Good morning. My name is Cass, and I will be your conference operator today. At this time, I would like to welcome everyone to the Amylyx Pharmaceuticals phase III LUCIDITY Top Line Data Conference Call. All participants will be in a listen-only mode. After today's presentation, there will be an opportunity to ask questions. To ask a question, please press star one on your telephone keypad. To withdraw your question, please press star one. Please limit to one question with one follow-up. If you have additional questions, you may rejoin the queue. Please be advised that this call is being recorded at the company's request. I would now like to turn the call over to Lindsey Allen, Vice President, Investor Relations and Communications. Please go ahead. Good morning, and thank you all for joining us today to discuss the top line results from the phase III LUCIDITY trial of avexitide in post-bariatric hypoglycemia, or PBH. The slide deck accompanying our remarks this morning will be available on the Investors section of our website for your reference following the conclusion of the call. With me on the call today are Josh Cohen and Justin Klee, our Co-CEOs, Dr. Camille Bedrosian, our Chief Medical Officer, Dr. Marilyn Tan, Principal Investigator of the LUCIDITY clinical trial and Clinical Professor of Medicine at Stanford University School of Medicine. Jim Frates, our Chief Financial Officer, and Dan Monahan, our Chief Commercial Officer, will join us for the Q&A portion of the call. 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, the therapeutic potential and safety of avexitide as a treatment for PBH, expectations regarding the timing for NDA submission with the FDA, the potential benefits of regulatory designations held with the FDA, the plan to present data at an upcoming medical meeting, and expectations regarding the timing and preparations for potential commercialization of avexitide if approved. Actual events and results could differ materially from these expressed or implied by any forward-looking statements as a result of various risks, uncertainties, and other factors, including those set forth in our most recent filings with the SEC and any other future filings that we may make with the SEC. 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'll turn the call over to Camille. Thank you, Lindsey, and thank you all for joining us this morning. It is with great enthusiasm that we share the positive top-line results from the phase III LUCIDITY trial of our lead asset, avexitide, an investigational first-in-class GLP-1 receptor antagonist in post-bariatric hypoglycemia, or PBH, following Roux-en-Y gastric bypass surgery. LUCIDITY met its FDA agreed-upon primary endpoint, demonstrating a 55% reduction in the composite rate of Level 2 and Level 3 hypoglycemic events compared to placebo, p-value of 0.000003. The trial also met all secondary endpoints, demonstrating consistent reductions in both Level 2 by self-monitoring blood glucose, or SMBG, and continuous glucose monitoring, or CGM, and Level 3 hypoglycemic events versus placebo. Importantly, avexitide was generally well-tolerated through the double-blind study period with a favorable safety profile. LUCIDITY is the sixth clinical trial of avexitide to generate statistically significant results in PBH and the largest and longest study conducted to date. Taken together, these findings support the potential for avexitide to become the first FDA-approved therapy for PBH, a condition with a profound unmet medical need. I would like to briefly recap the design of the phase III LUCIDITY trial. LUCIDITY is a multicenter, randomized, double-blind, placebo-controlled trial evaluating the efficacy and safety of avexitide in adults with PBH following Roux-en-Y gastric bypass surgery. The pre-specified primary endpoint was the composite rate of Level 2 and Level 3 hypoglycemic events compared to placebo through week 16. In addition, we evaluated secondary endpoints of Level 2 hypoglycemic events as measured by SMBG and by blinded CGM and Level 3 hypoglycemic events. Level 2 events are defined as glucose levels below 54 mg per deciliter, an established threshold for clinically significant hypoglycemia, and Level 3 events are defined by significant cognitive or physical impairment requiring assistance from another person. These endpoints capture hypoglycemic events that matter to patients and can have meaningful consequences for safety and day-to-day functioning. In a few moments, Dr. Tan will speak about the day-to-day impact of PBH on those living with this condition. In the trial, 78 participants were randomized three to two to receive either avexitide 90 mg once daily or placebo. The treatment groups were generally well-balanced. More than 90% of the participants completed the 16-week double-blind treatment period, and all eligible participants entered the ongoing open label extension portion of the trial. Avexitide met the primary endpoint, demonstrating a 55% reduction in the composite rate of Level 2 and Level 3 hypoglycemic events compared to placebo through week 16, with a p-value of 0.000003. It is important to note that these results are on top of current standard of care, medical nutrition therapy. We are deeply inspired by these results and the potential to address a longstanding unmet need for people living with post-bariatric hypoglycemia. In addition, LUCIDITY met all secondary endpoints, demonstrating consistent, highly statistically significant, and clinically meaningful reductions in Level 2 hypoglycemic events by SMBG, Level 2 hypoglycemic events by CGM, and Level 3 hypoglycemic events compared to placebo. Taken alone, each of the pre-specified primary and secondary endpoints yielded highly statistically significant and clinically meaningful results. Taken together, these efficacy findings demonstrate a compelling body of evidence for avexitide in PBH. Avexitide was generally well-tolerated in the double-blind portion of LUCIDITY, with a safety profile consistent with that observed across all PBH clinical trials completed to