All right, great. Thanks, everybody. All right, welcome back for another session. We have the Amylyx Pharmaceuticals Co-CEOs, Josh Cohen and Justin Klee. Thank you for joining us, guys. Maybe what makes sense is just a quick 60-second, two minutes on how we got here. You know what I mean? Just make sure everybody understands the company, where we came from, and what we're doing. You don't need to get into each of the programs that you're working on right now because we're going to get through those. It's just a very quick update on the founding of the company and where we are.
Very happy to. First, thanks so much for having us. Thanks to the Leerink team. Good to see some familiar faces, too. As Marc was saying, Justin, Co-CEO, Co-founder, alongside Josh, fellow Co-CEO and Co-founder. We started Amylyx about 12 years ago. We were very focused in neurodegenerative disease. We still are. I think with that focus, we've maybe broadened to say more rare disease. I think we focused exclusively, though, on areas of very high unmet need. Right now, as Marc said, we'll get into, we have programs in ALS, progressive supranuclear palsy on the neurodegenerative side, Wolfram syndrome on the neuroendocrine side, and then Avexitide in PBH. Our history as a company, our first drug was for ALS. We brought that through FDA approval and commercial launch, had a very successful orphan drug launch.
We ran a confirmatory study that was not as successful, so we withdrew that from the market. That same core team is still here today. We have four ongoing clinical trials, one with a pivotal readout next year. We are very much looking forward to hopefully taking advantage of that development and commercial capability soon, as soon as 2027. Excited to get into that.
That underlying molecule is one of the assets that's moving forward in a program.
Exactly.
Which we'll get into in a second. Let's start with Avexitide. Tell us what is this product and talk about the proof of concept data so far.
Yeah, so Avexitide is a GLP-1 receptor antagonist. People are probably very familiar with the GLP-1 receptor agonists, such as Ozempic and otherwise. Part of why those work is they increase your insulin response, decrease your blood sugar. One of the reasons they were approved for diabetes and otherwise. With a GLP-1 receptor antagonist, you blunt the insulin response and increase blood glucose, which can be very important in diseases where we have too much insulin and where we have resultant hypoglycemia or drops in blood sugar. Avexitide, our lead indication we're focused on is PBH or post-bariatric hypoglycemia. It has FDA Breakthrough Therapy Designation for the treatment of PBH. That's really built on five previous studies in people living with PBH.
have also been studies in healthy volunteers, which have shown a blunting of the insulin response, an increase in the post-meal glucose, and then over time, a reduction in the rate of people having significant hypoglycemic events. People with PBH will have their blood sugar drop, leading to them becoming dizzy, unconscious, confused, fatigued, et cetera. Being able to reduce those events is really meaningful for patients.
The dosing, just so everybody understands, is what?
It is once daily sub-Q and 90 mg once daily sub-Q. That is also what we are studying in the phase III, which, as Justin mentioned as well, we are actively recruiting the phase III trial, expect a readout in the first half of 2026, and then filing and hopefully commercialization.
The underlying cause of PBH is what?
Yeah, I'll say it's a newer condition. The term was only coined for the first time in 2008. It's a rare subset of people who get bariatric surgery. We estimate about 8% of people who get bariatric surgery will develop post-bariatric hypoglycemia, which, as Josh was saying, is really characterized by these treatment-resistant, persistent hypoglycemic drops. People's blood glucose just drops, often in reaction to a meal, but it can be sometimes without a trigger or to other triggers as well. What really pops out of the literature is that it seems that people with PBH, their bodies are overproducing and secreting GLP-1. People may have as high as 10 times normal levels of GLP-1. This happens particularly in response to a meal or other triggers. We really think that this is a GLP-1-driven condition, which makes sense as you think about it.
People are trying everything they can to control their diet, and yet they're still having these very strong blood glucose drops. If you're having too much GLP-1, then kind of no matter what you're going to do, your blood glucose is going to drop. That is where we also think an antagonist of the GLP-1 receptor makes a lot of sense. You prevent GLP-1 from interacting with the receptor, so you don't get those drops, and you raise the overall glucose level.
Describe to us the phase III study.
