Amylyx Pharmaceuticals, Inc.

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 Amelix Pharmaceuticals fourth quarter and full year 2025 earnings conference call. All participants will be in a listen-only mode, and after today's presentation, there will be the opportunity to ask questions. To place yourself into a queue, please press star and one on your telephone keypad. To withdraw your question, you can repeat the steps of star and one. Please limit yourself to one question with one follow-up today, and if you have additional questions, you are invited to rejoin the queue. 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 Lindsay Allen, Vice President, Investor Relations and Communications. Welcome, Lindsay.

Good morning, and thank you all for joining us today to discuss our fourth quarter and full year 2025 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, and Jim Fradies, 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 Avexatide, AMX 35, AMX 114, and AMX 318, 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 AMOX disclaims any obligation to update such statements unless required by law. Now, I'll 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 Avexotide, strengthened our financial position, which extended our cash runway into 2028, and positioned the company for what will be a transformative year in 2026. Importantly, in 2025, we initiated the pivotal phase three lucidity trial of our lead program of Exotide, 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 AMX318, a novel, long-acting GLP-1 receptor antagonist as a development candidate for PBH and other rare diseases. We also made strides in ALS. AMX114 received fast track designation and demonstrated a favorable safety and tolerability profile in cohort one of the phase one 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 PVH. We are focused on three objectives for Avexatide in 2026. One, deliver top line data from the pivotal phase three 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, strengthen launch readiness to support a potential 2027 commercialization of Avexatide 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're 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're 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've undergone bariatric surgery. From these studies, we estimate that there are approximately 160,000 people living with PVH in the U.S. out of the more than 2 million people over the last decade who have undergone the two 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 PVH 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 PBH, 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 three lucidity trial is evaluating Avexatide 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 two and level 3 hypoglycemic events through week 16. The lucidity trial is anchored in the robust data generated to date from five prior Avexatide clinical trials in PBH that demonstrated statistically significant reductions in hypoglycemic events. Most notably, Avexatide 90 milligrams once daily led to a 64% least squares mean reduction versus baseline in the composite rate of level two and level three hyperglycemic events with a p-value of 0.0031. Also of note, the phase two trial showed no placebo response. However, to be conservative, we modeled up to 50% placebo effect and 35% effect size 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 five prior vexatide clinical trials in PBH directly informed 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 this month. 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 Avexatide, we are actively ramping up our medical insights capabilities, disease education activities, KOL and community engagement, and evidence generation. These efforts will facilitate understanding of the Avexatide 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 Avexatide 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 AMX 35 for the treatment of ALS and PSP. The decrease was offset by increased spending related to the clinical development of Avexatide and 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 recognize $6.4 million of non-cash stock-based compensation expense for the quarter, compared to $6.8 million of non-cash 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 AMX 318, 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 Goober, 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 Avexatide is a potentially breakthrough treatment for PBH and are working hard to prepare it 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 Avexatide, 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 AMX318, which, as Justin mentioned, is our investigational, long-acting GLP-1 receptor antagonist. We selected AMX318 following a rigorous evaluation of a large number of peptides against key criteria. AMX318 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 318 are underway, with an IND filing targeted for 2027. For AMEX 114, we plan to present biomarker data from cohort one of our phase one Lumino 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 one investigating the first and lowest of four doses being evaluated. We presented initial safety and tolerability data from cohort one at the International Symposium on ALS and MND last December, and we're pleased to observe that AMX114 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 two of the Lumina trial this month. We look forward to sharing our progress in this dose escalation study. For AMEX35, we continue to work with the FDA on a phase three trial in Wolfram syndrome, following the long-term data from the phase two Helios trial that were presented last year. To close, Amelix 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.

And to our audience joining today over the phones, we will now begin the Q&A session. To ask a question simply press the star and one on your telephone keypad and to withdraw your question repeat the steps star and one will also remove you from our queue. We ask you to please limit yourself from to one question with one follow up today, and if you have additional questions, of course, you are invited to re signal and join the queue once again. At this time we'll pause momentarily to assemble our roster it's star and one ladies and gentlemen.

Our first question today will come from the line of Seamus Fernandez at Guggenheim.

