AMLX - NASDAQ

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. [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, Vice President, Investor Relations and Communications. Please proceed.

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.

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.

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, it's 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?

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 onetime 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.

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 Instructions] Your first question comes from Seamus Fernandez with Guggenheim.

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 time line that might come into play there?

Great. Thank you so much, Seamus. Great, great questions and important points on operations. So I think first, just to say at a high level, I think we're pleased with how the study is being executed, how it's progressing. The first participants are going into the open-label extension. And you raised really important points as well, which is our real focus -- is on quality, enrolling the right participants, ensuring the right data collection, especially in view of the 5 prior trials of avexitide in PBH, which demonstrated a very statistically significant and clinically meaningful reduction in hypoglycemic events. So the update is on the time line based on our most recent enrollment projections and estimates. And I would say that certainly, in every trial I've been a part of -- as you have all of the sites up and running -- recruiting participants, you tend to see a ramp in the enrollment rate. Now that could still happen. But so far, it's been a steady enrollment rate. And so that's why we're updating the projections to now estimated completion of recruitment in the first quarter. So I hope that helps, but I really appreciate your points on the quality of the operations. That's definitely where our team is focused as well, and we're pleased with our team's focus.

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 time line. 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 time line 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.

Your next question comes from Joseph Thome with TD Cowen.

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?

Sure. So probably within an ongoing trial, we don't necessarily kind of give interim data or interim updates. But what I can share is when you look at past studies with avexitide, it was often the case that people have had PBH 6, 7, 8 years. And the usual standard in PBH is certainly the dietary therapy. So most of these patients will -- we do expect that most of the patients, if not all of the patients, will have been on dietary therapy many years prior to entering. And we do require that the bariatric surgery was at least a year prior to entering the study. So everybody has had the bariatric surgery well in their past as well. In terms of screen fail rates, similarly, we don't kind of report interim data as we're going through a study. But certainly, our goal, as Justin suggested, is to enroll the right patients in the study and to focus on quality throughout getting patients who have the appropriate level of severity and who hopefully will be able to complete the study also. In terms of the AMX0114 presentation in early December, that will focus on safety at this time. We will have biomarker data. We expect to report on that in the first half of the coming year at a medical conference. The biomarker work just takes a little bit longer, hence that coming in the first half.

Your next question comes from Geoff Meacham with Citi.

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?

Thank you. And I would say -- as we've done more and more commercial preparations looking forward, I'd say it only increases our confidence in both the unmet need in the market. So we've looked at multiple claims-based analyses now, as well as there's been independent work out of Stanford looking at the total population. And our estimates continue to be that there are about 160,000 people today who have PBH. And we expect more to come as well. Bariatric surgery rates continue to be quite significant. And with that, we would expect the population to only continue to grow from already quite a substantial unmet need. The other thing that I think has really come out from being out in the field is the unmet need. It's severe hypoglycemia as defined by Level 2, Level 3 events. These are frequent occurrences for people with PBH. To put it in context, severe hypoglycemia according to the American Diabetes Association, a single event is a medical emergency. And these are people who are having frequent hypoglycemic events. So it's highly, highly debilitating. And what we hear from clinics is that they're very worried for their patients because, one, they really have very limited options to help them; and two, that these hypoglycemic events can occur often without warning and, again, so frequently. So I think all of our research just continues to bolster our confidence in the unmet need and the opportunity here that we have with avexitide.

Your next question comes from Corinne Johnson with Goldman Sachs.

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?

Good question. So maybe starting with kind of uncontrolled on diet. So in coming up with the 160,000 estimate -- which, as a reminder, is based on published prospective and retrospective data, as well as claims-based work and direct work with physicians treating PBH -- we tried to eliminate upfront those who were controlled on diet. So the 160,000 is intended to be those who are not controlled on diet, and who are continuing to experience unacceptable and clinically problematic hypoglycemic events. In terms of direct eligibility for the Phase III, that's not an analysis we've done directly through the 160,000. But again, we do view the 160,000 as people who are having, as Dr. Colleen Craig calls it -- from Stanford, medically important PBH, PBH, which is significantly impacting their daily life. And as Justin said, even a single significant hypoglycemic event is considered a medical emergency. So these are patients who, in effect, are having frequent medical emergencies.

