AMLX - NASDAQ

Good morning. My name is Jenny, and I will be your conference operator today. At this time, I would like to welcome everyone to the Amylyx Pharmaceuticals' Fourth Quarter and Full Year 2024 Earnings Conference Call. [Operator Instructions] 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, Head, Investor Relations and Communications. Please proceed.

Good morning, and thank you all for joining us today to discuss our fourth quarter and full year 2024 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's provision of the Private Securities Litigation Reform Act of 1995. These statements include, but are not limited to, our expectation 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 for joining us. As we look to 2025 and 2026, we're entering a pivotal stage for Amylyx with key milestones across 3 assets in 4 ongoing clinical trials, all targeting orphan diseases with few or no treatment options. We are excited to have started the pivotal study of avexitide for the treatment of post-bariatric hypoglycemia and anticipate top line results in the first half of next year. We also recently completed a financing, raising approximately $65.5 million to begin commercial preparations for avexitide and to extend our cash runway through the end of 2026. Over the next 12 to 15 months, we are focused on execution as we look forward to 3 key data readouts. Our lead asset, avexitide, is an investigational GLP-1 receptor antagonist with FDA breakthrough therapy designation in post-bariatric hypoglycemia or PBH, as well as orphan drug designation. PBH is a debilitating condition that leads to persistent and often progressive hypoglycemia. There are no treatments approved for the approximately 160,000 people living with PBH in the U.S. today. Avexitide has already been studied in 5 clinical trials of PBH that showed consistent dose-dependent, statistically significant reductions in hypoglycemia. We started recruiting LUCIDITY, our pivotal 16-week Phase III clinical trial in mid-February and expect that the first study participant will be dosed in March or April. We expect to complete recruitment of the approximately 75 participants by the end of this year and anticipate top line data in the first half of 2026. Next in our pipeline is AMX0035, a combination small molecule that is designed to target endoplasmic reticulum or ER stress and mitochondrial dysfunction. AMX0035 is currently being evaluated in Wolfram syndrome and progressive supranuclear palsy, or PSP, 2 diseases characterized by ER stress and mitochondrial dysfunction. Wolfram syndrome is a rare, fatal, monogenic, progressive diabetic and neurodegenerative disease, affecting an estimated 3,000 people in the U.S. There are no approved treatments. Like many child that onset monogenic diseases, the pathophysiology of Wolfram syndrome is well characterized. Our program is focused on people who carry mutations in the WFS1 gene, which encodes a protein called wolframin, that spans the membrane of the endoplasmic reticulum. These mutations in wolframin directly cause ER stress and mitochondrial dysfunction. Last year, we reported our first clinical data in people with Wolfram syndrome. In our 12-person Phase II open-label HELIOS study, participants showed improvement or stabilization across all measured outcomes. We are continuing to follow participants in the ongoing HELIOS trial and expect to share the week 48 data in the coming months. These data, along with regulatory interactions will inform the design of a Phase III trial. We are also anticipating an interim readout of our Phase IIb/III ORION trial, evaluating AMX0035 in PSP in the third quarter 2025. PSP is a rare progressive fatal neurodegenerative disease that affects an estimated 23,000 people in the U.S. at any one time and has no currently approved treatments. PSP is the most well-characterized pure tauopathy because all people with PSP have tau protein buildup in the brain. Genetics and model systems show that this abnormal tau buildup causes the characteristic brain degeneration and clinical presentation observed in the disease. AMX0035 previously demonstrated that it reduced tau measured in the cerebrospinal fluid of people with Alzheimer's disease. We believe AMX0035 is the first brain and cell penetrant agent that has previously shown significant tau protein reduction in CSF to be tested in PSP. The Phase IIb portion of our Phase IIb/III ORION trial evaluating AMX0035 in PSP was fully enrolled in January with a total of 139 participants randomized. We expect safety and efficacy data from an unblinded interim analysis in the third quarter of this year. These data will inform our decision whether or not to move into the Phase III portion of the trial. Powering analyses published in the PSP literature estimate approximately 80% power to detect a 30% slowing the rate of decline of PSPRS with the sample size. Our fourth clinical program is evaluating AMX0114 for the treatment of ALS. AMX0114 is an antisense oligonucleotide that knocks down calpain-2, one of the key proteases driving axonal degeneration. Last month, the Phase I multiple ascending dose LUMINA trial of AMX [Technical Difficulty] recruiting in Canada. We are working diligently to open additional sites in Canada and the U.S. We started recruiting LUMINA and expect the first participant dosed in March or April. We look forward to early cohort data from our Phase I LUMINA trial expected later this year. We are also actively working to build our pipeline in PBH and other rare diseases that may benefit from GLP-1 antagonism. Of particular note, at the end of last year, we announced a collaboration to develop a novel long-acting GLP-1 receptor antagonist with Gubra. Gubra is an industry leader in peptide-based drug discovery. We will continue to focus on clinical execution as we look forward to milestones in each of our programs over the next 12 to 15 months. I will now pass to Camille to speak further on our Phase III LUCIDITY clinical trial of avexitide in PBH.