Sure. It's a randomized placebo-controlled study in 75 people living with PBH. The primary endpoint is the composite of level two and level three hypoglycemic events. To kind of dive into that, a level two event is when your blood sugar drops below 54 mg/dL. A level three event is when you're so incapacitated that somebody has to rescue you. There was statistical significance on both level two and level three events in the phase II and in the phase IIb study. Probably most notably with the dose we're using, 90 mg in the phase IIb , there was a 53% reduction in level two events and a 66% reduction in level three events in the phase IIb with high statistical significance. As we go into this phase III, we're looking at endpoints that have previously shown evidence of effect with Avexitide.
Study 16 weeks with an open label extension. The idea is to see a difference in event rate between active and placebo over that 16 weeks.
In phase II, how long was the study?
Four weeks.
Four weeks. We know that, and the numbers that you were quoting, just to repeat them again, was 53% and 66%.
Six.
Okay. So that's level two and level three.
Yep, level three.
Okay. What about level one? What is level one and why are we excluding them now?
Yeah, yeah. No, so good question. Maybe starting with why do we measure blood glucose generally? The main outcome is our whole body needs glucose to function. In particular, our brains are the highest glucose utilizers in the body. What was recognized quite some time ago, originally studying in diabetes, but then other indications, was that as blood glucose dropped to particular levels, the brain stops functioning the way that it should. The technical term is called neuroglycopenia, which is just a fancy term for your brain needs more glucose. It was recognized that when the blood glucose drops below 54 mg/dL, that's really when your brain starts not functioning the way it's supposed to. That's what's level two. Level one is above that. Level one is sort of like, you know, you're getting into that range.
We all probably know the signs and symptoms and feelings of you skipped a meal or something like that. You maybe start to dip into the level one range there. Level two is where it really starts to be dangerous. That is why the ADA and other groups agreed on saying, okay, level one matters. In fact, in the Avexitide data.
It worked.
Level one.
It worked on level 1.
Absolutely, yes. It worked on level one. It is really level two and level three where things start to get serious. The FDA guidance for hypoglycemia is that having a composite of level two and level three events, that's an acceptable primary outcome because it is viewed as this is when things are getting really bad. That is why that is what we're also using as our primary outcome.
At phase II, though, those numbers you were quoting us were at four weeks.
Correct.
What do they look like at 16 weeks, for instance? Because the phase III is at 16 weeks.
Yeah, I mean, that's exactly why we're running the study. I think our hope would be to have similar effect size to what we saw in the phase II. Sort of putting this in context, when I say your brain's not functioning the way that it's supposed to, people get severe confusion. People may suddenly lose consciousness. They may have a seizure, right? These are really serious neurological manifestations. These 53% reduction in level two, 66% reduction in level three, this is really a big deal. In fact, in the exit interviews in the trial, people said, "Oh my gosh, I feel so much better." It makes sense. If you're constantly in fear of having these sorts of events, it's highly, highly debilitating.
In the phase II, were the patients followed past four weeks?
They weren't. That's probably the key difference between phase II and phase III, the duration of dosing. Now, the nonclinical studies, the preclinical studies all went substantially longer than that. There's no reason that we think there should be a waning of effect.
That's what I was going to ask you about, the waning of effect at all.
Yeah, exactly. We don't think so. The longest dosing clinically so far has been 28 days.
I'll also add this pathway doesn't show any evidence of waning of effect. It's the GLP-1 pathway. Probably people are familiar. People taking, for example, on the agonist side continues working for months, maybe even years. We don't have any anticipation that four weeks and 16 weeks are going to be so different.
Let's talk about just commercial opportunity for a second. What's the patient journey like here? What are they doing? What are they currently on? What's their standard of care?
Yeah. I'll say before we acquired Avexitide, this was a new area for us. Gosh, the more we learned about it, the more we realized this is a real unmet need and hopefully an area we can help. Patient journey right now, people get bariatric surgery. Most people will not develop PBH. Bariatric surgery is very effective for huge amounts of weight loss. I think particularly in people who are severely obese, maybe morbidly obese, bariatric surgery can be a great option. In a subset of people, we estimate about 8%, in the years following bariatric surgery, average one to three, but it can be even longer, people start to get these events where suddenly they're very confused, suddenly they feel terrible, suddenly they lose consciousness. Generally, they go to their PCP. Their PCP tries to help them out.