date. The majority of adverse events were mild to moderate, and there were no serious adverse events deemed related to avexitide treatment. The most common adverse events were diarrhea, injection site redness or erythema, and injection site bruising. Furthermore, there were no changes in body weight observed in either the avexitide or placebo groups over the 16-week double-blind period. To close, the LUCIDITY results demonstrated highly statistically significant and clinically meaningful reductions in hypoglycemic events, together with a favorable safety profile. Based on these positive data, we believe that avexitide has the potential to be the first ever FDA-approved therapy for PBH. I want to thank the PBH community for their collaboration and participation in the study, including the 21 LUCIDITY sites, investigators, study coordinators, and importantly, the participants. I also want to acknowledge our outstanding Amylyx team for their unwavering dedication to running such a robust and high-quality trial. Now, I would like to turn over to Dr. Tan, Principal Investigator of the LUCIDITY clinical trial, to give an overview of PBH and what these trial results mean to the PBH community. Thank you, Camille. It is my pleasure to be here today to discuss these exciting results and how they can make a difference for this underserved population. PBH is a rare chronic metabolic condition believed to be caused by an exaggerated GLP-1 response, primarily after food intake, resulting in recurrent and often debilitating hypoglycemia. These episodes can lead to neuroglycopenic symptoms, including cognitive impairment, loss of consciousness, and in some cases, seizures, or even worse. Patients frequently describe living with PBH as a constant cycle of highs and lows, with sudden and unpredictable glucose crashes that can be difficult to anticipate and manage. The impact extends far beyond just physical symptoms. The unpredictability of hypoglycemia can affect a person's ability to work, drive, care for family members, participate in social activities, or even remain alone safely. As a result, many patients structure their daily lives around the risk of hypoglycemic events, creating a substantial burden both on the patients and their loved ones. This burden is reflected in patient-reported data. In one study, more than 90% of individuals with PBH described themselves as living with a disability. This underscores the profound impact the condition can have on quality of life and day-to-day functioning. Based on a growing body of prospective and retrospective published literature, we estimate that PBH impacts approximately 5% of people who have undergone sleeve gastrectomy and 12% of people who have undergone Roux-en-Y gastric bypass, the two most common types of bariatric surgery. This corresponds to an estimate of approximately 160,000 people living with PBH in the U.S., who require medical management, but currently have only the option of medical nutrition therapy and off-label medications, which are usually inadequate. This is also why I am so excited about the potential for avexitide in this disease space. Looking mechanistically, individuals with PBH can present with more than 10 times normal physiologic GLP-1 activity. By binding to the GLP-1 receptor on pancreatic islet beta cells, avexitide is designed to reduce this exaggerated GLP-1 response and restore activity towards more physiologic levels. Today's positive results support the hypothesis that a GLP-1 receptor antagonist targets a central pathway of PBH pathophysiology. The top-line results show that avexitide significantly reduced both SMBG and CGM Level 2 and Level 3 hypoglycemic events, which can each be medical emergencies. Based on my clinical experience treating people living with PBH, they want more than anything to reduce the number of hypoglycemia events so that they can live independently without the fear of hypoglycemia. This is our hope for the approximately 160,000 people with PBH in the U.S. alone, who face a significant unmet need for treatment. Importantly, avexitide was generally well-tolerated with a favorable safety profile. Overall, these results build on positive results from five prior clinical trials of avexitide in PBH. Today marks a significant moment for the PBH community, who have a high unmet need for an FDA-approved treatment. PBH is a lifelong journey, and I believe that avexitide has the potential to be a first-in-class treatment for patients that will make a meaningful difference in their lives. Now, I would like to turn it back over to Josh, Co-CEO of Amylyx. Thank you, Dr. Tan. Our mission at Amylyx is to deliver novel therapies for communities with high unmet needs. Today's results are an important step forward towards achieving this goal. With these results in hand, we are acting with urgency to bring this potential treatment to the PBH community. We have been advancing NDA readiness and regulatory preparations so we can move rapidly now that we have positive top-line data. Avexitide has received Breakthrough Therapy Designation from FDA, and we are working expeditiously towards an NDA submission by the end of this year. Following the top-line data readout, we are also focused on presenting the LUCIDITY results through congress presentations and publications and deepening our understanding of PBH via expert engagement. We continue to execute against a comprehensive launch readiness roadmap to ensure we are fully prepared for commercialization of avexitide if approved in 2027. As part of our launch readiness efforts, we are continuing to build our understanding of the PBH market and making key hires in our medical affairs and commercial organizations. Additionally, we recently activated our disease state education campaign, Uncover the Mystery of Post-Bariatric Hypoglycemia, to address the educational need among HCPs and the PBH community. As part of this initiative, we launched uncoverpbh.com. This platform provides educational resources for both healthcare professionals and the PBH community. With over $250 million in