Good morning, my name is Liane and I will be your conference operator today. At this time, I would like to welcome everyone to the Amylyx Pharmaceuticals First Quarter Earnings Conference Call. All participants will be in a listen-only mode. After today’s presentation there will be an opportunity to ask questions. [Operator Instructions] Please limit your questions to one 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, and thank you all for joining us today to discuss our first quarter 2025 financial results. With me on the call today are Josh Cohen and Justin Klee, our Co-CEOs; Dr. Camille Bedrosian, our Chief Medical Officer; and Jim Frates, our Chief Financial Officer. Before we begin, I would like to remind everyone that any statements we make or information presented on this call that are not historical facts are forward-looking statements that are based on our current beliefs, plans and expectations and are made pursuant to the safe harbor provisions of the Private Securities Litigation Reform Act of 1995. These statements include, but are not limited to, our expectations with respect to avexitide, AMX0035 and AMX0114, statements regarding regulatory and clinical developments, the impact thereof and the expected timing thereof and statements regarding our cash runway. Actual events and results could differ materially from those expressed or implied by any forward-looking statements. You are cautioned not to place any undue reliance on these forward-looking statements, and Amylyx disclaims any obligation to update such statements unless required by law. Now I will turn the call over to Justin.

Good morning, and thank you all for joining us. 2025 is an important year of execution at Amylyx as we advanced 3 potential therapies across 4 clinical trials, each targeting diseases with high unmet need Already this year, we've achieved several meaningful milestones. Last month, we dosed the first participant in our pivotal Phase 3 LUCIDITY clinical trial of avexitide in post-bariatric hypoglycemia, or PBH. We also dosed the first participant in our Phase 1 LUMINA clinical trial of AMX0114 in ALS. In addition, we strengthened our financial position by raising approximately $65.5 million at the start of the first quarter, which extends our anticipated cash runway through the end of 2026. Now I'd like to briefly walk through each of our programs. Starting with our lead asset, avexitide, an investigational GLP-1 receptor antagonist with FDA breakthrough therapy designation for post-bariatric hypoglycemia, PBH is a chronic and often progressive condition that affects approximately 160,000 people in the United States. However, there are no approved treatment options. We believe avexitide has the potential to fill that gap. We are encouraged by the level of engagement from the clinical trial sites participating in our pivotal Phase 3 LUCIDITY trial. We continue to expect enrollment completion in 2025 and top line data in the first half of 2026. In addition, we are preparing diligently to be launch ready and if approved, we anticipate a commercial launch in 2027. Later during the call, Camille will share more details about avexitide and the lucidity trial. Turning to AMX0035, which is an oral small molecule therapy designed to target endoplasmic reticulum or ER stress and mitochondrial dysfunction. AMX0035 is currently being evaluated in Wolfram syndrome and progressive Supranuclear Palsy, or PST. Wolfram syndrome is a monogenic progressive neurodegenerative disorder with premature mortality and no approved treatment…

Thanks, Justin. We are very excited about the potential of avexitide, our investigational GLP-1 receptor antagonist. The GLP-1 receptor, a mediator of important well-characterized biology is an effective target to modulate this biology. The GLP-1 receptor is one of the key regulators of insulin and glucose. Unlike GLP-1 agonists, which increased insulin secretion. A GLP-1 receptor antagonist decreases insulin secretion and therefore, stabilizes for glucose levels. Avexitide has shown promise to treat post-bariatric hypoglycemia. And as a result, has FDA breakthrough therapy designation. Last month, we dosed the first participant in the 16-week randomized, double-blind, placebo-controlled Phase 3 LUCIDITY clinical trial, evaluating avexitide in approximately 75 individuals with PBH following rule on gastric bypass surgery. LUCIDITY is designed to have similar inclusion and exclusion criteria to the previous successful Phase 2 PREVENT and Phase 2b trials of avexitide in PBH. In addition, LUCIDITY is evaluating the FDA agreed upon primary outcome of reduction in the composite of Level 2 and Level 3 hypoglycemic events through week 16. PBH is a debilitating condition believed to result from an excessive GLP-1 response following bariatric surgery. PBH manifests as persistent recurrent and debilitating hypoglycemic events that can impose a life altering and enduring burden on a person's health, independence and ability to engage in everyday life. On average, the symptoms appear approximately 1 to 3 years following bariatric surgery. Once people have PBH, the condition is chronic and often progresses. We estimate, based on our projections from data and published literature and claims-based work that there are about 160,000 people in the U.S. who are living with PBH today. Additionally, bariatric surgery remains the standard of care for addressing obesity, particularly for people who require substantial and sustained weight loss. Therefore, we believe the unmet need in PBH will continue to grow. A…

