Company presenter at the BofA Annual Healthcare Conference. My name is Jason Gerber. I cover pharm and biotech. I'm pleased to be introducing Amylyx Pharmaceuticals and Joshua Cohen, Co-Chief Executive Officer. This is an interesting time for Amylyx on the cusp of pivotal phase III data expected in the third quarter, a transformational event. I imagine a lot of our discussion is gonna be focused on the lead program for PBH. Josh, thanks for joining us. Thank you so much for having us. You know, fresh off the 3Q and, you know, I guess, ahead of the pivotal LUCIDITY trial, maybe you could just talk a little bit about the trial design, some of the questions that it's designed to answer, and if successful, how this could be an advancement for patients with PBH. You know, just sort of, frame, and then we'll go from there. Sure. We're very excited about the Phase III readout expected next quarter. AVEXITIDE, our lead asset, has been through five prior trials, all of which showed highly statistically significant effects on glucose and insulin. In the phase II and phase II-B, we studied the rate of level two and level three hypoglycemia, which showed quite a strong effect as well. Under that backdrop for the phase III, our goal was to try to keep as much consistent as we possibly could. Very similar inclusion, exclusion criteria, looking at the endpoints in the same way. You try to replicate that success we saw previously. To your point about meaningfulness as well, this is a patient population that's completely underserved. You know, there are no approved therapies for PBH. The disease, you know, consists of having these frequent, recurrent, dramatic blood sugar drops, sometimes following a meal, but sometimes more out of the blue, you know, maybe after exercise or stress, or otherwise. When these occur, people can become very dizzy, they can lose consciousness. Most patients end up describing themselves as disabled because, you know, they can't, they can't drive. They may want somebody with them at all times, in case they lose consciousness or otherwise. You know, to have potentially the first and only therapy that can impact that disease would be, you know, transformational for these patients. Okay. I think you framed on your recent earnings call that, you know, the stat sig result would be a win on the primary endpoint. What does that mean relative to treatment options like acarbose that are used by doctors when you talk to them and they cite this as something that they're giving patients? Is there any ability to kind of tease out what sort of benefit patients get from existing modalities, even if they're not FDA approved? There have been some small trials of acarbose, and I'd say what happens in PBH is sort of what happens in a number of rare diseases where there's no available options. People try what they can, you know, even if it's not particularly effective. Acarbose is an alpha-glucosidase inhibitor. It basically makes it harder for your body to break down complex carbs. That doesn't really treat the underlying disease. People continue to have events. The other thing is when you cannot break down complex carbs, they end up getting broken down by the bacteria very late in your gut, so you get severe gas and kinda gastrointestinal side effects. Not uncommon that people have trouble being on acarbose for more than a couple weeks. You know, we don't see, you know, as we've talked to KOLs and otherwise, we really don't see much eagerness, excitement. It's sort of what they have, but, you know, doesn't really prevent the events and very hard drug to take. This would really be the first drug targeting what we see as the underlying mechanism. In PBH, people have faster nutrient transit, which leads to a dramatically increased GLP-1 response. After meals, patients with PBH may see 10 times normal, sometimes 20 or 30 times normal GLP-1 responses. With AVEXITIDE, we have a GLP-1 antagonist. We're going at what we believe is kind of the core of the condition, which is unique. You know, there's nothing else like that. Yeah. To maybe summarize, it sounds like, hey, we're the first with a positive RCT with a drug where mechanistically, there's a lot of sensible rationale in the eyes of HCPs, and that's gonna be enough to be kind of enough for physicians to wanna use this in most of their patients. Is that a fair summary? I think it is, and maybe I'd just add, just characterizing the burden that these patients go through, they're having frequent severe hypoglycemic events. The ADA defines a single level two or level three hypoglycemic event as a medical emergency. It's true. I mean, we've spoken to endocrinologists who have described patients passing away in their sleep due to severe hypoglycemia. Patients can have falls, car accidents, you know, all manner of things. It also is just dramatic and scary when you suddenly lose consciousness. You may need somebody to rescue you, wake up, you