Okay, great. Thanks for joining here this afternoon at day two of the Oppenheimer Healthcare Conference. My name is Frank Brisebois. I'm one of the biotech analysts at Oppenheimer. It's my pleasure here. The next company presenting is Amylyx. We have both CEOs here, Joshua Cohen and Justin Klee, to present.
What we'll do in terms of format is a presentation from them for about 20 minutes, and then there'll be some time for Q&A. So feel free to send some questions in the Q&A tab or to my email. But with that, thank you very much, guys, for taking the time, and I'll let you take it away.
Excellent. Thanks so much, Frank. Thank you, Oppenheimer, for hosting us. And yeah, we're very excited to share a bit about what we're up to at Amylyx. We have four ongoing clinical studies, and each in areas of high unmet need. I'm Justin, as Frank was introducing, one of the two Co-CEOs and Co-founders at Amylyx. And alongside me is Josh, my fellow Co-CEO and Co-founder.
First, as you know, before we get started, we will be making forward-looking statements. I'd please ask you to look through this disclaimer, as well as look for further information on our investor website. Overview of our pipeline. We have three assets in four clinical studies, all with exciting milestones this year and next year.
First, our lead asset is avexitide. It's a first-in-class GLP-1 receptor antagonist. It has FDA Breakthrough Therapy designation and orphan drug designation. Our lead indication is post-bariatric hypoglycemia. Post-bariatric hypoglycemia, there are no treatments available for people right now. It's a large orphan disease. We estimate about 160,000 people.
There have been five trials with avexitide showing great promise to help people with post-bariatric hypoglycemia. We're now going into our sixth and pivotal study, starting enrollment this quarter with readout next year. We're very excited about that.
AMX0035 is a combination small molecule targeting ER stress and mitochondrial dysfunction. We have two ongoing clinical trials. The first is in Wolfram syndrome. We announced very exciting data from our first trial, the HELIOS trial, last year. We are continuing to follow those participants, as well as engaging with FDA to determine next steps in that program.
In progressive supranuclear palsy, that's a rare and really tough neurodegenerative disease. AMX0035 in a prior trial showed very significant reductions in tau, and that led to this trial in tauopathy, progressive supranuclear palsy. We will have an unblinded interim analysis this year. So looking at efficacy and safety as our go/no-go decision.
And then finally, AMX0114 is an antisense oligonucleotide targeting calpain-2, which is one of the key actors in axon degeneration. We've seen promising preclinical data in axonopathies, including ALS. And we are now recruiting for our first clinical study in people with ALS. That's a multiple- ascending- dose study. And we expect to dose first people early this year as well. So very exciting pipeline, milestones this year and next year. And we'll dive in a little further.
So first on avexitide, which is our GLP-1 antagonist. As you might guess from the name, a GLP-1 antagonist lowers insulin secretion and raises the glucose nadir. Now, there are a variety of conditions characterized by hyperinsulinemic hypoglycemia or too much insulin secretion and rapid blood glucose drops. Our lead indication is post-bariatric hypoglycemia, which we believe is caused by the body's exaggerated GLP-1 response.
In the years following bariatric surgery, a rare group of people, we estimate about 8%, will develop a very excessive GLP-1 response. As you might expect, despite available intervention, if the body is just overproducing GLP-1, kind of no matter what people do, especially in response to a meal, they have very rapid blood glucose drops. This can be highly debilitating because really our brains need glucose to function properly. People will have sudden bouts of confusion, unawareness, even loss of consciousness or seizures.
I think what's particularly compelling, both in the unmet need and the opportunity here, is that we estimate there are about 160,000 people in the United States who are living with PBH today. Now, that's because there have been millions of bariatric procedures over the past couple of decades.
This is rare. It doesn't happen to most of the people who get bariatric surgery. It doesn't happen immediately. On average, it's about one- three years following the surgery that these symptoms tend to manifest. Once people have PBH, it unfortunately does not go away. This population will only grow, and treatment, we would expect to be chronic. There's very good literature studies looking both prospectively and retrospectively at cohorts. We've started to do our own claims analysis as well, which has corroborated this significant unmet need.
So as I mentioned, there have been five trials of avexitide previously. I'll highlight the two phase IIs that were done before now leading into this phase III. I'll go through the data in a moment, but I think as you'll appreciate, highly significant results at helping with hypoglycemic events, which is an FDA acceptable outcome.
