Okay, thanks, everybody. This is our last meeting of the day here at Guggenheim's second annual Healthcare Innovations Conference. I'm Seamus Fernandez, one of the biopharma analysts here at Guggenheim, and I'm really pleased to be joined by the Co-CEOs of Amylyx. To my far right is Josh Cohen, and my immediate right is Justin Klee. Josh, Justin, thanks for joining us. Maybe just to orient people to the Amylyx story and some of the changes that have occurred over the years, maybe you can just kick us off with the Amylyx story as it sits today.
Yeah, we'd be happy to. First, thanks so much for having us, and a pleasure to be here. At Amylyx, we have three drug candidates in three ongoing clinical programs. Our lead candidate is Avexetide. Avexetide is a competitive inhibitor of the GLP-1 receptor. It blocks the endogenous GLP-1 effect, thereby blocking the potentiation of insulin and raising the glucose nadir. It turns out that that may be very important in conditions of Hyperinsulinemic hypoglycemia. Right now, we're in a pivotal phase three study in post-bariatric hypoglycemia. That's a form of hyperinsulinemic hypoglycemia that we estimate affects about 160,000 people in the U.S. today. Very substantial unmet need.
There are no FDA-approved treatments for PBH, and we're coming into this pivotal study off of five prior successful studies, FDA Breakthrough Therapy Designation, and we expect to complete enrollment in Q1 next year and have top-line results in Q3 of next year. We're very excited about that program. We also have a small molecule in Wolfram syndrome, which is a rare neuroendocrine disease. We had positive phase II trial results earlier this year, and we're now working to plan for a phase three trial. Pending FDA alignment, we'll start that study in the second half of next year. We have AMX 114, which is an antisense oligonucleotide targeting calpain- 2 for the proposed treatment of ALS. That's in a multiple ascending dose study.
We just announced completion of our first cohort, and we'll have the early cohort data later this year, and then the biomarker data in the first half of next year. We're very excited across all of our programs. Probably a lot of the focus has been on Avexetide, given that's a pivotal study and a very substantial unmet need, and we're very excited about everything going on at the company.
Sounds good. We'll probably spend most of our time on Avexetide for appropriate reasons. I guess the first thing, though, is what actually drew you to PBH? I mean, you guys are known for having introduced an ALS drug to market, having an unfortunate sort of subsequent event, but then you already had Avexetide in your coffers. How'd you get it? Maybe you don't have to go through the entire story, but what drew you to PBH, and what drew you to Avexetide?
Yeah, great question. At the time where we were on the market, we were profitable in ALS as well. One of the things we were thinking about is how to build and grow our pipeline. During the time we were on the market, we ended up diligent in quite a number of assets to potentially bring into Amylyx. We were primarily looking at neuro and endocrine. Some of the experience with Wolfram had made us want to look a little bit more in the endocrine space as well. We ended up looking at over 300 assets and ultimately getting very excited about Avexetide, which we acquired in July of last year.
Some of the things that really got us excited about PBH were, upon first hearing about it, we started talking to physicians, we started diving into it, and it just stood out to us how much of an unmet need there was. Hearing from patients that they basically were functionally disabled by this disease, that they were unable to leave the home, that they may lose their license, be unable to drive, not be able to hold a job or achieve what they want to in their job due to this, want to have a caregiver around them. I think the unmet needs stood out, and I think then that was coupled with the strength of the data.
Five prior trials all showing the effects we would hope to see: FDA Breakthrough Therapy Designation, which is kind of the FDA's endorsement of both the unmet need as well as the strength of the data generated to date. I think it was kind of all of those things coming together that made us see this as quite an exciting opportunity and one that we really wanted to be a part of.
Great. I mean, I think what people don't fully understand or grasp is this indication was only nascent at that point in time. I mean, some of the experts that we've talked to, 2016 was the first establishment of their clinic, and you guys were looking at this asset in 2018. That means there's a lot to learn. I think in that context, interested to just have you help us understand the opportunity itself. What gets you to 160,000 symptomatic patients, and how do you think about the severe disease kind of breaking apart Roux-en-Y and gastric sleeve?
