Q2 2025 Amylyx Pharmaceuticals Inc Earnings Call

Speaker #3: 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.

Speaker #3: 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 on your telephone keypad. To withdraw your question, please press star two.

Speaker #3: Please limit your questions to one question with one follow-up. If you would like to add additional questions, you may rejoin the queue. Please be advised that this call is being recorded at the company's request.

Speaker #3: I would now like to turn the call over to Lindsey Allen of Vice President Investor Relations and Communications. Please go head, ma'am.

Speaker #4: Good morning and thank you all for joining us today to discuss our second quarter 2025 financial results and business updates. With me on the call today are Josh Cohen and Justin Klee, our co-CEOs.

Speaker #4: 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.

Speaker #4: 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.

Speaker #4: These statements include but are not limited to our expectations with respect to a vexatide AMX 35 and AMX 114, statements regarding regulatory and clinical developments, the impact thereof and the expected timing thereof, and statements regarding our cash runway.

Speaker #4: Actual events and results could differ materially from those expressed or implied by any forward-looking statements. Your caution not to place any undue reliance on these forward-looking statements and Amylyx disclaims any obligation to update such statements unless required by law.

Speaker #4: Now, I will turn the call over to Justin.

Speaker #5: 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 of vexatide is an investigational GLP-1 receptor antagonist with FDA breakthrough therapy designation being evaluated for the treatment of post-bariatric hypoglycemia or PBH.

Speaker #5: In April, we dosed our first participant in the pivotal Phase 3 Lucidity trial studying a vexatide in PBH following Roux-en-Y gastric bypass surgery. We continue to expect complete recruitment by year-end.

Speaker #5: We have been pleased by the level of engagement from the clinical trial sites. Just a few weeks ago, we hosted an educational investor event at Endo featuring a panel of KOLs, all experts in treating PBH, including investigators involved in the trial.

Speaker #5: Camille will share a few remarks on Endo shortly. If you were not able to attend or listen live, I encourage you listen to the replay available in the presentation section of our website.

Speaker #5: Importantly, we are preparing to be launch-ready and, if approved, we anticipate a commercial launch of a vexatide in 2027. We have been focused on the initial steps toward building the commercial organization and collecting insights on the market.

Speaker #5: This 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.

Speaker #5: Beginning with a vexatide 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.

Speaker #5: We are pleased with the progress we are making to develop a novel long-acting GLP-1 receptor antagonist. Initial efforts with 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.

Speaker #5: We are excited about this collaboration and will share more as timelines toward I&D enabling studies become clearer. Turning to the rest of our pipeline, AMX-35 is an oral small molecule therapy designed to target endoplasmic reticulum stress and mitochondrial dysfunction.

Speaker #5: We are studying AMX 35 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 US and has no currently approved treatments.

Speaker #5: We expect top-line data from the Phase 2B portion of the Phase 2B3 Orion trial this quarter, which will inform a go/no-go decision on whether we move into the Phase 3 program.

Speaker #5: Wolfram syndrome is a rare progressive monogenic prototypical stress disorder with no approved treatment that we estimate affects approximately 3,000 people in the US alone.

Speaker #5: Earlier this quarter, we presented long-term week 48 data which demonstrated that treatment with AMX 35 led to sustained stabilization or improvement over time in the study's clinical measures.

Speaker #5: These results and discussions with FDA are informing the design of a phase three trial of AMX 35 and Wolfram syndrome, and we expect to provide an update on the program this year.

Speaker #5: Now, turning to AMX 114, our investigational anti-sense oligonucleotide targeting calpane two for the treatment of amyotrophic lateral sclerosis or ALS. We continue to expect early cohort data from our phase one Lumina trial of AMX 114 this year.

Speaker #5: AMX 114 is designed to inhibit calpane two to prevent the breakdown of axons, which was a long fiber that carries signals from neurons to muscles.

Speaker #5: In preclinical studies, AMX 114 demonstrated improved neuronal survival and reductions in extracellular neurofilament light chain or NFL, a key biomarker of neurodegeneration across multiple disease models.

Speaker #5: In June, the FDA granted fast track designation to AMX 114 which provides us with the opportunity for more frequent interactions with the FDA and could allow for an expedited review process.

Speaker #5: Our pipeline progress reflects the focus in 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.

Speaker #5: Now, I'll turn the call over to Camille.

Speaker #6: Thanks, Justin. Touching briefly on the upcoming phase two B data readout in PSP, PSP is a tauopathy characterized by the accumulation of tau protein in the brain.

