Amylyx Pharmaceuticals Q3 2025 Earnings Call Transcript

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Provided by Quartr
November 6, 2025

Key Takeaways

  • Negative Sentiment: The pivotal Phase 3 Lucidity trial recruitment is now expected to complete in Q1 2026 (vs. prior guidance of end-2025), with top-line data moved to Q3 2026, as enrollment has been steady rather than ramping.
  • Positive Sentiment: The company is preparing its NDA and building medical affairs and commercial infrastructure and continues to expect a potential 2027 launch of Avexitide if approved by the FDA.
  • Positive Sentiment: Amylyx ended Q3 with a strong cash position of $344 million after a September offering (~$191 million net), which the company says provides runway into 2028 to support Lucidity and launch readiness.
  • Positive Sentiment: AMX0114 (antisense targeting calpain 2 for ALS) has fully enrolled cohort one in the Phase 1 Lumina trial, with early safety data to be presented in December and biomarker data expected in H1 2026; the program holds FDA fast track designation.
  • Positive Sentiment: AMX0035 for Wolfram syndrome is advancing toward a focused pivotal Phase 3 planned for H2 2026 pending FDA alignment, with the company engaging clinicians, researchers, and the patient community.
AI Generated. May Contain Errors.
Earnings Conference Call
Amylyx Pharmaceuticals Q3 2025
00:00 / 00:00

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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. All participants will be in listen-only mode. After today's presentation, there will be an opportunity to ask questions. To ask a question, please press star one on your telephone keypad. To withdraw your question, press star one again. 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.

Lindsey Allen
Lindsey Allen
VP of Investor Relations and Communications at Amylyx Pharmaceuticals

Good morning, and thank you all for joining us today to discuss our third quarter 2025 financial results and business updates. 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.

Lindsey Allen
Lindsey Allen
VP of Investor Relations and Communications at Amylyx Pharmaceuticals

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
Justin Klee
Co-CEO at Amylyx Pharmaceuticals

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 five 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.

Justin Klee
Justin Klee
Co-CEO at Amylyx Pharmaceuticals

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 a 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 successful launch.

Justin Klee
Justin Klee
Co-CEO at Amylyx Pharmaceuticals

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 the 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 one in the phase one Lumina trial.

Justin Klee
Justin Klee
Co-CEO at Amylyx Pharmaceuticals

We anticipate early cohort data later this year and plan to share the safety data at the 36th International Symposium on ALS and MND, which is being held from December 5th to the 7th. Based on biomarker collection and analysis timelines, 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
Camille Bedrosian
Chief Medical Officer at Amylyx Pharmaceuticals

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 five 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, endpoint, inclusion criteria, and surgical subtype.

Camille Bedrosian
Camille Bedrosian
Chief Medical Officer at Amylyx Pharmaceuticals

Lucidity is evaluating Avexitide 90 mg 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 two and level three 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 site. 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.

Camille Bedrosian
Camille Bedrosian
Chief Medical Officer at Amylyx Pharmaceuticals

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.

Camille Bedrosian
Camille Bedrosian
Chief Medical Officer at Amylyx Pharmaceuticals

Jim.

Jim Frates
Jim Frates
CFO at Amylyx Pharmaceuticals

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 in 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.

Jim Frates
Jim Frates
CFO at Amylyx Pharmaceuticals

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 recognize $7.1 million of non-cash stock-based compensation expense for the quarter, compared to $6.8 million of non-cash stock-based compensation expense in Q3 2024.

Jim Frates
Jim Frates
CFO at Amylyx Pharmaceuticals

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.

Josh Cohen
Josh Cohen
Co-CEO at Amylyx Pharmaceuticals

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.

Josh Cohen
Josh Cohen
Co-CEO at Amylyx Pharmaceuticals

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 five clinical trials of Avexitide and PBH. These findings, together with new analyses we shared last quarter at NDO 2025.

Josh Cohen
Josh Cohen
Co-CEO at Amylyx Pharmaceuticals

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

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

Seamus Fernandez
Seamus Fernandez
Senior Managing Director at Guggenheim

Oh, great. Thanks for the question, and I appreciate all the updates. 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. Just trying to get a better sense of the impact here. Is it site startup 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 three-week with the requirements for level three events, I could envision having an impact on enrollment, just given the careful design there.

