Okay, great.
Outstanding. Well, listen.
Okay. Welcome, everybody, to second day of Evercore ISI Conference. We have the pleasure of hosting the management team of Amylyx here. In attendance is Josh Cohen, Justin Klee, co-CEOs, as well as Camille Bedrosian, Chief Medical Officer of the company. Guys, thanks so much for making time for us. We appreciate the time. Before we delve into Q&A, we'd love to kind of hear your highlights of 2024 and what we can look forward to in 2025.
Yeah. Well, first, thanks so much for having us here. And so we're super excited about our upcoming year. So to start, our lead asset is avexitide. It's a first-in-class GLP-1 receptor antagonist. And the first two indications are post-bariatric hypoglycemia, as well as congenital hyperinsulinism. The asset has FDA breakthrough status for both. And we are entering the pivotal study in the first quarter of the coming year, with data readout in 2026. The reason I think we're so excited about it is the prior studies were very highly significant at reducing hypoglycemic events. And post-bariatric hypoglycemia is a very significant unmet need. So it's an orphan disease, but a large orphan disease. We estimate there are about 160,000 people in the United States who have post-bariatric hypoglycemia.
Given that it's a persistent condition and a condition where people, on average, are in their 40s, we expect chronic treatment as well. We're very excited about getting that study up and running at the start of the year. We just this morning announced the finalized design of the phase three pivotal study. Also, in the coming year, we have an ongoing program in progressive supranuclear palsy. That was based off of a prior trial in Alzheimer's with our drug AMX0035 that showed very significant reductions in total tau and phospho-tau181. Progressive supranuclear palsy is considered the sort of purest tauopathy, the most tau-driven neurodegenerative disease. We're running a phase two-three study. In 2025, we'll have an interim efficacy analysis. Looking at the PSP rating scale, as well as key biomarkers, imaging, tau, et cetera. We're very excited for that as well.
And then going through other two programs very quickly, our Wolfram syndrome program, we had exciting data this year. Wolfram syndrome is a rare neuroendocrine disease. And so we'll be working to get the phase three trial up and running in the coming year. And then our antisense oligonucleotide against calpain-2, which is going into a trial in people with ALS, we expect to get our first cohort-level data in the coming year. So we have a lot of exciting work. This is going after really tough neurodegenerative and endocrine diseases. And after 10 years of work at Amylyx, we couldn't be more excited for the future.
Outstanding. Maybe I want to perhaps kick it off with the trial. Maybe first remind us, perhaps the phase 3 trial you're starting up, when can we get a readout on that? Because I think investors are still trying to reorient on how fast could this develop from here.
Sure, so we're going to start recruitment in Q1 of 2025. We expect to complete recruitment by the end of 2025 and have data in 2026, and we do expect this to be the pivotal trial. We have submitted it to FDA, got their review, and we're running this study with the goal of driving towards a potential approval.
Got it. And so this is like mid-2026 type of readout because it's 24 or 16 weeks out to the primary endpoint?
We haven't given specificity yet. As we start recruiting, we'll obviously know more. But quality is the top goal for any trial, followed by, of course, getting to the readout as quickly as we possibly can.
But to your point, we do think it'll be an efficient trial. So we're seeking 75 participants across 20 centers in the United States, 16 weeks treatment. So.
So this could, in a very, very bullish scenario, be like a late Q1 type of readout in 2026. It could go super fast.
Well, we expect to complete recruitment by the end of 2025. So then it'll just be how quickly we can get through the rest of the study.
Thought process in sort of going forward to the 90 mcg dose and dropping the 45 mcg dose? The BID versus QD, obviously.
Yeah, 90 mcg is QD. And as we, oh, I'm sorry. I forgot I had this. Apologies. Yes. So.
It's good.
