AMLX

Good morning. My name is Kate. I will be your conference operator today. At this time, I would like to welcome everyone to the Amylyx Pharmaceuticals First Quarter 2026 Earnings Conference Call. All participants will be in a listen-only mode. After today's presentation, there will be an opportunity to ask questions. To ask a question, please press star one on your telephone keypad. To withdraw your question, press star two. Please limit yourselves to one question with one follow-up. If you have additional questions, you may rejoin the queue. Please be advised that this call is being recorded at the company's request. I would now like to turn the call over to Lindsey Allen, Vice President, Investor Relations and Communications. Please proceed.

Good morning, thank you all for joining us today to discuss our first quarter 2026 financial results and business updates. With me on the call today are Josh Cohen and Justin Klee, our Co-CEOs, Dr. Camille L. Bedrosian, our Chief Medical Officer, James Frates, our Chief Financial Officer, and Dan Monahan, our Chief Commercial Officer. Before we begin, I would like to remind everyone that any statements we make or information presented on this call that are not historical facts are forward-looking statements that are based on our current beliefs, plans, and expectations and are made pursuant to the safe harbor provisions of the Private Securities Litigation Reform Act of 1995. These statements include, but are not limited to, our expectations with respect to avexitide, AMX0035, AMX0114, and AMX0318.

Statements regarding regulatory and clinical developments and the impact thereof and the expected timing thereof, and statements regarding our cash runway. Actual events and results could differ materially from those expressed or implied by any forward-looking statement. You are cautioned not to place any undue reliance on these forward-looking statements, and Amylyx disclaims any obligation to update such statements unless required by law. Now, I will turn the call over to Justin.

Good morning, everyone, and thank you for joining us. The 1st quarter of 2026 was marked by execution across our pipeline. Most notably, we continued to progress the pivotal phase III LUCIDITY trial of avexitide, our investigational first-in-class GLP-1 receptor antagonist with FDA breakthrough therapy designation in post-bariatric hypoglycemia, or PBH. We are executing on the 3 strategic imperatives for avexitide that we outlined earlier this year. First, we are advancing the pivotal phase III LUCIDITY trial toward top-line data. Randomizing and dosing the last participant in late March was a significant milestone. We have a clear line of sight toward the completion of the 16-week trial, and we remain on track for a top-line readout next quarter. Second, we're advancing NDA readiness and regulatory preparations. We are already drafting NDA sections to support a potential submission. Third, we continue to strengthen our launch readiness.

We are executing against a comprehensive commercial readiness roadmap to help ensure we are fully prepared for commercialization of avexitide if approved in 2027. In addition to avexitide, we continue to make progress across our broader pipeline. For AMX0318, our long-acting GLP-1 receptor antagonist, IND-enabling studies are underway. We are targeting a 2027 IND filing. For AMX0035 in Wolfram syndrome, we anticipate presenting longer-term week 96 data from the phase II open-label HELIOS clinical trial at an upcoming scientific meeting. For AMX0114 in ALS, we fully enrolled cohort 2 of the phase I LUMINA trial in March. At the NEALS annual meeting this June, we expect to present early biomarker data from cohort 1, the first and lowest of 4 doses being evaluated in the trial.

We expect these data will provide initial information about the levels of the ALS biomarkers being assessed in the LUMINA trial from the first cohort. As we continue to advance our pipeline, we are simultaneously preparing for the potential commercial launch of avexitide. To discuss our launch readiness efforts, Dan Monahan, our Chief Commercial Officer, is with us on the call today. Dan joined Amylyx in January 2024, bringing more than two decades of experience. He was instrumental in the commercialization of Otsuka's REXULTI, Novartis' Cosentyx, and Sanofi's Lantus and Actonel, among others. With that, Dan, I'll turn the call over to you.