don't quite know where you are. These are really, really severe things for patients, and there's nothing available today that's been proven to do, you know, anything, to these hypoglycemic events. To potentially have a therapeutic that could impact that, you know, as we've done market research, you know, the intent to treat does seem high. They're really looking for an option for their patients. Okay. Can you talk a little bit about phase II to phase III? I imagine try to keep as many things consistent as possible, but what are some of the, maybe the risks of a phase II to phase III effect size compression? Is it more heterogeneous population, which is oftentimes the case in a lot of studies? Is it a slightly longer endpoint? What are some of the key variables from phase II to phase III translatability? Yeah. I mean, maybe highlighting your first point, we are trying to keep as much consistent as we possibly can. Probably the key inclusion criteria in these studies is the event rate of people coming into the study. We do have a run-in period. During the phase II and phase II-B, people were required to have at least two severe hypoglycemic events in two weeks. In the phase III, we're requiring at least three severe hypoglycemic events in three weeks. It's an event a week. To get into the study, you have to be having at least an event a week. We kept that consistent. In terms of the elements that are different, the phase II and phase II-B were four weeks. The phase III is 16 weeks. We don't really expect that to change treatment effect or otherwise. We haven't seen on the reverse side with the agonist a real attenuation, you know, over time, so we don't think with the antagonist, you'll see an attenuation. We don't see ADAs, you know, of any particular nature with this, with this drug either. Nothing that would really lead us to believe that the, you know, effect change is there. In terms of sites and otherwise too, we tried to keep the sites quite consistent. You know, the phase II was five centers. The phase II-B was a single center trial. The phase III, you know, includes just about all of those sites, and it is a U.S. only trial at kind of expert endocrinology centers and expert clinical trial centers. It's all, you know, it's all groups that we think were kind of handpicked and, you know, we believe can run a quality study. Okay. Correct me if my details are wrong. I think LUCIDITY, 90% power to detect 35% effect size, placebo response 50% is sort of the statistical assumptions here. I'd say that we are powered to that. We tried to be conservative in our statistical assumptions. I'd say we don't, we don't think there'll be a 50% placebo effect. Patients with PBH are already doing everything they possibly can not to have these events. We don't think, for example, they enter a trial, and they suddenly become much more successful at not having events. You know, I'd say we don't anticipate too much in terms of placebo effect. Similarly with effect size, we powered to see a 35% relative rate reduction, but in phase II we saw 55%. Yeah. In phase II-B, a 64%. I'd say we were conservative in all the statistical assumptions, in part because this is the first phase III. Yeah. You know, we've conducted with the compound. We believe we have an active compound. We wanna make sure we have more than enough power to detect that effect. Okay. Yeah, 'cause I think the two things that come up most commonly with the Amylyx story is placebo rate risk and market size. Maybe if we just dig in a little bit more on placebo. I agree. When we talk to physicians, they will tell us that they wouldn't expect much placebo response in this population. Echoing what you said, I do wonder, you know, what you learned from like the run-in period of the when you assess that, how much can be gleaned from natural history with this population as you think about that? Some people talk about Rezolute's CHI study and the placebo response there as a maybe an analog population where there was a higher than expected placebo response. What's the rebuttal on some of those points or just how would you contextualize that? Maybe I'd first underscore your first point from the KOLs. This is really a condition where people do everything they possibly can not to have these events. If you think about it, you know, if, you know, having one of these events meant that you're gonna become unconscious, you're just gonna feel incredibly bad, be incredibly confused, you really try actively not to have them. Patients are already really doing everything they possibly can. We don't expect that that's gonna change all that much when they enter a trial setting. You know, additionally, there have been other trials in the space, including a trial of dasiglucagon in PBH. There wasn't a placebo effect observed there either. I'd say again, we were conservative in our powering. We have enough power even if there is a placebo effect. I think