Yeah, happy to dive into all those factors. Yeah, post-bariatric hypoglycemia or PBH is a new market. That being said, it's a substantial unmet need, both in terms of the severity as well as the number of people, and I'll get into why those dynamics exist. PBH is a rare complication that can happen in the years following bariatric surgery. What we think happens physiologically is that with a bariatric surgery, it alters the nutrient transit in the GI tract. That altered increased nutrient transit rate seems to cause an upregulation of the production and secretion of GLP-1. I think in particular individuals, that becomes so significant. They have such significantly elevated GLP-1 levels that essentially their bodies become hyperreactive. What does GLP-1 do? Fundamentally, it's a potentiator of insulin and therefore glucose.
When people with PBH have up to 10 times normal levels of GLP-1, what happens is often in response to a meal, but sometimes in response to no trigger at all, suddenly their body has this flood of GLP-1, which causes this huge insulin spike, which what does insulin do? It controls glucose. People's blood glucose just plummets. That's what we hear from patients. People with PBH say, "Gosh, no matter what I do with my diet, no matter what I do with my lifestyle, I seem to just have these dramatic plummets of my blood glucose." What we're talking about here is severe hypoglycemia. The American Diabetes Association defines a single hypoglycemic event of this severity as a medical emergency. That's because really our brains are the highest glucose utilizers in the body.
When you have severe hypoglycemia, the medical term is neuroglycopenia, which means that the brain is starved of fuel, and so basically it starts shutting down function. People become severely confused. They may lose consciousness. They have all manner of neurological complications. This is a really severe unmet need. Certainly when we hear from the adult endocrinologists who care for people with PBH, they say, "Yeah, these are some of the most fragile patients I have under my care. They're having these medical emergencies very frequently. There's very little that we can do about it." The unmet need is very clear. Now, why do you get to such a substantial population and why is this new? It is a complication of bariatric surgery. It doesn't happen to most people.
We estimate about 8% of people who have bariatric surgery in the years following may develop PBH. There have been millions of bariatric procedures that have happened over the past 20, 25 years. If you take that 8% of the millions of procedures that have happened, that's how you get to about 160,000 prevalence. Now, since acquiring the asset, we've done our own claims-based work as well, looking at every claims database we can get our hands on. All of our analysis corroborates this about 160,000 people living with PBH today. The two main surgeries that occur for bariatric weight loss are Roux-en-Y gastric bypass and sleeve gastrectomy. Historically, Roux-en-Y gastric bypass was used most frequently. Now, sleeve gastrectomy is a bit more common because I think of the historical precedent of Roux-en-Y gastric bypass.
Of the 160,000 people with PBH in the U.S. today, we estimate about 120,000 of them had Roux-en-Y gastric bypass, and then the other 40,000 are from sleeve gastrectomy. Long way of saying, we think this is a substantial unmet need. There are many clinics around the country that we talk to who have many, many, many patients under their care. The feedback we hear is the same. This is a really severe unmet need, and they're really desperate for a treatment to address it.
Great. Let's talk a little bit about, and it seems like Stanford appears to kind of corroborate that with work that they've done. As you sort of work towards expanding into this population, let's assume Avexetide is successful, one of the complications I think that's hard to understand is the lack of an ICD-10. What kind of progress is Amylyx, or let's just call the treating community, making to actually bring us to an ICD-10? When is it most important for that to be in place to allow for a successful launch of Avexetide?
Sure. One, I'd say I don't think an ICD-10 code is essential for the success of Avexetide. I think an ICD-10 code helps in terms of being able to track patients and otherwise, but it is definitely a plus and is something that certainly would be great for the market as well. Back in September at the CDC meeting, some physicians expert in PBH did bring PBH to this kind of CDC panel that oversees the ICD-10 code. The CDC group now has until April to make a decision on that. If the decision is positive, it should go into effect October of next year. All this depends on government timelines, and there is no guarantee that it'll happen by October of next year, but it certainly could.
I think all of that follows with what seems to have been a pretty good groundswell of work in the treating community towards kind of elevating PBH. PBH recently showed up on the endocrinology board exams. We've seen PBH at Obesity Week just recently. There were multiple sessions at Endo this year. It seems both with the ICD-10 code, but also with a lot of other efforts, you're starting to see the treating community is really elevating PBH.