Thanks, Justin. We are very excited about the potential of avexitide to become the first approved treatment for people living with PBH. This debilitating condition is believed to result from an excessive GLP-1 response following bariatric surgery, leading to persistent, recurrent and debilitating hypoglycemic events that take a profound toll on a person's quality of life. There are no approved treatments for PBH. Despite dietary modifications and rescue measures such as glucagon, people with PBH still experience persistent symptoms with no sustainable management options. And a potential first-in-class GLP-1 receptor antagonist, avexitide is designed to bind to the GLP-1 receptor on pancreatic islet beta cells and inhibit the effects of excessive GLP-1 and PBH, mitigating hypoglycemia by decreasing insulin secretion and stabilizing blood glucose levels. In December 2024, we presented the design of our pivotal Phase III LUCIDITY clinical trial, evaluating avexitide in participants with PBH following Roux-en-Y gastric bypass surgery. In February of this year, we started recruiting LUCIDITY and expect to dose the first participant in March or April. The Phase III study is designed to have similar inclusion and exclusion criteria to the previous successful Phase II PREVENT trial that led to breakthrough therapy status and the subsequent Phase IIb trial of avexitide in PBH. LUCIDITY will evaluate the FDA agreed-upon primary outcome of reduction in the composite of Level 2 and Level 3 hypoglycemic events. We believe there are many contributing factors for overall optimism for the study. We are encouraged by the engagement of the sites as they are activated as well as the responsiveness of potential participants. The study team is fully engaged with the carefully chosen sites as they provide comprehensive training materials and facilitate site activation. Furthermore, the study has a number of blinded touch points and monitoring elements that will serve to support the study site staff and by extension, the participants throughout the study. The strength of the substantial clinical data generated to date for avexitide underpins our confidence in the potential of this program. Across 5 clinical trials of avexitide in people with PBH, there have been consistent dose-dependent effects that we believe support its potential to become the first approved treatment option for PBH. In multiple early-stage trials in PBH and in healthy volunteers, avexitide had a clear pharmacodynamic effect. Avexitide showed a rapid statistically significant decrease in post-meal insulin levels and stabilization in plasma glucose nadir. Data from 2 Phase II trials of avexitide demonstrated statistically significant and clinically meaningful reductions in hypoglycemic events and improvements in glucose control in PBH following Roux-en-Y gastric bypass surgery. In the Phase IIb trial, participants received 90 milligrams once daily of avexitide, the dose we are evaluating in our pivotal Phase III LUCIDITY trial. Most notably, treatment with 90 milligrams of avexitide led to a statistically significant reduction in hypoglycemic events, specifically a 53% reduction in Level 2 events with a p value of 0.004, a 66% reduction in Level 3 events with a p value of 0.0003. 90 milligrams once daily of avexitide also has demonstrated a favorable pharmacokinetic profile, maintaining exposure in the therapeutic range through 24 hours, supporting daily dosing. This property translated to a similar meaningful improvement in nadir glucose levels as measured by CGM, both during the day and overnight. Avexitide was generally well tolerated with a favorable safety profile replicated across the clinical trial. In summary, we are executing this important Phase III trial supported by compelling and consistent avexitide data and a dedicated study team. I will now turn over the call to Jim. Jim?

