Earnings Call Transcript - AMLX Q2 2025

Operator, Operator

Good morning. My name is John, and I'll be your conference operator today. At this time, I would like to welcome everyone to the Amylyx Pharmaceuticals Second 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 Lindsay Allen, Vice President, Investor Relations and Communications. Please go ahead, ma'am.

Lindsey Allen, Vice President, Investor Relations and Communications

Good morning, and thank you all for joining us today to discuss our Second 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 regulatory and clinical development, 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 B. Klee, Co-CEO

Good morning, and thank you all for joining us. During the first half of 2025, we made meaningful progress across our clinical programs. Our lead asset, Avexitide, is an investigational GLP-1 receptor antagonist with FDA breakthrough therapy designation, being evaluated for the treatment of post-bariatric hypoglycemia or PBH. In April, we dosed our first participant in the pivotal Phase III LUCIDITY trial, studying Avexitide in PBH, following Roux-en-Y gastric bypass surgery. We continue to expect to complete recruitment by year-end. We have been pleased by the level of engagement in the clinical trial sites. Just a few weeks ago, we hosted an educational investor event at Endo, featuring a panel of KOL, all experts in treating PBH, including investigators involved in the trial. Camille will share a few remarks on Endo shortly. If you were not able to attend or listen live, I encourage you to listen to the replay available in the Presentation section of our website. Importantly, we are preparing to be launch-ready. And if approved, we anticipate a commercial launch of Avexitide in 2027. We have been focused on the initial steps for building the commercial organization and collecting insights on the market, which includes learning from people living with PBH and mapping out early disease education and market access strategies. We are encouraged by the potential of GLP-1 receptor antagonism as a therapeutic approach, beginning with Avexitide in PBH and potentially extending to other rare diseases where this mechanism may be relevant. Reflecting our conviction in this target, last December, we initiated a research collaboration with Gubra, a global leader in long-acting peptide drug development. We are pleased with the progress we are making to develop a novel, long-acting GLP-1 receptor antagonist. Initial efforts at Gubra are already showing proof of concept with new molecules, demonstrating promising potency values, both in vitro and in vivo, and extended in vivo half-lives. We are excited about this collaboration, and we'll share more as timelines towards IND-enabling studies become clearer. Turning to the rest of our pipeline. AMX0035 is an oral, small molecule therapy designed to target endoplastic reticulum or ER stress and mitochondrial dysfunction. We are studying AMX0035 in progressive supranuclear palsy, or PSP and Wolfram syndrome. PSP is a rare, progressive and fatal neurodegenerative disorder that affects an estimated 23,000 people in the U.S. and has no currently approved treatments. We expect top line data from the Phase IIb portion of the Phase IIb/III ORION trial this quarter, which will inform a go/no-go decision on whether we move into the Phase III program. Wolfram syndrome is a rare progressive, monogenic prototypical ER stress disorder with no approved treatments that we estimate affects approximately 3,000 people in the U.S. alone. Earlier this quarter, we presented long-term Week 48 data, which demonstrated that treatment with AMX0035 led to sustained stabilization or improvement over time in the study's clinical measures. These results and discussions with FDA are informing the design of a Phase III trial of AMX0035 and Wolfram syndrome, and we expect to provide an update on the program this year. Now turning to AMX0114, our investigational antisense oligonucleotide targeting Calpain-2 for the treatment of amyotrophic lateral sclerosis or ALS. We continue to expect early cohort data from our Phase I LUMINA trial of AMX0114 this year. AMX0114 is designed to inhibit Calpain-2 to prevent the breakdown of axons, which are long fibers that carry signals from neurons to muscles. In preclinical studies, AMX0114 demonstrated improved neuronal survival and reductions in extracellular neurofilament light chain, or NfL, a key biomarker of neurodegeneration across multiple disease models. In June, the FDA granted Fast Track designation to AMX0114, which provides us with the opportunity for more frequent interactions with the FDA and could allow for an expedited review process. Our pipeline progress reflects the focus and executional rigor of our team. As we look ahead to the second half of the year and into 2026, we're encouraged by the strength of our position and the momentum we're building across all of our programs. Now I'll turn the call over to Camille.

