Amylyx Pharmaceuticals, Inc. (AMLX) Q4 FY2025 Earnings Call Transcript & Summary

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 positioned the company for what will be a transformative year in 2026. 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 through 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, strengthen 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 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 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 PBH that demonstrated statistically significant reductions in hypoglycemic events. Most notably, avexitide 90 milligrams once daily led to a 64% least squared 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 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 5 prior avexitide 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 avexitide, we are actively ramping up our medical insights capabilities, disease education activities, and KOL 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 Gubra, 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 breakthrough -- 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 avexitide, 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 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 AMX0114 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 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 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 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 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 dasiglucagon 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 Corinne Jenkins at Goldman Sachs.

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. 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 care. 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 board 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 have 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 PBH 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 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 toolkit 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.

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 standard 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 Condulis at Stifel.

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've continued to do work on this market and look at things like claims, do you think there's really this many very, very severe PBH patients that are going to the ER or 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 is 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. I might 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, too, we do -- pretty much every clinician we speak to will share stories about motor vehicle accidents, 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.

And 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 in LUCIDITY enough to see broad uptake?

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 levels, 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 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 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 Geoff Meacham at Citibank.

I know you guys called out 0318. I know you're thinking life cycle management and PAH, 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 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 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 acarbose? 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, Graig. Yes, very, very important. So I would start with 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. Acarbose 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 acarbose 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 hyper-reactive 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 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 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 securing one for PBH mean 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 if 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 dipped 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 a blood sugar below 54 in the time where they becoming capacitated.

Moving forward, Ananda Ghosh 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 diet evaluation. 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 with 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. 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 II 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 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 -- sorry.

Sorry, no. So the question was whether GLP-1 receptor blockade remains effective even if 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 one 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'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 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 traumatic 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 excursions.

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 Gubra 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 Gubra 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 Gubra molecule, one 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 Gubra'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.