Earnings Call Transcript - AMLX Q3 2025

Operator, Operator

Good morning. My name is Carly, and I will be your conference operator today. At this time, I would like to welcome everyone to the Amylyx Pharmaceuticals third quarter earnings conference call. 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.

Lindsey Allen, Vice President, Investor Relations and Communications

Good morning, and thank you all for joining us today to discuss our third quarter 2025 financial results and business update. With me on the call today are Josh Cohen and Justin Klee, our Co-CEOs; Dr. Camille Bedrosian, our Chief Medical Officer; and Jim Frates, our Chief Financial Officer. Before we begin, I would like to remind everyone that any statements we make or information presented on this call that are not historical facts are forward-looking statements that are based on our current beliefs, plans and expectations, and are made pursuant to the safe harbor provisions of the Private Securities Litigation Reform Act of 1995. These statements include, but are not limited to, our expectations with respect to avexitide, AMX0035 and AMX0114, statements regarding other development candidates, 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.

Justin Klee, Co-CEO

Good morning, everyone, and thank you for joining us. Q3 was a quarter of progress as we continue to focus on our lead program, avexitide, in post-bariatric hypoglycemia or PBH. Avexitide is our investigational first-in-class inhibitor of GLP-1 receptor activity with FDA breakthrough therapy designation. PBH is a condition characterized by recurrent hypoglycemic events, which can impose a significant and lasting burden on a person's quality of life. There is a robust body of data generated to date for avexitide, which includes 5 clinical trials, demonstrating statistically significant and clinically meaningful reductions in hypoglycemic events. Based on those results, we designed our pivotal Phase III LUCIDITY trial with the goal of replication. We remain focused on enrolling a similar patient population, collecting the data in a similar way and executing LUCIDITY with high quality. We continue to see high participant interest and broad engagement across clinical trial sites, which we believe supports the urgent need for an FDA-approved treatment. Our previous guidance for completion of recruitment was by the end of 2025, with top line data in the first half of next year. Based on our most recent projections, we now expect to complete recruitment in Q1 2026, with top line data expected in Q3 2026. We anticipated more of a ramp in the enrollment rate at this stage, but we have seen more of a steady enrollment rate in the last few weeks. Timing for potential launch remains unchanged. With early NDA preparation efforts underway, we continue to expect to be in a position to launch avexitide in 2027, pending FDA approval. Having launched a commercial product in the past, we're focused on key areas required for a successful launch. We are already laying the groundwork to be ready in 2027, if approved. We've been taking the initial steps towards building the medical affairs and commercial organizations with targeted investments in market research, insights, disease education, market access strategy, and commercial infrastructure. Our continued market research, claims analysis and engagement in the field support our confidence in our estimate of 160,000 people with PBH in the U.S., and bolsters our understanding of the unmet need. Turning to our broader pipeline. In Wolfram syndrome, we are advancing the clinical development of AMX0035, and pending alignment with FDA, we plan to initiate a focused pivotal Phase III trial in the second half of 2026. For AMX0114, our investigational antisense oligonucleotide targeting Calpain-2 in ALS, we are pleased to share that in September, we fully enrolled Cohort 1 in the Phase I LUMINA trial. We anticipate early cohort data later this year and plan to share the safety data at the 36th International Symposium on ALS and MMD, which is being held from December 5 to December 7. Based on biomarker collection and analysis time lines, we anticipate biomarker data will be available in the coming months and expect to present these at a medical meeting in the first half of 2026. We are excited by the potential of this novel mechanism and the fast track designation from the FDA. Across all of our programs, our team is focused on execution as we head toward a pivotal year in 2026 with top line data from LUCIDITY anticipated next year. Now I'll turn the call over to Camille.