Camille L. Bedrosian, Chief Medical Officer

Thanks, Justin. Touching briefly on the upcoming Phase IIb data readout in PSP. PSP is a tauopathy characterized by the accumulation of tau protein in the brain. Unlike other investigational agents that have targeted extracellular tau protein or focused on downstream effects, AMX0035 is both brain and cell penetrant. Notably, in our Phase II Alzheimer's trial, AMX0035 demonstrated significant reductions in tau protein in cerebrospinal fluid. With these characteristics, we believe AMX0035 may offer a differentiated and potentially disease-modifying approach in PSP. We have set a high bar for AMX0035 in PSP. Based on natural history data and feedback from clinical experts, we believe a clear slowing of disease progression of at least 20% on the PSP rating scale could signal meaningful clinical activity. We plan to base our decision-making for advancing to the Phase III portion of the trial on the totality of the data and the potential for clinically meaningful outcomes for those living with PSP. Now let's focus on Avexitide, our lead program. Post-bariatric hypoglycemia is characterized by recurrent hypoglycemic events, which can impose a significant and lasting burden on a person's quality of life. The condition often impairs the individual's ability to perform basic activities of daily living. There are currently no FDA-approved treatments. The pathophysiology of PBH is believed to be primarily driven by altered nutrient transit after bariatric surgery, which leads to exaggerated secretion of glucagon-like peptide 1 or GLP-1. In individuals with PBH, postprandial GLP-1 levels can be more than tenfold higher than normal, triggering excessive insulin release and subsequent hypoglycemia. Avexitide is our investigational, first-in-class GLP-1 receptor antagonist, which has been granted FDA Breakthrough Therapy designation. It is designed to inhibit GLP-1 receptor activity, thereby reducing insulin secretion and stabilizing blood glucose levels. At Endo 2025, we presented new exploratory analyses from the Phase II PREVENT trial in PBH following Roux-en-Y bypass surgery and the Phase IIb clinical trial in PBH following a variety of upper GI surgeries, including Roux-en-Y gastric bypass, sleeve gastrectomy, esophagectomy, Nissen fundoplication, and gastrectomy. These data show that Avexitide 90 milligrams once daily, which is the dose being evaluated in the pivotal Phase III LUCIDITY trial, led to a 64% least squares mean reduction in the composite rate of Level 2 and Level 3 hypoglycemic events from baseline in people with PBH with a p-value of 0.0031. Importantly, more than half of the participants receiving this dose experienced no Level 2 or Level 3 hypoglycemic events during the treatment period. Consistent reductions in the composite rate of Level 2 and Level 3 events were also seen with other Avexitide doses studied in the Phase II and IIb trials. Avexitide was generally well tolerated with a favorable safety profile replicated across the clinical trials. We also presented new pharmacokinetic and pharmacodynamic data at the Endo conference, demonstrating continuous pharmacological activity of the 90-milligram once daily dose for a full 24-hour period. These findings build on a consistent body of data from five clinical trials of Avexitide in PBH. When we designed our pivotal Phase III LUCIDITY trial, the goal was to be as consistent as possible with the previous successful Phase II study, which directly informed the dose, endpoints, surgical subtype and inclusion criteria. As a reminder, LUCIDITY is a multicenter, randomized, double-blind, placebo-controlled trial of approximately 75 participants with PBH following Roux-en-Y gastric bypass surgery. LUCIDITY is evaluating the FDA agreed-upon primary endpoint of reduction in the composite of Level 2 and Level 3 hypoglycemic events, through Week 16. In addition to the analyses presented, expert PBH clinicians and researchers shared new data and research findings at Endo 2025. For example, Dr. Colleen Craig and her colleagues at Stanford presented a U.S. prevalence model for PBH, which they have been working on for the past five years, including an assessment of prevalence and incidence based on surgical subtype. Dr. Craig and her team used historical census data going back to 1993 and found that there were approximately 1.3 million Roux-en-Y and 1.6 million sleeve gastrectomy surgeries during this time. Then using life expectancy estimates and disease state modeling, they found that nearly 400,000 people in the U.S. who previously underwent bariatric surgery experienced clinically important hypoglycemia, defined as glucose less than 54 mg per deciliter or three or more PBH symptoms. Of these, approximately 167,000 people experience recurrent events that are intense enough to require medical attention, which is a population considered to have medically important PBH. Further breaking down these numbers, approximately 119,000 had Roux-en-Y gastric bypass and approximately 48,000 had sleeve gastrectomy. These estimates reinforce our projections which are based on published literature and claims-based analysis and underscore both the urgency of the unmet need and a significant opportunity for Avexitide to make a meaningful impact for people living with PBH. From a clinical and mechanistic standpoint, we remain highly encouraged by the therapeutic potential of GLP-1 receptor antagonism. We view LUCIDITY as just the beginning for Avexitide. Hypoglycemia does not just occur after Roux-en-Y gastric bypass surgery, but after several other types of major upper GI surgeries, which may be conducted for weight loss, gastric or esophageal cancer removal, or severe gastroesophageal reflux disease. Additionally, GLP-1 receptor antagonism may hold importance in several other rare diseases. We continue to work through plans to evaluate Avexitide in these additional areas. But first and foremost, our focus is on LUCIDITY. We are pleased by our continued progress on the Avexitide program and the growing recognition of PBH as a serious underserved condition. We look forward to top line data from LUCIDITY expected in the first half of 2026. With that, I'll turn it over to Jim to discuss the financial highlights from the quarter. Jim?