Thanks, Camille. We ended 2024 in a solid cash position of $176.5 million, which does not include the approximately $65.5 million in net proceeds from our public offering, which closed on January 13, 2025. With these resources, we expect our cash runway to take us through 2026. Now turning to the financial results for the quarter. Total operating expenses for Q4 were $39.9 million, down 62% from the same period in 2023. Research and development expenses were $22.9 million compared to $44.9 million in Q4 2023, primarily due to a decrease in spending on AMX0035 for the treatment of ALS, payroll and personnel-related costs and a decrease in preclinical development activities. Selling, general and administrative expenses were $17.1 million compared to $52.2 million in Q4 2023, primarily due to a decrease in payroll and personnel-related costs and a decrease in consulting and professional services. During the quarter, our ongoing operating expenses used roughly $27 million in cash. In addition, we used roughly $31 million in cash for previously recognized items related to our voluntary discontinuation of RELYVRIO/ALBRIO

Thank you, Jim. We are entering this year with strong momentum. We are focused on executing our clinical trials and making meaningful progress on preparing for a potential commercial launch of a GLP-1 receptor antagonist. At the start of the year, we appointed Dan Monahan as Chief Commercial Officer. Dan is leading our commercialization strategy across our portfolio, beginning with avexitide. He brings more than 2 decades of commercial leadership experience, launching industry-leading medicines at Otsuka, Novartis and Sanofi. With a proven commercial and medical team in place, we believe we are well positioned for a potential [ first-to-market launch ] of avexitide in PBH. We estimate based on our projections from published literature and claims-based work that there are about 160,000 people in the United States who are living with PBH today, who have persistent symptoms despite dietary modifications and who face a significant unmet need. There is a new slide with these details in our updated corporate deck. PBH is rare. The condition doesn't happen to most of the millions of people who undergo bariatric surgery and PBH does not present immediately. On average, symptoms appear approximately 1 to 3 years following bariatric surgery. Once people have PBH, the condition is chronic, debilitating and often progressive. It can mean loss of work, inability to drive and a state of disability. Bariatric surgery remains standard of care for addressing obesity, particularly for people who require significant and sustained weight loss, meaning the unmet need in PBH is only expected to continue to grow. We are preparing diligently ahead of the Avexitide Phase III top line data expected in the first half of next year. And if approved, we anticipate commercial launch in 2027. In addition to avexitide in PBH, we have exciting milestones ahead this year that have the potential to make a meaningful positive impact on the other communities that we aim to serve. For AMX0035 in PSP, we expect top line data from an unblinded interim analysis of the Phase IIb portion of the ORION trial in the third quarter of this year. For AMX0035 in Wolfram syndrome, we are continuing to follow participants in the ongoing Phase II HELIOS trial and expect to share week 48 data in the coming months. These data, along with regulatory interactions will inform the design of a Phase III trial. And we expect early cohort data from our Phase I LUMINA-ALS trial in 2025. We appreciate your continued support and look forward to keeping you updated on our progress toward developing novel therapies for people living with serious and fatal neurodegenerative diseases and endocrine conditions. Now I would like to open the call up for questions.

[Operator Instructions] Your first question is from Michael DiFiore from Evercore ISI.

Congrats on the progress. Two for me. One on the PBH Phase III. Why limit the entry criteria to just Roux-en-Y gastric bypass procedures and not include sleeve gastrectomy, especially when considering the greater prevalence of sleeve procedures? And my follow-up is on the PSP ORION study. Could you remind us how efficacy will be interpreted in this study across regions given the use of the 10-item PSP rating scale in the U.S. as a primary and the 28-item PSP rating scale in ex-U.S. jurisdictions?