Hypoglycemic events are well defined by the American Diabetes Association and other groups, and it's in FDA guidance for trials targeting hypoglycemia that a composite of level two and level three hypoglycemic events is an acceptable endpoint. What those mean is level two are defined by a blood glucose reading less than 54 mg/dL. Level three is that people are so incapacitated that they require assistance or independent rescue.
The FDA has reviewed our phase III protocol, and we're starting recruitment this quarter. That will be a 16-week placebo-controlled double-blind study with an open- label extension. And we expect data in the first half of next year. So we're very excited to be getting that study ongoing now.
I think our goal with the trial is really to try to enroll a very similar population to what was seen in the prior phase II trials because the data are quite strong. As you can see on the left was the phase II, on the right the phase II-B, looking at different doses of avexitide in reduction in level two and level three hypoglycemic events.
As you can appreciate, there's a dose response. At the highest dose or daily dose tested, 45 mg twice daily or 90 mg once per day, the results were roughly equivalent. The reductions are very statistically significant, high effect size. I think it's important to mention as well, hypoglycemic events, while they mainly occur during the day, tend to be in response to a meal or other trigger. They can also occur at night, which is why the high dose is important.
With the 90 mg dose, we are in the therapeutic range for 24 hours, which is why, as we have looked at the continuous glucose monitor data, there is indeed similar reductions in hypoglycemic events during the day and at night, which I think is really important as we're trying to keep people safe around the clock. We will be going forward with the 90 mg once daily dosing. Again, FDA has reviewed the protocol, and we are all systems go.
Importantly as well, the safety profile was quite good. It was generally well tolerated and safe. As we looked at injection site reactions, the ISRs were pretty comparable between active and placebo groups. When they occurred, they were almost always mild, very occasionally moderate. There were no grade three or severe events in the studies, and all of the events resolved quite quickly as well.
So we're very excited about avexitide as our lead program. We're going into the study with Breakthrough Therapy designation, five prior positive clinical studies. FDA has reviewed the protocol, and we're starting enrollment this quarter. Our goal is to complete recruitment by the end of the year with data readout in the first half of next year. With an expected priority review for breakthrough status, that would mean commercialization in 2027 for people who really need help. There are no treatments available for people with PBH. And again, we estimate there are about 160,000 people in the U.S. today who have PBH.
All of this is on the backbone of very strong patents as well. The patents go to 2037. That's before patent term extension. And of course, there's orphan drug designation as well. So we're very excited about our lead asset. But as I mentioned, we have two other assets and three trials as well. And so for more on that, I will now pass to Josh.
Thanks, Justin. I'll walk through our other pipeline programs. Starting with AMX0035, this is a combination of two small molecules, sodium phenylbutyrate and taurursodiol, that was designed to try to target some of the underlying pathways of cell death, namely mitochondrial stress and mitochondrial dysfunction and endoplasmic reticulum stress. The diseases we're focused on are particularly those diseases where those pathways are incredibly important.
Starting with Wolfram, and shown here is Raquel and Stephanie. Raquel's a person living with Wolfram, and Stephanie's her mother, p atients and family that we've gotten to know quite well, but are really who inspire us as we're working hard in diseases like Wolfram syndrome.
Maybe next slide, a little about Wolfram syndrome. This is a monogenic disease, meaning one gene is at the root cause of the disease. That gene is WFS1. And when there are mutations in WFS1, it impacts multiple organs and systems, primarily the pancreatic beta cells and various neuronal populations. We estimate there are about 3,000 people living with Wolfram syndrome in the United States, and there are no therapies specifically approved for Wolfram syndrome.
Just going through the pathophysiology a little bit. I t starts by looking like diabetes, like type 1 diabetes, usually at six to nine years old. But patients progress to have blindness, diabetes insipidus, movement difficulties, and ultimately speech, swallowing, and breathing difficulties, usually leading to mortality at about 30 years old.
So in the literature, Wolfram syndrome is often called a prototypical disease of ER stress. Why is this? Because the WFS1 gene is kind of a natural regulator or brake on the ER stress response. And if it's faulty, the ER stress response somehow runs out of control, causing the cell to ultimately degenerate and die. So with AMX0035 targeting these pathways, it made a lot of sense to go into Wolfram syndrome.