cash on hand at the end of Q2, we believe we are well-positioned to execute on the next stages of our launch plans. We are excited about today's results and the potential to bring avexitide to people living with PBH as the first approved therapy of its kind. I'll now turn the call over to Justin for concluding remarks. Thank you, Josh. At the start of the year, we outlined three primary objectives for avexitide, to deliver top-line data from the LUCIDITY trial, advance NDA readiness to support a potential submission, and strengthen our commercial launch preparations. With strong top-line data in hand, we have achieved our first objective. We are well on our way to achieving our further objectives as we diligently prepare to advance avexitide through the regulatory process and ultimately, if approved, deliver this potential treatment to the PBH community. This is a remarkable moment for people living with PBH, their loved ones, and for Amylyx, and we are deeply grateful for everyone's support. I would like to once again thank the PBH community, investigators, and our team for their collective efforts. Now, I would like to open it up for Q&A. Thank you. We will now begin the question and answer session. To ask a question, please press star one on your telephone keypad. To withdraw your question, please press star one again. Please limit your question to one with one follow-up. If you have additional questions, you may rejoin the queue. At this time, we will pause momentarily to assemble our roster. Your first question comes from the line of Seamus Fernandez with Guggenheim Securities. Your line is open. Great. Thanks for the question and congratulations on the data. Maybe just one confirming question. As I look at the data and the way that it is presented, I think the most simplistic way to look at this without knowing the exact placebo response, maybe to draw us back to the phase II results where we saw 55%-60% absolute reduction in the events. Is that the right way to think about the data? It is just we have not seen slides posted yet, and so it is a little bit challenging to draw conclusions there. So if you could tell us the placebo response, that would be very helpful. If it is the right way to think about it, just go back to the phase II because you are preserving these results for publication and for a major medical meeting, that would be super helpful, I think, to everybody on the line. Separately, we have this outstanding question, and this is a question for the team and for Dr. Tan as well. Is there any reason to think that Roux-en-Y versus all other types of PBH or hypoglycemia brought on by bariatric surgery or even a gastric surgery would have a meaningfully different result than what we saw in this Roux-en-Y patient population. I ask that question just because it seems like there is a broader potential opportunity should the agency take a more flexible approach to the results that were just published. Hi, this is Dr. Tan—s orry. [crosstalk]. Oh, no problem. Yeah, possibly. I am happy to maybe take the first one on Dr. Tan, then I will pass to you right after that if it works. Sounds good. So maybe first, kind of confirming on your first question about the placebo. Yes, I think you are thinking about it right, and probably overall, our goal in LUCIDITY was to be as consistent with the prior trials as possible. I think we are quite excited to have seen that the results appear quite consistent with what we have seen in prior trials. Yes, the 55% is relative to placebo, very similar to the 55% reduction we saw in the composite relative to placebo in PREVENT, the phase II trial. Then, yes, on your question about Roux-en-Y versus other surgical types, I will pass to Dr. Tan. Thank you. As mentioned, the data from phase II-B in particular, we had reanalyzed looking at a similar endpoint, so we are very excited for the results compared to placebo. As you know, this study was in patients with Roux-en-Y gastric bypass, and increasingly we are seeing more vertical sleeve gastrectomy. However, there is still a very prevalent population of those with Roux-en-Y gastric bypass. In my personal practice, I have many patients actually with other subtypes of surgery as well, which you alluded to. Many patients who have had total gastrectomies for gastric cancer, Nissen fundoplications, other upper GI surgeries. While this study only included patients with Roux-en-Y gastric bypass, the phase II-B study did include patients with other surgical subtypes. When we separated out the VSG and gastrectomy patients, their response to avexitide was just as robust for reducing Level 2 and Level 3 events. We know that there is an exaggerated GLP-1 response in those patients as well. So, I am excited to have this option available, and I am fairly certain that most HCPs who are treating these patients would use it in PBH patients who have other surgical subtypes. Yeah, I will just add— Thanks so much. Just to give a little more context from our perspective and a bit on the landscape. I think the best current prevalence estimates come from the work from the team from Stanford, which found that the current U.S. prevalence of PBH is about 160,000 people. Of that group, the estimate is about 120,000 of the 160,000 had Roux-en-Y gastric bypass leading to their PBH. As Dr. Tan said, there are many different surgeries that can lead to this condition. I'd say from an FDA perspective, obviously it's early. We have yet to even submit our NDA. Our position is that PBH is PBH, and we have evidence that avexitide appears to work regardless of the surgical intervention. FDA can also take the stance that the phase III population was Roux-en-Y gastric bypass PBH. We'll see as we get into the NDA. Again, our belief is that PBH is PBH. However, if we need to run an additional study to show that comparability, we think we can do that in a pretty efficient manner, given that we can see the effect of avexitide in a single dose. Thanks. I'll drop back in the queue. Your next question comes from the line of Joseph Thome with TD Cowen. Your