They refer them to an adult endocrinologist. The adult endocrinologist is often the person who makes the connection and tests their blood glucose and says, "This is hypoglycemia." Standard of care right now is medical nutrition therapy, which is, again, a fancy way of saying, "Eat every two hours, don't eat carbs, eat small meals, and try to keep your blood glucose as stable as possible." Now, medical nutrition therapy by itself, I think, helps people manage. First of all, it's pretty draconian, right? It's not exactly a good way to lead your life. The second is that for many people, they still have hypoglycemic events despite this medical nutrition therapy.
Now, some people ask us, "Well, with a diet, was that going to affect the type of events you see?" Well, generally, because I hate to put it this way, people have such a strong negative feedback, right? They have a diet excursion. They feel it, and it's really terrible. So people are pretty careful to stick to their diet. Besides that, there are no treatments approved for PBH right now.
The drugs are, what drugs are they? Are they?
There's nothing approved specifically.
Right. What are they using?
People will use a couple off-label drugs known to kind of raise blood sugar, such as acarbose, octreotide, and some others. One, those drugs have kind of mixed results when you talk to clinicians and in the literature, and they have side effects. There is no specific drug for PBH, and the ones that they try off-label are kind of met with mixed success.
How many patients have this? You said 8% is what?
We estimate about 160,000.
How many of the 160,000 are on one of these two drugs, for instance?
From our research, people blow through them pretty quickly. Very few.
Maybe all 160 tried it, but you're saying there's very few that actually stay on it or very few ever even try it?
Yeah, I would say we haven't kind of put out kind of exact numbers there yet. If I had to guess, I'd say probably actually not that many. PBH is only so well known, and only so many people are going to kind of reach for an off-label medication to try to treat this. I think our experience is that most expert, most KOL individuals do use these compounds. Those who are maybe a little less close to PBH may very well not.
Let's talk about the indication that you would receive if this works. Is it important that it's broad versus the bariatric surgery? Because there's different types of surgery. I guess where I'm going with this is if you get approved, will it just be across the board for any surgery? How often do the other surgeries have the same problems?
Yeah, it's a great point. Maybe giving the landscape a bit. From what we can tell, any upper GI, any significant upper GI surgery can lead to this persistent hypoglycemia. That can be for weight loss. That can be for gastric cancer. That can be for GERD. That can be for all sorts of things. For bariatric surgery specifically, the two main surgeries that are used today are vertical sleeve gastrectomy or Roux-en-Y gastric bypass. Vertical sleeve gastrectomy is the most commonly used, but Roux-en-Y is used quite substantially as well. Over the past several years, Roux-en-Y gastric bypass has actually been sort of increasing in prevalence because it has higher weight loss than vertical sleeve. Historically, vertical sleeve is used more prevalently.
Between those two surgeries, we get to well over 200,000 procedures annually has been the run rate for the past five to seven years. In this trial, phase III, we are enrolling only people who had Roux-en-Y gastric bypass PBH, and we are not allowing people with ESG PBH. Now, pathophysiology, we think it's the same. We don't think there's any difference. I think cardinal rule in your phase III trial is try to maximize success and try to replicate.
That was your decision. That wasn't FDA guidance.
That was our decision.
As far as you know, the FDA would give you a label for post-bariatric surgery.
That's certainly what we'll pursue. We do have some data as well in the phase IIb . A broad set of surgeries were included, and the data was comparable across surgeries. We do think we have a good argument both mechanistically as well as with some clinical data. That's what we'll pursue. If we need to at some point generate additional data, we will. We think we already have a pretty good argument for a broader approach.
I know, I would think so too.
Yeah, to your point, we believe PBH is PBH.
Yeah. Yeah, yeah. Let's go back to the call point and what kind of commercial organization you think you need for this product.
