Day two of the Leerink Partners Conference. I'm Marc Goodman, one of the biopharma analysts. Thanks for, you know, for being here. We're lucky to have one of the CEOs of Amylyx Pharmaceuticals, Justin Klee. Thank you for joining us. Very exciting time. This is one of our favorite stocks, because we're expecting good data. I know you're expecting good data, you know, but let's make sure we have good data, please. Yeah, we're working hard. Anyway, before we jump into the specifics of the data, maybe just talk a little bit about avexitide and, you know, how it works and this population, the PBH, to give people a little bit of level set, and then we can jump into the data. Yeah, very happy to. Yeah. First, thanks so much for having us here and for the kind words. We're very excited about this year as well. Avexitide is a first-in-class GLP-1 receptor antagonist. It competes with endogenous GLP-1, and by blocking the GLP-1 receptor, it lowers insulin and it raises blood glucose. Why is that important? Well, there are a number of conditions characterized by the body overproducing GLP-1, which causes hyperinsulinemic hypoglycemia, so too much insulin and then not enough blood glucose. Now a lot of the world's been focused on hyperglycemia, but hypoglycemia is really much more dangerous. Hypoglycemia at the levels we're talking about, severe hypoglycemia, the medical term is called neuroglycopenia, which means that the brain is starved for glucose. Our brains are the highest glucose utilizers in the body. When your brain doesn't get enough glucose, it basically shuts down. The most prevalent acquired cause of hyperinsulinemic hypoglycemia is post-bariatric hypoglycemia. There are about 160,000 people in the U.S. who have post-bariatric hypoglycemia today. As you might expect from the name, it occurs not to everyone, but to a small percentage of people who get bariatric surgery. In the years following, they develop this really debilitating, persistent hypoglycemia and this is severe. People have quite frequent bouts of severe confusion, loss of consciousness, seizures, basically all manner of neurological complications because their brains are consistently being starved of blood glucose. There are currently no treatments for post-bariatric hypoglycemia, PBH. The only treatment, so to speak, is medical nutrition therapy. Basically, patients are instructed to try to control their blood glucose as best as they can, and yet they're still having this. The evidence, I think, is quite clear, going back to some of the fundamental studies on GLP-1. The surgery causes increased nutrient transit in the GI tract, which causes the body to secrete too much GLP-1, and the GLP-1 causes insulin to spike and blood glucose to plummet. It makes sense that regardless of what people are doing in their day-to-day lives, they continue to experience this, severe hypoglycemia because their body's just overproducing GLP-1. That's why avexitide, I think, makes so much sense and is so powerful in this condition. There have been five prior trials of avexitide in PBH, all with very significant reductions in hypoglycemia, hypoglycemic events, supported FDA breakthrough therapy designation. We're now in the sixth and pivotal study, the LUCIDITY trial, and we're eager for the top line results in the third quarter. Talk about what are these patients doing? You mentioned nutrition a little bit, but I mean, there's some drugs that they try. I mean, does anything work at all? Yeah. I'd say right now the mainstay is medical nutrition therapy, which means people are instructed to eat very small frequent meals. They are supposed to avoid triggers like simple carbs and basically try to avoid anything that would spike their insulin and cause hypoglycemia. The challenge is that all manner of things can change your insulin and blood sugar ranging from certainly what food you eat, but also exercise, stress, lack of sleep, also you know sometimes for no seeming reason at all. PBH is really a hyperreactive state. Because the body is overproducing GLP-1 really any of these triggers causes this massive GLP-1 spike that causes these events of severe hypoglycemia. People in a matter of minutes can suddenly become totally impaired because their blood sugar plummets so fast. There's, you know, people, you know, as typical for rare disease, people try off-label treatments right now, but nothing's approved for PBH, nothing works, and we really think that the mechanism is that it's a GLP-1 driven hyperinsulinemic hypoglycemia. If you don't target the root cause of the condition, being this GLP-1 spike, then ultimately you'll continue having these events. That's the current state, but also why I think we're so excited about the promise of avexitide. You mentioned these five studies that give you confidence that if avexitide's gonna work. Can you just describe some of that data? Like what, you know, what are those five studies? How, you know, how big are they? How important are they? Certainly, yeah. I think what really got us so excited is the consistency of the results from trial to trial. In many ways, I think the kind of eureka moment was in the first phase I study. I think the investigators thought that post-bariatric hypoglycemia was driven by too much GLP-1. The body, some people will have up to 10 times normal levels of GLP-1, so we're