James M. Frates, Chief Financial Officer

Thanks, Camille. We ended the second quarter with a cash position of $180.8 million compared to $204.1 million at the end of the first quarter. We believe we have the necessary cash to deliver our planned clinical milestones, which include top line data from the Phase III LUCIDITY trial of Avexitide expected in the first half of next year. Top line data from the Phase IIb portion of the ORION trial in PSP expected this quarter, and early cohort data from our LUMINA trial of AMX0114 in ALS expected by the end of the year. In addition, our cash supports early commercial preparations for the potential first-to-market launch of Avexitide. Turning now to our results for the quarter. Total operating expenses for the quarter were $42.9 million, down 43% from the same period in 2024. Research and development expenses were $27.2 million compared to $23.3 million in Q2 2024, primarily due to an increase in spending on Avexitide and AMX0035 for the treatment of PSP. The increase was partially offset by a decrease in spending on AMX0035 for the treatment of ALS. Selling, general and administrative expenses were $15.6 million compared to $21.6 million in Q2 2024, primarily due to a decrease in payroll and personnel-related costs and a decrease in consulting, professional and other services. We recognized $7.4 million of noncash stock-based compensation expenses for the quarter compared to $9.6 million of noncash stock-based compensation expenses in Q2 2024. With our current cash balance, we believe we're well positioned to execute on our clinical milestones. We expect our cash runway to last through the end of 2026. With that, I'll turn the call over to Josh.

Joshua B. Cohen, Co-CEO

Thanks, Jim. In closing, I'd like to take a moment to highlight what continues to inspire us. The experience of people living with PBH is often underappreciated, but it's central to understanding our work. As Camille described today, PBH is a serious and life-altering condition. People living with PBH often experience frequent, unpredictable hypoglycemic events that can severely limit their independence and quality of life. Many live with constant anxiety around meals, social isolation, and an inability to perform basic daily activities. These patient experiences are not outliers. They reflect a broader underserved patient population that we continue to learn about and which motivates us to move with urgency and precision. As we look ahead, we're increasingly confident in the strategic value of antagonizing the GLP-1 pathway and the potential to help many patients in need. We look forward to keeping you updated on our progress across our pipeline. Now I would like to open the call up for questions.

Operator, Operator

Operator Instructions. We now have our first question, and this comes from Seamus Fernandez from Guggenheim.

Seamus Christopher Fernandez, Analyst

So really, the question that I have is more on the understanding of the market opportunity. There's a lot of confusion, I think, in the marketplace in terms of how the moderate-to-severe patient population actually is broken up. And what would be a kind of clinically relevant result for this patient population? I know your event provided a lot of information along those lines, but I think it would be helpful to just know what you believe the sort of truly severe kind of baseline population for a rapid potential uptake of Avexitide would be? And then just a separate very quick follow-up question is just the pace of enrollment in your Phase III? Just hoping you might be able to give us a little bit of a sense. Your confidence in recruiting that study seems quite high. Just wondering how we should anticipate that enrollment to proceed given the timing of the Phase III data in the first half of next year.

