AMLX - NASDAQ

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, Inc. Fourth Quarter and Full Year 2025 Earnings Conference Call. All participants will be in a listen-only mode. After today's presentation, there will be the opportunity to ask questions. To place yourself into the queue, please press star then one. To withdraw your question, you can repeat the steps of star then 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. 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 Joshua B. Cohen and Justin B. Klee, our Co-CEOs; Dr. Camille L. Bedrosian, our Chief Medical Officer; and James M. Frates, our Chief Financial Officer. Before we begin, I would like to remind everyone 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, AMX035, AMX114, and AMX318; 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 Pharmaceuticals, Inc. disclaims any obligation to update such statements unless required by law. I will now 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 Avexatide, 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 Avexatide, a GLP-1 receptor antagonist in post-bariatric hypoglycemia, or PBH. In addition, our collaboration with Gubra progressed significantly, and in January, 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 1 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 three objectives for Avexatide 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 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 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 two most common types of 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 would now like to 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 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 Avexatide 90 mg 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. 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 mg once daily led to a 64% least 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 2 trial showed no placebo response. However, to be conservative, we modeled up to a 50% placebo effect and a 35% effect size relative to placebo for LUCIDITY, and under these assumptions, to detect clinically meaningful benefit, we believe LUCIDITY remains well powered. LUCIDITY was designed with the goal of replication. The five prior Avexatide 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. I will now turn the call over 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 AMX035 for the treatment of ALS and PSP. The decrease was offset by increased spending related to the clinical development of Avexatide 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 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 AMX318 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 would 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 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 will now turn the call over to Josh.

Thanks, Jim. While our immediate focus is on Avexatide, our broader pipeline strategy is designed to leverage 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 AMX318 are underway, with an IND filing targeted for 2027. For AMX114, we plan to present biomarker data from cohort one of our Phase 1 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 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/MND last December. We are 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 AMX035, we continue to work with the FDA on a Phase 3 trial in Wolfram syndrome following the long-term data from the Phase 2 HELIOS trial that were presented last year. To close, Amylyx Pharmaceuticals, Inc. 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 team's efforts as they work towards a potential launch in 2027. We will now open 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 star then one on your telephone keypad. To withdraw your question, repeat the steps; star then one will also remove you from our queue. We ask that you please limit yourself 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. Our first question today will come from the line of Seamus Christopher Fernandez at Guggenheim.

Great. Thanks so much for the question. So, I wanted to just ask the learnings that you have gained from the execution of the clinical trial so far, specifically the recruitment is now complete. We are going to see a lot going forward, but in terms of the run-in, was hoping you might be able to give us a little bit of color in terms of the quality of the 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, I will have a follow-up question in that regard. What have you learned during the run-in period about these patients and the patient population along the way that can basically maybe give us a little bit more color and, you know, certainly enthusiasm to match what we have heard from thought leaders in the space?

Yeah, thank you very much for the question. I will start with the inclusion criteria. The whole design of the study was really informed by the prior trials, particularly the prior Phase 2 trials. Those were very successful and showed very statistically significant, clinically meaningful reductions in hypoglycemic events, and so we carried all of that forward into the Phase 3. We do believe that we are recruiting the right participants. We believe that we are conducting the right study. What I can say, probably more anecdotally from the sites, is what has 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. You really hear that from the sites, that these are really challenging events. That is what makes PBH so challenging as a disease. We have also been very encouraged by the broad participation across the sites, and I think, again, it just underscores all of our market research as well, which is that this is a substantial unmet medical need. It is 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 is really just to try to control excursions as best as possible, but people continue to have these events regardless. So really, 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 have got 16 weeks of treatment versus a much shorter treatment period from the Phase 2. 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 2? Just trying to get a better understanding of some of those characteristics, what could actually impact the placebo response relative to what we have seen in the Phase 2. Thanks so much.

Yeah, great question. Maybe I will start by saying scientifically and based on prior data, we really do not expect much of a placebo response. When you look at the past Phase 2 trials, there really was not much of a placebo response at all. Actually, prior work from

Great. Thank you. Next question will come from Corinne Johnson 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 are doing now, how that has helped you, and where you are in terms of commercial prep? Then just a quick follow-up on the OLE. Can you give us some color on how many patients are currently having been enrolled into the OLE? Thank you.

