I think let's get started. Welcome, everyone. It's June 20th, day of the TD Cowen Healthcare Conference. I'm just here to present the team from Amylyx, who has a couple of slides that they want to show you. After that, we'll do a Q&A session. Here we have Joshua Cohen and Justin Klee, co-CEOs of Amylyx. I'll just get you over to you all. At the end, we'll do a quick Q&A session.
Excellent. Thank you. Yeah, thanks for coming to our presentation. Thanks to the TD Cowen team for inviting us to present. As mentioned, I'm Justin, one of the two co-CEOs and co-founders of Amylyx. With me is Josh, my fellow co-CEO and co-founder. First, before getting started, I think all of you know this, but we will be making forward-looking statements during this presentation. I'd please refer you to this slide as well as what's on our investor website. Going through our pipeline, first, we have three assets in four clinical trials, and we have significant milestones in each of our programs over the next 12-15 months. Starting with our lead asset, Avexitide. Avexitide is a potential first-in-class GLP-1 receptor antagonist. It lowers insulin. It raises glucose. Avexitide has FDA breakthrough therapy designation as well as orphan drug designation.
The first indication that we're focused on is post-bariatric hypoglycemia, or PBH, which we'll share a bit more about, but high unmet need, about 160,000 people in the U.S. who have this and no therapy is approved. We are starting our sixth and now pivotal study in people with PBH following two very strong Phase 2 trials, and we expect data readout in the first half of next year. Moving to AMX0035, which is a combination small molecule that targets stress and mitochondrial dysfunction. We're testing in two diseases characterized by stress and mitochondrial dysfunction, being Wolfram syndrome and progressive supranuclear palsy. We had positive data from our first Wolfram study last year looking at measures of both diabetic impact as measured particularly by C-peptide as well as the neurodegeneration that characterizes the disease. We'll go through that data a bit more later.
In PSP, we will have an unblinded interim analysis in the third quarter of this year. We just shared this morning on our earnings call that we enrolled about 139 participants in the study. With that, we will have about 80% power to see a 30% effect in our analysis in the third quarter. Last, our AMX0114, it's an antisense oligonucleotide targeting calpain-2, one of the key actors in axon degeneration. We are starting enrolling a study in people with ALS. We expect to dose the first participants in the next couple of months, and we should have our first early cohort data by the end of this year. Really exciting pipeline and events over the next 12-15 months.
As I was mentioning, Avexitide is a GLP-1 receptor antagonist, and we are very excited about the potential of a GLP-1 receptor antagonist. I'm starting with post-bariatric hypoglycemia, or PBH, which is our first primary indication. PBH is a rare condition that happens in the years following bariatric surgery. It doesn't happen to everyone. It's pretty rare, but it is caused because the body potentiates the GLP-1 response. The body produces, secretes too much GLP-1, often in response to a meal, but it can be due to a variety of different triggers, which causes a precipitous blood glucose drop. What happens when our bodies don't have enough blood glucose, the brain can't function the way it's supposed to. The technical term is called neuroglycopenia. As you might imagine, this is a highly debilitating condition because people have these very precipitous drops.
They may get very severely confused. They may lose consciousness. They may have a seizure. Now, a GLP-1 receptor antagonist blocks endogenous GLP-1 from interacting with the receptor, and that's why we think this is such a good approach for this unmet need. I said it was rare, but there have been millions of bariatric procedures that have happened over the past decade. 8% of the roughly 2 million people who have had bariatric procedures over the past decade get to a population of about 160,000 people. This population has been well studied in the literature in both prospective and retrospective studies that suggest you look at some of the studies that we have here on the slide, and you can see on our investor website. We started to look at claims-based analysis as well and found very similar numbers. This is a high unmet need.
There are no treatments approved and orphaned, but a very large orphan condition. I should mention also it's persistent. Unfortunately, once people have this condition, it doesn't go away. We're working with someone, for example, who's had PBH for 18 years. We think that this is a population we expect to continue to grow. We're going into our pivotal study now. This is off the first of two very strong Phase 2 trials. Our goal with this trial really is to, of course, have a trial that would support an approval, but also be as consistent with the Phase 2 trials as possible. We're using substantially similar inclusion criteria. Particularly, we're looking at people who will have at least one hypoglycemic event per week. That's the same as what was done in the Phase 2 trials.
I'll note that we're looking at people who had Roux-en-Y gastric bypass PBH. We don't think physiologically there's any difference between, you know, I think PBH is PBH, but what's been studied the most with Avexitide is people have Roux-en-Y gastric bypass and then PBH. Again, trying to be as consistent with the Phase 2s as possible. We're using the 90 mg dose, which was seen to be highly effective and safe in a prior trial, and it'll be 16-week placebo-controlled. As I mentioned, there have been five prior trials of Avexitide in PBH. Shown here are the two Phase 2 trials, the Phase 2 and the Phase 2 b study. I hope you can appreciate this is looking at reduction in hypoglycemic events. These are well-known, well-characterized outcomes for several decades now. Hypoglycemic event level two means that the blood glucose is below 54 mg/dL.