Camille Bedrosian, Chief Medical Officer

Thank you, Justin. As a reminder, PBH is a serious, persistent and life-altering condition with no FDA-approved therapy. People living with PBH often experience frequent unpredictable hypoglycemic events, driven by an exaggerated GLP-1 response that can severely limit their independence and quality of life. Many people with PBH live with a constant anxiety around meals, social interactions, and basic daily activities. Individuals with these experiences are not outliers. They reflect a broader underserved population that motivate our work. Avexitide is an inhibitor of GLP-1 receptor activity that reduces insulin secretion and stabilizes blood glucose levels. Based on the data and consistency from our 5 previous trials in PBH, we designed the pivotal Phase III LUCIDITY trial to optimize the potential for success by being as consistent as possible with the previous Phase II trials. Specifically, these studies directly informed the dose, endpoints, inclusion criteria, and surgical subtypes. LUCIDITY is evaluating avexitide 90 milligrams once daily in individuals with PBH following Roux-en-Y gastric bypass surgery. The FDA agreed upon primary endpoint is reduction in the composite rate of Level 2 and Level 3 hypoglycemic events through week 16. Based on prior Phase II data, we believe the trial is well powered to detect clinically meaningful benefit. We continue to be encouraged by the execution of the trial that prioritizes scientific rigor and operational excellence. All clinical trial sites are now activated and screening participants. There is high participant interest and engagement across our sites. In addition, investigators continue to report that participants are highly motivated to contribute to the study. Furthermore, participants have begun to move into the open-label extension portion of the trial. As awareness of PBH continues to grow, we are seeing increased recognition of the burden and the urgent need for a treatment option. We believe avexitide, which has been granted FDA breakthrough therapy designation, has the potential to be the first approved therapy for PBH and to meaningfully improve the lives of those affected. With that, I'll turn over the call to Jim to review our financials. Jim?

James Frates, Chief Financial Officer

Thanks, Camille. Our financial position is strong as we focus on careful execution of LUCIDITY and preparing the company for a launch in 2027, should avexitide be approved by the FDA. We ended the third quarter with a strong cash position of $344 million compared to $181 million at the end of the second quarter. This reflects the recent completion of our public offering in early September. This financing provided approximately $191 million of net proceeds; and together with our existing cash, positions us to support the potential launch of avexitide in 2027 and provides us with an anticipated cash runway into 2028. Turning now to our results for the quarter. Total operating expenses for the quarter were $36 million, down 53% from the same period in 2024. The decrease is primarily due to the one-time expenses related to the acquisition of avexitide that we incurred in the third quarter of last year. Research and development expenses were $19.9 million compared to $21.2 million in Q3 2024. This decrease was primarily due to decreases in spending on AMX0035 for the treatment of PSP and ALS. The decrease was offset by increased spending related to the clinical development of avexitide in PBH. Selling, general and administrative expenses were $16.2 million compared to $17.8 million in Q3 2024. This decrease was primarily due to a decrease in consulting, professional services and other expenses. We recognized $7.1 million of noncash stock-based compensation expense for the quarter compared to $6.8 million of noncash stock-based compensation expense in Q3 2024. In summary, the more work we do, the more we learn about the patients and providers, the more we believe that there is a major unmet need for people living with PBH. The key for us operationally is to execute the LUCIDITY study well and prepare for a positive outcome. We believe we have the scientific, operational, and financial resources we need to execute on our goals. With that, I'll turn the call over to Josh.

Joshua Cohen, Co-CEO

Thanks, Jim. Our conviction in inhibiting the GLP-1 receptor as a therapeutic approach remains strong. While LUCIDITY remains our primary focus, we also view it as a starting point, both for avexitide and for advancing research into GLP-1 receptor antagonism more broadly. For instance, our research collaboration with Gubra continues to show encouraging proof-of-concept data with new molecules demonstrating strong potency in vitro and in vivo, along with extended half-lives. We are very pleased with how the partnership is progressing to develop a novel long-acting GLP-1 receptor antagonist. We expect to make a decision on a potential development candidate in the next few months, and pending a candidate nomination, we are preparing to initiate our IND-enabling studies. Before we open the call up for Q&A, I would like to reflect on the urgent opportunity driving our work in post-bariatric hypoglycemia. PBH affects an estimated 8% of people in the U.S. who have undergone the two most common types of bariatric surgery: sleeve gastrectomy and Roux-en-Y gastric bypass. That translates to approximately 160,000 individuals living with PBH, many of whom experience frequent unpredictable hypoglycemic events that disrupt daily life and limit independence. Multiple lines of evidence support our belief in the significant unmet need in this market, including several robust published prospective and retrospective studies, and our ongoing claims-based work. Most compelling is what we are hearing directly from the field, which has continued to corroborate the substantial burden in PBH. We continue to be excited by the data generated to date in the 5 clinical trials of avexitide in PBH. These findings, together with new analyses we shared last quarter at ENDO 2025, reinforce the robust body of evidence and give us confidence as we advance LUCIDITY towards top-line results next year. We are committed to executing LUCIDITY and preparing to be launch-ready, following FDA approval, and we look forward to keeping you updated. Now I would like to open the call up for questions.