Joshua B. Cohen, Co-CEO

Thanks, Seamus. So maybe going one by one. Starting on the market, we've continued to learn and continue to dive in. We actually updated our slide in our deck as well. So you can see a little bit more information there on the market as well. I think as we've continued to learn about hypoglycemia, even a single hypoglycemic event can be very dramatic for patients. It could be a moment where they fracture a bone, could be a moment where they fall down stairs or potentially crash a car, and it's dramatic for individuals. And also just to try to prevent or reduce the rate of those hypoglycemic events, patients are forced to live a very limited life, both in terms of their diet, being on a very restrictive diet where they have very, very few carbs and aren't able to eat, are only able to eat very, very small meals, but also just from a sense of fear in terms of feeling like at any point they might fall into this hypoglycemia. So we think that this population, I'd say, in general, is very eager for treatment and for potential benefits. Breaking down a little bit, Dr. Craig did present recently at Endo, some information on prevalence as well. She estimated overall a prevalence of about 160,000 of what she called medically important PBH, which is defined by people that were seeking medical care for their PBH. She further subsetted that down to about 30,000 patients. That was what she called critical PBH, which were people who are potentially going to an ER or a hospital for an inpatient visit to manage their PBH. So I think we're still working a little bit on maybe your follow-up question of exactly who gets on drug first, what is the very first segment that we might tackle in the market. That's work we're still doing commercially. But I think overall, we do believe that there are approximately 160,000 patients who may ultimately benefit, over time, as we continue educating and building the market. You also asked about the pace of enrollment in the clinical trial. So we expect to complete enrollment by the end of the year with data in the first half of 2026. We're making good progress towards that goal, so we reiterated that goal today as well.

Operator, Operator

And the next question comes from Joseph Thome from TD Cowen.

Joseph John-Charles Thome, Analyst

Maybe the first one on the Phase III LUCIDITY trial design. Just because this treatment period is a little bit longer than the other Phase IIs, I guess, can you just remind us what you have in place to prevent patients from self-liberalizing their diet or maybe how that can be tracked? And then just a quick follow-up on the PSP program. What's going to be the most important determinant in deciding to move that forward? Is it just going to be a certain level of improvement on the PSPRS? Or are there any other secondary endpoints or safety measures that you're going to be looking at before you decide to make that step?

Camille L. Bedrosian, Chief Medical Officer

Sure. Thank you. So regarding the LUCIDITY trial, we actually have great training initially with the site and through them with the participants regarding the dietary modifications and dietary following. Everyone is already on medical nutrition therapy and beginning with the run-in period, and participants are asked to continue doing whatever they were doing during run-in throughout the trial. And this is double-checked throughout the study, individuals in the study also respond to questionnaires, attesting to their dietary habits, and the diet piece is reinforced throughout the study.

Joshua B. Cohen, Co-CEO

And maybe I may just add there as well. This is also consistent. In fact, if anything, even more close management than what was in the Phase II and Phase Ib. So just as Camille said, at every interaction with the site, at every visit, patients are reminded and kind of retrained on the appropriate diet for people with post-bariatric hypoglycemia. There was some dietary training in the Phase II and Phase IIb. This is even more significant. And as a reminder, the Phase II and Phase IIb showed quite significant results on the hypoglycemic endpoints that we're also looking at here. So maybe I'll pass back to Camille on PSP.

Camille L. Bedrosian, Chief Medical Officer

Sure. Yes. And just one more point about this. The participants, as we've learned from the PIs in the study, are highly motivated. So they do identify and follow the instructions based on their motivation, and that was observed in Phase II/IIb. With regard to the PSP program, as we remarked earlier, we are looking at a clinical endpoint, the progression rate as measured by the PSPRS as well as biomarker and imaging data. And all those elements will go into our go/no-go decision for PSP. And also, as a reminder, we are setting a high bar as noted earlier.

Operator, Operator

And the next question comes from Michael DiFiore from Evercore.