Yeah, I'd say we're still doing research. This is definitely a year where we're, in theory, two years out from launch where you start to gather a lot of insights and really build your knowledge on exactly what you're going to need for the best possible launch. I think the most clear call point is the adult endocrinologist. People end up getting referred over to their endocrinologist, who usually does the ongoing care for this indication. I think questions we have as well is how important is the bariatric surgeon in this whole approach as well? If you think all of these patients were initially at a bariatric surgeon, some years after they come down with the condition, usually at a point where they're beyond postoperative care. They might no longer be followed by the bariatric surgeon.
They find their way back into the healthcare system as they're having events and maybe going to a PCP and eventually to an endo. You could imagine in the future having a pathway where after bariatric surgery, there's some sort of regular glycemic testing, possibly coordinated through the bariatric surgeon or otherwise. I'd say in terms of physicians, there definitely are some sites that have serious expertise in this area, have large numbers of patients. There are almost definitely some sites that have less than a handful of patients as well. We'll have to figure out the degree to which we do it personally versus non-personally. How much is it digital? How much is it sales reps? We don't anticipate we're going to build a massive footprint to.
Maybe 100 people or something.
I think to your point, as we were looking at assets to acquire, we looked at what have we been, I think, good at historically. I think it's development and then commercialization in orphan disease. And so this is really orphan disease. I hate to put it this way, the orphan disease playbook, right? I think we should plan on specialty pharmacy, orphan pricing, targeted commercial efforts.
Yeah. It does seem like it should be the endo. I mean, I would think some of these bariatric places, like centers where there's probably endo and there's bariatric, those would be obvious areas too.
Yeah, I think so. One interesting thing we've started seeing pop up, I think especially in the age of the GLP-1 agonist, is this concept of a weight management clinic.
Exactly. That's what you're dealing with.
Yeah. Sometimes actually the bariatric surgeon and the endo are somewhat partnered, sometimes even with primary care or nutrition or some other specialties as well. That weight management clinic may end up being an essential part of the launch as well.
I think it's really exciting for both groups and for the whole weight management clinic to your point, because right now we have quite a few agents to help deal with hyperglycemia, too much glucose. We really don't have much or effective, well-tolerated treatments for hypoglycemia, which is just the other side of the same equation. We've heard a lot of excitement from all people sort of involved in this type of care.
Just to go back, this is a dosing. It's a daily sub-Q, but we're going to try to change that over time. Talk about the partnership you have and what the goals are.
Yeah, absolutely. We think this is a really exciting mechanism. We've talked our primary focus right now is PBH, but we think there's great promise beyond PBH as well. For example, I mentioned other surgeries that can lead to this form of persistent hypoglycemia. One that definitely comes to mind is gastrectomy for gastric cancer, gastric cancer being one of the leading causes of death in major Asian countries. I think just one example, the drug also has breakthrough therapy in congenital hyperinsulinism. I think it's a really powerful mechanism that we're targeting. Based off of that, we think it makes sense to invest for the future. At the end of the year, we started a research collaboration with Gubra. Gubra are one of the world leaders in peptide drug development. The goal there would be to try to develop a long-acting GLP-1 antagonist.
Early days, we've just started that collaboration, but they're super strong. I think our goal, we think of Avexitide as a great profile to bring to market, is to keep researching and then try to develop a long-acting.
Let's switch gears. PSP, you wanted to define it for us and help us understand what the proof of concept data so far is and why you're pursuing this.
Sure. PSP is a tauopathy. It's a neurodegenerative disease. People progress over time. It starts by looking like Parkinson's. People have gait disturbance, but people do not respond to dopamine therapy, which is one of the signs that it's PSP. They also start having other symptoms, such as the inability to look up and down and kind of an abducted arm posture and some balance difficulties. It will eventually progress such that they have swallowing and breathing difficulties, usually six to eight year survival after the diagnosis. It's a tauopathy. There's both strong genetic data implicating tau in the disease as well as strong postmortem and CSF data implicating tau in the disease. With AMX0035 in a past trial, actually in people with Alzheimer's disease, randomized placebo-controlled study, we saw a highly statistically significant reduction in CSF total tau and phospho-tau.
That led us to be interested in where might we study this in tauopathy. PSP being kind of the prototypical tauopathy became quite exciting for us. This will also be the first compound that gets both across the blood-brain barrier and into cells that reduces tau to be studied in PSP. We kind of view it as us testing the hypothesis that will a tau-reducing agent be effective in this disease?