line is open. Hi there. Good morning. Thank you for taking my questions, and congratulations on the data. Maybe one for Dr. Tan. Can you talk a little bit, assuming a broad label here, how quickly this would be adopted into your practice? Maybe, what proportion of your PBH patients would you recommend the therapy to upon approval? Then one for the company. Is there anything left on the pivotal path to the NDA submission related to CMC, or is it mostly just getting this data into the NDA now? Anything you can highlight there? Thank you. Thank you. My patients and I are extremely excited. The patients who have been on prior studies, the patients who are following this on the Facebook group are asking me. I literally had two ask me yesterday in clinic, "When can I be on this drug?" There is a lot of excitement. Despite it being a new therapy, people are ready for it. I don't think that there will be any hesitation. There is robust evidence in the PBH population. More importantly, there is just no other effective treatment for these patients. To actually have a dedicated treatment targeted for this disease that actually targets the underlying pathophysiology is extremely exciting. Yeah. As far as your second question on, excuse me, on the NDA submission. We have been working on the NDA this entire year given the confidence in the five prior trials in anticipation of these results. I will say these results exceeded even our high expectations, which is really exciting, with both the significant primary outcome and also the consistency across the secondary outcomes. As far as the NDA submission goes, our goal was really to be in a position where the last piece would be the phase III data and all of the writing associated with that. That is the position we are in today. We are in a very strong position with our NDA. The goal is to submit by year-end. We have a Breakthrough Therapy Designation for avexitide, which makes the product eligible for priority review. With that, that's how we are planning for a potential launch of avexitide, if approved, next year in 2027. Perfect. Thanks so much. Your next question comes from the line of Michael DiFiore with Evercore ISI. Your line is open. Hi, guys. Thanks so much for taking my question and huge congrats on the data. Very well deserved. Two questions from me. Would you be able to provide the mean and median absolute composite event rates for avexitide and placebo as well as for the three-week run-in? My second question is, what was the percent of avexitide patients with zero Level 2 or Level 3 events over the 16 weeks? I think your phase II-B showed that this proportion was greater than 50% who were event-free. Thank you. Yeah. Thanks, Mike. Here we're presenting the primary outcome, which to remind, we saw a 55% reduction with a p-value of 0.000003, which we're incredibly excited about. That's our primary outcome here. I think as Seamus brought up a little bit earlier, we do want to preserve some results for publication. We haven't given every nitty gritty detail at this point. What we have seen is consistent and strong results across, including hitting every single one of our secondary outcomes with high statistical significance. I think probably same answer on the question of percent with zero. I think you can probably tell from the p-value, the placebo and active groups are quite separated. Great. Thanks so much. Your next question comes from the line of Geoff Meacham with Citigroup. Your line is open. Hey, guys. Good morning. This is Jarwei on for Geoff. Just wanted to add our congratulations on the strength of the data as well. Maybe first for Dr. Tan, just a question on Level 2 versus Level 3 differences given it's very quite apparent that the placebo response and the avexitide response are quite separated. But at the end of the day, does it really matter the differences between Level 2 and Level 3? Or does the totality of the composite is just so compelling that it would be broadly applicable to patients living with PBH? Then for the Amylyx team, just thinking about the data that you guys generated, can it be utilized to maybe generate some pharmacoeconomic estimates? Just thinking about from the reimbursement perspective. Thank you. I can go first. As you noted, the data are just so compelling, and it was statistically significant for both Level 2 and Level 3. I would say that from a clinical standpoint, we make this distinction in research, right? We have to have cutoffs. We have to have a number cutoff, and we have to have an adjudication committee to verify that it is a Level 3 event. But, in the real world and in clinical practice, any hypoglycemia event can lead to a catastrophic accident or some other bad outcome. So really, any reduction in these clinically significant episodes of hypoglycemia is meaningful to these patients. Yeah. I would just add from a pharmacoeconomics perspective, we are continuing to evaluate and continuing to learn there. We did present a poster at ENDO earlier this year, where we began to describe the burden of PBH from a pharmacoeconomic perspective. Probably unsurprisingly, given how severe these events are, there is quite a large economic burden to the healthcare system from PBH. So, we do believe a drug that is able to impact that can have quite a significant benefit there as well. But, that is something we will continue to research as we go into our payer interactions. I will just add from a payer perspective as well. First of all, there are no treatments for PBH today. So, that is the landscape that we go into. However, payers are very aware of the dangers of hypoglycemia, given their long time coverage of insulin and other drugs that may be associated with hypoglycemia. So, I think they are very aware of just how dangerous severe hypoglycemia is for individuals, and I think that gives us a great position as we work toward the hopeful approval of what would be the first approved treatment for people with PBH. Great. Thank you. Your next question comes from the line of Marc Goodman with Leerink Partners. Your line