Level 3 is that someone is so severely impaired that they need independent rescue. These have been established for some time. They're also in the FDA guidance for trials looking at hypoglycemia, particularly that the composite of level 2 and level 3 hypoglycemic events is an acceptable primary outcome. That's what we'll be using in the Phase 3 trial. We're going forward with the 90 mg dose. As I mentioned, I think there is a dose-dependent response, but if you look, I think the 45 mg and the 90 mg dosing, you get to roughly equivalent results. We think that makes sense because with either of those regimens, you're within the therapeutic range for 24 hours. You're preventing endogenous GLP-1 from interacting with the receptor, and therefore you're protecting against these hypoglycemic events. Importantly, the safety profile was also very good.
Injection site reactions were virtually the same as placebo in both trials. When there were reactions, they were mostly mild, very occasionally moderate. We are very excited about this program. As I said, it is our lead asset and lead program. We have started recruitment. We started that in mid-February. We expect to dose the first participants in the study in the next couple of months. We expect to complete recruitment by the end of the year with data readout in the first half of next year.
This would support a potential commercial launch in 2027 for a significant unmet need in high population. I probably do not have time to go into it, but very strong patent estate as well. Patents go out to 2037, not including patent term extension. That is our lead program, but we have several other exciting programs as well, and we have milestones in those.
For those, I'll pass to Josh.
Sure.
I'll talk a little bit about our other pipeline programs, starting with AMX0035, which is our fixed dose combination of sodium phenylbutyrate and taurursodiol. We designed this drug originally on the basis of trying to target mitochondrial dysfunction and stress. These two compounds have existed for some time, including in the literature, often as tool compounds to target those pathways. It's really those pathways that led to the diseases that we're focused on at this point, Wolfram syndrome and PSP with AMX0035. Starting with Wolfram syndrome, to give a little bit about the wrong direction, to give a little bit about this disease, this is a monogenic disease caused by mutations in the WFS1 gene. WFS1 is an endogenous regulator of the stress response. When WFS1 has a mutation, patients can have an overactive stress response that leads to cell dysfunction and death.
Basically, with these mutations, patients see dysfunction in various neuronal populations and beta cell populations. How this manifests is initially people look like they have Type 1 diabetes, but as time goes on, they get progressive blindness. They get walking, speech, and movement difficulties. Ultimately, this will result in death in early 30s, typically usually due to kind of respiratory failure or aspiration pneumonia from swallowing difficulties. We estimate there are about 3,000 people living with Wolfram in the US today. Again, a monogenic disease. Mechanistically, Wolfram is often called a prototypical disease of stress, mainly built on the fact that WFS1 is a stress regulator protein. It made a lot of sense to use compounds with strong basis in stress and mitochondrial dysfunction in this disease.
We've conducted a number of preclinical experiments over six or seven years that included patient-derived beta cells, patient-derived neurons, as well as a mouse model of the disease, a double WFS1 knockout model where we looked to see how glycemic control progressed over time and saw a highly statistically significant benefit on glycemic control when dosing with AMX0035. This is really what led us towards a clinical trial in Wolfram syndrome. That trial is HELIOS, which is our ongoing Phase 2 trial, open-label trial with 12 people living with Wolfram syndrome. What we would expect in people living with Wolfram syndrome is progressive loss of glycemic control, meaning that their diabetes is getting worse and worse over time as the beta cells degenerate and die. We also expect progressive loss in visual acuity.
As you saw earlier, there are a number of other symptoms people with Wolfram syndrome experience. We also expect that on global metrics of symptomology that patients will get worse and worse. What we actually saw and have seen thus far in this trial is stabilization or improvement across these measures, both the measures of glycemic control, the measures of visual acuity, and the kind of global metrics of symptom progression. We are continuing to follow those patients. We expect to report on our Phase or on our week 48 data in the coming months, but really encouraging to see, in contrast to what we might expect in this disease, stabilization or improvement across multiple measures. From a safety perspective, AMX0035 has been in thousands of people, including through our ALS work.
Generally there, the safety profile has been very good, with the most common AEs being some diarrhea, some GI side effects. That is the same as what we saw in Wolfram with no new notable safety signals. Where do we go from here? As I said, we are expecting week 48 data in the coming months. We are going to, with that data, as well as talking with regulatory agencies, including the FDA, design the Phase 3 trial. We will come back with an update later on the design and scope of that Phase 3 program. Moving to progressive supranuclear palsy, the second indication that we are looking at with AMX0035. Diving in a little, what is PSP? PSP is a tauopathy.