talking substantial. You know, ultimately, you wanna run the right experiment, and I think they did in the phase I. These are investigators out of Stanford. They took a group of eight people with PBH. They had them fast, and they gave them what's called Glucola, which is a liquid sugar drink. It's really like the worst thing you can give to someone with this type of condition. Unsurprisingly, to a person, the Glucola caused hyperglycemia and then hypoglycemia, severe hypoglycemia. That was done in the clinic, so they were allowed to rescue, which is very important, you know. Otherwise, it really could have been catastrophic. They then gave the study participants avexitide, and to a person, the avexitide prevented 100% of the hypoglycemia. To me, that's just, you know, such a, I think, a elegant way to show that PBH, this hyperinsulinemic hypoglycemia, is really caused by this GLP-1 spike. If you block that GLP-1 spike with an antagonist, you prevent the downstream hypoglycemia. The next two studies were also phase I, dose ranging. They moved to a subcutaneous formulation. There were two phase IIs, the first with a run-in and then a placebo group, the second with a run-in straight to the trial. In both phase IIs, very highly significant reductions in hypoglycemic events, level II, level III, which are the most meaningful. We can get into that, as it's what the primary outcome of the phase III study, the composite of level II, level III hypoglycemic events. They tested different doses. The highest dose tested, highest daily dose tested, 90 mg once per day, gave the PK coverage for 24-hour coverage, and prevented a very significant amount of the hypoglycemic events, specifically in the phase II-B, looking at the overall level II, level III. It was significant on both, but just for brevity, the overall was a 64% reduction in the level II, level III hypoglycemic events with a p-value of 0.003. So that's what supported the FDA breakthrough therapy designation, very strong results. I'm happy to share a bit more on level II and level III if that's. Yeah, we wanna definitely get to that. All of that data was public. Yes. You acquired the asset. Yeah, we were in the right place at the right time. It seems kind of obvious that the drug is working, right? Yeah. Well, you know, fortune favors the prepared mind. I think we were, you know, we had an ongoing business development process where we were, I'll say, looking for assets that we thought had, you know, good proof of concept clinical data and, you know, for rare disease, but, you know, if helpful, could be a meaningful, you know, product. We were looking not just in the neurodegenerative disease space, where we spent a lot of our time, but some in the endocrine space as well because we've had a long-standing program in Wolfram syndrome, which is a neuroendocrine disease. Yeah. You know, there's quite some shared pathways across endocrine and neurological conditions. Yeah, we were aware of this asset. We were really excited by the pharmacology, the consistency of the results, as you said. When we were in the position to acquire it, we moved quickly. Amazing. All right. Set us up now. We got the phase III. Talk about the design of the phase III, and let's make sure we understand this whole level II and level III and why that's important. Yeah, great points. The level two hypoglycemia or level II hypoglycemic event is defined as a blood glucose value less than 54 mg/dL. The reason that's important is that's been the sort of agreed on international standard where the body starts to enter neuroglycopenia. That's where your brain is really starved for blood glucose. Unsurprisingly, our insulin glucose controls in our body is one of the most important balances that we have, right? All of our cells need glucose to function, but our brains need it more than anything. What happens when you get to that severe level of blood glucose is that the brain essentially is starved, so it starts shutting down function. That's why you get the symptoms of the severe confusion or even loss of consciousness and seizures. That's level II. It's a blood glucose measurement. Specifically in the phase III trial, it's as measured by finger stick blood glucose. A finger stick self-monitored blood glucose with a glucometer, as you can buy at your local pharmacy. That's still considered the gold standard. People in the study have a blinded continuous glucose monitor as well, but that's a secondary outcome, and it's blinded so that people can't monitor their blood glucose in real time. level III events really means that you've had the manifestations of hypoglycemia. You need independent rescue. You can't help yourself. An obvious one would be loss of consciousness, but there are plenty of others as well. Basically, you need someone else to help rescue you're so severely impaired. That is done by an eDiary. People in the study have a phone. They fill out a drop-down menu, and then that's adjudicated by an independent committee of expert endocrinologists. The goal here really is to be as consistent with the phase II trials as possible. To your point, the results were quite clear from those phase II trials, so we've tried to carry forward how we're measuring the level II, level III events. We have the same adjudication committee who are looking over the level III events