Speaker #6: Unlike other investigational agents, that have targeted extracellular tau protein or focused on downstream effects, AMX 35 is both brain and cell penetrant. Notably, in our phase two Alzheimer's trial, AMX 35 demonstrated significant reductions in tau protein in cerebral spinal fluid.

Speaker #6: With these characteristics, we believe AMX 35 may offer a differentiated and potentially disease-modifying approach in PSP. We have set a high bar for AMX 35 in PSP.

Speaker #6: 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.

Speaker #6: We plan to base our decision-making for advancing to the phase three portion of the trial on the totality of the data and the potential for clinically meaningful outcomes for those living with PSP.

Speaker #6: Now, let's focus on Vexatide, 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.

Speaker #6: 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 be primarily driven by altered nutrient transit after bariatric surgery.

Speaker #6: Which leads to exaggerated secretion of glucagon-like peptide one, or GLP-1. In individuals with PBH, postprandial GLP-1 levels can be more than tenfold higher than normal.

Speaker #6: Trigging excessive insulin release and subsequent hypoglycemia. A vexatide 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.

Speaker #6: At Endo 2025, we present a new exploratory analysis from the Phase 2 Prevent trial in PBH following Roux-en-Y gastric bypass surgery, and the Phase 2 B clinical trial in PBH following a variety of upper GI surgeries.

Speaker #6: Including Roux-en-Y gastric bypass, sleeve gastrectomy, esophagectomy, Nissen fundoplication, and gastrectomy. These data show that a vexatide 90 milligrams once daily, which is the dose being evaluated in the pivotal phase three lucidity trial, led to a 64% least squares mean reduction in the composite rate of level two and level three hypoglycemic events from baseline in people with PBH.

Speaker #6: With a P value of 0.0031. Importantly, more than half of participants receiving this dose experienced no level two or level three hypoglycemic events during the treatment period.

Speaker #6: Consistent reductions in the composite rate of level two and level three events were also seen with other vexatide doses studied in the phase two and two B trials.

Speaker #6: A vexatide 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.

Speaker #6: These findings build on a consistent body of data from five clinical trials of a vexatide in PBH. When we designed our pivotal Phase 3 Lucidity trial, the goal was to be as consistent as possible with the previous successful Phase 2 study.

Speaker #6: Which directly informed the dose, endpoints, surgical subtype, and inclusion criteria. As a reminder, lucidity is a multi-center randomized double-blind placebo-controlled trial of approximately 75% participants with PBH following Roux-en-Y gastric bypass surgery.

Speaker #6: Lucidity is evaluating the FDA agreed-upon primary endpoint of reduction in the composite of level two and level three hypoglycemic events through week 16. In addition to the analyses Amylyx presented, expert PBH clinicians and researchers shared new data and research findings at ENDO 2025.

Speaker #6: For example, Dr. Colleen Craig and her colleagues at Stanford presented a US 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.

Speaker #6: 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.

Speaker #6: Then, using life expectancy estimates and disease state modeling, they found that nearly 400,000 people in the US who previously underwent bariatric surgery experienced clinically important hypoglycemia defined as glucose less than 54 mg/dL or three or more PBH symptoms.

Speaker #6: Of these, approximately 167,000 people experienced recurrent events that are intense enough to require medical attention. Which is a population considered to have medically important PBH.

Speaker #6: 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 Further and claims-based analyses.

Speaker #6: And underscore both the urgency of the need and the significant opportunity for a xatide to make a meaningful impact for people living with PBH.

Speaker #6: 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 a vexatide.

Speaker #6: Hypoglycemia does not just occur after Roux-en-Y gastric bypass surgery, but after several other types major upper GI surgeries. Which may be conducted for weight loss, gastric or esophageal cancer removal, or severe gastroesophageal reflux disease.

Speaker #6: Additionally, GLP-1 receptor antagonism may be important in several other rare diseases. We continue to work through plans to evaluate a vexatide in these additional areas.

Speaker #6: But first and foremost, our focus is on lucidity. We are pleased by our continued progress on the vexatide program and the growing recognition of PBH as a serious underserved condition.

Speaker #6: 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.

Speaker #6: Jim?

Speaker #7: Thanks, Camille. We ended the second quarter with a cash position of $180.8 million. Compared $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 three lucidity trial of a xatide, expected in the first half of next year.

Speaker #7: Top-line data from the phase two B portion the Orion trial in PSP, expected this quarter. And early cohort data from our Lumina trial of AMX 114 and ALS, expected by the end of the year.