is open. Yes, good morning. Can you talk about the diarrhea adverse event? Was it relatively mild? Did it occur at the beginning of the 16 weeks? Was it lasting throughout the whole period? Maybe Dr. Tan, was it severe enough that anybody complained about it? And you think would prevent anyone from using the drug? Thank you very much. Happy to start, then we can pass to Dr. Tan. I'd say again, obviously these are the top line results, but I'd say generally the safety profile was quite good, and avexitide appeared to be quite well tolerated in line with prior studies. Generally, events such as diarrhea were mild or occasionally moderate. I would say just generally, we had very good compliance continuation in the study. All eligible participants went into the open label extension. Hopefully, that gives you a sort of population view. I'll pass to Dr. Tan for her comments on the study as well. Yeah. I can't speak to the exact details of all of the participants, but I can tell you that I did not have any participants discontinue, and all of them went on to open label extension. Just looking back at the prior trials that I've done with avexitide, and there have been four that I was the principal investigator, or three others that I was the principal investigator on. I have not had any drug discontinuations. Even patients who have had any GI events in the past have asked me repeatedly when they can get back on the drug. It has not been anything to the point where it discourages a patient from actively seeking out the treatment again. Can I just ask, Dr. Tan, how many patients do you have that would be eligible here for this drug? The vast majority of my patients, over 90%. I have a more severe patient population, which tends to be more moderate to severe, although I do have a couple of mild ones that I've just kind of incidentally diagnosed in my clinic. But, I would say anybody who is having any clinically important hypoglycemia would qualify for this medication. A nd for waiting, t hey're excited. They're ready. Over 90% of what absolute number? Well over 100. But, I don't focus so much on the number because I personally limit my clinic because I have no meaningful treatment for them. More importantly, I'd like to highlight that I literally get one or two new referrals each week, sometimes more, which I expect there will be more after this week, from all over the country, and from even outside of the country for PBH patients. So had I actually accepted all of those, I would have probably over 1,000 patients. I've literally had that number of referrals over the last couple of years. Thanks so much. Your next question comes from the line of Rami Katkhuda with LifeSci Capital. Your line is open. Hi, everyone. Just wanted to pass along my congrats on the data as well. Fantastic results. I guess, can you touch on how consistent the efficacy was across baseline disease severity? Did patients with the highest event burden derive a similar, greater, I guess, relative benefit? Could that influence whether the initial commercial focus is concentrated in more severe PBH patients? Yeah. So one, I'll just remind that everybody in the study was required to have at least an event per week during the run-in. So that was one of the key inclusion criteria of the study. I'd say based on the kind of difference you see here and the strength of the p-value, the groups are quite separated. No individual or no small set of patients is driving this. The groups are really not overlapping once they're on drug. We'll continue to share more details as we get towards publications and presentations as well. Rami, I'll just add a bit to that. So, of course, the primary outcome, 55% reduction and a very significant p-value. I think that gives a good picture. It's also the consistency across all secondary outcomes. Level 2 hypoglycemia, self-monitored blood glucose, Level 2 hypoglycemia by CGM, and Level 3 events, all consistent with the primary outcome, all highly statistically significant as well. Hopefully, that gives you the results were very robust. Has the strength of the LUCIDITY results changed or accelerated your plans for avexitide outside the U.S.? I would say that we went into the study with high confidence, given the five prior trials. These results, as I said, really even exceeded our high expectations. I would say, remind us of the unmet need in PBH, including, as you were saying, for other surgeries leading to hypoglycemia. I note that it depends on the region you're in the world, what surgery leads to hypoglycemia. We estimate in Europe that there's a similar prevalence as in the United States. In most major Asian countries, for example, Japan, there are very high rates of gastric cancer. People get a gastrectomy for their gastric cancer, and a significant portion of people develop this same chronic hypoglycemia condition. We have data from the phase II-B that avexitide appears to work regardless of the gastric surgery that led to the hypoglycemic condition. We're very excited about the opportunity internationally as well. We hear from people around the world, as Dr. Tan does, very consistently asking about avexitide. First and foremost, we also have to execute on what we have in front of us in the U.S. Our first objectives are really submitting the NDA, preparing for U.S. commercialization next year. We certainly have our eyes internationally as well. Thank you, and congrats again. Thank you. Your next question comes from the line of James Condulis with Stifel. Your line is open. Hey, thanks for taking my question, and congrats on the data. Great to see. Maybe one on efficacy. Curious if you can comment on any quality of life measures you looked at and what benefit you saw there, if any. Maybe more broadly for Dr. Tan, it would be helpful if you could just help us sort of characterize how meaningful these hypoglycemic data are in terms of translating into everyday life and improving quality of life. Thanks so much. Yeah, I'll comment very briefly, then pass to Dr. Tan. We're still analyzing data. Here we have kind of