as before. The, probably, particularly important part is the run-in period. We're looking for people who are having at least one of these events per week for a three-week period to randomize into the trial. In the prior studies, it was two events in two weeks, so same event rate that informs the ultimate powering. It's a 16-week randomized placebo-controlled trial with an open label extension. We're again trying to stay as consistent as we can given the very strong results. You know, we finished screening. We're just about fully enrolled and, you know, we expect very soon to be fully enrolled and top line in Q3. In Q3. Exactly. All right. How do we think about the placebo response here? I would say historically, there has not been an observed placebo effect in PBH. There have been probably two significant studies with the placebo group, the first being the first phase II of avexitide, the PREVENT study. There was a run-in period and then a placebo period. There's no difference in event rate in the run-in and the placebo group. Yeah. There's another drug, dasiglucagon, that was tested in PBH as well. Same thing. They did not see any difference between the run-in period and the placebo. It does not appear that simply being in a trial changes the overall event rate. I'd say that jibes with what we hear from patients and doctors as well. PBH is a triggered hypoglycemia, so people are doing everything they can not to trigger it, and yet they're still having these events. You know, as you asked before, there are no treatments available either. Right now, people are doing everything they can, and yet they're still having these events. Yeah. I think that's why we don't see much of an observed placebo effect. How long is an event? Sorry? How long is an event? Well, it's a great question. It varies. I would say the drops in blood glucose can happen very fast. It's because, again, this is being driven by this GLP-1 bolus. The blood glucose can drop in a matter of minutes. What can take a long time is the rescue. Unlike, for example, in type 2 diabetes where people may be instructed to take some fruit juice, the challenge with hyperinsulinemic hypoglycemia is that if you overshoot, you're right back on the roller coaster, 'cause your GLP-1 spikes again, your insulin spikes, and your blood glucose goes down. People have to rescue very slowly. Even once you rescue, you know, your body's in total fight or flight mode, so it may take people hours to rescue from a single event. When we get the data, let's just say it's statistically significant, wonderful, check the box. Does that also mean it's clinically meaningful and that the doctors are gonna be excited? Even those are the first drugs, so presumably they will be excited, patients will be excited. But I'm just saying, you know, sometimes they're different, clinically meaningful versus stat sig. I'm just curious how you view this. Yeah, yeah. No, it's a very important question. You know, we've done a good amount of market research. Yeah To prepare for this too. You know, what we've heard consistently is that any reduction in these hypoglycemic events would be meaningful. Yeah. I think, you know, looking at some of the materials from the American Diabetes Association, as well as hearing from the sort of blinded research, it crystallized for me. You know, the ADA very clearly says any severe hypoglycemia is a medical emergency, and that's what we kept hearing from doctors too. We almost, I would say, have felt this helplessness, right? They're consistently getting calls from their patients who are having these medical emergencies, and as a physician, there's really not much they can do about it, and that's really scary. Any one of these events might land you in the hospital. Any one of these events might cause a car crash. Any one of these events might, you know, leave you severely impaired. It's really traumatic. I think that's why we've heard from not just patients or from doctors, that if you can reduce these medical emergencies at any frequency, that's really meaningful. I think to your point, we think the overlap. The overlap. of stat sig They come into the study, they've had three in three weeks. Right Basically, right? Right. If they can go to two in three weeks. Yes. That's- That would be major. meaningful. Absolutely. You're saying? Yeah. 'Cause you'd think each one of these events has the chance. Right to be a catastrophe. Right. Let's just say that the study's positive, what do you think the label says? What does it say? Sure. Yeah, I would say, obviously we're not there yet. Yeah. I'll share, you know, I guess our current thinking. First, you know, I would think hope it would be for the, you know, treatment of post-bariatric hypoglycemia, you know. That's the trial, that's the indication. As you said, there are no, you know, currently approved treatments. I think we're kind of setting the precedent. Yeah Here, with the label. Whether on the label or with payers, I would not be surprised if there's some nod to medical nutrition therapy, because I think that is the mainstay. Again, I think that's, you know, it's a pretty straightforward from a payer perspective, that would just be a simple physician attestation. I think the one question as we go into the label will be the surgery that caused the post-bariatric hypoglycemia. The