Speaker #7: In addition, our cash supports early commercial preparations for the potential first-to-market launch of a vexatide. Turning now to our results for the quarter. Total operating expenses for quarter were $42.9 million.

Speaker #7: 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 a vexatide and AMX 35 for the treatment of PSP.

Speaker #7: The increase was partially offset by a rease in spending on AMX 35 for the treatment ALS. Selling general and administrative expenses were $15.6 million.

Speaker #7: 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.

Speaker #7: We recognized $7.4 million of non-cash stock-based compensation expense for the quarter. Compared to $9.6 million of non-cash stock-based compensation expense in Q2 2024. With our current cash balance, we believe we're positioned to execute on our clinical milestones.

Speaker #7: We expect our cash runway to last through the end of 2026. With that, I'll turn the call over to Josh.

Speaker #8: 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.

Speaker #8: 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.

Speaker #8: 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.

Speaker #8: 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.

Speaker #8: We look forward to keeping you updated on our progress across our pipeline, now I would like to open the call up for questions.

Speaker #3: Thank you. Ladies and gentlemen, we'll now begin the question and answer session. To ask a question, please press star one on your telephone keypad.

Speaker #3: To withdraw your question, please press star two. Please limit your question to one question with one follow-up. If you have additional questions, you may rejoin the queue.

Speaker #3: At this time, we'll pause momentarily to assemble our roster. Thank you for waiting. We now have our first question. And this comes from Seamus Fernandez from Guggenheim.

Speaker #3: Your line is now open. Please go head.

Speaker #9: Great. Thanks so for the question. so really the question that I have is, more on the understanding of the market opportunity. you know, there's a lot confusion, I think, in the marketplace in terms of how the moderate to severe patient population, actually, you know, is broken up.

Speaker #9: 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 a vexatide would be.

Speaker #9: And just sort of a separate, very quick follow-up question, is just the pace of enrollment, in your phase three. Just hoping, you might be able to give us a little bit of a sense, your confidence in recruiting that study seems quite high, I just wondering, how we should anticipate that enrollment to proceed, given the timing of the phase three data in the first half of next year.

Speaker #9: Thanks so much. Thanks, Seamus. so maybe going one by one. starting on the market, yeah, we've continued to, learn and continue to dive in.

Speaker #9: We actually updated our slide and our deck as well, so you can see a little bit more information there on the market as well.

Speaker #9: You know, I think as we've continued to learn about hypoglycemia, these are the, you know, even a single hypoglycemic event can be very dramatic for patients.

Speaker #9: It could be a moment where they fracture a bone, it could be a moment where they fall downstairs or, you know, potentially crash a car.

Speaker #9: and it's traumatic. you know, 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.

Speaker #9: you know, both in terms of their diet, you know, being on a very restrictive diet where they have very, very few carbs and aren't able eat, you know, are only able eat very, very small, meals.

Speaker #9: 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, you know, I'd say in general, is is very eager for treatments and, ou know, for potential, benefits.

Speaker #9: you know, and breaking down a little bit, you know, Dr. Craig did present, recently at Endo, some information on on prevalence, as well. she estimated overall, you know, a prevalence of about, 160,000 of what she called medically important PBH, which was defined by people that were seeking medical care.

Speaker #9: you know, for their, you know, PBH. she further subsetted that down to about 30,000 patients that was what she called critical PBH, which were people who were, you know, potentially going to an you ow, or a hospital.

Speaker #9: you know, for an inpatient visit, you know, to manage their PBH. so, working a little bit on, ou know, maybe your follow-up question of exactly who, you know, gets on drug first, you know, what is the very first segment, that we might, ou know, tackle in the market.

Speaker #9: that's work we're still doing commercially, but I think overall, you know, we do believe that there are, you know, you know, approximately 160,000 patients who may ultimately benefit, you know, over time, you know, we continue educating and building the market.

Speaker #9: you also asked about the pace of enrollment in the clinical trial. so, you know, we expect to complete enrollment by the end of the year.

Speaker #9: you know, with data in the first half of 2026, we're making good progress towards that goal. so, you know, we reiterated that goal today as well.

Speaker #7: Thanks so much.

Speaker #3: Thank you. And the next question comes from Joseph Thom from TD Cowen. Your line is now open. Please go head.

Speaker #10: Hi there. Good morning. Thank you taking my estion. maybe the first one on the phase three, lucidity trial design, just because this, treatment period is a little longer than the other, the phase twos.