we don't expect too much medically. You also mentioned Rezolute and CHI. I maybe mark that they're very different conditions. CHI is primarily a fasting hypoglycemia. You're basically people with CHI basically bleb out insulin somewhat constantly. If they don't eat very frequently, their blood sugar will drop, particularly a problem nocturnally. Their blood sugar can drop because of course, you're not eating during the course of the night. You can prevent most of the hypoglycemia in CHI if you just eat frequently and eat very slow-burning carbs like corn starch or otherwise. That's very different than PBH. PBH is a triggered hypoglycemia. It occurs, you know, following a meal. It gets triggered, and sometimes it's triggered out of the blue, you know, such as from exercise stress or otherwise. You can't just eat more and not have this hypoglycemia like you may be able to in CHI. Yeah. Okay. If data are positive, what are the outstanding work streams, operational work streams that are most critical just to enable a rapid NDA submission? Yeah. I mean, we have the benefit of having a very experienced team on this. You know, won't be the first NDA that Amylyx has submitted. We took the action of trying to get as much done as we possibly can ahead of the data so that it's really a process of sort of dropping in the data once the trial reads out compared to starting the NDA after the trial reads out. Everything's kind of proceeding in lockstep with that too, so there's not like a big, you know, CMC or otherwise thing that we have to wait on, you know, after the trial reads out to be able to submit. It is still a big document. NDAs are not infrequently hundreds of thousands or even millions of pages. It's a big document, and you wanna do it right. Our intention will be to submit, you know, as fast as possible following data, to enable a 2027 launch. We do a Breakthrough Therapy designation, so we'd expect, you know, the kinda two month filing period and the six month Review that you know, Priority Review that you get with a Breakthrough. Yeah. You know, can you speak to regulatory interactions that you've had so far? I imagine you're dealing with the endocrinology division, right? Some investors do flag that division as specifically, maybe some more unexpected review outcomes of late. I don't know, is there anything that you can say to the division and your regulatory interactions? The division we're in is actually sort of a subdivision. It's DDLO. Okay. that we interact with. Our interactions have been pretty business as usual. I'd say, you know, one, we have Breakthrough Therapy, which I think helps in any FDA interactions. I think we're also just very down the fairway. You know, whereas, you know, I think some of the cases where there have been maybe more contention with FDA have been open label trials or external controls or novel endpoints. Here we have a placebo-controlled study with a very well-established endpoint, you know, hypoglycemia, something that's been known for quite some time. We did submit our protocol, and it was reviewed, you know, prior to initiating our study. Yeah. We do believe we're running the study in a way that, you know, could support registration. Okay. Maybe let's talk about commercial and market size here. There's not a lot of great predicates out there, right? Can you look to things like Akero's utilization or anything in claims data to substantiate? I think you talk about a U.S. 160,000 for EPI, and then some segmentation factors to that. Anything that we can anchor to to get a little higher degree of comfort around who's in the treatment system, who will be accessible? I mean, ultimately, I understand that this is kind of a market build. Maybe first starting, we do believe there are about 160,000 people in the U.S. today with PBH. That's based both on a lot of literature. There have been large prospective studies looking at cohorts of people who got bariatric surgery, following them over multiple years. Those cohorts do find about 8% of people in general with bariatric surgery going on to get PBH. There's been over 2 million procedures in the last decade, you know, which gets you to 160,000. In addition, we've done quite a lot of claims work. You know, recently we do expect that the ICD-10 code will become available for PBH, October this year. What we've done, so far in absence of a official ICD-10 code, is looked at those people who had bariatric surgery who went on to have claims for hypoglycemia that couldn't be explained otherwise, that couldn't be explained by diabetes or drugs they're taking or otherwise. That similarly came out to about 160,000 as well. We went to sort of further validate that claims work by doing kind of blinded market research with a number of sites where unaided we asked them, you know, "How many patients do you see with PBH?" Then we compared that to our claims data to say, "Is our claims data accurately estimating, you