AMLX - NASDAQ

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. [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 Lindsay Allen, Vice President, Investor Relations and Communications. Please go ahead, ma'am.

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.

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 postbariatric 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 time lines 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 designed to inhibit Calpain-2 to prevent the breakdown of Axon which is a long fibers that carry signals from neuron 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.

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 accretion 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% lease squares mean reduction in the composite rate of Level 2 and Level 3 hypoglycemic events from baseline and people with PBH with a p-value of 0.0031. Importantly, more than half of 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 5 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 inform 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 analysis analysts 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 5 years, including an assessment of prevalence and incidence based on surgical subtype. Dr. Craig and 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 mgs per deciliter or 3 or more PBH symptoms. Of these, approximately 167,000 people experience recurrent events that are intense enough to acquire medical attention, which is a population considered to have medically important PDH. 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, GLP1 receptor antagonism may be important 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?

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 5 for the treatment of PSP. The increase was partially offset by a decrease in spending on AMX0035 5 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 expense for the quarter compared to $9.6 million of noncash stock-based compensation expense 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.

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

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.

Thanks, Seamus. So maybe going one by one. Starting on the market, yes, 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. These are the -- even a single hypoglycemic event can be very dramatic for patients. It could be a moment where they fracture 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.

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

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.

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 checks 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.

And maybe I may just add there as well. This is also consistent. In fact, if anything, even more close management as 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 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.

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 are -- they do identify and follow the instructions based on their motivation and that was observed in Phase II/IIb. With regard to 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.

And the next question comes from Michael DiFiore from Evercore.

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.

Sure. So I'm happy to start with that one. So we don't anticipate that. One, there's not really any solid clinical evidence that those therapies are effective in PBH, so that wouldn't be -- the payers wouldn't turn to that given the lack of clinical evidence for benefit. I'll also add, just as we've spoken to physicians, as we've spoken to patients with this disease, there's very minimal satisfaction with those therapies, both in terms of patients continuing to have significant amounts of events even when on those therapies as well as a number of side effects that they experience when taking them.

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.

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 in 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.

Okay. So basically, just the interval will just be at the 24-week endpoint for everybody that will be the analysis.

And yes, that will be the analysis, and we will also understand what longer-term treatment does for these participants as well.

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.

And the next question comes from Jeff Meacham from Citi.

This is [ Jarvey ] on for Jeff. Just a couple of quick questions from us. Again, on the PBH market opportunity, the lack of an ICD-10 code make it a little challenging at pinpointing an exact prevalence number and -- so that's -- secondly, you guys mentioned current efforts underway to get a better understanding of the market opportunity. And so as you talk to additional payers and additional KOLs, what do you think would be the easiest path forward to demonstrate the need for a therapy and the benefit that Avexitide could bring when you think about the need for educating the broader marketplace? And then a second question real quick on PSP, how would you characterize the patient community and its awareness of the Phase II HELIOS trial and the ongoing ORION study?

Sure. So maybe starting on the ICD-10 code. One, I'd say, stay tuned there. It's definitely an area of active work towards having an ICD-10 code in this condition. We've also done a good amount of claims work. While there isn't an ICD-10 code, we've been able to analyze the claims looking at those patients who have had bariatric surgery, who go on to have hypoglycemic events. And we've tried to eliminate other possible causes for those hypoglycemic events, such as various diabetic medications, and otherwise, that might be causative for the hypoglycemia. When we've done that analysis, we do get very similar numbers to both what Dr. Craig's analysis comes up with as well as what our analysis from the literature comes up with as well. You also asked about the need for therapy and education. I will say, as we've spoken to adult endocrinologists, it really isn't hard to hear messages about just how significant the need is. A number of endocrinologists have described this as our most fragile patient population. We've heard -- I definitely encouraged to, for all listening, to kind of go through the Endo presentation as well. But in that, there were a couple of patient stories, including a couple of patients who found their symptoms so severe, they ultimately decided to have their pancreas fully removed just to kind of prevent these kind of ups and downs of blood sugar and having your pancreas fully removed has a lot of downstream consequences. But that was the kind of risk-benefit analysis they made because of how severe PBH was and how significantly it was affecting their life. So it really has not been hard to find a number of physicians who have sizable groups of patients who are experiencing kind of consistent and progressive events as well. Maybe I'll pass over to Camille to talk a little bit about the patient community, as you were saying in PSP. And I think you asked about potentially Wolfram as well. Eric can touch on it either way.

