benefit at this point of getting to speak personally with a number of endocrinologists. And it's generally a consistent story of these are patients who have a really substantial unmet need. I really have nothing for them. I want to be able to do something for them. So I'd say kind of for our whole company, our mission is to try to help people who have these types of unmet needs and it makes us really thrilled about the potential in PBH.

Fantastic vision. Thank you very much.

Thanks so much.

[Audio Gap]

[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.

Maybe just to add a little perspective. An investor asked the other day, -- is this a difficult disease to diagnose. And it's interesting because in many ways, you could answer that both yes and no, right? And from the yes side, you say, well, if you're not looking for it, it can take some time for a patient on their patient journey, right?

Also 2 interesting fact. Most of the people who get bariatric surgery around the world are female, tends to be in their 40s, it's about 70-30. So it really is a difference from a male, female perspective, female male. So you've -- a lot of times, it's misdiagnosis, menopause or other things when they're struggling to find these symptoms. But if you're looking for it, right, if you know that you ought to be on the lookout for this, someone's had bariatric surgery, it's pretty easy actually to see because of the manifestations of this persistent hypoglycemia.

And so I think we have an opportunity here when we start commercialization to be very focused and very targeted on that group of people, who've been suffering with this disease for a long time and have sorted their way to the adult endocrinologist centers that we've talked about, and we can find a lot of folks there. At the same time, we can begin to do some education and start to make sure that it's a thing that physicians start to think about when they see patients that fit a certain -- a certain pattern.

And another interesting fact, nothing to do with us, but we've just heard recently a number of questions are starting to appear on the endocrinology board exams about post-bariatric hypoglycemia. So as the number of bariatric surgeries grow over time and the small 5% to 8% side effect, but again, in a population of now over 2 million people that have had surgeries in the last 2 years in the United States, it's starting to be something that endocrinologists are thinking a bit more even as they train for their board. So it's quite an interesting market when you look at it from being able to stage the growth, which is something a small company can do.

Makes sense. I think everyone is all looking forward to the first half of next year. When LUCIDITY reads out and see how data will be impactful for patients that of PDH. So maybe let's move on to AMX-0035. Just briefly, can you talk about the molecule, its mechanism and perhaps why it makes sense in Wolfram syndrome?

Sure. So AMX 35 is a combination of sodium phenylbutyrate and tauroursodeoxycholic acid. These are 2 compounds that have been around for some time, including in the literature, studied in many models and also in our hands, in part due to strong effects on the ER stress. They can even be used as tool compounds in different ER stress models because their ability to hit that pathway is so clear.

That's part of what led us into Wolfram syndrome. So about 8 years ago, we started speaking to a physician named Dr. Fumihiko Urano, who asked if we might want to collaborate to study the compounds in Wolfram syndrome. And his rationale was that Wolfram syndrome is often considered in the literature as the prototypical disease of ER stress. It's generally a monogenic disease caused by mutations in the WFS 1 gene, which is a gene in a protein that helps basically to shut off the ER stress response, so if the protein is not functioning, you end up with this kind of runaway ER stress response that leads to cell dysfunction and death.

So we did a number of years of preclinical work. They all looked quite good. A number of that -- or a good amount of that is published in the Journal of Clinical Investigation insight. And ultimately, that's what led into our clinical work with AMX 35 and Wolfram as well. To talk a bit about the disease, it's quite a rare disease estimated about 3,000 people in the U.S. who have Wolfram syndrome. It manifests initially looking like juvenile diabetes, like type 1 diabetes, as patients progress, though, they'll also see diabetes insipidus, with some hypothalamic dysfunction, they tend to go blind, ultimately fully blind as they get into laid adolescents and adulthood and ultimately, they'll see other neurodegeneration, including brain stem degeneration, which leads to breathing, respiratory type problems as well.

So usually, these patients pass away in their early-30s. So we ran a trial initially open-label study in 12 people living with Wolfram syndrome. We tried to track some of those cardinal symptoms of Wolfram syndrome. The 1 that changes the most over time is the diabetic outcomes. So those were our primary endpoint in the study, namely, we track them, C-peptide, hemoglobin A1c, blood glucose using continuous glucose monitoring, as well as vision and kind of a general symptom score as well.

And across all of those, we saw a stabilization or improvement in our initial study, which was consistent with what we had seen in the preclinic as well. Limitation that it's an initial -- it's a 12-patient open label, but we really did see what we would hope to see in that study. So now we're interacting with regulators. Our thought is that the next step would be a pivotal study in this disease, especially given that it is a rare disease.

It would also be the first pivotal study conducted in Wolfram. So we're working with the agency to determine the best path for that and endpoints. And certainly, our goal is for that to be as efficient as possible. I think when you're going after a disease with 3,000 patients, you don't want to run too large or too long of the study ultimately to enable getting into that commercial space ideally.

That makes sense. And I think you guys really hit the nail on the head with just how the rarity of disease it is and the urgency to get something to market. But AMX 35 did have a recent I would say, data readout from PSP that perhaps wasn't quite as anticipated. But might there be any read-throughs from those results to your ongoing discussions with FDA regarding the Phase III design for Wolfram.

Yes. I appreciate you asking. So no, I don't think there's any read through different divisions and different supporting mechanisms. So yes to cover that, so we ran a Phase IIb trial in Progressive Supranuclear Palsy PSP with the same drug, AMX 35. The rationale was that in a prior Alzheimer's study, AMX 35 had lowered tau, which is the key pathological protein we see in PSP. That being said, 1, sadly, no drug has ever worked for PSP.