Sorry, just to go back to that one point too on success at launch, I think what's nice is that while even before there's an ICD-10 code for PBH, it's pretty straightforward, the diagnosis, right? People have had a bariatric surgery. They have symptoms of hypoglycemia, and you measure their blood glucose. I would say that there are already many centers throughout the country. I know you've spoken with quite a few of them who have many patients under their care. I think an ICD-10 code is definitely nice to have, but I would say we already know where there are many, many people with PBH in the U.S., who's caring for them, who's treating them, and ultimately how they get diagnosed as well.
Great. Perfect. Let's turn to LUCIDITY. Maybe just as a starting point, help us understand the phase II data that you have so far, what the design of your phase three is based on those phase II results.
Sure. I think overarching, both the phase I trials and then the phase II trials thereafter were all quite strong, showed significant effects on insulin and glucose in the phase II and phase IIB, highly significant effects on level two and level three hypoglycemia. In particular, at the dose we're studying in phase three, 53% reduction in level two, 66% reduction in level three. Strong results from the past studies. Our overarching goal was to try to take that success forward into the phase three as much as possible, keep as much consistent as we possibly could, namely the endpoint. We're looking at level two and level three hypoglycemia. Level two is when your blood sugar goes below 54. Level three is when your blood sugar goes so low that you become incapacitated. It's defined clinically.
Those were both hit in the phase II and phase IIB. Our primary endpoint in the phase three is the composite of level two and level three. In terms of other inclusion/exclusion criteria, we tried to keep them as similar as possible from the phase IIs into the phase three. It is essentially a longer and larger format of the phase IIs that we're conducting in phase three.
By definition, I would assume that there's overlap in those level two, level three dynamics. Can you just help us understand how those are treated independently in your, or at least in the phase II data, how that was measured and integrated?
Sure. One, in the phase three, we're looking at the composite of level two and level three. It's basically treating all the events as equal. It's a level two event, it's a level three event, it counts as an event, kind of going into the analysis. There's not a distinction made between the two. We did kind of reanalyze the phase II phase IIB, looking at the composite as we are in phase three, and the results were highly significant. For example, at the dose we're testing in phase three, 64% reduction in the composite of level two and level three with a p-value of 0.003 in phase IIB. In effect, why do you do a composite? Often these two events or these two types of events can happen. They can kind of travel together.
Level 2 is when your blood sugar goes below 54. Level 3 is when you're incapacitated. Often, when your blood sugar goes below 54, you're on the track to incapacitation. Kind of treating them and bucketing them together makes sense rather than marking a large distinction between the two.
Okay. Help us just remind us that you have a run-in period, and then you also have the treatment period. What are the differences from phase II in the run-in versus the treatment period? How does that impact the powering of your study? How could it also impact the recruitment in terms of what needs to be confirmed in the run-in period?
Yeah. I would say the goal of the phase three trial is to get as close to replication of the phase IIs as we can. Very strong data in the phase II trials. We have tried to keep things as substantially similar as we can. In the phase II trials, they had a run-in period. In the run-in period, they were looking for two hypoglycemic events in two weeks. In this study, we are looking for three hypoglycemic events in three weeks. We are also saying that at least one of those events should be a level three. Slightly stricter criteria. Again, I think the event rate is what drives the powering of the study. I can go into that in a little bit. The event rate is the same as in the phase II trial.
The same design as well, having the run-in period where you're making sure that you have the right study participants and then randomize into the study. That's the same. We're using the 90 mg dose, which was the highest and best dose tested in the phase II trials. The way that we're collecting the events is the same. Level two events, we're measuring by fingerstick blood glucose. Level three events are done by an eDiary that then is adjudicated by an expert committee. The population, we are enrolling people who had Roux-en-Y gastric bypass, post-bariatric hypoglycemia. That was the same as in the phase II trial. In the phase 2b trial, they allowed different surgeries that led to PBH, and Avexetide looked effective across all of those different surgery-induced hypoglycemia.