Operator, Operator

Your first question comes from Seamus Fernandez with Guggenheim.

Seamus Fernandez, Analyst

I wanted to just get a quick sense of the enrollment update. With regard to a couple of things, as we've been speaking with physicians, there were a couple of dynamics in play here. One was the very careful decisions on the part of the company to ensure that there is a broad enough participation from a wide enough array of sites that it would take some time to basically start up those sites. So just trying to get a better sense of the impact here. Is it site start-up that has resulted in the estimated modest delay of a quarter? Is it the run-in period that is potentially impacting the enrollment? Because, again, a 3-week with the requirements for Level 3 events, I could envision having an impact on enrollment just given the careful design there. And then another factor would be just ensuring that the patients that are enrolled are actually fully dedicated and committed to limiting any potential changes in diet over the 16-week period that could negatively impact the study. So just wanted to get a better sense of some of the operational dynamics that could be coming into play as it relates to the study. Then just a very quick follow-up on the Gubra comments. The DC development candidate selection to IND, can you just give us a sense of the timeline that might come into play there?

Justin Klee, Co-CEO

Thank you, Seamus, for your questions and insights on operations. At a high level, we are pleased with the execution and progress of the study. The first participants are starting the open-label extension. Your concerns about quality, participant enrollment, and data collection are crucial, especially given the five previous trials of avexitide in PBH that showed significant reductions in hypoglycemic events. The update on the timeline reflects our latest enrollment projections. From my experience in trials, once all sites are operational, we often see an increase in the enrollment rate. While we are still seeing steady enrollment so far, we are updating our projections to estimate that recruitment will wrap up in the first quarter. I appreciate your emphasis on operational quality, which is also our team's priority, and we are satisfied with their focus.

Joshua Cohen, Co-CEO

Maybe just touching on your other questions, too. Included in that quality, certainly, is maintaining the dietary guidance throughout the whole trial. So just as a reminder, at every clinic visit, patients do receive dietary guidance. And the goal of that is to keep everybody following closely with the recommended PBH diet. And we have heard that patients are quite engaged, quite excited to participate in the study and wanting to follow the protocol as best as they possibly can. You also asked about the drug candidate nomination from Gubra, and a sense of the timeline. So first, I'll say we've been quite excited about the data from Gubra. We've seen really encouraging data both in vitro and in vivo, both on kind of efficacy outcomes as well as outcomes related to half-life and kind of the duration of the drug. We'll probably give more granularity on timeline as we do nominate or as we get to the point of making the decision to nominate a drug candidate. But certainly, our goal will be to move as expeditiously as we possibly can.

Operator, Operator

Your next question comes from Joseph Thome with TD Cowen.

Joseph Thome, Analyst

Maybe the first one, just on the Phase III study. Do you have a general idea of how long patients have trialed dietary therapy and still are not able to respond to that before entering the study? And maybe related to that, what's your kind of current screen failure rate for patients maybe not meeting the necessary events in the observation period? A follow-up if I can, on the ALS program. Can you just clarify a little bit what you're going to present later this year? Will you have early biomarker data from that first cohort already in this presentation? Or are you going to present all the biomarker data next year when you have a larger set?

Joshua Cohen, Co-CEO

Sure. While we are currently running a trial, we typically do not share interim data or updates. However, looking at previous studies with avexitide, it is common for participants to have experienced PBH for 6 to 8 years. The standard treatment for PBH is generally dietary therapy, so we expect that most, if not all, patients will have been on this therapy for several years before participating. Additionally, we require that any bariatric surgery occurred at least a year before entering the study, meaning all participants have undergone this surgery well in the past. Regarding screen fail rates, we also do not disclose interim data during the study. However, as Justin mentioned, our objective is to recruit suitable patients and maintain a focus on quality, ensuring that patients have the right level of severity and are likely to complete the study. As for the AMX0114 presentation in early December, it will concentrate on safety at this time. We anticipate sharing biomarker data in the first half of next year at a medical conference, as this work takes longer to complete.