We also conducted several years of preclinical work, including in patient-derived neurons and patient-derived beta cells, that showed quite strong results. We also conducted a mouse model experiment where, in a WFS1, or the main gene for Wolfram syndrome, knockout mouse model, that showed highly statistically significant benefits on glycemic control in the mouse with AMX0035. So all this encouraged us to move forward into a clinical trial together with Dr. Fumihiko Urano at WashU.
So describing that trial a little. T his was our initial trial. So it was a 12-patient open- label study in people living with Wolfram syndrome. And as I described, Wolfram's a progressive disease. I mean, this is a disease that ultimately results in people typically passing away in their early 30s.
And over the course of the disease, patients show progressive diabetes, s o their glycemic control gets worse and worse. And you can see that evidenced in the C-peptide getting lower and lower, the A1C getting harder to maintain, the time in target glucose range getting again harder and harder to maintain.
Patients also lose vision, s o they have progressive decline in visual acuity up until the point where they reach blindness. And then, as I described, there are also multiple other symptoms that patients are prone to experience, s o we also measure a global impression of change both from the clinician and patient perspective.
So going into the study, we expected all of these measures to progress, especially over 24 weeks, a year. What we actually saw was, across all these measures, stabilization or improvement. I'll particularly highlight on the C-peptide, which is our primary outcome. We saw improvement across the study population, which was unexpected and quite exciting for us, suggesting the potential for benefit in this population.
Maybe next slide. In terms of safety profile, AMX0035 has been in many thousands of patients. The safety profile we saw was generally consistent with what we've seen thus far, with diarrhea and gastrointestinal side effects being the most common and generally of mild severity.
Where are we going from here? We're working with the FDA on a phase III design, which we hope to come back with this year. We're also continuing to gather data from the study. Patients are continuing to be followed long term. We'll be excited to see if the benefits continue to be as apparent as they have been as we continue moving forward.
So then talking about AMX0035, also in progressive supranuclear palsy, second indication that we're looking at with AMX0035. So to describe PSP a little bit, PSP is a rare progressive fatal tauopathy. And when I say tauopathy, I mean that the disease is very strongly considered to be driven by excesses in the tau protein.
Some of the evidence that supports this is very strong genetic evidence linking certain variants in tau to the disease, as well as pathology, both postmortem and through imaging, where you can see an incredible amount of tau deposition in the particular regions of interest in the brain where the disease progresses. The disease is a rare disease but not super rare, r oughly seven in 100,000 people or around 23,000 people in the U.S. It is progressive and fatal, with people living on average six- eight years.
One of the things that got us excited about AMX0035's potential in PSP was data that we had seen previously in a placebo-controlled study in people living with Alzheimer's. As you'll see here, we saw a highly significant reduction, compared to placebo, in CSF total tau and CSF phospho-tau 181. With PSP being a tauopathy, a small molecule that can get across the blood-brain barrier and into cells and reduce tau is a really exciting approach. To our knowledge, this is the first time such an approach has been tried in PSP.
That study is. Yeah, we have an interim analysis that will occur mid this year. We're fully recruited for that interim analysis. It will be a full unblinded interim where we look at all of our endpoints, including the PSP rating scale, several secondary endpoints, and biomarkers as well. The goal of that interim analysis is to complete a go/no-go decision. Strong data will encourage us to move seamlessly towards a phase III study. If the data are weaker, we would proceed towards a no-go decision.
Then maybe lastly, I'll describe our AMX0114 program in ALS. ALS probably doesn't need too much of an introduction but certainly is a rapidly progressive and fatal disease and particularly characterized by neuronal and axonal degeneration. In ALS, neurons basically disconnect from the muscle and die back. The axon retracts and degenerates.
And over the last 10 years or so in Amylyx, we had looked through many pathways and many mechanisms to try to determine which ones we thought were most exciting and promising for the potential treatment of ALS. And along those lines, we got very interested in calpain-2 and in the process of axonal degeneration, c alpain-2 being one of the key effectors in the process of axonal degeneration.
Maybe unsurprisingly connected with that, calpain-2 levels are elevated in people living with ALS. There have been various models in the literature, both cellular and animal, where inhibition of calpain-2 has shown a benefit.