Thanks, Camille. We believe we're well positioned to achieve our goals. We ended the first quarter with a cash position of $204.1 million which includes approximately $65.5 million in net proceeds from our public offering, which closed in January of this year. We believe we have the necessary cash to deliver our planned clinical milestones through the end of 2026. These milestones are top line data from the Phase 3 LUCIDITY trial of avexitide in PBH, week 48 data from the ongoing HELIOS trial in Wolfram syndrome, Top line data from the Phase 2b portion of the ORION trial in PSP and Phase 1 data from our LUMINA trial of AMX 114 in ALS. In addition, our cash supports the advancement of our commercial preparations for the potential first-to-market launch of avexitide in PBH. Jeff, let's turn to our results. Total operating expenses for the quarter were $37.8 million, down 82% from the same period in 2024. Research and development expenses were $22.1 million compared to $36.6 million in Q1 2024. The primarily due to a decrease in spending on AMX0035 for the treatment of ALS, a decrease in payroll and personnel-related costs and in preclinical development activities. Selling, general and administrative expenses were $15.7 million compared to $57.8 million in Q1 2024, primarily due to a decrease in payroll and personnel-related costs and a decrease in consulting, professional and other services. We recognized $6.8 million of noncash stock-based compensation expense for the quarter. compared to $9.9 million of noncash stock-based compensation expense in Q1 2024. We also used roughly $6 million in cash related to product rebates and the settlement of purchase commitments for AMX0035 and that were established prior to the voluntary discontinuation of sales of RELYVRIO and ALBRIOZA in April of 2024. We recorded $1.4 million of expense in the first quarter of 2025 related to these payments. with the remaining expense recorded in prior periods. Going forward, the residual cash obligations related to the discontinuation of RELYVRIO and ALBRIOZA are $3.1 million, which we expect will be paid through the remainder of 2025. We're pleased with our cash position as we progress through the year, and we're reiterating our expected cash runway through the end of 2026. With that, I'll turn the call over to Josh for some closing remarks.

Thank you, Jim. As we look ahead, we remain grounded in our mission to develop novel therapies for diseases with high unmet needs. We are focused right now on strong execution across our 4 clinical trials, each targeting serious neurodegenerative or endocrine disorders. In the coming days, we are excited to share week 48 data from our HELIOS trial in Wolfram syndrome. And in the third quarter, we look forward to sharing unblinded Phase 2b data from the ORION trial in PSP. By the end of the year, we also expect early cohort data from the Phase 1 LUMINA trial of AMX0114 and people living with ALS. And in the first half of next year, we expect top line data from the Phase 3 LUCIDITY trial of avexitide in PBH. We continue to believe we have the necessary cash to advance our pipeline and to support commercial preparations with the potential first-to-market launch of avexitide in PBH. Thank you for your continued interest, and we look forward to keeping you updated on our progress. Now I would like to open the call up for questions.

Thank you. [Operator Instructions] Your first question comes from Michael DiFiore - Evercore ISI. Please go ahead.

Congrats on all the progress. Just two for me. One on avexitide. Just your recent commentary on avexitide for PBH suggests that a large patient education campaign will be required. My question is, is this because the 8% of symptomatic patients don't necessarily know they have PBH? Or will these educational efforts attempt to shore up and penetrate into less symptomatic patients? I have a follow-up.

Yes. Thanks, Mike. Good and important question. So I would say PBH, certainly among adult endocrinologists and sadly, among people who are suffering with PBH is pretty well known, including the signs and symptoms. I think sometimes it can be a bit of a connecting the dots because oftentimes, PBH takes years on average 1 to 3 years following a bariatric surgery to manifest. But adult endocrinologists when they can pretty clearly recognize the signed the symptoms of hypoglycemia. And then, of course, once they actually do testing in the clinic on blood glucose, then it becomes very clear as well as at home measures as like finger-stick blood glucose and CGM. So I think it's certainly well recognized. And unfortunately, it's quite a severe condition as well. People can have such severe events as sudden loss of consciousness or even seizures. And these are happening on a reasonably frequent basis. I think when we talk about the education, it's because this is kind of a classic rare disease there have not been treatments before for PBH. And I think as we find with many rare diseases, there are many unmet needs throughout the community. So we see it as really our job to make sure that we're educating the medical -- educating -- advocacy and people living with PBH and then hopefully, if avexitide is approved, educating them on the potential benefits of avexitide as well.