Thank you, Justin. Good morning, everyone. I'm pleased to be on the call today to discuss how we have been refining our launch strategies as we prepare for the potential commercialization of avexitide next year. The more we engage with the PBH community, the more we understand the profound unmet need that exists. We are operating with a deep sense of urgency. To date, our commercial efforts have been focused on gaining key insights into the PBH market. This includes gathering direct insights from people living with PBH and the healthcare professionals who are managing their condition. In addition, we are developing a deep understanding of the patient journey and continuing ongoing claims work to help us determine where patients are being treated. To enable our commercial preparations, we've made key hires across marketing, market access, and commercial operations.

Ahead of the potential approval and commercial launch of avexitide, our immediate focus is on disease state education. This includes raising stakeholder awareness of PBH with an emphasis on the pathophysiology, the importance of accurate and timely diagnosis. The profound unmet need and burden of the condition. We plan to launch this disease state education campaign this summer. Looking at the market opportunity, our independent claims analysis and ongoing field engagements continue to support our estimate of approximately 160,000 people living with PBH in the U.S., who have undergone the 2 most common types of bariatric surgery, sleeve gastrectomy and Roux-en-Y gastric bypass. Our estimates are firmly rooted in a growing body of prospective and retrospective published literature, including large long-term cohort studies evaluating hypoglycemia in people who have undergone bariatric surgery.

Importantly, our ongoing market research indicates that endocrinologists have a high intent to treat PBH if there were to be an approved medicine. To reach appropriate patients, we have initiated our marketplace sizing efforts and continue to identify key centers and endocrinologists that manage this condition. Building up to the potential launch, we will refine these efforts as more insights are generated. Our commercial preparations are advancing in lockstep with our clinical progress, and we look forward to sharing additional details as we move closer to the commercialization of avexitide, if approved. With that, I'll turn the call over to Camille to provide an update on our clinical and medical affairs progress this quarter.

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

Our pivotal phase III LUCIDITY trial is evaluating avexitide 90 milligrams once daily in individuals with PBH following Roux-en-Y gastric bypass surgery, using the FDA agreed-upon primary outcome of reduction in the composite of level 2 and level 3 hypoglycemic events through week 16. LUCIDITY was designed with the goal of replication. 5 prior avexitide trials in PBH, which demonstrated statistically significant results, including reductions in hypoglycemic events, directly informed the dose, the primary endpoint, inclusion criteria, and surgical subtype for LUCIDITY. Echoing Justin's earlier remarks, our clinical team remains deeply focused on the execution of the LUCIDITY trial, and we continue to work closely with our investigators as we approach our anticipated data readout next quarter. In parallel with our clinical trial execution, we are actively ramping up our field medical affairs team to facilitate on-the-ground engagement with KOLs.

I also am pleased to share that we recently launched a U.S. expanded access program to provide avexitide for up to 250 adults with PBH following Roux-en-Y gastric bypass surgery. This program is a direct response to the urgent need we are hearing from individuals who are struggling with the devastating daily realities of PBH and the physicians who treat them. Initial eligible patients include individuals who have either completed LUCIDITY or participated in previous clinical trials of avexitide in PBH. As a reminder, avexitide is an investigational drug and has not been approved by the FDA for any indication. Working directly with the PBH community and seeing the everyday impact of this devastating condition drives our continued commitment to our clinical and medical efforts. With that, I will now turn over the call to Jim to review our financials. Jim?

Thanks, Cam. Thanks, Camille. Our financial results for the first quarter were in line with our plans and reflect our focus on the phase III LUCIDITY trial and targeted investments in advancing our broader pipeline. We ended the fourth quarter with $279.8 million in cash and marketable securities, compared to $317 million at the end of the fourth quarter of last year. This capital funds our anticipated cash runway into 2028, including our key expected milestones. The LUCIDITY top-line readout expected in Q3 2026, potential FDA approval, and potential commercial launch of avexitide in 2027. Turning now to our results for the quarter. Total operating expenses for the quarter were $43.8 million, up 16% from the same period in 2025.

Research and development expenses were $27.6 million, compared to $22.1 million in Q1 2025. The increase was primarily due to an increase in spending related to the clinical development of avexitide in PBH. This quarter, we also recognized a milestone payment of $4 million to Gubra following the identification of AMX0318 as a development candidate for PBH and other rare diseases. The increase was offset by decreased spending related to the clinical development of AMX0035 for progressive supranuclear palsy. Selling, general, and administrative expenses were $16.2 million, compared to $15.7 million in Q1 2025. This increase was primarily due to an increase in consulting and professional services as we prepare for the potential commercial launch of avexitide.