Okay. Can you hear me now? Okay. Very good. So yes, we're going with the 90 mcg dose. In our phase 2, or Eiger's phase 2 program, there was a phase 2 study studying 30 mcg twice a day and 60 mcg daily, where there were significant reductions in Level 2 and Level 3 hypoglycemia events. A 50% increase in the dose showed a dose response in a higher rate of reduction in hypoglycemia events, highly statistically significant. The 45 twice a day and the 90 mcg daily were approximately the same in terms of reductions. And so we went with the more convenient dosing of once a day in the morning.
This one's a GLP-1 antagonist.
Antagonist.
it's a peptide dosed once daily.
Correct.
It's not a pill.
It is a subcutaneous dose.
Subcutaneous injection. And can you remind us the presentation? I remember looking at this on Byetta and Victoza way back. Victoza was a more convenient GLP-1. It was an agonist. Can you remind us the needle gauge and the presentation of this?
Yeah, so it will be a vial and a needle to start.
It's a vial initially. Okay.
Yeah. Yeah, yeah. And we appreciate the tremendous unmet need that these individuals have, and we don't want to delay with a more.
Can you not do a pre-filled syringe?
We can. And that's something in our life cycle management that we are considering for sure. Having said that, there were participants who had interviews after the studies and were asked specifically how they felt about the injections: twice a day, once a day. And 201, each one indicated that, "Oh, the injections were nothing. We barely felt them." And they're nothing compared to the multiple finger sticks we have to do to make sure that we're not dropping our glucose.
Oh, is that right?
Yes.
What do they currently do for their hypoglycemia episodes? These patients currently?
Yeah. So.
We're talking grade 2, grade 3 hypoglycemia.
Level two and Level 3.
This is not the very basic level.
Right. Yeah. Level two is a glucose less than 54 and with some symptoms for sure, autonomic symptoms. And Level 3 is an individual who cannot rescue themselves. They need someone else to help them, regardless of the glucose level. So these individuals, there is rescue with glucagon, which takes about 20 minutes to kick in to release the glycogen from the liver. So it's not an immediate fix by any means and not something sustainable over time for these individuals. The most consistent management really is medical nutrition therapy, which everyone receives. And it can be quite draconian, eating very small meals every two hours, focusing on protein, carbohydrates at all, complex carbohydrates.
Got it.
So.
Yeah, and maybe I know I jumped us right in, but for those less familiar with post-bariatric hypoglycemia, so it's a condition that manifests on average about one to three years following bariatric surgery. Now, these are the people who have particularly persistent symptomatic hypoglycemia, so to give a picture, in the prior trials, on average, people were having three Level 2 or Level 3 events per week, and Level 2 means you have neuroglycopenia. That means your brain's not getting enough glucose. Level three means you are so incapacitated, you need somebody to help rescue you, so this is quite a severe condition. The reason that we estimate there's such a large population is just because there have been so many bariatric procedures over the past 10-15 years, so this is a subset of people who get any hypoglycemia.
But it's around. We estimate about 8% of people who get bariatric surgery may develop this. But in terms of how debilitating this is, if you think, if you're very frequently having these type of events, you can't drive, you can't live alone, you often can't work, it's really, really debilitating. So I think as we think about the development, the life cycle management, it's very much a highly debilitating orphan condition, and that's how we're building. And this is not, so this market is not akin to where Lilly's Baqsimi and some of these intranasal glucagons launch because those are more general hypoglycemia. This is post-bariatric surgery.
Yes, that's exactly right. And the challenge, we believe, is that really the body is secreting excess GLP-1. And so the problem is that people have these very precipitous drops in glucose levels. And in fact, they often, their set point is off. And so the challenges with glucagon rescue are, first of all, it's rescuing, but it's not fixing the actual problem. The second is that when people have such persistent hypoglycemia, they often exhaust their glycogen stores. So then glucagon becomes even less effective. So again, when we've spoken with adult endocrinologists, many of them will say, "These are the most fragile patients I have. They're afraid to leave their houses." So we're really excited that I think this has the potential to be a life-changing therapy.
Justin, just to clarify that 160,000 prevalence number that you guys have in your slide decks, that's in reference to the more severe Level 2 and Level 3 cases, right?
Exactly.
Okay.