know, what these sites actually have?" That came back quite concordant. We do believe that we're successful in our claims data identifying the patients. There's one other element of your question. Yeah. I mean, just maybe sort of around segmentation, like, you know, what proportion do you think are kind of at the bottom of the funnel? Yeah, I mean, we're trying to target the 160,000. You know, certainly, as with any rare disease launch, our initial focus is gonna be on those centers of highest expertise as well as the centers that are most, you know, densely serving the patient population. You know, severe hypoglycemia is really, really bad. You know, one, you have the kind of the acute complications of, you know, possibly losing consciousness, seizures, car crashes, falls. You also have long-term complications. You look in the type 1 diabetes literature, people who have regular hypoglycemia are at much increased risk for heart challenges, for cognitive challenges, et cetera. These are things that should be treated if they can be treated. You know, our goal is to, for every eligible patient, you know, to try to get them on therapy if our drug is successful. Yeah. Is there an aspect of this when you launch where, you know, could there be leakage, loss of patients in the funnel at the referral stage? Not all these patients are in these higher volume centers, so to speak. There's gonna be, you know, an education and then, you know how do you envision that kind of playing out? Yeah, I think it goes to your point. There will be a build here as well. We think there's both, you know, a number of patients that are already under very active care who we think will be able to get on therapy quickly. There'll also be some time where we have to educate, continue building the index of suspicion. You know, not for all physicians right now, if somebody's had bariatric surgery and they lose consciousness, do they instantly go to, "Okay, this is probably a blood sugar problem," or, "This very well might be a blood sugar problem"? There's education we can do to kinda keep building this market and expand out from those more expert centers. I think it leads to a dynamic where we can keep growing this market year over year, which I think is a nice, you know, a nice thing to be able to grow into. I'd add with that too, we also wanna keep investing in this market. First and foremost, we have AVEXITIDE for PBH in the U.S. You know, that's what we want to launch in 2027. Beyond that, there are a number of other surgical types that can cause hypoglycemia, other surgeries that sort of alter the gut and speed nutrient transit. For example, people who get gastric cancer will sometimes have gastrectomy, which can lead to a very similar set of symptoms as what you get in PBH. People with esophageal cancer can get, you know, esophagectomy. People with various gastric reflux disorders can get various surgeries. There are quite a lot of ways you can find yourself towards having hypoglycemia, so we see that as sort of an expansion opportunity as well as looking at ex-US geographies. We're working on a long-acting version. I'd say first and foremost, we wanna serve those, you know, the patients with PBH in the U.S. that we can get to immediately. We also see this as kind of a multi-year expansion beyond that. Okay. Is that education both on the patient side and the doctor side? i.e., do you feel like a lot of patients might be out there and they need to kind of elevate what they're, you know, at risk of or dealing with, or just not aware of what they're dealing with and need a physician interaction. How does that dynamic look to you? Yeah, I think it is education on both the patient and the physician side. On the patient side, you know, right now, physicians really don't have much to offer their patients. There are some patients who have maybe gone to the endocrinologist several times, sort of heard the same advice every time, and may be less prone to go back to the endocrinologist at this point because they've, you know, they don't have something new to be told. There, there may be some patients we sort of have to reactivate now that there's a, you know, now that there may be a new treatment available for them. There are also those patients who are very actively under care today. You know, I think we'll see both in the market. Your expanded access protocol, if I understand right, is larger than the LUCIDITY enrollment. What are the criteria to get into the EAP? I just wonder, is this at all an indicator at all of market overall, right, a faster enrollment? Yeah. I wouldn't say it's an indicator of the market. We do expanded access programs mainly to provide, you know, free early access to drug, particularly in diseases that are very severe. You know, if we're able to, we like to get drug to people sooner. Initially, we're enrolling people who have completed LUCIDITY or who are in some of the past AVEXITIDE