Very helpful. My second question is on PSP. I just want -- as we head into the interim data, I just want to confirm the efficacy bogey on the PSP rating scale that we should be looking for in the interim. Just given that the placebo group in many prior PSP trials declined by 10 or 11 points over 52 weeks, should we expect roughly half of that in placebo. Furthermore, sources say that the minimally clinically meaningful difference on the PSP rating scale over 6 months is around 6 points. So taken together, should we expect maybe a flat to a 1 point improvement in the drug-treated arm.

Sure. So maybe first on the efficacy bogey. So the study has about 80% power to detect a 30% effect on the PSP rating scale. And I'd say the PSP rating scales are primary endpoint, certainly going to be one of the main things we look at. But we do have other secondary endpoints and markers as well. So ultimately, our decision on the next steps for the program will be driven by all the data not just the PSPRS. I'd say PSP has only had so much work in terms of clinical meaningfulness. We have assembled some doctors and spoken to them as well. And we've heard everything from a single point difference could be clinically meaningful. We've heard differences such as 20-year 30% change. And I think it maybe bears in mind to discuss what is actually happening in this disease. This is a disease that often has survival of 6 years, sometimes even less. And during that time, these patients almost in a way, reminiscent of ALS become eventually walk in the progressive motor impairment, progressive walking impairment, both speech and swallowing difficulties. So the ability to make that go a meaningful percentage slower I think our view and certainly many of the KOLs we've spoken to would be highly meaningful. So I won't put a specific line on it. We're going to look at all the data as it comes. But maybe just remind, we're 80% powered to see a 30% effect.

Your next question comes from Marc Goodman of Leerink.

This is Basma on for Marc. We had a question on PBH regarding the prevalent population of 160,000 patients. Remind us again how many are seeking treatments. So this is basically a follow-up question the previous one. So are all of these patients, again, are symptomatic. And also, if you can provide any color on new incidents, so we know that like 200,000 to 300,000 surgery per year. Should we still assume that 8% of the surgery -- of the patient who undergo surgery, you will eventually develop PBH in like 3 to 4 years’ time frame? Or should we assume something else?

Yes. Thank you for the great questions on the PBH population. So starting with your first question on the $160,000, are those people seeking treatment. I'd actually say there's a larger group seeking treatment. And I can walk you through that. If you look at the number of people who have hypoglycemia following bariatric surgery in any form and any frequency it's as high as 30%, 40%, 50% of the population depending on the methodology you use. Now people with hypoglycemia following bariatric surgery are counseled to use medical nutrition therapy, sometimes off-label prescriptions like acarbose. So that, if you look at just even over the past decade of people, you're looking at a population of 0.5 million to 1 million people in that group. When we're talking about PBH, we're talking about the people who have tried those things and yet still have persistent hypoglycemia. That's how we get to about 8% or about 160,000 people. So this is pretty rare. We're talking single-digit percentage of people who get bariatric surgery and again, years to manifest but it's a single-digit percentage of a population of millions of people who have had bariatric surgery. So in terms of seeking treatment, as you might imagine, people who have such a debilitating condition where they're having sudden and from what they can tell, unexplained drops in blood glucose that leads to neuroglycopenia, which means the brains aren't functioning as they're supposed to, are certainly seeking medical attention. Back to the first answer, I think with rare disease, what often happens, if you don't have a treatment, then -- and hopefully, we can deliver one with avexitide then I think suddenly, you have options that weren't there before. And I think as we were able to do with ALS, access is certainly important, and education is very important as well. Your second question on should we continue to model 8% in the population. We certainly think so. I think as Camille mentioned, the new -- the 2023 numbers from the ASMBS on bariatric procedures came out, still well in 270,000 procedures in the year. And we know that with these upper GI surgeries, that there is a portion of people, again, single-digit percentage, but a portion of people who will develop persistent hypoglycemia. So we think that one of the major drivers of that is that the body seems to have a potential accelerated GLP-1 response. We think that's why a GLP-1 receptor antagonist makes a lot of sense in this condition. And we see that continuing. But again, I'd remind this is a single-digit percentage. So it's not everyone, but it's a very large population of people who are getting bariatric surgery.