Great. Thanks so much for the question. So I wanted to just ask the learnings that you've gained from the execution of the clinical trial so far, specifically, you know, 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, you know, certainly enthusiasm to match what we've heard from thought leaders in the space.

Yeah, 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 two trials, 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 three. We do believe that we're recruiting the right participants. We, you know, 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 on that the unmet need here, you know, 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 two, level three 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 know, you've got 16 weeks of treatment versus, you know, a much shorter treatment period from the Phase II. Also, an 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 zero in the phase two. 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 two. Thanks so much.

Yeah, great question. So maybe I'll 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 two trials, there really wasn't much of a placebo response at all. And actually some prior work from, you know, a Zeeland farmer with dasaglucocon 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, you know, vexatide is an active drug. You know, going through the five prior trials, you know, we see consistent effect. So I think strategically, as we were designing the phase three, 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 power in this study.

We'll take our next question. Thank you.

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

Good morning. This is Kevin on for Corinne. 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.

Thank you.

So I would differentiate two things. So, you know, priority one is our execution of the lucidity trial. I do think, again, it underscores the unmet need and opportunity here. But, you know, 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 PVH 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 it 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, you know, we see you have 100 patients, 120 patients under your care. Is that right? You know, who are the primary health care 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 PVH today. There's a growing awareness of PVH as well. PVH is now on the endocrinology board exams. 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 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.

Thank you. Our next question will come from the line of Mark Goodman at Lear, Inc.

Partners.

Yeah. 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 have you actually checked out? Are you checking out large ones, medium size, like small ones? Just give us a sense of what it looks like out there as far as, you know, numbers of patients in these sites, like how many have over 100? How many are in the 50 to 100? You know, just so we understand, like, the concentration. Thanks.

Yeah, good question, Mark. So maybe, you know, we'll probably get more into that as we kind of get closer to, you know, our kind of commercial, you know, 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, you know, natures of center, you know, as you suggest. trying to make sure that, you know, what our claims are identifying are real, that they're not, you know, that there's not some issue in 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, you know, 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 into the best way to reach these centers. I will say that our data continues to suggest that this is, you know, 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, you know, I think that all lends itself well to, you know, 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 really want to underscore the unmet need that we hear again. We've talked to a substantial number of clinics now, and the story is the same again and again, which is that PBH is a really difficult condition for patients. It's a really difficult condition to manage as a physician because people are hyperreactive. They sometimes have triggered events, but sometimes it's for no seeming trigger at all. And as a physician, I think they feel overwhelmed. a little helpless because they really don't have tools to either prevent or really treat these hypoglycemic events. And going back, each one 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, and there's very limited tools in your toolkits to help manage that. And again, across the many, many, many clinics that we've spoken with, that story is the same. And so I think it just underscores the opportunity we have.

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

Hi, guys. Thanks so much for taking my question. I just want to examine the Vectortide Phase 2B trial for a bit. I noticed that the In phase 2B, the standard deviations for hypoglycemia were very large, especially in the 90 milligram arm, which would suggest that there could have been non-responders or at least some sub-responders to therapy. So were there non-responders or sub-optimal responders? And if so, to what extent might they have played a role in driving the hypoglycemic event rates? Thank you.

Yeah, good question. So going to the Phase IIb and the 90-meg arm, so maybe just to start with, we saw a very strong effect there, you know, roughly 66%, you know, effect with a very strong p-value, you know, less than 0.01, you know, as well. And the median effect, the median patient actually had their event rate go to zero, which gives you a sense of just how strong the results, you know, we saw are. Yes, there is some variability. You know, some people have, you know, more events. Some people have less events, you know, which I think does account for that standard deviation. But, you know, by and large, we were seeing the response, you know, across the cohort that was studied. And I think that shows up also, you know, frankly, in the p-value, which is, you know, showing that the effect is much larger and the noise that was observed, you know, in that trial.

And I would add, that's one of five trials, right, that showed the same thing. So vexatide in all five trials showed substantial reductions in hypoglycemia, hypoglycemic events, and that's what ultimately supported FDA brachytherapy designation as well.

Very helpful. Thank you. We'll hear next from James Kondoulas at Stiefel.