Speaker #10: I guess, can you just remind us what you have in place to prevent patients from self-libilizing their diet or maybe how that can be tracked?

Speaker #10: 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 be a certain level improvement on the the PSP RS?

Speaker #10: 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? Thank you so much.

Speaker #6: 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.

Speaker #6: Everyone is already on medically medical nutrition therapy beginning, with the run-in period. And participants are asked to continue doing whatever they were doing during run-in throughout the trial.

Speaker #6: 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.

Speaker #9: And maybe I might just add there as well, you know, this is also, you know, consistent. In fact, if anything, even more, close management as what was in the phase two and phase two B.

Speaker #9: so just as, as Camille said, at every interaction with the site, at every visit, patients are, you know, reminded, kind of retrained, on the appropriate, diet for people with post-bariatric hypoglycemia.

Speaker #9: you know, there were some dietary training in the phase two and phase two B. This is even more significant. And as a reminder, the phase two and phase two B showed, you know, quite significant, you know, results on the hypoglycemic endpoints, that were that we're looking at here.

Speaker #9: so maybe I'll pass back to Camille on PSP.

Speaker #6: Sure. Yeah. 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, you know, they do, identify and follow the instructions.

Speaker #6: Based on their motivation. And that was observed in phase two, two B. With regard to PSP program, as, we remarked, earlier, we are looking at a clinical endpoint.

Speaker #6: The progression rate, as measured by the PSP RS, as well as biomarker and imaging data, will all factor into our go/no-go decision for PSP.

Speaker #6: And also, as a reminder, we are setting a high bar, as noted earlier.

Speaker #7: Great. Thank you y much.

Speaker #3: Thank you. And the next question comes from Michael DiFiori from EverCore. Your line is now open. Please go head.

Speaker #7: Hi, guys. Thanks so much for taking my questions. Two for me. One on the PBH market. what's the potential for payers to, h, force step edits on on these non-approved therapies such as dizoxide and octreotide?

Speaker #7: I an, recognizing that most of these patients will probably have been already on them. especially the the severely affected patients. But for new, newly diagnosed patients, what's the potential for, step step therapy edits?

Speaker #7: I have a follow-up. Thank you.

Speaker #9: sure. So 'm happy to start with that one. So we don't anticipate that. you know, one, there's not really any solid clinical evidence that those therapies, you know, are effective in PBH.

Speaker #9: So that, you know, n't be the, you know, payers wouldn't turn to that given the lack of clinical evidence. for benefit. I'll also add just, you know, as we've spoken to physicians, as we've spoken to patients with this disease, there's very minimal, you know, satisfaction with those, therapies.

Speaker #9: Both in terms of patients continuing to have, you know, significant amounts of events, even when on those therapies, as well as, you know, a number of side effects that they experience, you know, when taking them.

Speaker #7: Got it. That's, that's very helpful. and my second question is on the PSP trial. I mean, as we headed, into the internal analysis for this trial, how should we think about the variation in treatment duration across patients given that, you know, all patients will have been treated for 24 weeks, but I think you mentioned before that that some patients will have been treated for much longer.

Speaker #7: So I guess what I'm asking is, is what, is the potential for these longer, duration patients to really drive the signal? versus the, the ones who are just treated for 24 weeks.

Speaker #7: Thank you.

Speaker #6: Yep. Thank ou, Mike. all participants will have completed 24 weeks of treatment. And that's the analysis that we'll be doing. And you are correct.

Speaker #6: We will also look data through 52 weeks for those who have, progressed and advanced through 52 weeks. All the data will be taken into account, not one or another driving more or less our o-no-go decision.

Speaker #7: Okay. So basically just the, the interim just be at the 24-week endpoint for everybody. That'll be the analysis?

Speaker #6: And, and yes, that will be the analysis. And we will also, understand what longer-term treatment does for these participants as well.

Speaker #9: Yeah. We'll, we'll use all available data in the analysis. you know, I think as Camille mentioned, at least everyone will have crossed that week 24 time point.

Speaker #9: if there are, you know, important differences between week 24 and, you ow, going out to, you know, full duration time point, we'll definitely explore those and share those, you know, as well.

Speaker #7: Got it. Thanks so much.

Speaker #3: Thank you. And the next question comes from Jeff Meacham from City. Your line is now open. Please go head.