Both when you look pathologically, you can see clear accumulation of tau in brain regions that are affected by the disease, but also there's an incredibly strong genetic association with certain variants in the tau gene and PSP. This has led the field to look at PSP as strongly as a tauopathy. How does the disease present? People start with gait disturbance. This is why it's often called an atypical Parkinson's, because people may have walking or movement disabilities. It becomes clear it's not just Parkinson's when people don't respond to dopamine and have a series of other issues such as speech and swallowing, balance, and other movement difficulties that kind of go above and beyond Parkinson's. With these, patients typically pass away in six to eight years. While it's an orphan disease, it's a fairly large orphan disease at approximately 23,000 people in the United States.
Again, building off the fact that PSP is a tauopathy, AMX0035 had previously been studied in a randomized placebo-controlled study in people living with Alzheimer's disease. What we saw in our CSF biomarkers was a highly statistically significant reduction in tau and phospho-tau in the CSF in people with Alzheimer's disease. This got us interested in looking at AMX0035 in tau-driven disease. I'd also add AMX0035 is a small molecule. While there has been some interest in tau approaches in PSP, there has not been one that can get intracellular and that can cross the blood-brain barrier. We do believe this is the first time that such an approach is being studied. We've recruited 139 people in a Phase 2b study in PSP. We expect to report an interim analysis in the third quarter of this year.
That will be an unblinded interim analysis. We'll have data on the PSPRS as well as several other outcomes. We expect with the sample size that we have about 80% power to detect a 30% effect on the PSPRS based on the published literature. Maybe lastly, I'll jump through our AMX0114 program in ALS targeting calpain-2. AMX0114 is an antisense oligonucleotide targeting calpain-2. Basically, it results in less production and expression of the calpain-2 protein. Calpain-2 is a protein that's been intimately linked to the axonal degeneration process. It's a protease that kind of destroys the cytoskeleton, leading to the neuron pulling back its axon from the muscle and desynapsing from other neurons as well. The connection to ALS is strong. There's been evidence of significant upregulation in samples from people living with ALS.
Benefits have been seen in mouse models and other models with the inhibition of calpain. And it's been linked to some of the genetic and other pathological elements of ALS, such as TDP-43 and some of the other genes. I'll also note calpain-2 has a close link with neurofilament. In ALS, one interesting observation, we note that neurofilament is much higher in ALS compared to healthy control, but it's not actually the full-length neurofilament. When you look at the Western blot on the right of the slide, you see that the neurofilament we observe is actually a fragment. Neurofilament is a 68 kilodalton protein. One of the primary proteases thought to cleave neurofilament is calpain-2. It's possible when we're measuring this neurofilament, we're actually measuring indirectly calpain-2 activity. I'll say going through our preclinical data as well.
We have tested with our ASO in multiple preclinical models. In the interest of time, I probably won't go through them one by one, but both models that are genetic models of ALS, as well as models where we chemically induce axonal degeneration. Across those models, we see a reduction in neurofilament, improvement in cellular survival, and improvement in axon integrity with AMX0114. Where do we stand now? We're actively recruiting in LUMINA, which is a placebo-controlled multiple ascending dose trial. We're actively enrolling the first cohort. This will look at both safety and tolerability as it is a first in humans. Of course, safety is very, very important. Additionally, we'll be looking at pharmacodynamics such as neurofilament levels and other biomarkers relevant to ALS and relevant to the calpain pathway.
Summing up with all of this, one, we have cash that gets us through the end of 2026. We just raised additional financing at the start of the year. That will get us through milestones in all of these key programs. Just recapping some of those milestones for Avexitide, we're actively recruiting our Phase 3 program. Expect to finish recruitment by the end of the year and have data in the first half of 2026. With AMX0035, we'll have additional data from the HELIOS trial, the 48-week data in the coming months. That will help inform, along with our regulatory interactions, our Phase 3 program. In PSP with AMX0035, we expect to have data from an unblinded interim analysis on 139 participants in the third quarter of this year. With AMX0114, we're actively recruiting for LUMINA.
We expect to have early cohort data before the end of the year as well. Thank you all so much. We're quite excited about the pipeline we're advancing to hopefully help many patients with significant unmet need. I think there's Q&A, so I'd open up for questions as well. Maybe there's not Q&A.
Questions from the audience.
I have a couple of quick ones.
Sure.
Yeah, just on the Avexitide phase 3 program, what level of improvement in hypoglycemic events do you think physicians are looking for when they kind of evaluate new treatments in the space? Does it matter that you see a similar level of improvement on the level two and the level 3 events, or does one matter more than the other?