We recognized $6.1 million of non-cash stock-based compensation expense for the quarter, compared to $6.8 million of non-cash stock-based compensation expense in Q1 2025. Turning to our balance sheet, our cash usage was slightly higher in Q1 compared to Q4 because of our Gubra milestone payments and the payment of our annual corporate bonus during the quarter. We're in the midst of a pivotal year for Amylyx, with the top-line data readout from LUCIDITY expected in Q3. The team will continue to focus on scaling our business with discipline, and we're actively laying the groundwork for a potential commercial launch. This focus positions us well, particularly for our work with avexitide. We continue to believe avexitide has the potential to be a breakthrough treatment for PBH. With that, I'll turn the call over to Josh.

Thanks, Jim. To close, we are focused on the execution of the LUCIDITY trial as we track toward our anticipated top-line readout next quarter. PBH is a chronic lifelong condition with symptoms that often emerge 1-3 years following bariatric surgery. Many people who receive bariatric surgery are in their 40s, suggesting that if they develop PBH, they may have decades of life impacted by this condition. The broader medical community continues to recognize this critical need in PBH. In March, Dr. Colleen Craig and her colleagues at Stanford published the first U.S. prevalence model for PBH in Surgery for Obesity and Related Diseases, the official peer-reviewed journal of the ASMBS. In April, CMS published their annual list of ICD-10 codes to be potentially effective October 1, 2026, which includes an ICD-10 code specific to PBH.

The planned adoption of an ICD-10 code shows the growing recognition of this condition by the medical community. We believe that avexitide, if approved, could play a meaningful role in addressing this highly underserved patient population. In parallel with LUCIDITY, we are actively preparing for a regulatory submission following top-line results, while simultaneously scaling our commercial and medical teams to support a strong commercial launch of avexitide in 2027, if approved. With that, I would like to now open the call up for questions.

We will now begin the Q&A session. To ask a question, please press star one on your telephone keypad. To withdraw your question, please press star two. Please limit yourselves to one and with one follow-up. If you have additional questions, you may rejoin the queue. At this time, we will pause momentarily to assemble our roster. Your first question comes from the line of Seamus Fernandez with Guggenheim. Your line is open.

Great. Thanks for the question. I hope you'll bear 2 for me quickly. You know, the first question is really on the initiation of the EAP. You know, typically we see companies sort of waiting for the completion of their phase III, and then, you know, the announcement of an EAP in the wake of a positive phase III. Just wanted to get a better sense of, obviously, you know, how you were able to execute this and get it approved. Also, you know, how you were really responding to the community with the implementation and announcement of the EAP. Just a quick follow-up question.

Wanted to get a sense of just sort of that relative impact that working on the NDA now could actually have from a filing perspective. Typically, when we see biotech companies with positive phase III data, it'll take as much as, you know, 6 to 9 months to see that file. Just wanted to get a sense of how working on the NDA now might advance that ahead of those types of timelines. Thanks so much.

Thank you very much, Seamus. This is Camille. For the EAP, indeed, we are responding to the community, where there is currently no approved therapies for PBH, we recognize and have received several requests and demands. Importantly, we're starting the EAP now because we wanna be sure there's continuity of treatment for people in the LUCIDITY study who are completing the OLE portion of the LUCIDITY trial. That, that drives the timing for the EAP. Now, with regard to your question about NDA preparation, yeah, we're sort of not typical, for sure, and we are working, as noted, on NDA preparations. We do hope that that will, you know, allow us to be most efficient as we reach top-line data next quarter.

Because there is a great sense of urgency, there are no treatments for people with PBH. If positive, we wanna be sure that we're providing the opportunity for access as promptly as possible.

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

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

Your next question comes from the line of Joseph Wong with TD Cowen. Your line is open.