Speaker #10: Hey, guys. Good morning. This is Jarway on for Jeff. just, a couple of quick questions from this. Again, on the PBH market opportunity, you know, the lack of an ICD-10 code has made it a little challenging to pinpoint an exact prevalence number.

Speaker #10: and to that effect, ou know, you guys mentioned, you know, current efforts underway to, to, to get a ter understanding of the market opportunity.

Speaker #10: And so as you talk to additional, you ow, payers and, and additional KOLs, you know, what do you think would be the, the, the easiest path forward to, to demonstrate, you know, the need for a therapy and, and the benefit that a vexatide could bring?

Speaker #10: When you think about the need for educating the broader marketplace, and then a question real quick on PSP, how would you characterize the patient community and its awareness of the Phase 2 Helios trial and the ongoing Orion study?

Speaker #10: Thanks.

Speaker #9: Sure. so maybe starting on the ICD-10 code, you know, one I'd say, you know, stay tuned there. It's definitely an area of active work.

Speaker #9: towards having an ICD-10 code in this, condition. We've also done a good amount of claims work. you know, while there isn't an ICD-10 code, we've able to analyze the claims looking at, you know, those patients who have had bariatric surgery, who go on to have hypoglycemic events, and we've ed to eliminate, other possible causes for this hypoglycemic events.

Speaker #9: Such as various diabetic medications, you know, and otherwise that, that might be, you ow, causative for that hypoglycemia. when we've done that analysis, we do get very similar numbers to both what, Dr. Craig's analysis, you know, comes up with.

Speaker #9: As well as, you know, what our analysis, you know, from the literature. you know, comes up with as well. you also asked about the, you know, need for therapy and education.

Speaker #9: I will say as we've oken to adult endocrinologists, it really isn't hard to, you ow, hear messages about, you know, just how significant the need is.

Speaker #9: you know, a number of endocrinologists have described this as, you ow, our most fragile patient population. you know, we've heard, you know, I, I definitely encourage two to, you know, for all, all listening to kind of go through the endo present, endo presentation, as well.

Speaker #9: But in that, there were a couple patient stories including, you know, a couple patients who, you know, found their symptoms so severe they ultimately decided to have their pancreas fully removed.

Speaker #9: you ow, just to kind of prevent these kind of, you know, you ow, ups and downs, of blood sugar. And having your pancreas fully removed has a lot of downstream consequences.

Speaker #9: But, you know, that was the kind of risk-benefit, analysis they made because how severe, PBH was and how, you know, significantly it was affecting their life.

Speaker #9: so it, really has not been hard to find, you know, a number of physicians, who have, you ow, sizable, you know, groups of patients, who are experiencing kind of, you know, consistent and, you know, progressive, you know, you ow, events as well.

Speaker #9: Maybe I'll pass over to Camille to talk a little bit about the, you ow, patient community as you were saying in, PSP. And I, I think you asked about, you know, potentially Wolfram as well or, or I way.

Speaker #6: Yeah. Yeah. Thank you. Yes. just as a reminder, there are no approved treatments for PSP and it is a devastating disease that is ultimately fatal.

Speaker #6: 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.

Speaker #6: We do see this and appreciate the sense urgency to identify a treatment that will favorably impact these individuals. Having said that, you know, we, we do understand also from, patient community as well as the, investigator and treating community, that, a clinically meaningful improvement in or improvement in progression rate relative to placebo is about 20% in the PSP RS, the clinical rating scale.

Speaker #6: 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, AMX 35 could provide a very meaningful, benefit to these patients.

Speaker #9: and just briefly, I, you know, I think you asked about helios and Wolfram as well. really I ess in a way across all of the patient communities we serve, both our work and, you know, maybe just kind of continue awareness from the community, has driven more and more interest, more and more, you know, patients, you know, kind of getting, aware of these conditions.

Speaker #9: so, you ow, 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 him, you know, Wolfram syndrome.

Speaker #9: you may have seen there was ally just a Washington Post article that described, one patient's experience, with Wolfram syndrome. But I think it is indicative of this.

Speaker #9: You know, something, you know, in the Washington Post. So, you know, overall, we believe there's about, 3,000 people in the United States who have Wolfram syndrome.

Speaker #9: And, you know, I, I'd also just, you ow, mention as well, that, you know, we are one of the first, you know, phase threes to be conducted.

Speaker #9: And the condition, so it really is, you know, quite an opportunity to bring, you know, excitement and awareness, to the space.

Speaker #7: Awesome. Thank ou.

Speaker #3: Thank you. And the xt question comes from Corinne Johnson from Goldman Sachs. Your line is now open. Please go head.