You know the molecule.
Yeah.
It's the same.
Exactly. This is the treatment that we developed for ALS. We think this is even closer to the mechanism here because PSP, we know it's a tau-driven neurodegenerative disease. Stress and mitochondrial dysfunction are central. To Josh's point, we have tau-lowering data from a prior Alzheimer's study.
Yeah, yeah, yeah. Okay. Let's talk about the phase III study and what are the expected outcomes. What are we looking at here?
Yeah. It is a seamless phase IIb/III, which could be confusing. To kind of break it down, we're basically reading out the phase IIb portion, and that's going to serve as a go, no go, whether we go into phase III or if the results are less strong, whether we reprioritize resources elsewhere. We randomized 139 patients to the phase IIb portion. It will look at several outcomes, the primary of which is the PSP Rating Scale. We expect we have about 80% power to see a 30% effect on the PSP Rating Scale with the sample size. We do think it is possible we'll see some clinical changes in this study. We also have several other rating scales as secondary outcomes, some biomarkers, some imaging outcomes as well. We will look at it. It is an unblinded analysis.
We will look at everything at that time and ultimately make our go, no go decision. Now, I'd say in our view, we have very exciting programs. We are going to have a high bar. Certainly, what we need to see are some strong data to support investing forward into the phase III when we get that result.
When will we get some data here?
Third quarter of this year. Third quarter, we'll have an unblinded look. And to Josh's point.
That's the interim.
That's the interim, exactly.
You chose to do that because why?
We want to be confident before enrolling for a large phase III study. I think with PSP, the scale appears to be quite linear, and it's also been quite consistent trial to trial. Based off of that, as Josh was saying, we have quite good power, 80% power to see a 30% therapeutic effect with the population we have. We'll be looking at 139 people, six months through at least six months treatment. For people who have had longer treatment, we'll use all available data. I think the goal here will be, do we think we have a real potential treatment?
The interim is everybody beyond six months minimum, is what you just said.
Exactly.
That's the critical point. The endpoint that you're looking at to make the go, no go is.
The key is the PSP Rating Scale. It is a commonly used scale in PSP that measures the progressive impact of the disease. We will also be looking.
It's a functional.
It's a functional scale, exactly.
Functional scale.
We will also be looking at associated biomarkers. For example, there's a very particular pattern of brain degeneration that happens in PSP as well as some other scales as well.
NFL.
NFL, exactly. I think the goal here will be, do we have high confidence that this could be a meaningful treatment for PSP? Maybe just to share for those who haven't looked at PSP much, it is a tough neurodegenerative disease. It's progressive, it's fatal, and there is nothing approved for PSP right now.
Okay. Six months, patients are all on, take an interim look. Is there some clinical meaningful bar that you need to hit? Is it flat-out statistical significance? What are we looking for to decide the go, no go?
Yeah. I mean, I think we want to be confident. I know that's kind of a vague answer, but I think we want to be confident, which I think does mean seeing something relatively strong. I probably won't set the bar exactly at statistical significance, but something relatively strong on the PSPRS with corresponding concordant outcomes on the secondaries and otherwise. I don't think we want to be looking for a needle in the haystack for a signal. We want it to be pretty concordant and strong. In terms of meaningfulness, it depends what physician you ask. We've heard everything from a single point is meaningful to those who believe that an effect needs to be larger.
One point out of how many points?
It's 100 points. Scale, ultimately.
Okay. One point would be.
We've heard that argument, yeah.
Yeah. I think to the point, even comparing to other neurodegenerative diseases, and this is hard, right? These are some of the worst diseases there are. You think with Alzheimer's, with Parkinson's, with ALS, with Huntington's, there's at least something, right? Wholly inadequate, completely inadequate. There's at least something. There's nothing for PSP. I mean, it's sad, but for physicians and for people with PSP, anything would be better than what we have today.
Was that planned from the very beginning or you guys added that in?
We always planned to do an interim analysis. I'd say that as we've gotten more certainty around enrollment and around the trial, now we've been more specific on the timing and the powering analyses to go with that.