Hey, this is Jacob on for Joe. Thanks for taking our question. We were wondering how the baseline for the enrolled phase III population would compare to the patients in the phase II studies. What the expected placebo response in phase III might be versus what we know about the patients in phase II and the differences in the running periods. Thanks.

Sure. The study is ongoing and blinded, we will not really comment on the details of this ongoing study. Having said that, we are very much looking forward to top line data next quarter where we'll share the top line data with you and hope you're sharing our excitement as well for this possibility. With regard to the placebo, remind as well we've had 5 prior highly successful trials. The phase II trials showed statistical significance and clinically meaningful reductions in the composite as we presented at ENDO. In the PREVENT study, 55% reduction with a highly statistically significant value and with, in the phase II-B with a 90-milligram dose, the dose in LUCIDITY, 64% reduction with a P value 0.0031.

Those P values do take into account all aspects of the trial, including the possibility of any placebo effect. We designed LUCIDITY, with the goal of replicating these prior successful trials. We powered, we're highly powered 90% to detect a clinically meaningful reduction in events, even under the most conservative circumstances.

Great. Thank you.

Yeah, you're welcome.

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

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

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

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

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

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

Thank you, Mike. I think, first in terms of, you know, top line disclosure, you know us well. We're a transparent company, our goal is always to present things as they are. I think what's important in this study is probably two things to remind. The first is that the primary outcome, which is level 2, level 3 hypoglycemic events, not only is it the primary outcome, it's in FDA guidance, it's also very well known by endocrinologists, it's inherently clinically meaningful. Level 2 events being less than 54 milligrams per deciliter blood glucose.

which is the blood value at which neuroglycopenia occurs. Level 3, of course, means that the clinical manifestations of hypoglycemia have already occurred. Those are inherently clinically meaningful. I think a second important point is that there are currently no treatments for PBH. What we have heard consistently, not just from people with PBH but from physicians as well, is that any reduction in hypoglycemic events is meaningful. Each one of these events is a medical emergency. What we hear from physicians often is that they are worried for their patients, and they have really very few tools to help prevent these medical emergencies. Any reduction in these hypoglycemic events is meaningful.

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

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

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

Well, thanks, Mark. Appreciate the question. Just to talk a little bit about the claims analysis. Within the claims databases, we start with identifying patients that have a presence of bariatric surgery. Then we look at patients who also have documented hypoglycemia, so non-diabetic hypoglycemia. After that, we'll then apply, and we have applied, additional signs and symptoms associated with PBH such as fatigue, dizziness, seizures, even blood glucose tests, or even ER visits. To add to that, we can look at it from how many of those type of events they've also had within the claims databases. That's really how we've continued to look at the databases.

I'll say we've done it several times, and each time we do it, we are confident in the 160,000 patient population that we've mentioned a few times.

Yeah, I might just add, too, you know, some added work the team's done too is both speaking, you know, to many of the sites and doing kind of market research with many of the sites, to validate what we're finding in claims. You know, for example, if the claims are saying, you know, a site has 50 patients, you know, actually checking with the site and seeing if they do have 50 patients. So far, those have been quite confirmatory as well.

I'll also just add, from the call today, we also, you know, received notification, you know, kind of through the CMS manual list that there's likely to be an ICD-10 code for PBH, going live in October, which will provide a, you know, an additional tool, kind of to track the claims data as well.

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

Thank you.

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

Great. Morning, guys. Thanks for the question. Have 2 quick ones. Ahead of LUCIDITY top line, I know the primary outcome measure is level 2 or 3 events as a composite. Is there a thought of looking at, you know, each one of those separately, in particular level 3, just to have a cleaner, you know, look at the profile from maybe a more commercial context? The second question, as you guys begin to focus on commercial and further evaluate the PBH prescriber base, you know, how has your thinking evolved in terms of size and scope of sales force and MSL teams? Thank you.