And I'd just add one small other detail. What we've observed in the literature and talking to KOLs is usually PBH appears on 1 to 3 years following surgery. So it's possibly a little sooner than the 3 to 4 years you mentioned.

Got it. Thank you so much. That’s very helpful.

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

Good morning. This is Susan on for Tim Anderson. We're really looking forward to the upcoming HELIOS data next week. My question is on the ongoing discussions with the FDA on trial design. What are some of the remaining questions or debates that you guys are having with the FDA on trial design? And what are we expecting to learn from the 48-week data that will help inform one way or the other, some of the decisions that will need to be made on trial design.

Yes. Thank you for the question. This is Camille. We too are looking forward to presenting the week 48 data next week at the Endo Scientific Medical Meetings. And I'm going to answer your second question first, what to expect? I Ask you to recall the ISPAD data that were presented for the week 24 data for Wolfram in the Wolfram study last year, and now we have twice as much time for those participants in the study. So we will be looking at similar endpoints and change in and the C-peptide response to a mixed meal tolerance as well as other glycemic measures, such as hemoglobin A1c as well as visual acuity and overall global impressions have changed. So I invite you to look at those data and see how things have evolved over an additional 24 weeks, recalling that -- these are adults with this genetic disorder, and it is a neurodegenerative and beta cell degenerative disorder where progression is expected in these folks. Your first question was regarding the Phase 3 and the FDA. So we really do not go into the details of our interactions and discussions with the FDA. Having said that, for sure, the week 48 data will inform and is informing our Phase 3 program. And when we have additional information and alignment with the agency on the Phase 3 protocol, we expect to be able to share that information. Just to remind also, this is the very first clinical trial of agent to potentially impact Wolfram syndrome. So there's no template for the design of a trial in Wolfram syndrome. And so we're having those discussions with the FDA.

Our next question comes from Graig Suvannavejh with Mizuho.

This is Sam on for Greg. Maybe a couple on avexitide. First, will there be any kind of subgroup analysis within the study separating level of severity of PBH in terms of number of episodes and such? And then also assuming approval, do you anticipate any kind of step-up or restrictions from a payer perspective that would limit access based on either severity of the disease or type of surgery or anything like that?

Good questions. So I'd say maybe first, our kind of focus on the study is in the full study population, we are enrolling a population, all of which are required to be having during a run-in period. We have a 3-week run-in period. and people have to be having at least one Level 2 or Level 3 event per week. So we are enrolling a population that is having frequent events. So all of the patients we have will have that characteristic as well. In terms of step therapy, there are no currently approved therapies for PBH. So I would say we do not anticipate step therapy in this indication. And certainly, as we get closer to launch, we'll spend time interacting and educating payers. But we do believe we have a quite exciting and differentiated approach here. We have FDA breakthrough therapy designation, 5 prior trials showing differences in patients who are already trying the very best to reduce these symptoms. And we're still seeing those differences even in that context.

Yes. And I would say that access is very important to us if we believe if you have a treatment that can help people, you need to make sure that people can access it efficiently. So our team is already working on that. And I'd just remind for what I was saying earlier, that we're already talking about people who have been on medical nutrition therapy, which is really standard of care right now and yet still have these persistent hypoglycemic events, which are very, very debilitating. And I think that's important because it's -- we're talking about a population that really needs help. And from a physician and payer perspective, these are people who have to regularly seek medical attention for very dangerous events. So I think those will be very important messages as we do our market access education.

That’s helpful color. Thank you so much.

Your next question comes from Joe Beatty with Baird.

My question relates to avexitide. GLP-1 Antagonist seemed to have many favorable short-term and long-term health effects. So with that in mind, in that context, what gives you confidence that GLP-1 antagonist like avexitide won't cause some type of safety issue. And then I have a follow-up.