Got it. Got it. Wolfram's? I don't know which one.
Yeah.
Which one of you want to take Wolfram?
Sure. We've been working in Wolfram about, actually at this point, it's probably more like eight years. We started in Wolfram actually through talking with an academic clinician, physician researcher at Washington University, who's one of the top Wolfram experts named Dr. Fumihiko Urano. He approached us because Wolfram is often considered the prototypical disease of stress. Throughout all the literature, the WFS1 gene, which causes Wolfram, is strongly associated with stress. We proceeded to do several years of preclinical work with him, including in patient-derived neurons, beta cells, ultimately in the mouse model, all of which looked really strong, which is what encouraged us to go towards clinic. Just giving a picture of this disease, it's a monogenic disease, so it's caused by mutations in the WFS1 gene.
Patients start by looking like they're type 1 diabetics, so they get insulin-dependent diabetes, but they go on to have many other symptoms such as loss of vision, loss of hearing, walking difficulties, eventually breathing and swallowing difficulties that usually lead to their death approximately 30 years old. In our trial, we are conducting an initial proof of concept study with 12 people living with Wolfram syndrome. We focused on glycemic outcomes, diabetic outcomes such as hemoglobin A1c, C-peptide, and time in target glucose range. We also looked at things like visual acuity, and we included some outcomes of a kind of global burden of symptom change, CGIC and PGIC or clinician global impression of change and patient global impression of change.
What we saw, or what we've seen thus far across those outcomes, is all of them have stabilized or improved over time, which again is surprising given that the normal course of this disease is progressive blindness, progressive diabetes, progressive symptomatic progression. Right now we're collecting data through 48 weeks. We expect to have that in the coming months. We're also interacting with FDA and planning our phase III program. We're quite excited about the data to date, especially in this disease that similarly people do their best to manage the diabetic and other symptoms, but there's nothing specifically approved for Wolfram.
Twelve patients out practically a year. And we'll get that data when?
In the coming months.
In the coming months. Okay. So good data will be what?
I think what was surprising in a very positive way is that, as Josh was saying first, all of the outcomes, stable or improvement, and particularly C-peptide, which is a direct measure of how the beta cells in the pancreas are functioning and producing insulin, we expect over time it to decrease. We saw an increase, and in fact, it seems like that increase has sustained or maybe even improved over time. I think what we'd like to see is do we still see that sustained increase? To our knowledge, this is the first diabetic trial that has ever shown an overall increase in C-peptide. That's particularly exciting alongside all of the other outcomes going in the right direction.
The C-peptide increases were at what time point?
We've seen it at every time point. I think to the point, the longer data, the more people out to that time point seeing that sustained increase, that's really exciting.
Yeah. As of the last analysis, all 12 of the participants had made it through 24 weeks. Only six of the participants had made it out 48 weeks at that time. At this time point, all the people will have crossed the 48-week time point.
Okay. That's the point where you'll decide, okay, we're going to go into a phase III study and get this done.
Yeah. I think we're already very excited about the data, which is why we're planning for the phase III, but more longer data.
We're seeing patients the whole time.
Yeah, exactly.
We kind of know what's going on.
More longer data is always better.
Yeah, yeah, yeah. In our last 30 seconds, the last program, the Calpain- 2?
Yeah.
Just a quick.
Calpain- 2 has been researched for decades. It's a key protein in axon degeneration. We know in ALS and in other neurodegenerative diseases, one of the hallmarks is the axon retracts and degenerates. With Calpain- 2, we've shown in our preclinical studies that if you knock that down, you can prevent axon degeneration. This is an antisense oligonucleotide dosed intrathecally, and we are recruiting for a study in ALS patients right now. We expect to dose the first patients in that study this month or next, and we should have our first early cohort data by the end of the year looking first at safety, but also biomarkers like neurofilament, given that Calpain- 2 cleaves many axon proteins, including neurofilament. We see that it may be a signal of both disease, but also target engagement.
Got it. Good. Thank you. Thanks for joining us. Appreciate it.
Thanks so much, Marc.
Thank you so much, Marc.
Yep. Good. Great to see you.