reason I say that is specifically in the phase III trial, we are testing only in people who had Roux-en-Y gastric bypass post-bariatric hypoglycemia. Now we did that because we have the most data in Roux-en-Y gastric bypass post-bariatric hypoglycemia. We do have data from the phase II-B trial that the physiology appears to be the same. The body doesn't really know what the name of the surgery is. It only knows that the gut was altered. That's what you would think. It appears to be GLP-1 driven, and avexitide seemed to work regardless of the surgery that led to the PBH. We think the physiology is the same, but we have the most data in Roux-en-Y gastric bypass PBH. I think there's the potential that FDA says, you know, that's the population we're gonna label for at least initially. If that's the case, I think it's pretty straightforward for us to show, you know, some additional data to say, "Look, these are not different, and avexitide appears to work regardless of the surgical. If that is the case, Roux-en-Y is what percent of the surgeries? I would say, currently, it's the second most common bariatric surgery. The most common right now is sleeve gastrectomy. We're still talking about huge volumes right now. I'd say the current prevalent population, our best estimate is from the Stanford work on prevalence they shared at ENDO last year. They suggest that about 120,000 of the 160,000 people in the U.S. with PBH today had Roux-en-Y gastric bypass. This is a very substantial orphan population. Yeah Even if it's just the Roux-en-Y. I would also emphasize, even if we're in that scenario, I anticipate it would be for a very short period of time because, again, I think we can run a pretty efficient study if needed to show that. Yeah You know, avexitide seems to work. Where are these patients and, you know, like percentages? Usually in these rare diseases, you know, centers of excellence, but are there centers of excellence for this? Yeah. Well, it's a great point and because it's a rare disease, but it's a large rare disease. Yeah. Yes, there are centers of excellence. You know, in your given geography, there might be a kinda mega center that sees 400 or 500 people or so. You know, there are a lot of clinics out there that might have 100 people, that might have 60 people under their care. As you might imagine with 160,000 people, it's a good size population. Now these are adult endocrinology centers. Last year our team spent a lot of time in the sort of claims universes to really understand the patient journey and understand where patients are cared for today. What we've been doing lately is reaching out directly to the centers and really understanding basically is our market data correct. I'd say it's come back very positive. It's you know it looks like our claims universe is accurate. what center or maybe if you don't know specifically, but a center Sure Has the most patients? Like, have you found one that had 500 or? Oh, yeah. For sure. Yeah, I would say it's kind of, you know, there's a spectrum. There's the Joslin Diabetes Center in Boston or a Stanford or, you know, there's a handful of other clinics that really have, you know, very substantial populations under their care, you know, 400 or 500 plus people. There are a good number of centers that have 100 plus people under their care. You know, there are smaller centers that, you know, might have, you know, 10, 20, 30 under their care. I would say just generally, and this is one of the things that also persuaded us. You know, you said, "Hey, the data looks really clear." I think the, you know, maybe the question that, you know, we had a bit of a head start on was the market opportunity. Yeah. It was really, it was not hard to find endocrinologists who said, "Oh yeah, I have a good number of people under my care. This is a really severe condition. I have nothing for them." I'll say it's, this is one of the, you know, in rare disease you always worry like, are there really patients out there? Yeah. Can we find them? I'd say absolutely in this. In this exercise where you $500 here, $500 there, what have we added up to? I'd say in our claims universe, we see the line of sight to about 160,000 people. You've gotten there? Yeah. Literally. But I- In two different ways, one was the literature that came out, and then two, you adjudicated, like, "Okay, we've added up to this number. Exactly. Now we found them. Yeah. Yeah, exactly. On top of that, then the Stanford group independently did their own, sort of, chart reviews and, The one you were just referring- The one I was referring to at Endo. That was totally independent of us. Right. In fact, I think at first they were a little worried we were trying to scoop them or something. Right. Right. no, that was totally independent research, and they came to very- Oh, interesting. similar numbers as we did. They came to about 167,000 in the U.S. Huh. What other indications could avexitide be good for? I'm glad you asked. We think there's so much to do here, and I haven't even gotten to talk about our long-acting GLP-1 receptor antagonist. Yeah ... we're working on too. I'd say, I mean, I hate to put it this way, but almost the low-hanging fruit are all sorts of upper GI surgeries that can cause the same hyperinsulinemic hypoglycemia. We have data from the phase II-B trial that avexitide appears