Sure. Great question. So one, we do have a good amount of safety data, both nonclinically and clinically on avexitide. And to date, avexitide has generally been well tolerated. So I'd say, first, empirically what we've seen is a good safety profile thus far. I'd also maybe add that avexitide is a competitive antagonist. So it's not running the GLP-1 receptor in reverse. It's attenuating the GLP-1 that you have endogenously. And so I'd add with that, we don't really see or we haven't seen weight gain, hyperglycemia, any other things you might think about in that context. So maybe I'd say that, overall, we've seen a good safety profile to date and just kind of highlighting as well, in the animal studies, we even dosed many fold above from a human equivalent dose perspective, many fold above what we're dosing in the human clinical trials. And even there, we don't see particular adverse events of concern.

Great. That makes sense. And then as a follow-up, How are you currently thinking about potential business development activities.

So I would say, one, we're very excited about our pipeline. We have major milestones across each of our 4 clinical trials over the next 12 to 15 months, which is very exciting. And each is in a disease where there is no treatment or substantially an adequate treatment. So we're very excited with the potential in each one of these programs. Our mission is to help people who have unmet medical needs. And so with that, we're always making sure that we stay on top of what's promising. But our focus right now, as I was mentioning in my remarks, is really on execution because we have some very exciting milestones ahead.

Your last question comes from Ananda Ghosh of H.C. Wainwright & Company. Please go ahead.

Congrats on the quarter. Maybe one question with respect to the ALS trial. Given the importance of NfL in this trial and especially with the preclinical data showing the effect of knocking down CAPN2. Can you remind me if the inclusion criteria for the trial, like during the inclusion criteria of the trial, did you consider the initial levels of the ALS patients, which might be higher compared to the natural history? Or how did you think about the trial given the focus on NfL.

Yes. Ananda, that's a great question. It's actually something we discussed a lot as we were planning and designing the study as well. We do not have an inclusion criterion that requires particularly high NfL levels going into the trial. I think a couple of things went into that. One, just to put context on it as well. In the CSF and ALS, NfL levels are often 10x as high as normal, and it's quite a stark separation as well. So you can generally expect an ALS that particularly when you're measuring CSF, you're going to see pretty high levels. And then additionally, given that this is our first in human with the drug, we didn't want to over subset and potentially miss populations or signal that could be quite important. So we definitely will be looking at that, looking at those patients who maybe come in with higher as compared to lower neurofilament, but we didn't want to exclude them from the trial in the initial trial.

Got it. Makes sense. Thanks.

We still have one question from Dan Akschuti of Pareto Securities.

Thank you for taking. Congrats on the progress. I'm excited for the HELIOS readout next week. Just a more general question, how you compare it of avexitide to other drugs that could enter the space that are more inhibiting insulin and GLP-1 secretion like somatostatin analogs and how you see the placebo response with in post-bariatric hypoglycemia for the Phase 3?

Yes. Good questions. So maybe first, I'd remind, we're in Phase 3 with avexitide. We have breakthrough therapy designation built on 5 prior successful trials. So we think the profile of avexitide is quite strong, both in terms of what we've seen thus far in terms of safety and efficacy. I think any other programs in the space are quite a bit earlier and have a number of hurdles I would say, to overcome. And so we're focused on exited at this time and do believe that has the best profile we've seen thus far.

Yes. And I'd just reiterate, too, the reason that avexitide was granted FDA breakthrough therapy designation is because PBH has a high unmet need and because of the promising data from Phase 2 breakthrough therapy means benefit over existing treatments. And of course, right now, there are no existing treatments or approved treatments for PBH. So we're very excited about the potential, and that's why we're focused on rigorous execution in this study.

Yes. And I realized you also asked about placebo rate. So in the Phase 2 study, there was a placebo period as well, and we did not see a meaningful difference between the run-in and the placebo. So I'd say empirically, we haven't really seen much of a placebo effect in this indication. That being said, when we did the powering analysis for the study, we certainly thought about that, and we do believe our power is robust that even if there is some degree of placebo in fact, we should have enough power regardless in the study.

Yes. And this is Camille. I would just also comment that these individuals have tried and are trying everything to manage this very debilitating condition. And that really isn't going to change whether they're in a clinical trial or not. So their daily life will not be changing because of being in a clinical trial.

There is no question 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 Lindsay. We hope you have a great rest of your day.

[Operator Closing Remarks]