trials. Those patients, many of them have reached out to Amylyx, are very eager to get back on therapy. That's kind of the initial cohort. We do envision kind of expanding beyond that, as we get kind of up to the 250. I think, you know, as expanded accesses go, I think it's actually a fairly large one. You know, there's only so large you wanna go prior to launch as well. Okay. If AVEXITIDE is a daily subcut, can you talk about, I don't know, any observations with past trials that have been done? How do you think patients are gonna adhere to a daily injection? Yeah. Well, when we look at the past trials to start, adherence was very good. In the phase II and phase II-B, we didn't have dropouts. Treatment compliance was very strong. I think it starts from how severe this disease is. Patients are really looking for treatment. In the phase II and phase II-B, there were structured interviews of a number of the patients. You could hear in the interviews, you know, they described feeling a difference as well. When you know, when you get severe hypoglycemia, you feel terrible. You know, patients know that. When you have a treatment that potentially is reducing the rate of that or helping that, you know, you hope patients can feel that as well. This is also not a particularly needle phobic population. Just to manage their disease, they're doing regular finger sticks for blood glucose. When we've done market research and asked about, you know, what do you think about a daily subcutaneous, particularly with a super thin needle and all of that, patients really don't describe that much anxiety or fear about that. We don't, we don't think that's gonna have a significant impact, you know, in this market. Okay. I'm gonna preface by saying I'm not asking you what you're gonna price the drug at because I know you won't answer that question. Do you at least know in your mind where you'll price it if you produce, you know, stat sig benefit? Or do you think that based on the strength of the data, that could have an impact on pricing power here? Yeah. You know, we do a lot of research as we kind of, you know, approach the pricing. Included in that research, we bring our data in front of sometimes retired payers, you know, sometimes different KOLs, patients, et cetera, to try to get kind of a multi-stakeholder view and to learn as much as we can. Yeah, a little early on the price. What I will say has been encouraging for us is looking at various other launches in the rare endocrine space, some with, you know, healthy price points as well. We've seen generally good coverage. I think there's general recognition among payers and really among the medical community more broadly, that hypoglycemia is a severe and can be a very bad thing, can even lead to death. You know, I think there's an appreciation, I think that if you have a drug that impacts that, you know, that's really bringing value. What do you think one of these patients, you know, cost the system, right? In terms of these attacks, like how many hospitalizations or ER visits are we talking about that could be money saved? I'm just trying to think through the pharmacoeconomic arguments. Yeah. I'd say, stay tuned. You know, we'll probably have more of that data as time goes on. Certainly, you know, our kinda HEOR team is working hard on kinda getting more exact numbers. I do believe these are high healthcare utilizers. You know, even as we've gone through our claims data, you see a much higher than normal hospitalization rate, in these patients. You see a lot of complications, you see a lot of drug use, you know, to treat various, you know, comorbidities, in this population. I do think that this is a pharmacoeconomically, you know, expensive, population as well. Okay. On the competitive front, some data from Recordati, I believe recently. Your thoughts on that? Yeah. you know, probably don't comment too much on competitors, I'll say, you know, unfortunately, trial from Recordati did not see differences on level two or level three hypoglycemia. This is with pasireotide, which is an approved drug, has an approved label. you know, I think overall, I think we see ourselves as very well-positioned. Breakthrough status, phase III. I think there's nothing else out there that has a profile like AVEXITIDE. Yep. Okay. You framed cash runway into 2028, right? That's getting you through early launch. Is it fair to say you won't be resource constrained in 2027 go to market? Yeah. We tried to put ourselves in a very strong financial position. We raised last September. As you said, cash into 2028. We also did not include revenue in our cash modeling just to be conservative. When you add revenue in, and cash might even go longer than that, you know, as well. I think we'll in Q3 when we have our data, we'll be in a very strong financial position. Yep. Okay. You know, what does the timeline look like for your follow on once weekly of, I don't want to call it