Thank you. I would differentiate two things. Priority one is our execution of the LUCIDITY trial. I do think, again, it underscores the unmet need and opportunity here. In addition to that, we are also doing substantial commercial preparations, particularly across our medical affairs and commercial organization. I can share what has really come through there. In 2025, we tried to get a real handle on the market. We spent a lot of time first in the literature assessments, talking with key opinion leaders, going to conferences. After that, we spent a lot of time with various claims databases and other medical information systems so that we got a real sense of how many people with PBH there are, where they are being treated, what is the patient journey, those sorts of elements. I will say that first, all of our research really triangulated to this about 160,000 prevalence number, and that is 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 have had PBH for 15 or 20 years. What we have 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 100–120 patients under your care. Is that right? Who are the primary health care professionals who care for them? What is the frequency of visits? Those sorts of things. Everything has come back really corroborating our claims work. 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 is a growing awareness of PBH as well. PBH is now on 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 is a growing unmet need and underscores the importance of a potential treatment in the future. For your question on the OLE, I will pass to my colleague, Camille.

Sure. Thank you. 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 in Q3 of this year. Thank you.

Our next question will come from Marc Harold Goodman at Leerink 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, 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 the concentration.

Yeah. Good question, Marc. We will probably get more into that as we get closer to our hopeful commercial launch in 2027. What I would 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 is not some issue in how the claims data is finding patients. One thing that is 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 into 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 orphan disease strategies that you might typically see in a commercial launch.

I will just add as well, I really want to underscore the unmet need that we hear. We have 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 is a really difficult condition to manage as a physician because people are hyper-reactive. They sometimes have triggered events, but sometimes for no seeming trigger at all. As a physician, I think they feel a little helpless because they really do not have tools to either prevent or really treat these hypoglycemic events. Going back, each one of these events is a medical emergency. Think from the physician's point of view, you have a patient who is very frequently having medical emergencies and there are very limited tools in your toolkit to help manage that. Across the many clinics that we have spoken with, that story is the same. I think it just underscores the opportunity we have.

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

Hi, guys. Thanks so much for taking my question. Just want to examine the Avexatide Phase 2b trial for a bit. I noticed that in Phase 2b, the standard deviations for hypoglycemia were very large, especially in the 90 mg 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 suboptimal responders? If so, to what extent might they have played a role in driving the hypoglycemic event rates? Thank you.

Yeah, good question. Going to the Phase 2b and the 90 mg arm, maybe just to start with, we saw a very strong effect there, roughly a 66% effect with a very strong p-value, less than 0.001 as well. 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 we saw were. Yes, there is some variability. Some people have more events, some people have fewer 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. I think that shows up also in the p-value, which is showing that the effect is much larger than the noise that was observed in that trial.

I would add, that is one of five trials that showed the same thing. Avexatide in all five trials showed substantial reductions in hypoglycemic events, and that is what ultimately supported FDA Breakthrough Therapy designation as well.

Very helpful. Thank you.

We will hear next from James Condolas at Stifel.

Hey, thanks for taking my question, and congrats on the progress. I wanted to ask another commercial one. One of the more interesting data points that we have seen coming out of some of the work that Stanford did in terms of this market is that there are 30,000 critical PBH patients. As you continue to do work on this market and look at things like claims, do you think there are really this many very, very severe PBH patients that are going to the ER, being admitted to the hospital, etc.? 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 is an important question. This is something we started to look into in our market research and our interactions with clinics. What has 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 has not been that much differentiation between someone who is very frequently in and out of the ER and somebody who maybe is having hypoglycemic events on a less frequent basis. I think the reason is that physicians believe that any one of these events could land somebody in the ER. Each one of these events as a medical emergency has the potential to be a catastrophe. 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. Again, that is why I keep underscoring the unmet need here. That has just come through again and again and again. I think all of this is informing our go-to-market strategies and the type of commercial opportunity we have ahead of us.

I might just add too, anecdotally, as we have talked to sites—and I think this bears out in the claims-based work that we have been doing too—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. I would add that it is not just the direct consequences of hypoglycemia—the failures of the brain to function due to low glucose—it is also all the indirect effects: falls, accidents, things like that as well. Pretty much every clinician we have spoken to has their stories about seeing those really severe outcomes come to manifest.