to work in those surgery-induced hypoglycemias as well. I'd say, probably particularly notable, gastrectomy and esophagectomy for gastric and esophageal cancers. Very prevalent, particularly in Asia. You know, Japan alone does 100,000 gastrectomies every year. In fact, it looks like perhaps an even higher percentage of people develop this persistent hypoglycemia versus bariatric surgery, I think because it's a more substantial GI surgery. Yeah. There are no treatments for that. We estimate that the PBH prevalence in Europe is about the same as in the US. Lower rates of bariatric surgery, but bigger population, so you get to fairly, you know, similar order of magnitude. You know, even in the US, there are all sorts of I mean, we've gotten all sorts of requests from surgeons and academic groups saying, "Hey, I have this surgery-induced hypoglycemia. It appears to be GLP-1 driven. I have this condition. It appears to be GLP-1 driven." You know, I think we've seen GLP-1 receptor agonists obviously be very powerful across indications. We see the same potential here with the anti- In 3Q, data comes out, it's positive, great. We've got at least one indication. Is it okay, let's go and invest in some others now? Oh, yeah. We're Like, you're thinking about it now. You're planning. Yeah. No. We see a long-term opportunity here. That's why we're working. Can you go right to pivotal studies with these other indications? See, I don't want to overpromise, but I'd say we're working on those. You're trying to decide whether you can or not. Yeah whether dosing's the same or something like that. Yeah. Exactly. I would say that's why I start with the surgery-induced. Right Hypoglycemias. I mean, we think the physiology is the same. Yeah. You know, as one surgeon put it to us, you know, "Your body doesn't know that your stomach was partially removed for weight loss or for cancer. Right. It just, you know, knows that you're missing part of your stomach." The physiology here is the same. We have data saying avexitide works just the same in those conditions. Yeah. Interesting. Talk about how the drug is administered and why you think a long-acting would be helpful, I guess, you know? Yeah. Yeah. Leading question. That's a good one. Yeah, that's a good one. Avexitide is a daily subcutaneous injection. I would say given that this would be, you know, first to market, and fingers crossed, we see the sort of efficacy we've seen historically with avexitide, you know, we think that that's, you know, perfectly appropriate for a severe unmet need like this. Now, if we can get to the same level of efficacy and safety and have a longer-acting molecule, then that would be even better. We established a collaboration with a company called Gubra last year. They're one of the world experts in peptide drug development. We announced earlier this year a lead candidate from that program, AMX0318. That's in IND-enabling studies now, and we're working to have that in the clinic next year. Yeah. I'd say the goal, so we have cash runway into 2028, and that includes launch of avexitide in 2027. '27. Hopefully, we have the long acting, you know, GLP-1 once a week or better, in clinical trials next year as well. Got it. Just quickly, I think we should talk about Wolfram. Mm. I mean, I know we don't have a lot of time left. Sure whatever, but just quickly, like, what's the study? What are we working on here? Yeah. Wolfram syndrome is a neuroendocrine disease. It's a monogenic disease caused by mutations in WFS1, which encodes for the Wolframin protein. Wolframin is an ER transmembrane protein. It helps with ER quality control, protein folding, that sort of thing. When you have these mutations, you get ER stress, mitochondrial dysfunction, and then downstream dysfunction and death. The cells that are affected are those that are highly expressive of WFS1 and also ones that are, you know, more or less resistant to that type of stress. Wolfram syndrome presents as early onset diabetes, then becomes a neurodegenerative disease because those are the cell types that are affected. Unfortunately, sadly, early mortality, generally in late 20s, early 30s. We've run our first study. It's still, you know, ongoing, although in, you know, a sort of a long-term, more maintenance phase now, in Wolfram syndrome. 12 people, we looked at measures of the cell types affected, first and foremost the pancreatic beta cells. We saw not just slowing of progression, but actually a partial reversal, overall increase in C-peptide- Mm Which is a direct measure of the beta cell function, because it's a direct measure of insulin production. We also looked at things like visual acuity. We have looked at things now in a more open setting, bladder functioning and visual fields. Everything's gone in the right direction, so I think the data looks very promising. We're still working on alignment with FDA on a phase III trial design. You know, we wanna make sure this is a trial that supports approval. Yeah. Yeah. We're very excited about the data. Very interesting. Thank you. Thanks for joining us. Appreciate it. Yeah. Yeah, it's fun. Thanks so much. Thanks for having us. All right. We're holding our breath. Yes, sir. Crossing our fingers, whatever else we need to do. Thank you. Get this thing over the goal line. Yes, sir. All right. Thank you. Thanks, everyone.