Exactly. And the people for whom it's persistent. So I think if you look at anyone following bariatric surgery who has hypoglycemic events, it's closer to 20%-40%. So it's hundreds of thousands of people. The people who have this particularly persistent hypoglycemia, we're talking five, 10, 20 years out is how we're defining PBH. And that's the 160,000 number.
Justin, one question that I'm sure you get a lot of the time, we still continue to get, is how do the surge in GLP use and incremental therapies use, how would that affect the addressable market? Our channel check research suggests that bariatric surgery will never go away. It'll always have a maintenance. But what are the facts according to your research on this?
Sure. So I think the first thing is bariatric surgery kind of came to prominence starting in the early 2000s. The surgery existed before, but the kind of boom in numbers started in the early 2000s. This is a surgery that on average is conducted in people who are about 40 years old. So the original bariatric surgery patients are only 50-60 on average, let's say, today. So first thing to state is the 160,000 people who have PBH today are very much here to stay. We've interacted with a number of patients who have had PBH 10-15 years, and it seems to just persist. So the first thing to say is those patients are here to stay. Additionally, as you said, bariatric surgery is not going away. We see it as kind of differentiated in a way from the GLP-1s.
Most people who want to lose 20, 30, 40 pounds never would have done bariatric surgery in the first place. It's the people who wanted to lose 100 pounds, 100+ pounds, who really focused on bariatric surgery and I think still are because it still is the kind of most significant kind of weight loss option on the market. So we do think that there will continue to be that, and that continues to kind of grow that prevalent pool. And one other thing to say is we do think this will be chronic therapy. One thing that was particularly notable that I think was pretty striking for us as we were learning about this drug, there were participant interviews from the study. So after the study, patients were asked to provide an interview, how was it, how was the trial, et cetera.
To a person, they described being able to feel the benefit. I think that that's quite powerful. When you're hypoglycemic, you feel terrible. You feel like you're dying. You can be shaky. You can be dizzy. You aren't thinking straight. I think that helps too from a concept of persistence because patients will hopefully, presuming the data continues to bear out, will hopefully feel what it's doing. If they go off it, they'll feel that as well.
Yeah. Maybe the last thing too, I'll say to your point too. I thought really interesting statistics came out this summer from the CDC, which found that while obesity rates were decreasing for the first time, maybe since we've been measuring, morbid obesity continues to rise. And so I think my own view is I think it's going to be the right medicine for the right patient. And that's what we've been hearing from the weight management clinics as well.
Got it. Got it. One last question, at least from me on the actual trial. I noticed that I had a three-week run-in period. Maybe explain why you're doing that.
Sure. Yes. That's actually a very important feature of the study to ensure we're enrolling participants who have a certain frequency of Level 2 and Level 3 events. It's akin to what was done in the phase 2 and phase 2b, and that was one aspect that we wanted to ensure we were consistent as much as possible.
So if they are having those events, it'll be obvious in three weeks, and then you'll render them.
Correct, and they will not be able to enroll in the study and be dosed.
And I think you mentioned this too, but that's also consistent. In the past studies, there was a run-in. They needed at least an event a week during the run-in. Similarly here, during a run-in, they're needing to have at least an event a week.
I think the whole concept here is looking at the phase 2 studies, there were 60%+ reductions in hypoglycemic events, very highly statistically significant. So our goal here is to be consistent with those prior trials going into it. And I'd say the unmet need, the efficacy, the safety profile, collectively, that's why the asset has two breakthrough statuses.
What kind of treatment effect is the FDA looking for at the end of the day?
I think this is an unmet need. So I would say generally the bar is fairly low. But I think based on what we saw in the phase two, I think that would be what we're aiming for. That being said, the phase three trial is very highly powered. So we'll be able to see an effect size quite substantially.