the top-line results. We'll expect to have our PROs later on. I would say, part of the goal and the primary outcome of Level 2 and Level 3 hypoglycemia, these are clinical events that have inherent significance. I'll pass to Dr. Tan to talk more there. Yeah. Clinically, I would actually think back to that first slide that was shown with our patient with PBH. I don't know if any of you have seen a video that was her in her home talking about how being on avexitide made her feel like she could take care of her own children, gave her the confidence, actually, to have another child. That is how life-altering just her couple of weeks on avexitide was for her, to show her that she could, at some point, have the hope to function independently. That is obviously a very extreme situation, but that is the degree of impact the hypoglycemia has on these patients. As mentioned, we will have more data on the quality of life later, but just based on individual patient testament, the patients who just tell me, "This changed my life. My husband can now go to work during the day," things like that. It's just life-altering, not only for the patients, but also for their families. Makes sense. Thank you. Your next question comes from the line of Graig Suvannavejh with Mizuho. Your line is open. Hey, good morning. Thanks for taking my questions, and congrats on the data. I have two, one for Dr. Tan. Dr. Tan, in the future potential of avexitide being approved for your PBH patients, if we go on an assumption, just an assumption, that the label is restricted to patients who have had Roux-en-Y procedures, can you talk about what you think it would be like for patients who have not had Roux-en-Y surgeries to be able to get avexitide? I am trying to get your sense of what you think the work would be involved on either your end or others to have the drug used in patients who have had surgeries or procedures done otherwise, and them being able to get on treatment. My second question is for the company. Team, again, congrats on the data. I was wondering if you could just review kind of where we are in the competitive landscape. I saw a development last week that a phase II company working in the space went public, and just wanted to get your thoughts on where you think kind of the competitive landscape is right now. Thanks. Yeah, maybe I will comment very briefly, then pass to Dr. Tan as well. I think for any drug, it is only appropriate to be prescribing the drug on label. That would be our focus, depending on whatever label we ultimately are able to receive from the FDA if we are potentially approved in 2027. Maybe I will just touch the competitive comment, and then I can pass to Dr. Tan if she wants to add anything as well. I think, especially with these results today, there really, in our view, is nothing that has the profile of avexitide. Our focus is on getting it to patients who can potentially benefit if approved in 2027. Well, just adding one other point as well. I think, again, I go back to first the prevalence estimates today of the current people in the U.S. who have PBH. We estimate that about 120,000 out of the 160,000 had Roux-en-Y gastric bypass leading to their PBH. If we find ourselves in the position, where FDA requires additional evidence to show that avexitide works in other surgeries that led to the same hypoglycemic condition, again, we think we can do that pretty efficiently, given the now six studies supporting the effectiveness of avexitide. The fact that we can see it in a single dose, and I think this all gets the point that we really think we're getting to the heart of PBH with the GLP-1 receptor antagonist. Okay, and I can follow up on that. As Josh noted, the target is on-label use with this trial. But as a clinician and healthcare provider caring for patients with PBH, I can tell you that people with other surgical subtypes will be doing anything possible to get on this therapy, whether it's on-label or off-label. I am not advocating for off-label use per se, but I'm confident that if another trial were needed, I have a list of patients with VSG and gastrectomy and other surgeries who are anxiously waiting, and literally asking me every week when they can be in a trial and when they can be on the drug. I don't think that another trial would be a challenge in any way. Okay. Thank you. Your next question comes from the line of Jason Gerberry with Bank of America. Your line is open. Hey, thanks for taking my question. One for me, just for Dr. Tan. I guess it would seem like there's a complex referral pattern to get these patients to endocrinology specialists. But your comment about an expectation for a pretty quick ramp to a larger patient population. Maybe what gives you the confidence in how you see this referral pattern sort of settling out over time? Do you just think it's word of mouth and education more broadly in the community that an option's out there? Because I guess one would wonder, it's a pretty rare population, so how you see that dynamic playing out? Thanks. Yeah. When I first started my work with avexitide over 10 years ago, it was hard to find patients because there wasn't a large community. There was no ICD- 10 code, which we're excited to share, if you're not aware already, will be coming later this year. But, the awareness has really increased significantly over the last 10 years, and you can see that reflected in the fact that there will be a diagnostic code, that there's a large patient Facebook group, and actually not just for PBH patients, but also there is a large support group for total gastrectomy patients with gastric cancer where they talk about the hypoglycemia. Furthermore, as one of the earlier questions were about the competitive landscape, you can see that there is obviously awareness from other companies as well, that there is this increasing unmet need. My referrals have only increased over the last 10 years as I've done more and more of these studies, and I'm confident that the referrals will continue and will increase after this week. And I have to create space