Speaker #11: Good morning, guys. so maybe one from us. I think in the FDA 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 ink, to your phase three design.

Speaker #11: 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 that contributes to the incidence or prevalence of PPH from here?

Speaker #11: Thanks.

Speaker #9: Yeah. Great question. so yes, in our phase three study, to most of the past studies with a vexatide, you know, enrolled with Roux-en-Y, as a background, the phase two B did actually enroll people who had multiple surgical types and the effect looked very similar.

Speaker #9: across all those surgical types, but going in phase three, we wanted to go in a population where we had the absolute most confidence, the absolute most data.

Speaker #9: so that's y we ran it in the Roux-en-Y population. ultimately label and indication will be, you know, determined, you know, later. by the FDA, but we do believe, you know, we will have arguments, you know, to make, you know, we do believe pathophysiology is similar.

Speaker #9: you know, across these, you know, surgery types. And if we have to generate additional data, that's something that we think we can do, you know, very efficiently.

Speaker #9: from a trends in 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.

Speaker #9: Really in the early 2010s, VSG, passed it, in terms of, you know, the 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.

Speaker #9: over, kind of the 2010s and even more recently, longer-term outcome studies have come out that in fact, you know, it doesn't appear that VSG is really, you ow, safer, than the, than Roux-en-Y.

Speaker #9: And Roux-en-Y causes, you know, more significant weight loss. So if you look at the last maybe three or four years, you see Roux-en-Y starting to take some share back, from VSG.

Speaker #9: And I'll say anecdotally when we've spoken to, surgeons, especially in this era of, you know, kind of ight management and otherwise, we have heard kind continued excitement towards Roux-en-Y.

Speaker #9: including because it causes, you know, deeper and longer-lasting weight loss. Ultimately with a, you know, in their view, kind of a similar side effect, profile.

Speaker #9: so I'd say, you know, hard to know exactly what the future may hold, but at least from our conversations, we think Roux-en-Y is, you ow, continuing to, ou know, maybe take some share, back, as well.

Speaker #9: But maybe just reiterating initially, we believe our drug, you know, there's no ason our drug shouldn't work across all these surgeries and ur phase two B, supports that as well.

Speaker #9: So, you know, that's definitely our ultimate plan is this, you know, to be a drug that, that spans across surgeries.

Speaker #3: Thank you. And the next question comes from Mark Goodman from Learink Partners. Your line is now open. Please go head.

Speaker #12: Yes. Good morning. Can ou talk about where these patients, are? Like, you know, are there centers of excellent? What kind infrastructure would you need to build to, reach these patients?

Speaker #12: And then secondly, just, Camille, if you could talk about the powering of phase three, lucidity trial and what assumptions you have for the placebo reduction of, levels two and three.

Speaker #12: Thanks.

Speaker #8: sure. So starting with where are the patients. So we've, spoken to, you know, many different clinical sites. and, you know, physician sites, so primarily the call point seems to be adult endocrinologists.

Speaker #8: who are most often caring for these patients. we've spoken to adult endocrinologists who have over 100 patients, sometimes hundreds patients, under their care. We've oken to ones that have tens and 've spoken to ones that have a handful.

Speaker #8: so it does seem that, you know, different endocrinologists, you know, proportionally have different, numbers of these patients as well. There are, you know, a number of KOLs who have kind of arisen in this space.

Speaker #8: 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.

Speaker #8: You know, there is a sense that, you know, there are number of sites that have become KOLs recently and there are a number of ones that are, kind of rising KOLs, if you want to put it that way.

Speaker #8: you know, who are, you know, becoming, you know, realizing that they have a pretty sizable patient pool. And kind of becoming, you ow, I guess you could kind of tomorrow's experts, you know, in this space as well.

Speaker #8: So I think overall, we think that there's a, you know, identified, you know, a significant pool of identified patients who are at, you know, major academic centers that will definitely be really important.

Speaker #8: You know, it’s kind of early in our launch, but also quite an opportunity to continue building and growing market share over the long term as we keep educating and expanding out to the broader pools of physicians as well.

Speaker #8: maybe I'll pass over to Camille for the, the powering of the phase three study.

Speaker #6: 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.

Speaker #6: Just, just to let you ow. We are, we, as, as is usual for Amylyx, we are conservative in our powering assumptions for lucidity. So first, if we see similar results, to the phase two B trial of vexatide with the same 90 milligram once daily dose, of approximately 53% reduction in level two and 66% reduction in level three, both highly statistically significant.