Operator, Operator

Your next question comes from Geoff Meacham with Citi.

Unknown Analyst, Analyst

It's Ross on for Jeff. We are curious about your sense of PBH and kind of the addressable market; and how has that continued to evolve?

Justin Klee, Co-CEO

Thank you. As we have increased our commercial preparations, our confidence in the unmet need in the market has grown. We have conducted multiple claims-based analyses, and there has also been independent research from Stanford assessing the total population. Our estimates suggest that approximately 160,000 people currently have PBH, and we anticipate that number will rise. Bariatric surgery rates remain significant, indicating that the population with this condition is likely to expand due to the substantial unmet need. Furthermore, our interactions in the field have highlighted the severe hypoglycemia associated with PBH, characterized by frequent Level 2 and Level 3 events. According to the American Diabetes Association, a single occurrence of severe hypoglycemia is considered a medical emergency, and many individuals with PBH experience these events regularly. Clinics express concern for their patients, as they have limited options for support and these hypoglycemic episodes can arise unexpectedly and frequently. Our research continues to strengthen our confidence in the unmet need and the opportunity we have with avexitide.

Operator, Operator

Your next question comes from Corinne Johnson with Goldman Sachs.

Kevin Strang, Analyst

This is Kevin on for Corinne. Just wanted to follow up on the addressable market question in terms of the 160,000 PBH patients. As you do more work on that, what percentage of those patients do you think would be uncontrolled on diet? And what percentage of those patients do you think would be eligible for your Phase III?

Joshua Cohen, Co-CEO

Good question. To begin with, regarding those uncontrolled on diet, the estimate of 160,000 is based on various published data and insights from physicians treating post-bariatric hypoglycemia (PBH). We aimed to exclude individuals who are managed through diet. Therefore, this estimate refers to those who are not diet-controlled and are facing significant and clinically concerning hypoglycemic events. We haven't specifically analyzed the 160,000 for direct eligibility for the Phase III trial, but we interpret this group as individuals experiencing what Dr. Colleen Craig from Stanford describes as medically significant PBH, which notably affects their daily lives. As Justin mentioned, even one serious hypoglycemic event is a medical emergency, indicating these patients frequently experience such emergencies.

Justin Klee, Co-CEO

We believe that PBH occurs because the body significantly increases the production and secretion of GLP-1, leading to levels that can be up to 10 times higher than normal. This increase in GLP-1 is the reason we hear from both clinics and patients that, regardless of their efforts, they continue to experience drops in blood glucose. With such elevated GLP-1 levels, their blood glucose is likely to decrease substantially. This is also why we think avexitide could be very effective, as we believe that addressing the GLP-1 surge is essential to tackling the root cause of PBH, which ultimately results in hypoglycemia.

Operator, Operator

Your next question comes from Marc Goodman with Leerink Partners.

Marc Goodman, Analyst

Just to revisit the delay in the timeline, can you provide more clarity on this issue? Someone raised a question about it, but I'm not sure if it was answered. We are discussing 75 patients across 20 sites, correct? This is a 3:2 randomization. Could you help us understand what's happening here? Do we need to add more sites? Are we working with the right sites? Please help us to clarify this matter. You mentioned that these patients are moving into the open-label extension trial. Can you discuss the side effects observed? Is everything generally consistent with what we've seen in the Phase II studies? Have there been any unusual findings?

Joshua Cohen, Co-CEO

Sure. Thanks, Marc. So first, I wouldn't characterize this as an issue. I'd say that as we continue to go along the study, we've updated our timeline to expect to complete recruitment in the first quarter of next year, with data coming out in Q3 of next year. We have seen a lot of excitement across the trial. I'd remind that that timeline would still be recruiting a Phase III study in under a year. And Phase III studies entail not just finding the patients, but also all the work that goes into activating sites, everything else. So we actually do see that as a very good timeline for a Phase III as well. We probably won't report, at this point on, side effects or otherwise. We don't report interim data from a trial. But I think as we mentioned, we are excited to see quite a lot of participant engagement and patients moving into the OLE as well. So excited overall about the execution of the study and our team's great efforts in this space.