I guess what I was going to say is folks would agree with the clinical data, the odds of replicating it. Folks would agree with the magnitude of data, et cetera. But on the commercial opportunity side, is there something more recent given that GLPs are ramping up so right? Is there something more recent where you're seeing bariatric surgeries in first quarter this year, first quarter last year, second quarter, like sequential and year over year? Is there something that shows that steady nature of the. Could you speak to some dynamic like that? Because that would be highly relevant in putting a value on this in 2026, 2027.
Yeah, it's a good question. There are kind of different data sources. We've certainly looked at some of the surgical vendors who provide kind of some of the surgery equipment for bariatric surgery and otherwise, and I think what a lot of them, it's also a little hard to disentangle from COVID and some of the other things that had impact on the number of surgeries, but what we've heard from looking at those reports and otherwise is maybe there was a slight dip, but not too large, to be honest, and that there's also a tailwind of people being more excited about weight management as a class generally, which I think is also maybe somewhat of an offsetting tailwind as well. In terms of precise data, the ASMBS does put out data. They haven't put out 2024 yet, so we'll certainly see that when they do.
But one other anecdote is just talking to bariatric surgeons. Many of them, we've asked a couple of bariatric surgeons, "What have you seen? What have you experienced?" And I think what one of them said to me is, "I'm having no trouble filling all my slots." So I definitely think there's still quite a lot of demand for surgery as well.
I'll add to your point too. I think specific to post-bariatric hypoglycemia. We estimate there's about 160,000 people today. That's a persistent condition. The population will only grow. The other thing is there's quite a delay in when people have their bariatric procedure and when the symptoms manifest or become symptomatic enough that they're seeking physician's help. I think, for example, in the prior trials, people had had the condition on average eight, nine years, some considerably longer than that. I think the people who had bariatric procedures in the prior years were still waiting, I think, to see the PBH develop over time.
Outstanding. One last, and this is a crazy question. Is there any possibility that with some of these longer half-life GLP-1 agonists that are in development that there could be scope for something which requires a bit of an antidote to them? So for example, even within GLP-1s, we're seeing a lot of approaches heading towards monthly GLP-1s now. Amgen's got something that wants to do every two months, et cetera. Is there any pocket you guys foresee where outside of the bariatric surgery where someone's on a GLP-1? In rare cases, again, we're talking millions of people that are on it even already, a GLP-1 antidote could be clinically relevant and how you guys could fit in. Is there an indication like that that has not been thought through so far?
I think there certainly could be. Yeah.
Many.
Yeah. I would say that in terms of the potential of a GLP-1 antagonist, the way I think about it is we're targeting half the equation right now, right? Too much glucose is bad. Too little glucose is bad. What we focus mostly on are conditions or diseases associated with hyperglycemia. There are a whole heck of a lot of diseases that either are because of or are augmented by hypoglycemia. So this would be the first-in-class GLP-1 antagonist. To your point, specific to GLP-1 agonist use, there are challenges when people go for surgery. They're at risk of aspiration. There's challenges with gastroparesis. So there are all sorts of manifestations like this. There are also other diseases and conditions like congenital hyperinsulinism that are causes of hyperinsulinemic hypoglycemia. So we think there's tremendous potential.
Could you post a trial next year on something along those lines? Because that could completely transform the amount of interest in this program, as you can imagine.
We think there's a tremendous opportunity with post-bariatric hypoglycemia. It has breakthrough status. That's why we're jumping to do that first. But we think there's plenty more to do after.
There could be a GLP-1 trial coming as well, like a GLP-1 antidote effectively.
I'm certainly not going to promise a trial right here, but I think the lifecycle management, new indications, further opportunities here are tremendous.
Yeah, this is clearly a drug where continuing to study it in, as you've said, different conditions where it might have a benefit makes a lot of sense. We feel pretty strongly that GLP-1 antagonism is not just going to be useful for PBH, but likely useful for a number of other areas.
We've already had a number of investigators and scientists reach out to us about where they believe a GLP-1 antagonist could have benefit. Stay tuned, please.
Outstanding.
I could talk another half hour on your remaining pipeline, but unfortunately, we're at time. But thank you so much for making time for us. Very informative discussion. And best of luck in 2024.