Great question. I'd say right now, there are no treatments approved for PBH. Right now, unfortunately, the bar is low. I think maybe starting from the patient perspective, talking with patients, they'll say, "My gosh, anything would help," because these are just incredibly debilitating. It's also not just that they have these events. Their set point is off. They're kind of always flirting with hypoglycemia, which we all know the feelings of being you skipped a meal and you feel really bad. Imagine that times like 10, and that's just your stable level. I think for patients, really, any relief would be helpful. For doctors, I think the way they think about it is they want to keep their patients safe. Level two is a physiological measure that means that it's at the range where your brain stops functioning the way it's supposed to.
Level 3 means you've had one of these events where you're so incapacitated, you need someone to help you. I think for physicians, both matter because level two means that you're in danger. Level 3 means it already happened. I think going to your question on what % would be meaningful, certainly the results that we're seeing in Phase 2 are very strong. I mean, I think that's what supported FDA breakthrough therapy designation. Based on the powering, we are powered to see even half of that effect in the Phase 3 trial. I think going back to what's meaningful, right now, there's nothing for people with PBH. I think the bar is unfortunately low.
Just to add, I should talk to the list. To add one additional comment as well. In the past trials, there were patient interviews. After the trial, a subset of the patients were interviewed to ask how their experience was on trial. One of the questions was, "How would you rate the efficacy you experienced on a scale of 1 to 10?" Every patient but one rated it 10. The other rated it 9. In their kind of verbal description of why they gave it that rating, it was that, one, they felt protected from these significant hypoglycemic drops, but also, even on the maybe less deep hypoglycemia, they felt more energy. They felt more focus, things like that, that when your blood sugar is consistently low, you just do not function well.
I guess on the Wolfram program, just given that there are no approved treatments, how do physicians kind of manage their patients with this condition? I guess what has seemed to resonate the most with these physicians when you show them the AMX0035 profile?
Great question. Again, and you'll maybe notice the theme, there are no treatments for Wolfram syndrome right now. Right now, if you think about it, Wolfram starts as an early onset diabetes. People very quickly get on insulin. They're often on closed-loop systems and stuff because the beta cells are degenerating. They actually get periods of hypo and hyperglycemia. Over time, it degenerates further and further. They constantly need sort of different levels of insulin and more insulin over time. With the, it becomes a whole body system disease. Physicians just try in each domain to do therapy. For example, progressive vision loss leads to blindness. Kids have to learn Braille and learn how to use a walking stick and the like. As well as, as you might imagine, there can be quite significant depression.
They try to help with that. It's really people try to help with a variety of different symptoms, but there's nothing that changes the progression. I think there's probably two things that we've heard the most. One is, I think the totality of the data, every outcome went in the right direction, which given that this is a whole body disease, I think that's very exciting. I'd particularly highlight, though, the C-peptide. C-peptide is a direct measure of the body's insulin production and secretion. We're not aware of another study in any diabetic indication where C-peptide is increased. When we've talked with endocrinologists or specifically diabetologists, they kind of say, "Wow, I don't think I've ever seen a trial where C-peptide actually increases." Not only would you expect a decrease over time, but we're actually seeing it go in the opposite direction.
I think that's what's gotten people particularly excited. We think it's because we're getting at the heart of the disease. We know that the disease caused by the WFS1 mutations causes the stress and mitochondrial dysfunction. That's what we're trying to target with AMX0035.
How important is diagnosis? Is it just a clinical diagnosis? And how heterogeneous is the presentation?
Yeah, great question. I'd say today, it mostly is clinically suspected and then genetically confirmed. There are genetic panels. There are commercial genetic tests where you can quickly test and confirm Wolfram syndrome. What we hear most often talking to people is that when a Type 1 diabetic starts to show progressive vision loss, it becomes suspected. It's usually that combination. Particularly if it's optic atrophy compared to diabetic retinopathy, it leads people to think that this may be potentially Wolfram syndrome. You could imagine, though, a future state where people do some screening of Type 1 diabetics or otherwise, possibly not just for Wolfram. There are a number of monogenic diabetes, and people have started making commercial panels with multiple of the different genes for genetic diabetes.
You could imagine a world where when somebody has an early onset diabetes diagnosed, that they check if there's a particular genetic cause.
I'd say to your question on heterogeneity, the natural history is pretty good. There's one U.S.-based study we're now working to get. There's a U.K.-based study as well. I'd say, as you might expect, there is some heterogeneity, but the pattern is pretty consistent. Kids typically get early onset diabetes, 6, 7, 8. It is usually the vision loss and then sort of the neurodegeneration, the other diabetic implications sort of show. There is some heterogeneity. I guess going back to Josh's point, clinical suspicion, genetic confirmation, you get, I think it lessens a lot of the variability you might see.
I think that we're just at time. I think that we'll probably end it here. Thank you all for coming, and I hope you all have a great rest of the conference.
Excellent. Thank you.