We have the most data in Roux-en-Y gastric bypass PBH, so that's the population we're studying in phase three. I'd say the key difference is that it's longer. The phase II trials were each 28-day trial dosing periods. In this, we're looking at a 16-week dosing period. Going from roughly four weeks to 16 weeks. We don't have any reason to believe that a longer dosing period should change anything. We don't suspect any sort of technical axis or anything like that, but that's probably the key difference. In terms of powering, we believe the study has very good statistical powering, and it really starts with that event rate. If you just multiply the one event per week that we're seeking over 16 weeks times 75 participants, that would be 1,200 events.
Now, of course, we expect that to be lower with the treatment effect, but the point is with that many events, you get to very good powering. And our sort of powering estimates are that we're about 90% powered to see a 35% therapeutic effect. Notably, as Josh just mentioned, in phase IIB, we saw a 64% treatment effect. So we're 90% powered to see a substantially lower treatment effect in the study. So overall, again, goal is to be as close to replication as we can, and we're pleased with the conduct thus far.
Great. One dynamic that is a question that we get a lot is on just diet, diet control. Does the run-in period help with that at all? Diet liberalization when a patient is actually, we've also heard from some of the doctors who were in the phase II program, just how good these patients can feel on drug, it sort of begs the question, what happens with diet liberalization and how do you avoid that in your phase three?
Yeah, great question. Diet is certainly something we manage very closely in the study. Patients receive dietary training and kind of coaching at every single clinic visit. At every visit, patients also have to attest that they're basically following all the kind of core tenets of the PBH diet. Those are elements that we think will help to ensure that patients maintain on the diet. The other thing I'd say is if you imagine a patient who begins to liberalize, if they liberalize so far that they then have a significant hypoglycemic event, they're probably not going to do that again. These events are quite traumatic. They can involve loss of consciousness. They can involve seizures. You just really do not feel good.
We really don't expect patients would liberalize to a point of inducing events, even if they were feeling good and things like that.
Just to clarify and confirm, I think it's important to understand this, but this isn't a time-to-event analysis. This is a cumulative event analysis across the entire 16-week period.
Exactly. With, as Justin said, an expectation of a huge number of events as well, given the event frequency. We're screening for people who are having at least an event a week. You expect there to be quite a lot of events during the study.
Okay. I would go back to one of the phase I trials. The investigators did what's called an oral glucose tolerance test, which means that study participants were instructed to drink what's called glucola. It's basically liquid sugar. What does that do? It causes a dramatic rise in glucose, and then it causes a dramatic drop in glucose. People were rescued. Unsurprisingly, people with PBH, the eight participants, had surges and then dramatic hypoglycemia. With administration of Avexetide, it 100% blocks hypoglycemia. I think it speaks to even with such a strong glucose test as that liquid sugar, people were still prevented from having hypoglycemic events.
Great. Let's just talk about FDA because it happens to be something that everybody's a little bit anxious about right now. Hopefully, you guys aren't. Your interactions with the agency and just in terms of the sort of well-defined endpoint, how has that sort of progressed? How much can breakthrough designation be helpful?
Yeah, for us, I'd say really across our programs, it's been business as usual. It's been the same people, the same divisions. Probably in part, that's fortunate. With our Avexetide program, we're in DDLO. The same leadership is there. To your point, we're also running a placebo-controlled randomized study. FDA reviewed the phase three protocol ahead of time. The outcomes we're looking at are in FDA guidance as acceptable outcomes for a study. These have been well-defined by the American Diabetes Association and other groups. I think we're paying attention to FDA like everyone else, but I would say with our programs, especially with breakthrough designation, we've seen a high level of engagement. I think we're confident that we're running the right pivotal study to support this program.
Great. Maybe just in the last minute, unfortunately, that's all we have time for. Two quick questions. First, your cash position and your runway. And second, the timing of your phase three LUCIDITY results, or at least your target timing. I know there's a little bit of a push out, but maybe you can just remind us of those two things.
Sure. We had $344 million cash on hand as of the third quarter results. That gives us cash into 2028. We expect to complete enrollment in the LUCIDITY trial in Q1 with data in Q3, and that would lead to a potential launch in 2027. That comes kind of off of the financing we did in September, which extended that runway out to 2028.
Super. You guys nailed it. Six seconds left. Thanks so much for joining us. Wish we had time to cover the other programs, but I wanted to make sure we got to Avexetide. We'll see you at dinner later tonight.
Excellent. Thanks so much.
Thank you so much.