Speaker #6: We have substantially more than 90% power to detect and affect over placebo. If we, if the effect is approximately 35% reduction versus placebo, we still have 90% power.

Speaker #6: to detect a difference. So very well powered for detecting clinically meaningful improvement under even the most conservative assumptions.

Speaker #7: Thanks.

Speaker #3: Thank you. And the next question comes from Ananda Garth from HE Wainwright & Co. Your line is now open. Please go head.

Speaker #13: Hey, hi. Thanks, guys. two questions from me on a vexatide. It's, you know, based on the endo discussion, look like educating PSP, PCPs on early diagnosis is an, you ow, a factor that needs to be considered.

Speaker #13: as well as, you know, already discussed the PBH codes. so, you know, might be helpful to understand how are you thinking these issues as you kind of, you know, approach that phase, during the a vexatide development.

Speaker #13: And the second question is, as you speak with the KOLs, what has been, you know, how, how has been the definition of clinical significance, looks like?

Speaker #13: for, for, for, for PBH.

Speaker #9: Yeah. Absolutely. So maybe starting, we definitely see this as a, you know, endocrine-centered launch. So, you know, yes, you know, ultimately PCPs do probably, you ow, refer and kind of help triage the patients, to the endocrinologists.

Speaker #9: But, you ow, our anticipation is that this will be, you know, you know, kind of a targeted launch where we're focused on the endocrinologists, particularly with, you ow, kind of our personal promotion, you ow, efforts as well.

Speaker #9: And those endocrinologists already have, you know, quite a significant, you know, number of patients as well. so, you know, there's quite a lot of opportunity, in that as well.

Speaker #9: in terms of clinical significance, the question I ally got asked, directly at the endo present, you ow, at the end of discussion as well, and, the physician's response and kind of what we've heard as we've spoken to KOLs is, even one, you know, significant hypoglycemic event is a, is a clinically meaningful change.

Speaker #9: You know, any one hypoglycemic event could be the moment where somebody fractures a bone, crashes a car, you know, has basically a permanent change in their life, based on the, you know, downstream consequences of that, of that event.

Speaker #9: So even prevent, even reducing the risk or preventing, you know, one event, was viewed as clinically meaningful by, by the KOLs we spoke to.

Speaker #7: Great. Thank you.

Speaker #3: Thank you. And the next question comes from Tim Anderson from Bank of, America. Your line is now open. Please go head.

Speaker #14: Hi. Good morning. This is Susan on for Tim. Thanks for taking our questions. So my question is on the clinical trial timelines for Lucidity.

Speaker #14: Given that lucidity does primary endpoint is event-driven, what can you, can you talk about the risks of the trial might be delayed, due to the lack of events accrued?

Speaker #14: And then just as a follow-up, can you talk a little bit more about the assumptions underlying the first half 26 timeline that, you've reiterated?

Speaker #14: Thank you.

Speaker #9: Sure. I'll pass that over to Camille.

Speaker #6: Sure. So, actually, we don't believe there will be, in, so I'll, I'll, I'll again. this is, an interesting question. What we saw in the phase two and phase two B 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 two events.

Speaker #6: 66% reduction in level three. And as we described during the endo presentation, endo conference on our poster, with the composite, we also saw a 64% reduction in the composite of level two and level three.

Speaker #6: So that, those results are, you know, a, a framework against which we're, we've planned and are basing our idity trial. We don't anticipate event rates having an impact.

Speaker #8: Yeah. And maybe just adding to reiterate our timelines, you know, 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, you know, when, you ow, recruitment completes.

Speaker #8: you know, we track all patients, you know, for, for events. and ultimately when the last patient's in, that kind of, I guess, you know, starts them towards, you know, completing the 16-week study.

Speaker #8: so, you know, from every, we're making good progress against our, you know, against our goals for that. So we reiterated today as well, you know, our anticipation of completing enrollment, you know, by the end of the year with data in the first half of '26.

Speaker #3: Thank you. And, yes, the next question comes from Craig. You've gone ahead from Mizuhu Securities. Your line is now open. Please go head.

Speaker #15: Hi. This is Sam on from Craig. Thanks taking our question and congrats on the progress. maybe two for me. First, do you anticipate any issues with compliance for a vexatide given the daily injection and, and do you think that would potentially limit, you know, the, the population in terms of severity of the disease of, who would potentially take it?