Michael Gennaro DiFiore, Analyst

Two for me. One on the PBH market. What's the potential for payers to force step edits on these non-approved therapies such as diazoxide and octreotide, meaning recognizing that most of these patients will probably have been already on them, especially the severely affected patients. But for newly diagnosed patients, potential for step therapy edits. I have a follow-up.

Joshua B. Cohen, Co-CEO

Sure. I'm happy to start with that. We don't anticipate that happening. There isn't solid clinical evidence that those therapies are effective for PBH, so payers are unlikely to consider them due to the lack of evidence supporting their benefits. Additionally, in our discussions with physicians and patients suffering from this condition, we've found very low satisfaction with these therapies. Patients continue to experience significant events while on them and report various side effects.

Michael Gennaro DiFiore, Analyst

That's very helpful. And my second question is on the PSP trial. I mean, as we headed into the interim analysis for this trial, how should we think about the variation in treatment duration across patients, given that all patients will have been treated for 24 weeks, but I think you mentioned before that some patients will have been treated for much longer. So I guess what I'm asking is what is the potential for these longer duration patients to really drive the signal versus the ones who were just treated for 24 weeks?

Camille L. Bedrosian, Chief Medical Officer

Yes. Thank you, Mike. All participants will have completed 24 weeks of treatment, and that's the analysis that we'll be doing. And you are correct, we will also look at data through 52 weeks for those who have progressed into advance through 52 weeks. All the data will be taken into account, not one or another driving more or less our go/no-go decision.

Joshua B. Cohen, Co-CEO

Yes. We'll use all available data in the analysis. I think as Camille mentioned, at least everyone will have crossed that Week 24 time point. If there are important differences between Week 24 and going out to the full duration time point, we'll definitely explore those and share those as well.

Operator, Operator

And the next question comes from Jeff Meacham from Citi.

Unidentified Analyst, Analyst

This is Jarvey on for Jeff. I have a couple of quick questions. First, regarding the PBH market opportunity, the absence of an ICD-10 code makes it challenging to determine an exact prevalence number. You mentioned that you have ongoing efforts to better understand the market opportunity. As you engage with more payers and key opinion leaders, what do you think would be the most effective way to demonstrate the need for a therapy and the benefits that Avexitide could offer in educating the broader market? My second question is on PSP. How would you describe the patient community's awareness of the Phase II HELIOS trial and the ongoing ORION study?

Joshua B. Cohen, Co-CEO

Sure. Regarding the ICD-10 code, we are actively working on it and trying to establish one for this condition. Although there isn't an ICD-10 code yet, we have analyzed claims data from patients who underwent bariatric surgery and later experienced hypoglycemic events. We’ve excluded other potential causes of these events, including various diabetic medications, and our findings align closely with both Dr. Craig’s analysis and the literature. You also inquired about therapy and education needs. From discussions with adult endocrinologists, it's clear that this is a significant issue. Many have characterized this group as our most vulnerable patient population. I encourage everyone to review the Endo presentation, which includes stories of patients so severely affected that they chose to have their pancreas completely removed to avoid severe fluctuations in blood sugar levels, despite the serious consequences of such a decision. This demonstrates the severe impact of PBH on their lives. Many physicians have large groups of patients facing similar ongoing issues. Now, I'll turn it over to Camille to give more insights regarding the patient community and also to address your question about Wolfram.

Camille L. Bedrosian, Chief Medical Officer

Yes. Thank you. Yes, just as a reminder, there are no approved treatments for PSP, and it is a devastating disease that is ultimately fatal. And there isn't even the possibility of treatment for these individuals, unfortunately. So the patient community is very supportive and enthusiastic about the possibilities as are we. We do see this and appreciate the sense of urgency to identify a treatment that will favorably impact these individuals. Having said that, we do understand also from the patient community as well as the investigator and treating community that a clinically meaningful improvement in progression rate relative to placebo is about 20% in the PSP Rating Scale. And that is one of the measures that we're using to make our go/no-go decision. We do want to be sure that AMX0035 could provide a very meaningful benefit to these patients.