And one other interesting connection with calpain-2, one of the things it does is cleave various cytoskeletal elements, including neurofilament. And when you look in ALS, you don't actually observe [audio distortion] neurofilament. Regarding the Western blot on the right side of the slide, full-length neurofilament is about 68 kilodaltons. You actually observe cleaved neurofilament. And one of the sources of this cleaved neurofilament may very well be calpain activity.
So going through a little bit of our preclinical data. W e have seen preclinically highly significant reductions in neurofilament in different cellular insult models, including models of axonal degeneration, such as on the left. We've seen rescues in various models where you drive cell death, including using oxidative stress through things like hydrogen peroxide. And we've studied ALS-specific models where you have a mutation in a gene of interest in ALS, here a mutation in TDP-43, and where with AMX0114 you see a very significant reduction in cell death in that model as well.
So right now, we are recruiting. We've just started recruiting for LUMINA, our clinical trial in ALS. This is a placebo-controlled multiple- ascending- dose study. So we'll have placebo and active in every single dose arm. And our goals are, of course, to look at safety and tolerability, but also to get an early assessment of pharmacodynamics, including markers like neurofilament light. And we expect early cohort data before the end of the year.
So maybe stepping back and highlighting, first, we have a strong cash position that allows us to get through these milestones across all of our programs. We just recently completed a public offering at the start of the year, which gives us the cash to get through the end of 2026 and through all of the milestones I laid out.
And maybe just to highlight those. M aybe first, avexitide, our lead asset which is a GLP-1 receptor antagonist with FDA Breakthrough Therapy designation. We've just started recruiting for the phase III trial. We expect to complete recruitment by the end of the year, with data in the first half of 2026.
AMX0035 is in two clinical trials, one in Wolfram syndrome, where we expect to provide an update on our phase III plan this year, as well as in PSP, where we expect to have data from interim analysis in the middle of this year. And finally, AMX0114, where we've just begun recruiting for the LUMINA trial, a gain a multiple- ascending -dose placebo-controlled study where we expect to have safety and biomarker data from early cohort by the end of the year.
So thank you so much for having us today. I think at Amylyx we're really driven by the patients we're serving. And we're excited to be advancing multiple programs to, hopefully, help many patients. So I'll open up for questions.
Awesome. All right. Thank you very much, guys. There's a lot going on here, and I had a couple of questions on maybe avexitide. Can you talk about the history behind this molecule a little bit? Where does it come from? When did you guys get it? A nd yeah, we'll start with that.
Yeah, very happy to. So avexitide was originally developed at both Stanford and CHOP. It was licensed to a company called Eiger, who developed it and ran the five trials in post-bariatric hypoglycemia that I mentioned, as well as actually congenital hyperinsulinism. They ran three studies in that indication as well and actually got Breakthrough Therapy designation in both indications, which I think highlights the unmet need but also the strength of the data.
As I said, we're advancing PBH first as our lead indication. We acquired the asset last July. Our team, as we got our arms around it, then had the protocol written, reviewed by FDA, and now we're running the pivotal study. It's really an exciting program.
Before acquiring it, we had evaluated hundreds of assets over the years looking for just that right mix of great development, disease or condition of high unmet need, focusing in more orphan markets, and hopefully something where we could run a pivotal study and get treatment to people very effectively as we did with our first ALS asset. So it really checked all the boxes for us. And we're tremendously excited for the opportunity with PBH ahead as well as the additional work that we think one can do with a GLP-1 receptor antagonist.
GLP-1 is not an on-off switch. It's much more of a thermostat. And just as we've seen GLP-1 receptor agonists be effective in a number of indications, we think we're going to find the same with the receptor antagonist. But first things first, we have something really exciting right ahead of us with PBH.
Okay, great. And is anyone else working on a GLP-1 antagonist?
So there is one company, MBX Biosciences, working on a GLP-1 receptor antagonist. They're in phase I, b ut we're very excited about our position with Breakthrough Therapy designation, multiple positive trials, and excited to go into the phase III trial looking at endpoints that already have shown evidence of benefit in the phase II and in the phase II- B.
Okay, great. And then on the PBH side, what have been the challenges maybe in the past? Who else has tried it? You said Eiger had a program in it. Just a little history for investors on PBH.
So PBH is newer. And the reason it's newer is because bariatric surgery really took off in the early to mid-2000s. So now, over the past two decades, there's been well over 2 million procedures that have happened in the U.S., but it's a relatively recent phenomenon. Also, it takes years following the surgery for these symptoms to manifest, if they manifest at all. As I mentioned, we estimate about 8% of people may develop PBH, but that means 92% won't. So it's a newer indication.