Speaker #15: And then second, I'm just curious what the overall feedback has been from the physician com, community from the, the recent endo conference. If there's any, feedback whether positive or negative, thank ou.

Speaker #9: Yeah. Maybe I'm happy to start and then maybe pass to, you know, Camille to add a little at the end as well. So starting on the compliance, you know, study's still ongoing, of course, but, you ow, if you look back through the past of vexatide trials, you know, compliance was nearly, you know, 100%.

Speaker #9: 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.

Speaker #9: And by and large, we've, you know, heard very little concerns from patients about, you know, the daily injectable. Including comments from the patients such as, you ow, they're often doing finger sticks and describing that a finger stick, you know, actually hurts more.

To hear a great Outreach. Um, we've had a number of different, um, Physicians, ask, um, if they can be part of the study, um, we've had a number of them kind of refer patients, um, that, you know, they, they may have, um, you know, to potentially be in the study as well. Um, so we get pretty constant, um, Outreach and excitement, um, from patients as well, you know, including requesting compassionate use and otherwise. Um, and I think Endo just, um, drove that even further because it was, maybe another moment of, um, putting a spotlight on pbh, um, probably said a lot, but you know, Camille. I don't know if there's any any additions you want to make sure. Thank you, Josh. Thanks. Uh, yes, I do have a couple of points. Uh, first regarding the compliance and injections, uh, you you I just reiterate. The efficacy is most important for these individuals and with regard to the study in particular, we've heard.

From the pi that their participants or potential. Participants are highly motivated and are very, um, 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 endow. Yes, uh, notably as well. There has been a a quite an exponential uptick in the information about pbh during this year's Endo relative to last year uh 2024. So um clearly the uh awareness is increasing uh more to come for. Sure. And uh as well we heard from um a number of endos there that if they have people and many do have have patients who have pbh, and they reiterate, how fragile these individuals are. So all very exciting and very very positive.

Powerful color. Thanks so much.

I had 1 on.

Diagnosis rates, um, kind of diagnosis, protocols for pbh. So you know, the society for endocrinology, you know, came out with with new guidelines. I think it was last year um, in the hopes of standardizing, you know, diagnosis of PVH

What have you heard um from conversations with providers, you know, about the potential impact, those more standardized, um, you know, diagnosis guidelines might have and I do have a follow-up.

Basically sum up that the diagnostic, you know, guidelines is that, um, it's actually a relatively easy diagnosis to make, um, once a physician suspects it. Um, so I think that's the most important thing that a physician, you know, maybe has a patient in front of them, who's having things like dizziness, um maybe has had some um events of syncope you know of loss of consciousness um events of confusion or slurred speech or otherwise and you know, to put the dots together that they've had a bariatric surgery and that, you know, glucose and blood sugar might be at, um, you know, might be the culprit, um, for what they're experiencing. Um, so it's actually quite um, you know, in a a straightforward diagnosis to make, um, you know, once once it expects it, I think by and large going with that as well. We have seen kind of a continued uptick in kind of awareness and understanding of this disease, um, we did hear from a couple endocrinologists who are, you know, interested in the pbh space that they were really excited that this year for the first time

Um, on the, um, annual, you know, Endo boards where you have to get kind of rectified as an endocrinologist, that there were questions on PBH. Um, you know, PBH is kind of also now in the endocrinology, um, textbook, um, you know, as well. Um, so I do think there's, you know, things like the guidelines also, you know, as you called out too, there's a number of different initiatives that are going that, you know, kind of continue to build the awareness and the, you know, suspicion. You know, when a patient has these types of symptoms and they've had Barry after.

Surgery that pbh might be might be at play.

Great, very helpful. Um, and then just real quick, you know, I know you can go too deep into details on on Lucidity. Um, but just wondering if you can offer, just some color on, you know, anything you're hearing on durability of effect, you know, outside of of 28 days, um, and and what gives you confidence that, you know, you'll continue to see that durability of effect, um, you know, through the 16 weeks,

Yeah, I'd say we we try to make sure not to um you know, analyze you know, the factor efficacy. You know, early in the study it is a blinded study. Um, but I will say we are, you know, happy that we do have patients that have gone out, um, you know, beyond, you know, the 28 days, you know, the past studies and are certain, you know, continuing on therapy as well.

Yeah, and I'll just add that. We don't anticipate any tactical access based on the mechanism of of Exile.

Helpful, thank you so much.

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

Thank you. Um, so thank you everyone for joining us today. Really appreciate the questions. And, you know, 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.

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