Joshua B. Cohen, Co-CEO

And just briefly, I think you asked about HELIOS and Wolfram as well. Really, I guess, in a way across all of the patient communities we serve, both our work and maybe just kind of continued awareness from the community has driven more and more interest, more and more patients kind of getting aware of these conditions. So in Wolfram, one of the things we've heard from Dr. Urano is that ever since we started HELIOS, he's had more and more referrals, more and more patients coming to them with Wolfram syndrome. You may have seen there was actually just a Washington Post article that described one patient's experience with Wolfram syndrome, but I think it is indicative of this something in the Washington Post. So overall, we believe there's about 3,000 people in the United States who have Wolfram syndrome. And I'd also just mention as well that we are one of the first Phase IIIs to be conducted in the condition. So it really is quite an opportunity to bring excitement and awareness to the space.

Operator, Operator

And the next question comes from Corinne Johnson from Goldman Sachs.

Corinne Johnson, Analyst

So maybe one from us. I think in EPI data, you see that Roux-en-Y surgery contributes a bit more significantly to the prevalence of the patient population, and that does align, I think, to your Phase III design. How should we think about that from both a label perspective and also with respect to trends in bariatric surgery approaches, and sort of how that contributes to the incidence or prevalence of PBH from here?

Joshua B. Cohen, Co-CEO

Yes, that's a great question. In our Phase III study, most previous studies with Avexitide included participants with Roux-en-Y as the background. The Phase IIb trial had participants with various types of surgeries, and the effects were quite consistent across these types. However, as we approached Phase III, we aimed to focus on a population where we had the highest level of confidence and data, which is why we concentrated on the Roux-en-Y population. Ultimately, the FDA will determine the label and indication later, but we believe we will have compelling arguments to present. We think the underlying biology is similar across these surgical types, and if additional data is needed, we believe we can efficiently provide it. Regarding trends in surgery, it's been interesting to observe that early in the 2010s, Roux-en-Y was the predominant procedure, but VSG surpassed it in the number of surgeries performed due to perceptions that VSG might be a safer option. However, recent long-term studies have shown that VSG may not be significantly safer than Roux-en-Y, which actually leads to greater weight loss. In the last few years, we've noticed Roux-en-Y regaining some market share from VSG. Anecdotally, discussions with surgeons indicate a growing enthusiasm for Roux-en-Y, particularly because it offers deeper and longer-lasting weight loss, while maintaining a comparable side effect profile. It's hard to predict the exact future, but from our talks, it seems Roux-en-Y is starting to reclaim some share. We believe our drug should be effective across all surgical types, supported by our Phase IIb results. Our goal is for this drug to be applicable across various surgeries.

Operator, Operator

And the next question comes from Marc Goodman from Leerink Partners.

Marc Harold Goodman, Analyst

Can you talk about where these patients are, like are there centers of excellence? What kind of infrastructure would you need to build to reach these patients? And then secondly, just Camille, if you could talk about the powering of the Phase III LUCIDITY trial, what assumptions you have regarding the placebo reduction of Levels 2 and 3?

Joshua B. Cohen, Co-CEO

Sure. Starting with the patient distribution, we have engaged with a variety of clinical and physician sites. The primary focus appears to be on adult endocrinologists who frequently care for these patients. We have talked to endocrinologists managing over 100 patients, and some have even hundreds, while others have only a few. It seems that the number of patients managed varies among different endocrinologists. There are several key opinion leaders emerging in this area, and it's important to note that bariatric surgery began gaining popularity in the U.S. in the early 2000s, which makes this a relatively new field. Many sites are becoming recognized as key opinion leaders, realizing they have substantial patient bases, and positioning themselves as future experts in the field. Overall, we believe there is a significant pool of identified patients at major academic centers that will be crucial during our initial launch. There's also a substantial opportunity for market growth as we continue to educate and reach out to a wider array of physicians. Now, I’ll turn it over to Camille to discuss the powering of the Phase III study.