Hey, thanks for taking my question and congrats on the progress. I wanted to ask another commercial one. And I think one 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 30,000 critical PBH patients. And I guess the question is, as you continue to do work on this market and, you know, look at things like claims, do you think 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? Thanks so much.

Yeah, thank you, James. It's an important question. And I'll say, you know, again, this is something we started to look into in our market research and our interactions with clinics. And I'll say, you know, 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, you know, 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, you know, really critically impaired, they really believe that PBH by itself, excuse me, is a very dangerous condition. And so, um, again, that's why I keep underscoring the unmet need here. Um, that's just come through again and again and again. So I think, uh, for us, you know, I think all of this is informing our sort of go-to-market strategies, uh, and, uh, uh, and, uh, the, you know, type of, uh, uh, commercial, uh, opportunity we have ahead of us.

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

Yeah. And I'll also add here for individuals, not every individual may go to the ER or be hospitalized because, again, 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.

Makes sense. Thanks for the call, Eric. And our next question today, we'll move forward to the line of Rami Katakouda at LifeSci Capital.

Hi, Gene. Thanks for taking my questions as well. 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 updates?

Right. So, the, what we've heard from physicians certainly is ultimately what they'd like to see is 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, level two, level three, each one is a medical emergency. So the physicians also say, and the patients too, that they would like reduction in just one 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 Avexatide.

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

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

Awesome. Thank you very much. We'll hear next from Jeff Meacham at Citibank. Please go ahead.

Hey, guys. Morning, and thanks for the question. I know you guys call out 318. I know you're thinking lifecycle management and PAH, but maybe help us with the timing. Is there a fast path to a pivotal, you know, once you finish the initial phase one and with lucidity experience in hand? And then related to 318, are there other indications, rare or otherwise, that at this point look interesting to you or still too early to tell? Thank you.

Yeah, so maybe starting with 318, maybe I 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 tried 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, the in vivo activity, manufacturability, things like that as well. So certainly we're, you know, moving that compound ahead as quickly as we can. But I think going to your other point, we really do see this as, you know, part of our kind of broader excitement about GLP-1 antagonism. You know, we've heard from clinics and we've, you know, 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 reflux 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, you know, cancer related surgeries in Europe as well. So, you know, I'd say we kind of look at the, you know, efforts to make a long acting kind of in that context that we think that this is a really exciting approach, you know, GLP-1 antagonism, and we want to keep investing in it and moving the science forward.

Our next question this morning will come from Greg Souvaneve at Mizuho.

Hey, good morning. Thanks for the progress and thanks for taking my question. If I could just go to the market opportunity for Avexatide and PBH, can you just remind us of the current patient and physician experience with Acarbose? And on the assumption that Avexatide gets to the market, whether existing use of Acarbose by PBH treaters might represent in any way a potential hurdle to uptake of Avexatide. Thanks.

Thanks, Greg. Yeah, very, very important. So I would start with, you know, Acarbose 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 A carbose helps with potentially one 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, a carbose is really not well tolerated In our, as we looked through, for example, the prior trials and experience of people with, on a carbose, it was not uncommon for people to come off a carbose in a matter of weeks because it's just, you know, has, is really not well tolerated, very significant GI discomfort and symptoms. And the, 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 hyperreactive because the body is, has substantially increased its GLP-1 response. GLP-1, the GLP-1 response is often up to 10 times normal. And so with the up to 10 times normal response, that's what causes the insulin spike 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 a carbose in any way is solving the challenges with PDH, nor do we think that that will impact the uptake of a vexatide.

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

Good morning. Thanks for taking my question, and 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 securing one for PBH mean for Avexatide, 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? Thank you.

Yeah, 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, you know, there's a particular medical condition and it's of 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, you know, these efforts were, you know, 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 as a very difficult condition and a growing prevalence, uh, has, uh, has really become front and center. Um, so, uh, we're, you know, we'll, we'll, we'll hear more, uh, in, uh, in April. I think it's important to mention as well. Um, we don't, uh, we don't need an ICD-10 code, uh, for future reimbursement, you know, if the product is approved, uh, because this would be through pharmacy benefit. It's a take-home product. Uh, but an ICD-10 code certainly helps with, uh, 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.

Thank you.