Operator, Operator

Your next question comes from Rami Katkhuda with LifeSci Capital.

Rami Katkhuda, Analyst

I guess in LUCIDITY, are you measuring diet adherence via the blinded CGM? And can you intervene based on blood glucose levels if the patient is kind of liberalizing their diet as they start to feel better?

Justin Klee, Co-CEO

Rami, great question. So I would say that our team as well as the monitors are looking at all of the available blinded data, including CGM, as you mentioned, which we get in virtually real time. And the goal there is really to make sure that, one, yes, people are adhering to diet; and two, that people are collecting events as we would expect in the study. So yes, our teams are continuing to do that. And if we see significant deviations that we think need addressing, then our team will indeed reach out to the site and retrain as necessary.

Rami Katkhuda, Analyst

Got it. Makes sense. And then I know I'm jumping the gun a little, but a number of KOLs are excited to use avexitide for hypoglycemia associated with other GI surgeries as well. I guess have you talked to the FDA on the regulatory path forward there? Would you have to run a study in each population? Or is there a potential for kind of a basket study across a number of these surgery types?

Joshua Cohen, Co-CEO

The Phase III study involves participants who have undergone Roux-en-Y gastric bypass. It's still early for discussions about labeling, so we cannot definitively state what an FDA label might encompass. However, since the study focuses on Roux-en-Y, there is a potential risk that this aspect could influence the label. That said, we are confident that, physiologically, the biology underlying these various surgeries is similar, which explains why individuals are experiencing post-bypass hyperglycemia across different procedures. Our Phase IIb study also included participants with various surgical types, and the effects observed appeared consistent across these groups. Therefore, we are keen to explore this further. We've received significant interest from both academics and practitioners regarding surgeries beyond Roux-en-Y, such as gastrectomy for gastric cancer and Nissen fundoplication for gastroesophageal reflux disease. We are genuinely enthusiastic about pursuing this area, so stay tuned for updates.

Operator, Operator

Your next question comes from Graig Suvannavejh with Mizuho Securities.

Unknown Analyst, Analyst

This is Sam on for Greg. Can you just remind us of the manufacturing and CMC processes for avexitide in terms of the commercial doses and the process there, and if you anticipate any stags moving forward?

Justin Klee, Co-CEO

Yes, important question. So I would say we're doing all of the expected work as we move toward commercialization, hopefully with commercialization on the CMC side. So I'd probably touch on a number of points. So first, as you may expect, we have manufactured our registration batches and they're up on stability. I'd say, second, the suppliers that we're working with, both on the drug substance being the peptide and the drug products being the final finished product are manufacturers that have multiple commercial products and have very good inspection histories as well. And I would say then on the internal side, we're focused on all of the quality parameters, inspection readiness activities, as you might expect, with the anticipated approval in 2027. So I'd say our team is laser-focused on all of the things that would be required for both NDA submission and then eventual approval.

Operator, Operator

Your next question comes from Chris Chen with R.W. Baird.

Christopher Chen, Analyst

Just going back to the LUCIDITY and the clinical sites. Have you noticed any differences in the ramp between sites? And are you kind of maybe learning from those sites that maybe are enrolling faster to kind of overall just make the ramp increase across those sites?

Justin Klee, Co-CEO

Thanks, Chris. And I would say in a clinical trial, you always have differences across sites, and that's why we have 21 sites. All sites are activated. And I would say, again, in my experience, as you have all of the sites activated and you go into the latter part of the study, that's when you tend to see an increase in the enrollment rate. So that could still come. But so far, in the last few weeks, we've seen more of a steady enrollment rate. Again, our goal is to conclude enrollment as expeditiously as possible. But of course, making sure that we're enrolling the right participants and we have the right clinical oversight as well. I'd say on the sort of site engagement level, the main message, I would say, is that the unmet need here is very real. I think we have high engagement from the sites. They're very eager to have a potential treatment option for their patients. So that's really come through in all of our engagements.