Camille L. Bedrosian, Chief Medical Officer

Thank you. Just as a reminder, LUCIDITY has around 75 participants, and we expect to complete recruitment by the end of this year. As is typical for Amylyx, we are conservative in our powering assumptions for LUCIDITY. If we see results similar to the Phase IIb trial of Avexitide, with a 90-milligram once daily dose showing approximately a 53% reduction in Level 2 and a 66% reduction in Level 3, both highly statistically significant, we have significantly more than 90% power to detect an effect over placebo. Even if the effect is about a 35% reduction versus placebo, we still maintain 90% power to identify a difference. Therefore, we are very well powered to detect clinically meaningful improvements under even the most conservative assumptions.

Operator, Operator

And the next question comes from Ananda Ghosh from H.C. Wainwright & Co.

Ananda Kumar Ghosh, Analyst

Two questions from me on Avexitide. Based on the Endo discussion, it looks like educating PCPs on early diagnosis is a factor that needs to be considered as well as, already discussed, the PBH codes. So it might be helpful to understand how you're thinking about these issues as you kind of approach that phase during Avexitide development. And the second question is, as you speak with the KOLs, how has the definition of clinical significance looked like for PBH?

Joshua B. Cohen, Co-CEO

Yes, absolutely. We see this as a launch primarily focused on endocrinologists. While primary care physicians likely refer and assist in coordinating patients to endocrinologists, we expect this launch to concentrate on endocrinologists specifically through targeted promotional efforts. These specialists already manage a substantial patient base, presenting significant opportunities. Regarding clinical significance, this topic was directly addressed during the Endo discussion. Physicians indicated that even a single severe hypoglycemic incident is a clinically significant change. Such an event could lead to serious outcomes like a bone fracture or a car accident, potentially resulting in permanent life changes. Consequently, even the reduction of risk or prevention of just one such incident is considered clinically meaningful by the key opinion leaders we consulted.

Operator, Operator

And the next question comes from Tim Anderson from Bank of America.

Unidentified Analyst, Analyst

This is Susan substituting for Tim. My question is about the clinical trial timelines for LUCIDITY. Considering that LUCIDITY's primary endpoint is event-driven, could you discuss the risk of potential delays in the trial due to insufficient events being accrued? Additionally, could you provide more details about the assumptions behind the timeline for the first half of '26 that you've reiterated?

Camille L. Bedrosian, Chief Medical Officer

Sure. This is an interesting question. In the Phase II and Phase IIb studies, we observed a significant reduction in event rates during the run-in period, with a 53% decrease in Level 2 events and a 66% decrease in Level 3 events. Additionally, as we presented at the Endo conference, there was a 64% reduction in the combined Level 2 and Level 3 events. These findings form the basis for our planning of the LUCIDITY trial, and we do not expect event rates to affect it.

Joshua B. Cohen, Co-CEO

Yes. To reiterate our timelines, we expect to complete recruitment by the end of the year and have data available in the first half of 2026. The event rate does not dictate when recruitment ends. We monitor all patients for events, and ultimately, when the last patient is enrolled, it triggers the start of the 16-week study. We are making good progress towards our goals, and we reaffirm our expectation of completing enrollment by the end of the year with data in the first half of 2026.

Operator, Operator

The next question comes from Graig Suvannavejh from Mizuhu Securities.

Unidentified Analyst, Analyst

This is Sam on for Graig, and congrats on the progress. Maybe 2 for me. First, do you anticipate any issues with compliance for Avexitide given the daily injection? And do you think that would potentially limit the population in terms of severity of the disease of who would potentially take it? And then second, I'm just curious what the overall feedback has been from the physician community from the recent Endo conference. If there was any feedback, whether positive or negative?