Just to give a picture of what we believe is going on from a pathophysiology perspective, the -- we believe that PBH is caused by the body dramatically upregulating the production and secretion of GLP-1. So people will have up to 10x normal levels of GLP-1. And so the reason that we think -- we hear from both clinics and patients that kind of no matter what they do, they continue to have these drops in blood glucose is because of this GLP-1 effect. So if you think no matter what they do, their body is producing up to 10x normal levels of GLP-1, their blood glucose is going to plummet. And that's also why we think avexitide has such potential because really to get to the heart of PBH, we believe that you need to blunt that GLP-1 bolus, which is ultimately what's causing the hypoglycemia.

Your next question comes from Marc Goodman with Leerink Partners.

Just to kind of come back to this delay in the time line. Can you help us understand like -- someone asked the question, but I wasn't sure if the answer was given about. -- I mean, we're talking about 75 patients and 20 sites, right? And this is 3:2 random. I mean, what -- help us understand what's going on here. Like do we need to add more sites? Do we have the right sites? Like what -- help us just understand what that issue is. You talked about these patients moving into the open-label extension trial. Talk about the side effects that you've seen? Is everything generally the same as what we've seen in the Phase II studies? Anything unusual?

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 time line 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 time line 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 time line 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.

Your next question comes from Rami Katkhuda with LifeSci Capital.

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?

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.

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?

Sure. So the Phase III study is in people with Roux-en-Y gastric bypass. It's early to -- label discussions happen later in the process, so it's early to say what an FDA label would or wouldn't be. But given that the study is in Roux-en-Y, that is a potential risk that we -- that element finds its way into a label or otherwise. That being said, we do believe both physiologically based on the biology of these different surgeries that the pathophysiology is similar or the same for why people are getting PBH across them. And in addition, our Phase IIb study included people with multiple surgical types and the effects look similar across those surgical types as well. So it's certainly something that we want to pursue. We do exactly, as you suggested, get a lot of interest from academics and otherwise with surgeries beyond Roux-en-Y, including people who have had gastrectomy for gastric cancer, Nissen fundoplication for gastroesophageal reflux disorder and otherwise. So it's definitely an area we're quite excited to pursue. And yes, I'd say stay tuned in that regard.

Your next question comes from Graig Suvannavejh with Mizuho Securities.

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?

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.

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

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?

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, 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.

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

This is Susan on for Tim. I have a couple of questions. First question, given that you now have a time line 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.

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 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.

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

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 time line for a Phase III, overall.

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

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?

Thank you, Ananda. So two important questions. So first, coming off of 5 prior trials of avexitide in people with PBH, that showed statistically significant and clinically meaningful reductions in hypoglycemic events, the goal really here is replication. So to try to enroll a similar patient population, collect the events in the same way, et cetera. So for the primary outcome, Level 2 events are done by fingerstick blood glucose and Level 3 is an eDiary that's adjudicated by an expert committee. So that's how the data are collected. People can collect those during the day or during the night. Now people also have CGMs on, which have continuous monitoring. And so obviously, we will be looking at both. In the Phase IIb trial, where they use the 90-milligram dose that we're using in the Phase III, there were significant reductions, both as measured by the fingerstick as well as by the CGM day and night. But again, our goal really here is with replication. So we're trying to keep things as consistent as possible. In terms of use of GLP-1 receptor agonist or really any therapeutic that could alter blood glucose, we have a washout period before people can be randomized into the study, so that we don't have things that could affect people's blood glucose levels -- given that, of course, that is a key part of the study.

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?

Yes, they're weighted equally.

The next question on the ALS program, if you can -- like how are you measuring the calpain and NfL levels in terms of -- and also given the short trial, what magnitude of NfL change might be practically feasible?

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.