Yes. Mike, this is Camille. Thank you for the question. With regard to Roux-en-Y in our LUCIDITY trial, we have the most experience with avexitide in people who've experienced Roux-en-Y and then develop PBH. Having said that, we recognize that the pathophysiology is consistent across bariatric surgeries. To minimize heterogeneity, though, we are limiting the enrollment to Roux-en-Y gastric bypass and expect later for avexitide to be available for people with PBH generally.

Yes. And just going to the market dynamics as well. So I think first, just underscoring Camille's point that we think that pathophysiology is the same is really for trial criteria. So we'll have those discussions when appropriate with FDA. But Roux-en-Y gastric bypass, there have been about 600,000 people who've gotten Roux-en-Y gastric bypass over the past 10 years. And there are roughly 60,000 people each year who get a Roux-en-Y gastric bypass. So with 8%, we estimate about of people who get a bariatric procedure who get -- who will develop PBH in the years following surgery, that's still a very substantial market. But to say as well, we think the pathophysiology is the same. So our ultimate intention is we think that this should be a treatment that would be used for PBH period.

Yes. And on your question on PSP, about the 10-item versus the 28-item. So different regulators in different regions are interested in different ways of analyzing the PSP rating scale, as you mentioned. Our experience, however, is that these are pretty consistent. It's not a big divergence to kind of look at the PSP 10-item versus the PSP 28-item. So frankly, in the study, we'll be looking at both. But again, we expect the results from both to be very similar.

Your next question is from Tim Anderson from Bank of America.

This is Susan on for Tim Anderson. Two questions from us. The first one, what is the target profile that you guys are looking to achieve with the long-acting GLP-1? And if you can, how does this profile compare to other long-acting GLP-1s like Amgen's MariTide and Metsera's MET-097i?

Yes. So maybe I'll take those in reverse, actually. So this is a GLP-1 antagonist. Those are GLP-1 agonists. So to date, avexitide is the only GLP-1 antagonist that has consistently shown reductions in insulin, raising the glucose nadir, reductions in hypoglycemia in people with PBH. And we think that a GLP-1 antagonist may have not just application in people with PBH, but potentially other diseases as well that are either characterized or accelerated by hyperinsulinemic hypoglycemia. Because we're quite excited about the mechanism, we think it makes sense to invest for the future. So that's why we started the research partnership with Gubra to develop a potential long-acting GLP-1 antagonist. But we also think avexitide has great potential. So we really see this as investing for the future.

And just one more. So on your PBH market sizing, how are you guys forecasting future patient numbers? I guess I'm just trying to understand, I think the market will shrink, right, over time, given current use of GLP-1s, which would mean that fewer patients probably get bariatric surgery. And of course, bariatric surgery is a once and done type of procedure.

Yes. So maybe a couple of things. So first, our information actually is that the market will continue to grow. And maybe breaking that down. So first, bariatric surgery started becoming common in the United States in the early 2000s. And it's typically done in some -- to folks who are generally in the early 40s. So the population who've had bariatric surgery in the U.S. today are generally in their 40s or 50s. PBH is chronic. Once people have PBH, they generally have it for the rest of their life. So all of those folks who have had bariatric surgery and now have PBH will have it for multiple upcoming decades. Then talking about kind of the ongoing bariatric surgeries. One, in talking to physicians and bariatric surgeons, we do hear that there continues to be significant demand for bariatric surgeries. And a lot of people describe that there is a differentiation, that the bariatric surgery is often used for those who are looking for very significant deep weight loss, in some cases, looking for over 100 pounds of weight loss, whereas they might use the GLP-1 in cases that maybe are less significant in terms of total weight loss. So one, we hear that this continues to be quite in demand, which will continue to grow that pool that already exists today and will have it for the rest of their lives.

Yes. And just underscoring that last point. So we estimate there are 160,000 people with post-bariatric hypoglycemia today. PBH does not go away. For example, we're working with someone who's had PBH for 18 years. So PBH is persistent, it doesn't go away. So the market will only continue to grow, not shrink.