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 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 PSPRS, the clinical rating scale. And that is one of the measures that we're using to make our go/go no decision. We do want to be sure that AMX0035 could provide a very meaningful benefit to these patients.

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.

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

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 like 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?

Yes, great question. So yes, in our Phase III study, to most of the past studies with Avexitide enrolled people with Roux-en-Y as a background, the Phase IIb did actually enroll people who had multiple surgical types and the effect look very similar across all those surgical types. But going into Phase III, we wanted to go in a population where we had the absolute most confidence, the absolute most data. So that's why we ran it in the Roux-en-Y population. Ultimately, label and indication will be determined later by the FDA, but we do believe we will have arguments to make. We do believe pathophysiology is similar across these surgery types. And if we have to generate additional data, that's something that we think we can do very efficiently. From a trends on surgery perspective, it's actually been interesting to hear. If you go back to kind of the early days of bariatric surgery, Roux-en-Y was the dominant surgery really in the early 2010s, VSG passed it in terms of kind of the incident surgeries that were happening. And that was mainly due to a lot of kind of messages that were coming out that VSG might be the potentially safer surgery. Over -- kind of the 2010 and even more recently, longer-term outcome studies have come out that, in fact, it doesn't appear that VSG is really safer than Roux-en-Y and Roux-en-Y causes more significant weight loss. So if you look at the last maybe 3 or 4 years, you see Roux-en-Y starting to take some share back from VSG. And I'll say anecdotally, when we've spoken to surgeons, especially in this era of kind of weight management and otherwise, we have heard kind of continued excitement towards Roux-en-Y, including because it causes deeper and longer lasting weight loss, ultimately with, in their view, kind of a similar side effect profile. So I'd say, hard to know exactly what the future may hold, but at least from our conversations, we think Roux-en-Y is continuing to maybe take some share back as well. But maybe just reiterating initially, we believe our drug -- there's no reason our drug shouldn't work across all these surgeries and our Phase IIb supports that as well. So that's definitely our ultimate plan is for this to be a drug that spans across surgeries.

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

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 Phase III LUCIDITY trial, what assumptions you have the placebo reduction of Levels 2 and 3.

Sure. So starting with where are the patients. So we've spoken to many different clinical sites and physician sites. So primarily, the call point seems to be adult endocrinologists who are most often caring for these patients. We've spoken to adult endocrinologists who have over 100 patients, sometimes hundreds of patients under their care. We've spoken to ones that have 10s, and we've spoken to ones that have a handful. So it does seem that different endocrinologists proportionately have different numbers in these patients as well. There are a number of KOLs who have kind of arisen in this space. But I'd maybe remind as well that bariatric surgery started becoming popular in the U.S. in the early 2000s. So this is a somewhat newer phenomenon too. There is a sense that -- there are a number of sites that have become KOLs recently, and there are number of ones that are kind of rising KOLs, if you want to put it that way who are becoming -- realizing that they have a pretty sizable patient pool and kind of becoming, I guess, you could say kind of tomorrow's experts in this space as well. So I think overall, we think that there's a identified significant pool of identified patients who are at major academic centers that will definitely be really important kind of early in our launch, but also quite an opportunity to continue building and growing the market over the long term as we keep educating and expanding out to the broader pools of physicians as well. Maybe I'll pass over to Camille for the powering of the Phase III study.

Sure. Thank you. Thanks, Mark. Just as a reminder, LUCIDITY is approximately 75 participants. And also, we expect to complete recruitment by the end of this year, just to let you know. We are -- as is usual for Amylyx, we are conservative in our powering assumption of LUCIDITY. So first, if we see similar results to the Phase IIb trial of Avexitide with the same 90-milligram once daily dose of approximately 53% reduction in level 2 and 66% reduction in Level 3, both highly statistically significant, we have substantially more than 90% power to detect an effect over placebo. If we -- if the effect is approximately 35% reduction versus placebo, we still have 90% power to detect a difference. So very well powered for detecting clinically meaningful improvement under even the most conservative assumptions.