Hi, Jeff. I'll take your first question and then pass to Dan for your second. Our, as you say, our primary endpoint, which is FDA agreed upon, a reduction. We're looking at the reduction in the composite of level 2 and level 3 events. That is well established in the ADA, Diabetes Association literature and community as well. We do intend as well, our secondary endpoints are looking separately at level 2, which is by a finger stick of blood glucose level of less than 54 grams per deciliter, and separately level 3, which is independent of glucose level, of signs and symptoms that require individuals to have another individual help or signs and symptoms that would have required someone else to help them if no one else is around.

That is adjudicated by an independent group of experienced endocrinologists who are blinded to the data as well. They do that adjudication on an ongoing basis.

I'll just add too from the sort of commercial point of view, you're right. Absolutely level 3 means the person has had the manifestation of hypoglycemia, of course that's important. Level 2 being less than 54 is very well established too. I think, I think endocrinologists will be interested in both. If you think about the outcome, it's really a nice.

Mix. You have a blood value which indicates severe hypoglycemia, so you kind of know what's happening in the body. You have a clinical outcome in level 3 where you know the person has had the impact of severe hypoglycemia. For your question on prescriber base, I'll pass it to Dan.

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

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

Hi, team. Thanks for taking my questions as well. I guess, can you touch on the degree of natural variability there is in level 2 and level 3 hypoglycemic events for PBH patients? Do you expect a massive difference from one week to another? Secondly, from a commercial perspective, are these PBH patients generally managed at centers of excellence, or would you need to target endocrinologists more broadly?

Sure. Maybe starting with the variability. You know, all that's taken into account in our powering analysis, and I think we were quite conservative in our powering, both on the effect size and on the placebo effect. You know, whereas we saw a 50% and 64% effect size at the 60 and 90 mg doses, you know, we powered to a 35% effect. Of course, you know, retaining power up to a 50% placebo effect even though I, you know, I don't think we expect that in this condition. You know, you can certainly look at the, you know, variability kind of from previous studies, but again, that's all kind of accounted for, you know, in our, in our powering analysis. Generally, it's a chronic condition.

Generally, people, you know, are not able to, you know, prevent these events from occurring. Often if people are having events, that will be a continuous thing. You know, they don't kind of come in fits and starts, you know, so to speak, all that often. In terms of the question of, you know, how we'll target centers of excellence versus the broader endo community, I'll pass over to Dan.

Sure. Thanks, Josh. I appreciate the question on the potential launch, Rami. On the where the patients are potentially treated. We have initiated that work, and we are aware, and Josh mentioned this earlier, but there are Centers of Excellence, there are also Key Opinion Leaders, and that's likely where we'll start from a launch perspective. We know that there's, you know, potentially 50 to 60 patients at certain centers, and some centers have been even mentioned even more. We'll start there. We know there's a concentration, as our disease state education efforts take a foothold, we'll expand into the broader endocrinology community.

Your next question comes from the line of James Candalis with Stifel. Your line is open.

Hey, this is Mark on for James. Thanks for taking our question. One for me on Recordati. I believe we should be getting some data this quarter. Just curious your thoughts here as it relates to potential placebo effect and, you know, what the implications are for Incivity and whether really this is something that can actually be sort of, you know, read through onto your trial. Thanks.

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

The mechanism of the drugs are very different as well.

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

Hi, this is Aman for Graig. Thanks for taking our questions. Maybe switching over to AMX0114 with the ALS data coming up shortly. Can you just remind us of the specific biomarkers to potentially look out for? I know there was some prior analysis done by you guys, highlighting certain biomarkers, but maybe just a reminder and then also some of the expectations you guys have or we should be thinking about going a ahead into the data. Thank you.

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

Just to add as well, you know, as Camille said, study's proceeding incredibly well. You know, I think as Camille was mentioning, we've completed enrollment in cohort 2 and, you know, we're now recruiting for, you know, cohort 3 as well.

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

Hi. Good morning. This is Dina Ramadine on for Jason. Thank you for taking our question. Maybe just a couple of commercial questions on avexitide. I think you've mentioned before that the ICD-10 code was not necessary for successful commercialization. Just curious how ultimately having an ICD-10 code kind of alters your confidence in identifying and capturing patients at scale. You know, I know you've outlined the centers you're targeting and what your commercial strategy is. Just curious if it impacts how you're approaching your commercial plan. Just a second quick follow-up. I believe you plan to position avexitide as a chronic therapy. I'm just curious what assumptions you're making around expectations for persistence and adherence in the real world. Thank you.