Now, different companies have tried various assets that are known to help with hypoglycemia or to control the glycemic index in PBH, recognizing that this is such a high unmet need a nd again, unfortunately, only a growing population, b ut this is the one that's really been furthest in development and is now in a phase III study. So we think it's a really important area.
When we talk to endocrinologists, many will say, "These are some of the most fragile patients I have under my care." You can just imagine you're constantly worried that you might have a sudden loss of consciousness or such confusion that you're not aware of where you are. It's really debilitating. So we're very excited to have an opportunity to help people who really need it.
Are these patients very variable in terms of this sudden loss of consciousness? Or is this like, how recurring is it? How common is it? Or is there different levels of mild, moderate, and severe PBH?
Yeah. So out of people who have bariatric surgery, there's a little bit of variability in the literature, but generally, upwards of 20%-40% will experience some hypoglycemia, and that meaning some times where their hypoglycemia actually gets to a level two range. We kind of further subset that down to about 8% of people who have persistent kind of recurrent hypoglycemic events that are really impacting their life.
Yes, even within that, there is a spectrum of severity, but when you think about this condition, safety is often top of mind. If you're at risk of suddenly losing consciousness or becoming confused, if you're behind the wheel, if you're behind a school bus, that can be incredibly impactful. And so it's very, very important to try to minimize these events as much as possible and to get ahead of that before a patient has a much more significant complication if they have a fall or something like that.
It's more of an at-risk kind of population. Everyone that's at risk could benefit.
I'd say yes, though many of these patients will experience multiple events a week, some even experiencing multiple events a day. So it really does disrupt their lives. Talking to many patients, many are unable to hold a job, don't have a license, etc., because of the complications of this disease.
Yeah. To paint a picture, in the prior trial, the requirement for entry was at least one event per week. We're doing the same. There's a run-in period. A nd those trials recruited very quickly, so while there is a spectrum, it's not unusual, as Josh said, for us to come across people who have an event a week or much more.
A nd again, that's that 160,000 population that we're talking about. There's a much larger population who maybe have less- severe forms, but we're first and foremost focused on the people who really have this symptomatic persistent hypoglycemia.
Okay, great. And then on that market size, because that is a very big rare disease, right, 160,000. It kind of reminds me of the size a little bit. Narcolepsy is similar in terms of a rare disease that's quite big. I was just wondering, with the GLP-1 agonists out there, do we expect there to be less bariatric surgeries? Or what's the thought process on the size of the market based on the GLP-1 agonists?
Yeah, it's a great question. So maybe going through a couple of things. First, as Justin said, bariatric, maybe starting with the prevalent population and then also talking about the incident population as you're saying as well.
First to say, people get bariatric surgery, on average, at about 40 years old, and these only started becoming common in the early 2000s, so this prevalent population is very much here to stay. Most of them are 40, 50 years old, have their whole life ahead of them, and this condition does persist. We've interacted with patients who have had this well over a decade and longer.
In terms of bariatric surgeries, what we've heard as we've spoken to people is that they're actually pretty differentiated in a way from the GLP-1 receptor antagonists. Most of the studies where people have evaluated bariatric surgery are in people with BMIs well over 40. So converting that into pounds, for a typical male, that might be 300- 400 lbs body weight. And for example, in the past Eiger studies, one of the questions was, "How much weight did you lose from your bariatric surgery?" And the average was greater than 100 lbs .
So I think bariatric surgery is often the tool that's used when people need to lose weight at kind of that order of magnitude, whereas the GLP-1 receptor agonists were primarily studied in people about 100 kg and have significant weight loss but I think is maybe a slightly different population. So a broad way of saying, as we've talked to people, they do think bariatric surgery is here to stay and that it's somewhat differentiated in terms of which patient might go for one option versus the other.
Great. Okay. I think we're coming up on time. Is there anything that we should have mentioned that maybe wasn't brought up in the Q&A?
No, I just once again say thank you very much for having us here. We're very excited to have multiple programs advancing at the same time, with milestones this year and next year, and particularly with the top line results in the first half of next year for avexitide. So thank you and we look forward to following up with you more.
Absolutely. All right. Thanks, guys. Appreciate it.