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

Good morning. This is Dina Onford. Jason, thank you so much for taking our question. We just had a quick maybe follow-up to a prior discussion point on the events in the lucidity trial. Curious if in your market research, you similarly hear that clinicians are more focused on a reduction in level three hypoglycemic events as opposed to the regulatory composite endpoint. And can you just remind us, what is your expectations for how events should skew at baseline between, you know, percentage level two versus level three? Thank you.

Yeah, great question. So, you know, maybe just to kind of give context to, you know, why the different levels were selected. So level two was really defined by, you know, a number of research studies, you know, 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 two was defined. It's the level where symptoms start to get, you know, frequently start to get severe for individuals. Level three is when the symptoms have become so severe that you're incapacitated and, you know, that rescue becomes warranted. you know, for people, you know, who dip deep into hypoglycemia. So as we speak to clinicians, I don't think they, I think they view a level two as both a symptomatic and very risky event. People who are having a level two may be, you know, right around the corner from having a level three. And I think that's also why there's the value in the composite endpoint as well, because these events often travel together. You know, often level two is turning into a level three, you know, fairly quickly. So, you know, 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 two than level three 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 know, you would quickly have a patient going from level two to level three, or logging a blood sugar, you know, below 54, you know, in the time where they become incapacitated.

Thank you. Moving forward, Ananda Ghosh at HC Wainwright.

Your line is open. Please go ahead.

Hey, hi. Thanks, guys. 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 diet degradation. So I was wondering, you know, how during the design of phase three, these factors were incorporated.

So with regard to diet, we provide diligent training to sites and detailed information to the participants that 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 conducting lucidity with replicating many of the features of the prior successful phase two 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.

Yeah, 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. The safety profile of the vexatide, both from the non-clinical and clinical studies, has been very good. And so as we look forward to the results in the third quarter, as Camille said, you know, we designed the study, we're conducting the study obviously, to support regulatory approval, but really with the phase two elements in mind.

Very great. Maybe a quick follow-up question. You know, is there any, like, mechanistic or rational which shows that whether a GLP-1 receptor blockade remains effective even if patients kind of increase their carbohydrate intake?

So I think it might have 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 practice. Oh, sorry?

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

Oh, great question. Yeah. So, you know, we do believe that the effect of exotide is quite strong. And, you know, maybe as one example of that in the phase one studies, the kind of paradigm of those studies was that they gave people with PBH a large bolus of glucose, either with or without of exotide. And what they saw, you know, in people who were receiving placebo was after the large bolus of glucose, the people with PBH's 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 a vexatide, particularly in the first phase one, but also in the other phase ones 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 vexatide are robust, you know, to a pretty significant carbohydrate load. Of course, though, in PBH, the recommendation and, you know, really what patients have been, you know, doing for years to avoid these really traumatic events is to, you know, 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, you know, avoid meals that will result in big glucose excursions.

Thanks very much.

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 Shamish Fernandez at Guggenheim.

Oh, great. Thanks for the question here. Just wanted to ask about the tolerability profile of of Avexatide in particular, and then what you would hope the, you know, to learn in the early phases of the, you know, Gubra asset development, particularly as it relates to things like anti-drug antibodies, injection site reactions, you know, the factors that you think are most important to advancing the Gubra asset. and ensuring that it provides a profile consistent with, you know, the market expansion opportunities beyond Avexatide? Thanks so much.

Yeah, great question. So maybe starting with the tolerability of Avexatide, it's been quite excellent, you know, through our studies to date. You know, we, you know, when you look at the five prior trials, there really were not, you know, dropouts. People were able to stay on the drug. you know, 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, you know, not really associated with much, you know, when they occurred. As it relates to the grouper molecule, one of the things we did look for was immunogenicity. You know, in the animals that we studied, we did try to make sure we selected a molecule that, you know, was not, you know, immunogenic, at least in animals, you know, of course, as we translate to humans, that will be something we continue to evaluate. But, you know, our goal is definitely to select a molecule that does not have, you know, significant, you know, ADAs or ISRs. And, yeah, I think it, you know, it also comes down to doing, you know, to leaning a little bit on Guber's experience as well, as we try to select peptides that, you know, avoid those types of liabilities.

And to our phone audience joining today, this does conclude the Amelix 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.