We're going to get started with our next session. I'm Andrew Tsai, Senior Biotech Analyst at Jefferies. Thanks for tuning in. It's my pleasure to have the Amylyx team with me today. To my direct left, Josh Cohen, Co-CEO, and then to his left, Justin Klee, Co-CEO as well. Welcome, both of you.
Thank you.
Thanks, Andrew.
Thanks for having us.
For those in the audience who may be less familiar with the Amylyx story, spend a couple of minutes talking about what you're working on, what you're trying to achieve, what kind of milestones we can expect for the next 6 or 12 months.
Sure, absolutely. At Amylyx, we're developing therapies for significant unmet needs, particularly rare, all rare diseases that we're focused on as well. Our lead asset is a compound called avexitide, which is a competitive inhibitor of GLP-1. We are using that in diseases of hypoglycemia, particularly focused in post-bariatric hypoglycemia. This is a rare condition that people get in the years following bariatric surgery that results in them having sudden, persistent sudden blood sugar drops, often in response to a meal, but sometimes in response to exercise, stress, other triggers. Having that chronically means that people end up living a fairly sheltered life. They may be unable to drive a car. They may be unable to—they may have lapses and challenges with a job or daily living. A disease that really, really has a substantial unmet need.
Avexitide has been studied in five past trials in PBH, all of which showed significant benefits on glucose and insulin measures, as well as in the phase II and phase II-B , significant reductions in hypoglycemic events, including at the dose that we're taking into phase III, a 53% reduction in level two hypoglycemic events with a p-value of 0.004, and a 66% reduction in level three hypoglycemic events with a p-value of 0.0003. Based on that, we have breakthrough therapy designation. We're conducting a phase III study that we expect to complete recruitment by the end of the year with data in the first half of 2026, and pending good data, plan to submit and hopefully get approval and launch in PBH. In addition to that, and I'll talk very quickly, we have two other assets across three trials, AMX0035, which we're studying in PSP and Wolfram syndrome.
In Wolfram syndrome, we just released 48-week data from an ongoing study, which showed whereas Wolfram is a progressive disease, you expect multiple measures to get worse over time. We're actually seeing an improvement across the measures that we've been studying. Based on that data, we're defining a potential phase III trial, and we expect to share plans for that later this year. We also have data coming out from a clinical trial in PSP with AMX0035 in Q3 of this year, based on the science and pharmacology that we've seen with tau reduction with AMX0035. That is what's made us excited about the potential in PSP. Finally, we have AMX0114, an antisense oligonucleotide targeting calpain-2, which is one of the critical proteins in axonal degeneration, also one of the critical proteins in processing of neurofilament.
We've seen preclinically significant effects on axonal degeneration and on neurofilament with our ASO AMX0114. That is ongoing in a clinical trial in ALS, placebo-controlled ascending dose study, and we expect to have some data before the end of the year. We also just got a fast track on that program as well. I'll stop there. Lead assets of avexitide and multiple other assets in progress as well behind that.
Thanks. That's a great overview. I'd like to start by digging into the PBH program. Can you help us frame the market opportunity for avexitide ultimately? How big is the market? If approved, would it be used in level two, level three? How big is that market? Just help us frame or give us context how many patients are out there in the U.S.
Yeah, thank you. That's critical. Post-bariatric hypoglycemia, or PBH, is a condition that affects an estimated 160,000 people in the United States. That number will only continue to go up. It's a rare complication that can happen in the years following bariatric surgery. The reason you get to quite substantial numbers is that there have been millions of bariatric procedures just in the past 10 years alone. The most recent data on bariatric procedures is that there have been about 270,000 procedures annually. Even with the GLP-1 agonists in 2023, there were about 270,000 procedures. The reason is because bariatric surgery is still the best option we have for people who are morbidly obese, people who need to lose 100, 150 lbs. We think bariatric surgery will continue to be used. It has great data on improving all-cause mortality outcomes.
That also means that we're going to continue to have post-bariatric hypoglycemia, which also is a condition once someone has it, unfortunately, it doesn't go away. In terms of level two and level three events, PBH is characterized by very persistent hypoglycemic events. For example, in type 2 diabetes, oftentimes people are worried if there's a single hypoglycemic event because it's so dangerous. People with PBH may have an event a week. They may have more than one event per week. When we talk to adult endocrinologists, they describe people with PBH as some of the most fragile patients they have under their care. Currently, the mainstay treatment is medical nutrition therapy. There are no treatments specifically approved for PBH. Essentially, people with PBH are told to try to keep their glycemic control as best as possible by eating very frequently and avoiding simple carbs.
Even despite that, they're having these significant hypoglycemic events. As you might imagine, when people's blood sugars drop this way, they may suddenly lose consciousness. That may happen when they're driving. The majority of people have their licenses taken away. They're in the hospital very frequently. People may have seizures. This is a really significant unmet need. This program is the furthest in development. We're very optimistic that we may be able to make a big impact in this unmet need.
Hence your breakthrough designation on good data. As we think about the peak sales opportunity, what is the price point you're trying to achieve? Are there any analogs to justify that price range?
Yeah. So we haven't priced the drug yet. I think we will wait until we have our phase III data and get closer to launch to ultimately price the drug. I think we've been—one, this is an orphan disease. We have orphan drug designation. I think we've been encouraged to see a number of different products coming through the pipeline in other rare endocrine disorders. Whether you look at some of the recent drugs from Zealand Pharma or from Kiniksa Pharmaceuticals or from Ascendis Pharma, there have been a number of recent rare endocrine drugs that have kind of helped develop this kind of rare endocrine space. Again, we haven't selected a specific price, but we're definitely looking at this as a rare disease.