And second, it was the first study of AMX 35 in people with PSP, so we have that data readout very recently. And unfortunately, there is no difference between active and placebo. What I think is very different with Wolfrom syndrome, this first Wolfrom syndrome is a monogenic disease. So we understand the pathophysiology much better. What we see in cells is what we saw in mice, is what we see in people.

The second is that our first clinical study in Wolfram syndrome, every outcome went in the right direction. In fact, we saw improvement across many of the measures, including the measures of glycemic control, which is very exciting. So I'd say, whereas our first trial in PSP with AMX 35, unfortunately, there wasn't a clear benefit. Our first trial in Wolfram syndrome, there was a very clear benefit. And so that's why we're working on the Phase III program now.

And maybe the same type of questions on Wolfram, just from a commercial context. I mean, what work have you guys done looking at the unmet need and obviously, a rare disease, but I wasn't sure the -- like how active the patient community is and what visibility maybe the study has among other drugs. There's not a lot out there in the pipeline for Wolfram fortunately for you guys.

Yes. Great question. So 1, similar to some other rare disease spaces, the advocacy is a lot driven by mothers. There's a number of mothers, who have really made a mission to see a difference in this disease. They're quite well organized, quite impressive individuals, who are advocating for Wolfram as well. The top clinic in the country is definitely clinic out of Washington University, run by Dr. Fumihiko Urano. He personally maintains a registry of people living with Wolfram syndrome, that's over 400 patients.

So I think this is definitely the type of rare disease, where it's -- we expect it to be rather concentrated, approximately 3,000 patients overall, but already 400 of those in Dr. Urano's Registry. I'd also say from a diagnostic path, a monogenic disease, so you can diagnose it using a genetic test, but genetic testing is not often conducted in diabetes. You could imagine a path where if you have somebody with juvenile diabetes or Type 1, particularly, if they're antibody negative, which would suggest a somewhat atypical presentation of type 1 potentially conducting a genetic test and being able to pick up these patients, particularly if you see any optic or otherwise disturbances or diabetes insipidus, in them as well.

But so clearly, this could be better diagnosed. I think when we've seen and talked to patients and otherwise, there's usually quite a diagnostic delay. But encouraging even with that that we see at least 400 patients in a registry at a single site also. And maybe lastly, I'll say, since we've started the trial, we have heard from Dr. Urano and from the patient advocacy groups as well. They have seen a major uptick in awareness and interest. I think Dr. Urano often says I've been getting a referral every week, which again suggests that there's a lot more people considering this when they see juvenile diabetes, particularly with an atypical presentation or other symptoms coming at the same time as well.

Okay. That's super helpful. Maybe talk a little about just to round out the pipeline, maybe the collaborations, the Gubra deal. Maybe just give us a little bit of context for that. The strategy there, the -- maybe the -- how you got there, selection of it and then we can go from there.

Yes. We're very excited about that collaboration. So thank you. So I think we -- as I said, the more work we've done with vexatide, the more work we've done with PBH, the more excited we get. And in fact, something else entirely that we didn't get to talk about is -- it turns out that other upper GI surgeries, basically any upper GI surgery can cause the same persistent hypoglycemia as well.

So I think that's an opportunity for future work. So whether that's gastrectomy for gastric cancer, esophagectomy for esophageal cancer, there are many other surgeries can cause the same persistent hypoglycemia and there are no treatments available. So we think there's really a lot of work to do now and in the future.

The currently avexatide is taken as a daily subcutaneous injection. Now for a population, high unmet need, no treatments available, I think that's very appropriate for market. I think there are other good examples of that even recently in the endocrine space. And when patient interviews have been conducted, patients say, "Look, I'm pricking my finger multiple times a day to test my blood glucose, that's a lot more bothersome than having to take an injection in the morning." so we feel very confident in going to market with avexatide as it exists today.

That being said, all else being equal, and that's the important point. efficacy safety being equal, longer acting would be better and the technology to take peptides and make them long acting, I think, has been really nicely developed over the past couple of decades. So we did what we try to do in various spaces as we talk to the experts and several of the kind of brain trust to have developed these peptides over the years or in Denmark as people may be very well aware of.

And they pointed us to this company called Gubra, who are a Danish biotech who have built this really robust peptide platform. And so we started discussing the potential of developing a long-acting inhibitor of the GLP-1 receptor with Gubra -- and they just -- they and we felt like it was just a great partnership opportunity -- they -- as you might imagine, have been working on the GLP-1 receptor for a long time.

They have all of those assays up and running already. They have a very robust library and platform for developing peptides. And so we signed a research agreement at the end of last year, and now we're off to the races. So we haven't given explicit time lines yet. But I'll say we've been very impressed with the work they've done so far. And I think as we get a little further in development, we'll give more -- we'll give more details on the time lines. But that's a program we're very excited about.

And maybe just only small out there. We did share our earnings as well that we already have seen compounds with strong in vitro and in vivo potency as well as extended half-lives as well. So more work to be done, but it does seem that the project is progressing as we would like to see.

Fantastic. Well that, we're out of time, guys. So thank you very much. Really appreciate the conversation.

Great. Thanks so much for hosting us.

Thank you so much.