I will 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 constrained and narrow—staying in the home. People with PBH learn to understand what they can and cannot do, and try and avoid the accidents or the profound hypoglycemia that leads to unconsciousness or seizures. Even though someone does not go to the ER, it does not mean they are not severely, severely constrained, living at home, needing a companion, etc.

Makes sense. Thanks for the color.

Our next question today will move forward to the line of Rami Katkhuda at LifeSci Capital.

Hi, team. 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 in LUCIDITY enough to see broad uptake?

Right, so what we have heard from physicians certainly is ultimately what they would like to see is an approved drug for people living with PBH. Leading up to that, as we have been articulating today and as the American Diabetes Association clearly states on their website, hypoglycemia of the level—level 2, level 3—each one is a medical emergency. Physicians also say, and the patients too, that they would like a reduction, and just one event will be absolutely meaningful. Having said that, of course, we are conducting LUCIDITY, and we would say that a statistically significant reduction will be 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 readout?

We are still considering, but I think as we look at this study, it is a pretty quick turnaround, given that it is only a 16-week study. We will continue considering that, but I think mostly we are excited about data coming out in Q3.

Thank you very much.

We will hear next from Jeff Meacham at Citibank. Please go ahead.

Hey, guys. Morning, and thanks for the question. I know you guys call out AMX318. I know you are thinking life cycle management in PBH, but maybe help us with the timing. Is there a fast path to a pivotal once you finish the initial Phase 1, and with LUCIDITY experience in hand? Related to AMX318, are there other endocrine indications, rare or otherwise, that at this point look interesting to you or still too early to tell? Thank you.

Maybe starting with AMX318, I will reiterate we are 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, in vivo activity, manufacturability, things like that as well. Certainly, we are moving that compound ahead as quickly as we can. Going to your other point, we really do see this as part of our broader excitement about GLP-1 antagonism. We have heard from clinics and we have seen the literature as well that it is not just bariatric surgery that can result in these dangerous hypoglycemic events. People get these events after surgery for gastric cancer—gastrectomies—esophageal cancer—esophagectomies. People may have surgeries for peptic ulcer disease, gastroesophageal reflux disorder, etc., all of which can lead to these recurrent hypoglycemic events. I would also add that it is 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. We look at efforts to make a long-acting agent in that context; we think that this is a really exciting approach—GLP-1 antagonism. We want to keep investing in it and moving the science forward.

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

Hey. Good morning. Thanks for the progress, and thanks for taking my question. Could you go to the market opportunity for Avexatide in PBH? Can you just remind us of the current patient and physician experience with acarbose? 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, Graig. Very important. 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. What I mean by that is that physicians are willing to try whatever they can to help their patients. Acarbose helps with potentially one small aspect of what causes the hypoglycemia, which is the general digestion of carbs. However, one, that is only a limited part of what can trigger these hypoglycemic events. Two, acarbose is really not well tolerated. As we look through, for example, the prior trials and experience of people on acarbose, it was not uncommon for people to come off acarbose in a matter of weeks because it is just really not well tolerated—very significant GI discomfort and symptoms. Probably the most important thing I would say is that we really do not think it is targeting the root cause of PBH. What characterizes PBH is this very hyper-reactive state, and people are hyper-reactive because the body has substantially increased its GLP-1 response. The GLP-1 response is often up to 10 times normal, and with the up to 10 times normal response, that is what causes the insulin spike and therefore the hypoglycemic events. If you are not targeting the root cause of what is causing this hyperactivity, then people are going to continue to have events. Again, this is what we have 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 solving the challenges of PBH, nor do we think that will impact the uptake of Avexatide.

Our next question today will come from Christopher W. 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, you mentioned, Justin. Can you talk a bit more about, for those unfamiliar, what an ICD-10 code specifically is and what would securing one for PBH mean for Avexatide in your view? Then, can you just put a finer point on the nature of those discussions currently? Are you able to actively engage in those discussions? Thank you.