Joshua B. Cohen, Co-CEO

Maybe I'm happy to start and then maybe pass to Camille to add a little bit at the end as well. So starting on the compliance, the study is still ongoing, of course. But if you look back through the past Avexitide trials, compliance was nearly 100% through those past trials. So we've seen very great compliance with this drug in the past. We've also done market research about injections in this patient population. And by and large, we've heard very little concerns from patients about the daily injectable, including comments from the patients, such as they're often doing finger sticks and describing that a finger stick actually hurts more, fingers are quite sensitive that a finger stick can hurt more than a subcutaneous injection and otherwise. And some of these patients are doing 10, 20 finger sticks a day. The other thing is the efficacy is a big aspect too. Hypoglycemic events are really quite traumatic. Patients describe that often even just psychologically, it can take them several hours before they feel kind of back to normal after a hypoglycemic event occurs. So that's kind of what they're balancing in the equation as well. The idea of a quick daily injectable seems far outweighed by the ability to potentially reduce the incidence of having those events or otherwise, again, from our market research. And then from Endo and the physician community, we've just kind of continued to hear great outreach. We've had a number of different physicians ask if they can be part of the study. We've had a number of them kind of refer patients that they may have to potentially be in the study as well. So we get pretty constant outreach and excitement from patients as well, including requesting compassionate use and otherwise. And I think Endo just drove that even further because there's maybe another moment of putting a spotlight on PBH. Probably said a lot, but Camille, I don't know if there's any additions you want to make?

Camille L. Bedrosian, Chief Medical Officer

Sure. Thank you, Josh. Thanks. Yes. I do have a couple of points. First, regarding compliance and injections. I'll just reiterate, the efficacy is most important for these individuals. And with regard to the study, in particular, we've heard from the PIs that their participants or potential participants are highly motivated and want to participate in the study and do their best possible in the study, including the injections on a daily basis. With regard to Endo, yes, notably as well, there has been quite an exponential uptick in the information about PBH during this year's Endo relative to last year in 2024. So clearly, the awareness is increasing, more to come for sure. And as well, we heard from a number of Endos there that if they have people, and many do have patients who have PBH, they reiterate how fragile these individuals are. So all very exciting and very positive.

Operator, Operator

And the next question comes from Chris Chen from Baird.

Christopher W. Chen, Analyst

I had one on diagnosis rates, kind of diagnosis protocols for PBH. So the Society for Endocrinology came out with new guidelines I think it was last year in the hopes of standardizing diagnosis of PBH. What have you heard from conversations with providers about the potential impact of those more standardized diagnosis guidelines might have? And then I do have a follow-up.

Joshua B. Cohen, Co-CEO

Yes, I can start there. To broadly summarize the general diagnosis for post-bariatric hypoglycemia (PBH), it's quite simple. After someone undergoes bariatric surgery, it’s important to confirm persistent hypoglycemia without any other causes. The diagnostic guidelines can essentially be boiled down to that. Diagnosing PBH is relatively straightforward once a physician considers it. A physician may see a patient experiencing symptoms like dizziness, fainting, confusion, or slurred speech, and connect those symptoms to the patient’s bariatric surgery, suspecting that glucose and blood sugar issues could be the cause. Overall, diagnosing PBH becomes clear once accepted. Additionally, we've noticed an increased awareness and understanding of this condition. This year, some endocrinologists expressed their excitement that the annual recertification exams included questions on PBH for the first time, and it is now mentioned in endocrinology textbooks. Therefore, initiatives like the new guidelines are contributing to a growing awareness and suspicion among physicians when patients with these symptoms have a history of bariatric surgery, indicating that PBH may be involved.

Christopher W. Chen, Analyst

Great. Very helpful. And then just real quick, I know you can't go too deep into details on LUCIDITY. But just wondering if you can offer just some color on anything you're hearing on durability of effect outside of 28 days? And what gives you confidence that you'll continue to see that durability of effect through the 16 weeks?

Joshua B. Cohen, Co-CEO

Yes, I'd say we try to make sure not to analyze a factor of efficacy early in the study. It is a blinded study. But I will say we are happy that we do have patients that have gone out beyond the 28 days of the past studies and are certainly continuing on therapy as well.

Camille L. Bedrosian, Chief Medical Officer

Yes. And I'll just add that we don't anticipate any tachyphylaxis based on the mechanism of Avexitide.

Operator, Operator

Thank you. And there are no further questions at this time. I'll turn the call back over to Mr. Josh Cohen. Please go ahead, sir.

Joshua B. Cohen, Co-CEO

Thank you. So thank you, everyone, for joining us today. Really appreciate the questions. And if you have follow-up questions, please reach out, and we're happy to find time. Thank you all. Have a great day.

Camille L. Bedrosian, Chief Medical Officer

Thanks, everybody.

Operator, Operator

Thank you. This concludes our conference call for today. Thank you all for participating. You may now disconnect.