Seamus Fernandez
Seamus Fernandez
Senior Managing Director at Guggenheim

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. I 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. 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? Thanks so much.

Justin Klee
Justin Klee
Co-CEO at Amylyx Pharmaceuticals

Great. Yeah, thank you so much, Seamus. Great, great questions and important points on operations. Yeah, 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. 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 five prior trials of Avexitide and PBH, which demonstrated a very statistically significant and clinically meaningful reduction in hypoglycemic events. The update is on the timeline based on our most recent enrollment projections and estimates. 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.

Justin Klee
Justin Klee
Co-CEO at Amylyx Pharmaceuticals

A ramp in the enrollment rate. Now, that could still happen, but so far, it's been a steady enrollment rate. That's why we're updating the projections to now. Estimated completion of recruitment in the first quarter. I hope that helps, but I really appreciate your points on the quality of the operation. That's definitely where our team is focused as well. We're pleased with our team's focus.

Josh Cohen
Josh Cohen
Co-CEO at Amylyx Pharmaceuticals

Maybe just touching on your other questions too, included in that quality certainly is maintaining the dietary guidance throughout the whole trial. Just as a reminder, at every clinic visit, patients do receive dietary guidance. The goal of that is to keep everybody following closely with the recommended PBH diet. 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. 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.

Josh Cohen
Josh Cohen
Co-CEO at Amylyx Pharmaceuticals

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. Certainly, our goal will be to move as expeditiously as we possibly can.

Operator

Our next question comes from Joseph Thorne with TD Cowen.

Operator

Hi there. Good morning, and thank you for taking my questions. 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? 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? Thank you.

Josh Cohen
Josh Cohen
Co-CEO at Amylyx Pharmaceuticals

Sure. Probably within an ongoing trial, we do not necessarily kind of give interim data or interim updates. What I can share is when you look at past studies with Avexitide, it was often the case that people had had PBH six, seven, eight years. The usual standard in PBH is certainly the dietary therapy. 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. We do require that the bariatric surgery was at least a year prior to entering the study. Everybody has had the bariatric surgery well in their past as well. In terms of screen fail rates, similarly, we do not kind of report interim data as we are going through a study.

Josh Cohen
Josh Cohen
Co-CEO at Amylyx Pharmaceuticals

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 114 presentation in early December, that will focus on safety at this time. We will have biomarker later. 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.

Josh Cohen
Josh Cohen
Co-CEO at Amylyx Pharmaceuticals

Great. Thank you very much.

Operator

Your next question comes from Jeff Meacham with Citi.

Operator

Hi, guys. It's Ross on for Jeff. I guess thanks for taking our question. We're curious about your sense of PBH and kind of the addressable market and how. Has that continued to evolve?

Justin Klee
Justin Klee
Co-CEO at Amylyx Pharmaceuticals

Yeah, thank you. I would say as we've done more and more commercial preparations, looking forward, I'd say it only increases in our confidence in both the unmet need in the market. 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. Our estimates continue to be that there are about 160,000 people today who have PBH. 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 two, level three events. These are frequent occurrences for people with PBH.

Justin Klee
Justin Klee
Co-CEO at Amylyx Pharmaceuticals

To put it in context, severe hypoglycemia, according to the American Diabetes Association, a single event is a medical emergency. These are people who are having frequent hypoglycemic events. It is highly, highly debilitating. What we hear from clinics is that they are 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. 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.

Justin Klee
Justin Klee
Co-CEO at Amylyx Pharmaceuticals

Thank you.

Operator

Your next question comes from Corinne Johnson with Goldman Sachs.

Kevin Ong
Kevin Ong
Investment Banking Analyst at Goldman Sachs

Hi, this is Kevin Ong for Corine. Good morning. 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? Thanks.

Josh Cohen
Josh Cohen
Co-CEO at Amylyx Pharmaceuticals

Yeah, good question. Maybe starting with kind of uncontrolled on diet. 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. 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. 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. As Justin said, even a single significant hypoglycemic event is considered a medical emergency.

Josh Cohen
Josh Cohen
Co-CEO at Amylyx Pharmaceuticals

These are patients who, in effect, are having frequent medical emergencies.