Yeah, thank you very much. An ICD-10 code is a medical code that designates particular conditions, and there is a government process to determine whether ICD-10 codes are necessary. Generally, it is that there is a particular medical condition and it is of substantial enough importance—and at times population as well—that there should be a new code introduced. The fact that they are considering an ICD-10 code for PBH just speaks to the growing awareness of this condition, of its importance, and of the substantial population. I will say that these efforts have been really led by the medical community. As I also mentioned, PBH is now on the endocrinology board exam. I think really the awareness of PBH as an unmet medical need and as a very difficult condition with a growing prevalence has become front and center. We will hear more in April. I think it is important to mention as well we do not need an ICD-10 code for future reimbursement if the product is approved, because this would be through pharmacy benefit—it is a take-home product. But an ICD-10 code certainly helps with, for example, as we are looking in claims databases, as big health systems are looking for people with PBH, making sure they are cared for appropriately. That is where this designation really helps. Again, we just think it speaks to the overall growing awareness of this condition.

Yeah, great question. Maybe just to give context to why the different levels were selected. 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. They found that that level was often when you get below 54 mg/dL. That is why level 2 is defined; it is the level where symptoms frequently start to get severe for individuals. Level 3 is when the symptoms have become so severe that you are incapacitated and rescue becomes warranted—people who dip deep into hypoglycemia. As we speak to clinicians, I do not think they view a level 2 as asymptomatic and not risky; it is a very risky event. People who are having a level 2 may be right around the corner from having a level 3. I think that is also why there is the value in the composite endpoint as well, because these events often travel together. Often level 2 is turning into a level 3 fairly quickly. In previous studies, there was maybe slightly more level 2 than level 3, but generally, the events were occurring with similar frequency. I would add too, it was not uncommon in previous studies that they occurred together and that you would quickly have a patient going from level 2 to level 3, or logging the blood sugar below 54 at the time where they become incapacitated. Thank you.

Moving forward, Ananda Kumar Ghosh at H.C. Wainwright. Your line is open. Please go ahead.

Hey, hi. Thanks, guys. One of the common questions we have been getting is the assumption of extended LUCIDITY trial compared to prior trial and the impact on the diet evaluation. I was wondering how, during the design of Phase 3, these factors were incorporated.

With regard to diet, we provide diligent training to sites, and detailed information to the participants that focuses on maintaining consistency in diet—the medical nutrition therapy—throughout the study, each phase of the study. This point is reinforced at various points throughout the study, and participants actually are asked to reaffirm that they are adhering to the dietary guidelines that we have set out for LUCIDITY. Important to note also, and reiterate, that we are conducting LUCIDITY while replicating many of the features of the prior successful Phase 2 studies, and dietary consistency is one of them. I will also 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. We are really pleased with how LUCIDITY is being executed. Thank you for the question.

I will 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 Avexatide, both from the nonclinical and clinical studies, has been very good. As we look forward to the results in the third quarter, as Camille said, we designed the study and are conducting the study, obviously to support regulatory approval, but really with the Phase 2 elements in mind.

Okay. Great. Maybe I have a quick follow-up question. Is there any mechanistic or rationale which shows whether GLP-1 receptor blockade remains effective even if patients increase their carbohydrate intake?

Great question. We do believe that the effect of Avexatide is quite strong. Maybe as one example of that, in the Phase 1 studies, the paradigm of those studies was that they gave people with PBH a large bolus of glucose either with or without Avexatide. What they saw in people who were receiving placebo was, after the large bolus of glucose, the people with PBH’s blood sugar would go up and then it would drop precipitously into the hypoglycemic range, and patients would need to be rescued. For people who were on Avexatide, particularly in the first Phase 1 but also in the other Phase 1s that were conducted, nearly all participants did not go into that hypoglycemic range. Those studies evaluated levels of glucose such as a 75-gram bolus of glucose. We do believe that the effects of Avexatide 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. 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.

Got it. Thanks very much.

Ladies and gentlemen, we would like to thank everyone that did signal for a question today. At this time, we will take a follow-up from Seamus Christopher Fernandez at Guggenheim.

Oh, great. Thanks for the question here. Just wanted to ask about the tolerability profile of Avexatide 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 anti-drug 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 Avexatide. Thanks so much.

Yeah, great question. Maybe starting with the tolerability of Avexatide, it has been quite excellent through our studies to date. When you look at the five prior trials, there really were not dropouts. People were able to stay on the drug quite successfully. 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. 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 immunogenicity in the animals that we studied. We tried to make sure we selected a molecule that was not immunogenic, at least in animals. Of course, as we translate to humans, it will be something we continue to evaluate. Our goal is definitely to select a molecule that does not have significant ADAs or ISRs. It also comes down to leaning a little bit on Gubra’s experience as well, as we try to select peptides that avoid those types of liabilities.