for these patients in my clinic. We do have other providers in our clinic as well, but there's a lot of excitement over this, and even our fellows, for example, are so excited to see these cases because they present these really I guess, they're challenges, but in a very satisfying way when you get a good result from these patients. Thank you— Jason, if I just may, I will add a couple more comments there. Just from initial market research that we have done, there is a very high intent to treat amongst the endocrinology community. So with the patients that they have in front of their setting, we have tested this, and again, there is a high intent to treat. That would be the first point. The second is we have launched our disease state educational efforts, and we have received great feedback from both the community as well as from the endocrinology community. So as these educational efforts take hold, the market will continue to grow over time. So yes, there are patients in these various settings of care that we are aware of, but as we continue to educate the endocrinology community, I think we will see more and more comfort from community endocrinologists and their willingness to prescribe as well. Thank you. Your next question comes from the line of Ananda Ghosh with H.C. Wainwright. Your line is open. Hey. Hi. Congrats on the fantastic data, guys. Two questions. Given the data, what did the trial teach you in terms of the placebo response, blinded CGM unmask, the fear of unmasking, daily injection issues? And probably more importantly, what it taught about the mechanism itself? Is there a window beyond 55% that keeps an option for developing a franchisee-based pipeline over the period of time? Also, can tolerability be managed like the GLP-1s? Thank you. Yeah. Great question. I think first and foremost, we tried to design LUCIDITY based on the prior trials. The goal was to replicate as closely as possible those very strong results we had seen in the past studies. I think what we were quite excited about was, as I mentioned earlier, PREVENT the phase II study at a 55% reduction in the composite. Here, we also saw a 55% reduction in the composite. I think we were able to take the learnings from the past study as we designed and executed the phase III as well. I think on your question on tolerability, the drug was very well tolerated. More than 90% of people completed the study, and everybody who was eligible for the OLE went into it as well. I think it does continue, even from some of the early work at Stanford and otherwise, there has been a strong link that GLP-1 is one of, if not the main driver of this disease. I think seeing the strong efficacy just kind of further supports that kind of mechanistic understanding that GLP-1 seems to be sort of at the center of why these patients are experiencing hypoglycemia. Ananda, I will just add with that is why we started investing in our next generation candidate, AMX0318, our long-acting GLP-1 receptor antagonist. That is in IND- enabling studies now. Our goal is to submit the IND next year, and to have that in clinical development alongside the potential launch of avexitide. We really do think that this exaggerated GLP-1 response is at the center of PBH. So, we really do see many opportunities to continue to innovate, and continue to try to help as many people with PBH as we can. Thanks. Thanks, guys. Congrats again. Sorry. I just had a couple things to add. There were a couple of parts about that question. Yeah, sure. Hopefully I addressed all of it. Yeah. There was a question about the CGMs, and I have actually received many questions about the alarms. We had thought about this and very thoughtfully considered where to set that alarm cutoff. Primarily, our concern was safety for this patient with a high degree of hypoglycemia unawareness. I think some people had asked me, are we worried that the alarm might make us miss hypoglycemia events? Clearly from the data, with that 55% reduction, we did not have events missed. The CGM did not interfere. As Josh and Justin noted, compared to the prior studies where we did not have alarms, we saw similar results. Tolerability to me is not of concern. As noted, we have not had any significant treatment-related adverse events. In my prior clinical trials, I have not had any patients discontinue due to any tolerability issues. I think there was a question about the daily injections, I know that the long-acting version was mentioned. I can tell you that this population is extremely motivated. While medication adherence in some other chronic diseases may be variable, I think that's largely driven by the fact that many chronic diseases are asymptomatic. For example, if you miss a shot of insulin, maybe your CGM alarms you that you're high, but you don't really feel it unless you're in severe dangerous hyperglycemia. If you miss a dose of your statin or your injectable cholesterol medicine, you probably won't have symptoms. However, if you have PBH and you miss a shot of your avexitide, you will be symptomatic once you eat. That in itself is a daily reminder and motivator for these patients. I would say that the adherence with symptomatic disease and the willingness to continue with therapies with symptomatic disease far exceeds that of other chronic diseases that are less symptomatic. Got it. Thanks very much for the color. Your next question comes from the line of Christopher Chen with Baird. Your line is open. Good morning. Thanks for taking my question, and let me add my congratulations. Great data. First for Dr. Tan, just regarding standard of care for PBH currently, could you just provide a rough estimate of your patients who are on acarbose? Of those on acarbose, how well their symptoms are being managed and how willing they are to try avexitide. Then just for the team, regarding regulatory, I know you have breakthrough designation. Any thoughts on pursuing priority review or rolling review or both? Thank you. Yeah. The question of acarbose, it is off-label therapy, but I agree that it is essentially the