Justin Klee
Justin Klee
Co-CEO at Amylyx Pharmaceuticals

Just to give a picture of what we believe is going on from a pathophysiology perspective. We believe that PBH is caused by the body dramatically upregulating the production and secretion of GLP-1. People will have up to 10x normal levels of GLP-1. 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. 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. That is 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 is causing the hypoglycemia.

Kevin Ong
Kevin Ong
Investment Banking Analyst at Goldman Sachs

Thank you.

Operator

Your next question comes from Marc Goodman with Leerink Partners.

Marc Goodman
Marc Goodman
Senior Research Analyst at Leerink Partners

Yeah, just to kind of come back to this delay in the timeline. Can you help us understand? Someone asked a 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, help us understand what's going on here. Do we need to add more sites? Do we have the right sites? Help us just understand what that issue is. And then 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 study? Anything unusual? Thank you.

Josh Cohen
Josh Cohen
Co-CEO at Amylyx Pharmaceuticals

Sure. Thanks, Mark. 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 timeline would still be recruiting a phase III study in under a year. Phase III studies entail not just finding the patients, but also all the work that goes into activating sites, everything else. 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.

Josh Cohen
Josh Cohen
Co-CEO at Amylyx Pharmaceuticals

I think, as we mentioned, we are excited to see quite a lot of participant engagement and patients moving into the OLE as well. Excited overall about the execution of the study and our team's great efforts in this space.

Operator

Your next question comes from Rami Katkhuda with LifeSci Capital.

Rami Katkhuda
Rami Katkhuda
Managing Director and Senior Equity Research Analyst at LifeSci Capita

Hey, guys. Thanks for taking my questions as well. 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
Justin Klee
Co-CEO at Amylyx Pharmaceuticals

Yeah. Hi, Rami. Great question. 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. 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. Yes, our teams are continuing to do that. 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
Rami Katkhuda
Managing Director and Senior Equity Research Analyst at LifeSci Capita

Got it. Makes sense. 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 potential for kind of a basket study across a number of these surgery types?

Josh Cohen
Josh Cohen
Co-CEO at Amylyx Pharmaceuticals

Sure. The phase III study is in people with Roux-en-Y gastric bypass. It's early to. Label discussions happen later in the process. It's early to say what an FDA label would or wouldn't be. 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. In addition, our phase II B study included people with multiple surgical types, and the effects look similar across those surgical types as well. 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.

Josh Cohen
Josh Cohen
Co-CEO at Amylyx Pharmaceuticals

People who have had gastrectomy for gastric cancer, Nissen fundoplication for gastroesophageal reflux disorder, and otherwise. It is definitely an area we are quite excited to pursue. Yeah, I would say stay tuned in that regard.

Rami Katkhuda
Rami Katkhuda
Managing Director and Senior Equity Research Analyst at LifeSci Capita

Sounds great. Thank you.

Operator

Your next question comes from Greg Sivaneve with Mizuho Securities.

Operator

Hi, this is Sam with on for Greg. Thanks for taking our question. Can you remind us of the manufacturing and CMC processes for Avexitide in terms of the commercial doses and the process there? If you anticipate any snags moving forward? Thank you.

Justin Klee
Justin Klee
Co-CEO at Amylyx Pharmaceuticals

Yeah. Hi, Sam. Yeah. An important question. I would say we're doing all of the expected work as we move toward commercialization, hopefully with commercialization on the CMC side. I'd probably touch on a number of points. First, as you may expect, we have manufactured our registration batches, and they're up on stability. 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. 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.

Justin Klee
Justin Klee
Co-CEO at Amylyx Pharmaceuticals

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.

Justin Klee
Justin Klee
Co-CEO at Amylyx Pharmaceuticals

That's very helpful. Thanks for the color.

Operator

Your next question comes from Chris Chin with RW Baird.

Operator

Morning, team. Thanks for taking my questions. Just going back to the Lucidity and the clinical sites, have you noticed any differences in the ramp between sites? 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
Justin Klee
Co-CEO at Amylyx Pharmaceuticals

Yeah, thanks, Chris. I would say in a clinical trial, of course, you always have differences across sites, and that is why we have 21 sites. All sites are activated. 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 is when you tend to see an increase in the enrollment rate. That could still come, but so far in the last few weeks, we have 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 are enrolling the right participants, we have the right clinical oversight as well. I would say on a sort of site engagement level, the main message I would say is that the unmet need here is very real.