Your next question is from Joel Beatty from Baird.

For the Wolfram syndrome trial, could you discuss what you're looking for in the week 48 data that will help inform regulatory interactions? And then for avexitide, can you discuss the potential to develop that agent for other indications beyond PBH?

Thank you, Joel. This is Camille. Yes, as we described in October of last year, the week 24 data and some individuals out to week 36 and week 48, we saw improvements in C-peptide response to a mixed meal, which is indicative of improved beta cell function, which is uncharacteristic for a disease that is neurodegenerative and beta cell degenerative. All other hypoglycemic control measures also moved in the same direction. And we are anticipating and looking forward to the possibility that at week 48 we'll see continued sustained improvements in all those measures, in addition to which the visual acuity, an indication of retinal ganglia cell health, we expect that -- and look forward to the possibility of seeing stabilization or improvement in visual acuity as well. Recall that these individuals are adults having lived with this genetic disorder all their lives. So we're looking forward to that possibility. And that should also provide the FDA with continued confidence in the potential of AMX0035 for people living with Wolfram who have nothing at this time to treat their condition.

And then speaking to avexitide and other indications. So first, I'll say, PBH is already a large and exciting area and a significant unmet need. So certainly, our first focus is in PBH. We do believe, though, that there are multiple other indications where the mechanism of a GLP-1 antagonist could be important, including diseases of hyperinsulinemic hypoglycemia and potentially diseases where other elements of the GLP-1 pathway may be helpful. But again, our focus for right now is on PBH.

[Operator Instructions] Your next question is from Marc Goodman from Leerink.

This is Madhu on the line for Marc. We've heard from some physicians that there are some patients who exhibit PBH without the postprandial hyperinsulinism. So we're curious if you're screening for patients who specifically show a spike in insulin levels post meal. Has your research shown like a specific proportion of patients who show this in PBH? And then also, how should we be thinking of the pricing for avexitide? We know it's early, but just wanted to get like a ballpark idea.

Sure. So maybe starting with the postprandial hyperinsulinism. So one, I think we have generally seen the hyperinsulinism going through at least our review of the literature, you see that across quite a number of studies and quite a number of patients. But I think also important to note, our inclusion/exclusion criteria are very similar, nearly identical to what was used in Phase II and Phase IIb, where we saw large effect size and high statistical significance. So we think we're well positioned for that as we go into the Phase III study. Then on the pricing side, of course, too early to give anything definitive on pricing quite yet before we have our data. But I'd encourage you to look at other orphan analogs. This is an orphan drug. And additionally, of course, the efficacy will drive things. And I do think it is quite an impact in people's lives to bring their glucose control to a much more normal measure. These patients do describe being in kind of an ongoing state of disability and being able to bring that back more near towards normal would be a huge change for these individuals.

Yes. And just going back to the first question as well. So -- and just to talk through the pharmacology a little bit. So hypoglycemia can happen certainly as -- after a meal, postprandial. But it can happen at any time, it can happen for a variety of different triggers. That's very true. We think that's why it's important that you want to have a molecule that can protect against these hypoglycemic events throughout the day. And so with 90 mg once daily dosing, we are in the therapeutic range for 24 hours, so preventing those hypoglycemic events for the full day with daily dosing. With PBH though, what we know from a pharmacology perspective is the reason for these very precipitous blood glucose drops is because there's a very strong insulin response that seems to be due to a very strong endogenous GLP-1 response. So GLP-1 levels can be up to 10x normal in people with PBH. That causes very significant insulin secretion, which then lowers glucose very precipitously. And that's why, of course, the GLP-1 antagonist makes a lot of sense for this indication.

There are no further questions at this time. I will now turn the call back to Mr. Klee.

Thank you, operator, and thank you all for your time. We look forward to seeing many of you in the coming weeks and months. If you have any follow-up questions, please reach out to Lindsey. I hope you have a great rest of your day.