once weekly of AVEXITIDE, but it's effectively the same API, just in different types of delivery technology? It is a novel molecule. We did work with Gubra, who are excellent, to develop basically as optimized a long-acting GLP-1 antagonist as we possibly could. Basically, Gubra's sort of secret sauce is they can screen quite a large number of peptides very quickly. They screened all manner of different, you know, variants, peptides to try to find ones with long-acting, a long-acting profile, but also good potency, manufacturability, lack of immunogenicity, good in vitro and in vivo data. You know, we designed it to be at least once weekly, if not better. We'll know the profile more accurately once we're in clinic. You know, we don't wanna promise the exact PK curve in humans until we have a PK curve in humans. Right now we're going through IND-enabling studies. We'll expect to submit an IND in 2027. You know, I do believe this disease sort of lends itself throughout the development as well. We haven't outlined the exact, you know, clinical studies we might do, I think the main questions to answer will be optimal dose and then, you know, confirming that we're having the effect that we want and, you know, in a larger group. Okay. Maybe we'll just, a few on the earlier stage pipeline, the phase II Wolfram syndrome program. What in the phase II is sort of the bar for advancing into phase III from your perspective? What are you focusing in on here? Yeah. We've presented week 48 data from the phase II. We'll be presenting week 96 data. This is for AMX0035 in Wolfram syndrome. Wolfram syndrome is a monogenic disease of a protein called Wolframin, coded for the gene WFS1. It's a autosomal recessive disease, so it's, you know, basically complete loss of function of this Wolframin gene, and it's considered a prototypical disease of ER stress, which AMX0035 is thought to address. In our trial thus far, up to 48 weeks, we've generally seen stabilization or improvement across the outcomes we've measured. We've been quite excited. Wolfram syndrome is a disease where people pass away on average in their early 30s. It starts by looking like juvenile diabetes, but it becomes clear it's not just juvenile diabetes when people start getting vision loss, hearing loss, eventually kind of walking difficulties, speech and swallowing difficulties, breathing difficulties. These are what eventually lead to death for people with Wolfram. Our trial was really focused on the diabetic outcomes as well as the visual outcomes because those move a little quicker, as well as kind of a global outcome of, you know, global impression of change, both from the patient and the clinician. All of those moved in the direction of stabilization or improvement in a disease where you'd expect them to progress. That was for the one-year data, the 48 week data. You know, we'll be excited to have the 96 week data. I think we see that data as, you know, as good to kind of, you know, progress to the next study. What we're still working on, you know, with FDA is what exactly does a phase III look like in Wolfram syndrome. It is a disease that has multiple systems involved, so the exact primary endpoint and the exact design, you know, takes a little time to kind of work through. Yeah. Does this asset, you know, if developed through Amylyx, make sense to keep in-house? Is it a partnership candidate? Yeah, I'd say we always consider our options. You know, It's quite a rare disease. You know, about 3,000 people we estimate have Wolfram in the U.S. We don't estimate we're running a unduly large or long trial here. We don't think that this will be much of a, you know, financial strain, if you want to put it that way. Yeah. Yeah. I guess it's do you see strategically, you know, some rare orphan-focused companies, there's a core competency in patient finding commercially in the organization and does it fit from that perspective with an asset like AVEXITIDE, and your ALS pipeline that you have as well? Yeah. I mean, I think it does. I mean, Wolfram has components of both an endocrine disease and components of a neurodegenerative disease, generally treated by pediatric endocrinologists who are often in a, you know, similar center as, you know, adult endocrinologists and otherwise. I do think there's an overlap in competency. We look at similar outcomes as well on the kinda glycemic side for Wolfram. Overall, first and foremost, you know, our focus is on, you know, AVEXITIDE. I think we see if we're successful with LUCIDITY and hopefully a very strong launch that enables us to do more things. From a kinda capital and human resources perspective, our main focus is make sure we keep our eyes on the prize with AVEXITIDE and, you know, try to get it as best we possibly can. All right. Great. Well, we're out of time, so thank you for joining us at the conference. Thank you so much. Really appreciate you having us. All right. Have a good one.