Justin Klee
Justin Klee
Co-CEO at Amylyx Pharmaceuticals

I think we have high engagement from the sites. They're very eager to have a potential treatment option for their patients. That has really come through in all of our engagements.

Justin Klee
Justin Klee
Co-CEO at Amylyx Pharmaceuticals

Thank you.

Operator

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

Operator

Hi, good morning. 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? I'll follow up with my second question.

Camille Bedrosian
Camille Bedrosian
Chief Medical Officer at Amylyx Pharmaceuticals

Great. Thanks very much. This is Camille. As we have indicated, based actually on the HELIOS data and AMX0035 for Wolfram syndrome and the very encouraging results out to 48 weeks, we are advancing the clinical development of 35 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. We are seeking alignment across all those stakeholders.

Camille Bedrosian
Camille Bedrosian
Chief Medical Officer at Amylyx Pharmaceuticals

Thank you. 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. Rates have been steady. Why do you think this is? Would you characterize this more as a system-wide issue or specific to the Lucidity trial?

Josh Cohen
Josh Cohen
Co-CEO at Amylyx Pharmaceuticals

Yeah, 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 we possibly can. Given the current rate, we expect Q1 of the coming year. I'd 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

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

Ananda Ghosh
Ananda Ghosh
VP, Research Analyst, and Biotech Equity Research at H.C. Wainwright

Hi, guys. Thanks for taking my question. I have two, one for Lucidity and the other from the ALS program. Maybe the first question, how is the level two or three weighed in for the composite scale? Is there a way to, kind of, like, the nocturnal and the diurnal rates differ? 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 agonists?

Justin Klee
Justin Klee
Co-CEO at Amylyx Pharmaceuticals

Yeah, thank you, Ananda. Two important questions. First, coming off of five 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. To try to enroll a similar patient population, collect the events in the same way, etc. For the primary outcome, level two events are done by fingerstick blood glucose, and level three is an eDiary that is adjudicated by an expert committee. That is 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. Obviously, we will be looking at both.

Justin Klee
Justin Klee
Co-CEO at Amylyx Pharmaceuticals

In the phase II B trial, where they used the 90 mg 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. Our goal really here is with replication. We're trying to keep things as consistent as possible. In terms of use of GLP-1 receptor agonists 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 this study.

Ananda Ghosh
Ananda Ghosh
VP, Research Analyst, and Biotech Equity Research at H.C. Wainwright

Great. Thanks. Maybe just one question on this is that how are those level two or three weighed in the composite scale? How are they weighted? Are they weighted equally?

Josh Cohen
Josh Cohen
Co-CEO at Amylyx Pharmaceuticals

Yes, they're weighted equally.

Ananda Ghosh
Ananda Ghosh
VP, Research Analyst, and Biotech Equity Research at H.C. Wainwright

Got it. The next question on the ALS program, if you could, how are you measuring the calpain and NFL levels in terms of, and also given the short trial length, what magnitude of NFL change might be practically feasible?

Josh Cohen
Josh Cohen
Co-CEO at Amylyx Pharmaceuticals

Yeah. The calpain, I'd say we're measuring kind of different points in the pathway. We're certainly working to measure mRNA in the CSF. We are also looking at measures of calpain activity, including things like a spectrum breakdown product 145 or SBDP 145, which is a specific protein cleavage fragment that calpain makes and is an element of calpain activity. 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.

Ananda Ghosh
Ananda Ghosh
VP, Research Analyst, and Biotech Equity Research at H.C. Wainwright

Great. Thank you, guys.

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.

Executives
    • Camille Bedrosian
      Camille Bedrosian
      Chief Medical Officer
    • Jim Frates
      Jim Frates
      CFO
    • Josh Cohen
      Josh Cohen
      Co-CEO
    • Lindsey Allen
      Lindsey Allen
      VP of Investor Relations and Communications
    • Justin Klee
      Justin Klee
      Co-CEO
Analysts
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