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

2 questions from me on Avexitide. Based on the Endo discussion, look 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 are you 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, what has been -- how has been the definition of clinical significance looks like for PBH.

Yes, absolutely. So maybe starting -- we definitely see this as an endocrine centered launch. So yes, ultimately, PCPs do probably refer and kind of help triage the patients to the endocrinologists. But our anticipation is that this will be kind of a targeted launch where we're focused on the endocrinologists, particularly with kind of our personal promotion efforts as well. And those endocrinologists already have quite a significant number of patients as well. So there's quite a lot of opportunity in that as well. In terms of clinical significance, the question actually got asked directly at the Endo discussion as well. And the physician's response and kind of what we've heard as we've spoken to KOLs is even one significant hypoglycemic event,is a clinically meaningful change. Any one hypoglycemic event could be the moment where somebody fractures a bone, crashes a car, has basically a permanent change in their life based on the downstream consequences of that event. So even reducing the risk or preventing one event was viewed as clinically meaningful by the KOLs we spoke to.

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

This is Susan on for Tim. So my question is on the clinical trial time lines for LUCIDITY. Given that LUCIDITY's primary endpoint is event driven, what -- can you talk about the risk that the trial might be delayed due to the lack of events accrued. And then just as a follow-up, can you talk a little bit more about the assumptions underlying the first half '26 time line that you've reiterated?

Sure. I'll pass that over to Camille.

Sure. So actually, we don't believe there will be -- so I'll begin again. This is an interesting question. What we saw in the Phase II and Phase IIb studies were that the event rates from the run-in period were reduced substantially as we noted in from the data and the results, 53% reduction in Level 2 events, 66% reduction in Level 3. And as we described during the Endo conference poster with the composite, we also saw a 64% reduction in the composite of Level 2 and Level 3. So that -- those results are a framework against which we've planned and are basing our LUCIDITY trial. We don't anticipate event rates having an impact.

Yes. And maybe just adding to reiterate our time lines, so we anticipate completing recruitment by the end of the year with data in the first half of 2026. The event rate doesn't actually drive when recruitment completes. We track all patients for events and ultimately, when the last patient is in that kind of I guess, starts them towards completing the 16-week study. So from every -- we're making good progress against our goals for that. So we reiterated today as well our anticipation of completing enrollment by the end of the year with data in the first half of '26.

The next question comes from Graig Suvannavejh from Mizuhu Securities.

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?

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, 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 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. And the idea of a kind of 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 do you want to make?

Sure. Thank you, Josh. Thanks. Yes. I do have a couple of points. First, regarding the 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 are very much want to participate in the study and do the 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 and they reiterate how fragile these individuals are. So all very exciting and very positive.

And the next question comes from Chris Chen from Baird.

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.

Yes, maybe happy to start there. So I think maybe broadly characterize the general diagnosis for PBH is in very simple terms, once somebody has bariatric surgery, confirming that they have hypoglycemia, persistent hypoglycemia and that there's not another explanatory cause. You can basically sum up the diagnostic guidelines as that. It's actually a relatively easy diagnosis to make once a physician suspects it. So I think that's the most important thing that a physician maybe has a patient in front of them who's having things like dizziness, maybe has had some events of syncope, loss of consciousness, events of confusion or slurred speech or otherwise. And to put the dots together that they've had a bariatric surgery and that glucose and blood sugar might be at -- might be the culprit for what they're experiencing. So it's actually quite a straightforward diagnosis to make once one accepts it. I think by and large, going with that as well, we have seen kind of a continued uptick and kind of awareness and understanding of this disease. We did hear from a couple of endocrinologists who are interested in the PBH space that they were really excited this year for the first time on the annual Endo boards, where you have to get kind of recertified as an endocrinologist that there were questions on PBH. PBH is kind of also now in the endocrinology textbook as well. So I do think there's -- things like the guidelines also, as you called out, too, there's a number of different initiatives that are going that kind of continue to build the awareness and the suspicion when a patient has these types of symptoms and they've had bariatric surgery that PBH might be at play.

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?

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.

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

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.

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.

Thanks, everybody.