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

To your other question too, about kinda chronic therapy and persistence, it's probably early to comment there. You know, we're quite excited, you know, about avexitide and, you know, PBH is a chronic condition where the needs do not go away over time. Certainly, we do think that, you know, patients will have an ongoing need for therapy.

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

Morning. Thanks for taking my question, and congrats on the progress. Just a quick one on the OLE. Can you just remind us what the setup is specifically for that? You know, are you able to kind of share high level how enrollment in that is going?

Sure. Are you speaking of the OLE or the EAP? Just so that I'm clear, please.

The OLE for LUCIDITY.

Label extension.

the Open-Label Extension. Yep.

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

Yeah. You asked the OLE setup.

Yeah

add there as well. You know, we expect the randomized double-blind study is the study that, you know, we'll, you know, we expect to use in our, in our NDA, you know, to support potential commercialization. The OLE itself, though, also has a part A and a part B. During the part A, we keep the study very similar to how it's conducted during the double blind. That allows, you know, to look at, you know, kinda data, you know, in a similar way to we look at, as the double blind.

Later, they enroll in the OLE B after 8 weeks in the OLE, at which point it's a little more, you know, there's less burdensome kind of trial participation at that point. Overall, just to kind of reiterate what Camille said as well, we're very pleased with the conduct of the study. You know, there's a lot of excitement, you know, from sites and otherwise as well. We'll look forward to reporting our data in Q3.

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

Your next question comes from the line of Ananda Ghosh with H.C. Wainwright & Co. Your line is open.

Hey. Hi. Good morning, guys. Thanks for the question. Maybe one question. You know, people have been focusing on U.S. opportunities. One question would be, have you done work with respect to avexitide on ex-U.S. opportunities? You know, what are you hearing from the payers or stakeholders? Then I have one follow-up question on LUMINA.

Absolutely. Thank you, Ananda. There's a tremendous unmet need globally for post-bariatric hypoglycemia. Our focus is very much on the U.S. right now. With 160,000 people in the U.S. who have PBH today, that's a substantial unmet need and people to help and address. First of all, bariatric surgeries occur globally. Also, as we've mentioned before, virtually any gastric surgery has the potential to cause the same debilitating hypoglycemia. For example, in major Asian countries, gastric cancer rates, esophageal cancer rates are very high, and so gastrectomy or esophagectomy is often indicated. For people with those surgeries, they also have the potential of developing the same debilitating hypoglycemia.

We have data from the phase II-B study of avexitide, that avexitide may be beneficial for people who had those surgeries leading to this debilitating hypoglycemia as well. The pathophysiology is the same regardless of the surgical intervention. Our focus is really on the U.S., really on the U.S. population of post-bariatric hypoglycemia, but absolutely there's a huge unmet need internationally. We get compassionate use requests from people around the world constantly.

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

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

I'll add too, Anand, to your point. Our goal is to have a picture of, first, are we replicating the biology that we saw in the pre-clinic to the clinic? Are we seeing the implications of calpain-2 knockdown? Then are we seeing effects on biomarkers that we believe to be prognostic for ALS as well? That is indeed the goal of the biomarkers in all of these cohorts, is to try to get a picture of, are we seeing the impacts of calpain-2, and are we seeing potential impacts on ALS as well?

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

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

Thank you, everyone. You can now disconnect. Thank you.

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 Zealand Pharma with dasiglucagon also did not see much of a placebo response in PBH. So we really do not expect one. But what I would say is we do believe that Avexatide is an active drug. Going through the five prior trials, we see consistent effect. So I think strategically, as we were designing the Phase 3, we wanted to make sure we were very well powered. I would 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.

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.

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

Good morning. This is Dina on for Jason. Thank you so much. We just had a quick 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 endpoint? Can you just remind us what is your expectation for how events should skew at baseline between percentage level 2 versus level 3? Thank you.

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.

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