standard of care for these patients for a couple of reasons. We have a lot of experience with it from long-term use as a diabetes drug. It is fairly well-tolerated with minimal risk, aside from some bloating. Importantly, it is inexpensive. However, the issue is just that it is really not effective. While some small studies have shown fairly convincing data with oral glucose tolerance testing and mixed meal tolerance test, the reality in clinical practice is that probably about 5% of my patients actually get some relief from acarbose. I have more patients where I just keep them on it, because in my mind, if it provides any bit of relief when there is really not much else that is effective. If it helps reduce their hypoglycemia by 5% even, we will take it, right? There is nothing else available currently. But, I would say that in my patient population, it is fewer than 5% that are reasonably controlled on acarbose alone. Thank you, Chris. On the regulatory front, so we are working hard on the NDA. Goal is to submit by the end of the year. With Breakthrough Therapy Designation, that does make that medication eligible for priority review, so we will be seeking priority review. We could also be eligible for rolling NDA submission. However, we have been working on all sections of the NDA all year, with the goal of submitting the whole package at once. So our plan is to submit the full NDA by the end of year, and to seek priority review as well. Very helpful. Thank you, and congrats again. Your next question comes from the line of Ferdi Li with Wolfe Research. Your line is open. Hey, thanks for taking my question, and congrats again on strong data. I have a question. Can you talk about the plan to continue to build your GLP-1 antagonist franchise? Maybe talk about the timeline strategy for avexitide label expansion, but also importantly for the long-acting play with AMX0318. Thanks. Yeah, great question. I think exactly as you mentioned, we remain incredibly excited about our GLP-1 antagonist franchise opportunity as well. First and foremost, as you heard from Dr. Tan, this is a really serious condition, and we want to get this therapy to patients who can potentially benefit in the U.S. as quickly as possible. However, as we've continued to learn, PBH does not just occur in the U.S. It occurs worldwide with similar numbers of bariatric surgeries overall occurring in Europe. And also people getting hypoglycemia from other surgeries of the upper GI tract, whether that's gastrectomy for gastric cancer, esophagectomy for esophageal cancer, Nissen fundoplication for severe gastric reflux disease, et cetera. So those are certainly things that we're thinking about. And then also, w hile avexitide, as Dr. Tan has said, we don't believe that the once-daily injectable will be a challenge for people living with PBH. We are continuing to invest in additional presentations including a longer-acting AMX0318. Just to remind, that came out of a collaboration with Gubra, who are a company really focused in peptide drug discovery and development. We worked with them to try to make as optimized a GLP-1 receptor antagonist as we possibly could. So, we screened a very large number of peptides, tried to arrive at ones that had great drug-like properties, great potency, great half-life, et cetera. The goal with that would be to have an agent that is once weekly or even less frequently administered than that. But we'll see as we get our IND filed, which we expect in 2027, and then as we get clinical data thereafter. Thank you. Your next question comes from the line of Seamus Fernandez with Guggenheim Securities. Your line is open. Oh, thanks so much for the follow-up. Just a couple of quick ones. Just hoping you guys could give us a sense of the OLE participation rate, the early access program participation rate, and if you could just help us understand, are there any gating factors to expanding the EAP, whether it's manufactured product or access to manufactured product? Is an expansion of the EAP a possibility? Then just as it relates to the longer half-life opportunity, just wanted to understand a little bit. Are you seeing opportunities in the data itself for avexitide, where a longer half-life drug could provide even better coverage than your 90 mg of avexitide? We have the four-week phase II data. We've got the headline results here for your 16-week data. So just trying to square the circle on what you see as the opportunity for a weekly. Is it convenience or perhaps even better efficacy? Sure. Maybe go one by one. For OLE participation, every eligible patient who could participate in the OLE did. So a very strong OLE participation. EAP, it is still early days, but I think as Dr. Tan said, there is quite a lot of excitement about the potential to try avexitide. So I would expect continued interest in the EAP as well. We will be working now that we have the top-line data towards that expansion. We will provide more details there in the future as well. Given that the long-acting is not yet in clinic, I think we do not want to speculate too much on exactly what the profile might be. But I will just remind, as we worked with Gubra, the goal was to make as optimized a GLP-1 receptor antagonist as we possibly could. At least pre-clinically, we do believe we have developed a molecule with quite a good profile here. Awesome. Thanks again. Congrats. Thanks, Seamus. Thank you. I'm not showing any further questions in the queue. I would now like to turn it back over to Justin for closing remarks. Thank you all very much for joining. On behalf of Amylyx, we would like to extend our sincere gratitude to everyone whose dedication and commitment made this research possible, including people living with PBH, the trial participants, their families, the LUCIDITY investigators, the team at Amylyx, and our shareholders. Thank you all for joining us today, and we look forward to talking more as we embark on this exciting new chapter. Ladies and gentlemen, this concludes today's conference call. Thank you all for joining. You may now disconnect.