Operator, Operator

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

Susan Chor, Analyst

This is Susan on for Tim. I have a couple of questions. First question, given that you now have a timeline estimate for the pivotal Wolfram syndrome trial, what can you tell us about the potential trial parameters? And just how have your discussions with the FDA gone? And I'll follow up with my second question.

Camille Bedrosian, Chief Medical Officer

Thanks very much. This is Camille. As we have indicated, based actually on the HELIOS data in AMX0035 for Wolfram syndrome and the very encouraging results out to 48 weeks, we are advancing the clinical development of AMX0035 for Wolfram and plan to initiate our focused pivotal trial in the second half of 2026. We are pending, of course, FDA alignment, and we're actively seeking that alignment now, not only with the FDA, but also we are engaging a number of additional stakeholders, clinicians who treat people with Wolfram syndrome, researchers who study the disease, as well as the Wolfram community itself, and we're seeking alignment across all those stakeholders.

Susan Chor, Analyst

Sorry to keep coming back to this, but you've mentioned a couple of times that you typically see a ramp in enrollment when all trial sites are activated, yet the rates have remained steady. What do you think is causing this? Would you describe this more as a system-wide issue or specific to the LUCIDITY trial?

Joshua Cohen, Co-CEO

I don't think I would characterize this as a system-wide issue or an issue really. I think just as we're updating our projections, we're trying to be as accurate as you possibly can and given the current rate we expect Q1 of the coming year. But remind that's still enrolling a Phase III trial in less than a year, which I think is a good timeline for a Phase III, overall.

Operator, Operator

Your final question comes from Ananda Ghosh with H.C. Wainwright.

Ananda Ghosh, Analyst

I have two; one for LUCIDITY, and the other from the ALS program. So maybe the first question, how is the Level 2 or 3 weighed in for the composite scale? And is there a way to kind of like the nocturnal and the diurnal rates differ? Or how is that kind of taken care of? The other question you might have discussed beforehand, but just to reiterate, how are prior therapies handled like GLP-1 agonist?

Joshua Cohen, Co-CEO

Thank you, Ananda. There are two important questions. First, following five previous trials of avexitide in individuals with PBH, which demonstrated statistically significant and clinically meaningful reductions in hypoglycemic events, our primary goal is to replicate those findings. We aim to enroll a similar patient population and collect data in a consistent manner. For the primary outcome, Level 2 events are determined by fingerstick blood glucose, while Level 3 events are recorded in an eDiary and reviewed by an expert committee. Data collection can occur both during the day and night. Participants also have continuous glucose monitors (CGMs) for ongoing tracking, and we will analyze both types of data. In the Phase IIb trial, where the 90-milligram dose we are using in Phase III was utilized, there were significant reductions as measured by both fingerstick testing and CGM readings throughout the day and night. Our focus remains on replication, so we strive for consistency. Regarding the use of GLP-1 receptor agonists or other therapies that could influence blood glucose levels, we implement a washout period before participants are randomized into the study to avoid any impact on blood glucose, which is a crucial aspect of the study.

Ananda Ghosh, Analyst

Great. Maybe just one question on this is that how are those Level 2 or 3 weighed in the composite scale? Like how are they weighted? Are they weighted like equally?

Joshua Cohen, Co-CEO

Yes, they're weighted equally.

Ananda Ghosh, Analyst

The next question on the ALS program is about how you are measuring the calpain and NfL levels and considering the short trial, what magnitude of NfL change might be practically feasible?

Joshua Cohen, Co-CEO

So the calpain, I'd say we're measuring kind of different points in the pathway. So we're certainly working to measure mRNA in the CSF. We are also looking at measures of calpain activity, including things like spectrum breakdown product 145 or SBDP-145, which is a specific protein cleavage fragment that calpain makes and is an element of calpain activity. And then as you mentioned, downstream, looking at markers of axonal degeneration like neurofilament to kind of see that downstream effect of potential calpain inhibition. I'd say in initial study, we don't quite know yet what the kinetics of changes in those markers might be. In our preclinical work, we have seen changes on multiple of those markers, which certainly makes us encouraged, but we'll have to see clinically how that bears out.

Operator, Operator

There are no further questions at this time. If you have any follow-up questions, please reach out to the company. This concludes today's conference call. Thank you for joining. Have a great rest of your day.