That's helpful. Remind us—you did mention it in the prepared remarks—just remind us one more time, just the efficacy summary that you saw and the safety summary that you saw that led to this breakthrough designation. That would be helpful.
Yeah, absolutely. We are now in the sixth and pivotal study in post-bariatric hypoglycemia with avexitide. We were excited just a month and a half ago to dose the first participant in that study. As Josh said, we expect to complete recruitment by the end of this year and have data in the first half of next year. What supported the FDA breakthrough therapy designation were those five prior trials in people with PBH, and particularly the two phase IIs. In the phase II-B trial, which used the 90 mg dose, which is what we're now using in the phase III, there was a 53% reduction in level two events with a p-value of 0.003 or 0.004. There was a 66% reduction in level three events with a p-value of 0.0003.
Very significant reductions and very meaningful reductions in what are considered quite significant events. Now going into this phase III, our goal is to try to keep the patient population as consistent as possible with what we saw in the phase II. We are looking at the same outcomes, the same ways of measuring those outcomes. I think if we see a recapitulation or anything close, I think this would be a really meaningful therapy for people with PBH.
Do you need to see a recapitulation for this to be approved, or is there a cushion where you can show maybe less efficacy but yet still get approval? What did you agree with the FDA?
Yeah. First, I'd say one advantage of having breakthrough therapy designation is you do get very frequent and kind of extra kind of collaboration with the FDA as well. We did submit our protocol to FDA. We got feedback from them. We do believe the study we're running is pivotal, would be the study to support approval. In terms of effect size, that's not—I think as we've talked to physicians and as we've talked to FDA, I think the view is that if you are showing a significant reduction in these events, that is very meaningful for patients, particularly maybe going through the two types of events. A level three event is when you need a rescue from somebody else, which means you are so incapacitated that you cannot self-rescue your blood sugar and things like that.
You can picture that as losing consciousness, becoming so weak, becoming so confused that you're no longer able to self-rescue. Level two is when you're in the range that's considered neuroglycopenia. It's the range where your blood sugar is less than 54 mg/dL. When you're at that level, you don't think clearly. You can be very shaky. You really don't feel good at all. Seeing a reduction in those events would be quite meaningful. From a powering perspective, definitely going into a phase III trial, you want to ensure that you've given yourself the absolute best chance for success. We powered the study. Whereas we saw a 53% effect on level two and a 66% effect on level three in the phase II-B , we've powered this study so that we have at least 90% power if it's only a 35% effect.
We even put some conservative assumptions about placebo effect and otherwise in that powering analysis as well. We view this study to be very well powered even under conservative assumptions.
Speaking of placebo, how do we—is there a placebo risk in an indication like this? What are you assuming for placebo?
We do not believe there is a placebo risk, as you said, in this study. The reason is we did not see it in the phase II. In the phase II, which was a crossover design but had a screen-in portion, then a placebo portion, and then two different dose groups, there was no difference in event rates between what we saw in the run-in and what we saw in the placebo period. That being said, it is always prudent to model conservatively. In our modeling, we modeled up to a 50% placebo effect and 35% effect size, and we are still well powered to see that. We are taking a conservative approach with our statistical powering, but ultimately, we do not expect much of a placebo effect. I think the reason is that people are already doing everything they can to try to control their blood glucose.
They stick very closely to their diet. And very unfortunately, if they have excursions, they have quite significant events. I think people really, really try to maintain their lifestyles as best as they can.
Understood. Can you remind me how long the phase II studies were? Is the phase III different in trial length? Does that change things by much?
Yeah. The phase II and phase II- B were four weeks of active treatment. The phase III will be 16 weeks of active treatment. It is longer. I'd add, though, we do not have any reason to believe that the treatment effect is going to be different weeks one to four compared to weeks five through 16. This mechanism is a well-studied mechanism. GLP-1 does not seem to have some sort of counter-regulatory response. If you look at the agonist side, many of those trials are 18 months, and you continue to see the benefits accrue through 18 months. We also have not seen anything with neutralizing antibodies or anti-drug antibodies that would suggest any tac of [laxus]. We believe that the effect will just continue to accrue. We have dosed for longer in animals as well. Similarly, no expectation that there would be any attenuation over time.
Interesting. Speaking of the open label data that you shared, is that part of another set of updates you could share later this year? What are you sharing from the prior phase II studies later this year if you are?
The prior phase II studies have completed. The data is what it is. Again, they were very strong, which supported breakthrough therapy designation. The phase II data are published. The phase II-B were presented at the ENDO conference a couple of years ago. That was just in a presentation. At this year's upcoming ENDO conference in July, we will have several presentations, including more on the PKPD, particularly supporting the 90 milligram dose, which is what we are studying in the phase III trial, as well as the composite outcome of level two and level three events, which is the primary outcome. The data from the prior phase II-B trial. Actually, there are other presentations or posters from other researchers on PBH. I'd point out, including the inventors of avexitide from Stanford, have a presentation on the prevalence estimates of PBH.
They use different methodology than we did, but actually came to quite similar overall numbers, in fact, a little higher than our estimates. That was nice to see that independent work is coming to similar market size, is what our research has shown.
Okay.
Just one comment to add to the past studies. The past studies were controlled studies, not open label studies as well, even back to the phase I studies, which were single dose and multi-dose crossover studies, but crossover between a placebo and an active.
Understood. Thanks for clarifying. Going back to the phase III study, in terms of baseline characteristics, are there any differences compared to the phase II, such as surgery type and so forth that you mentioned that are different?
Our goal, again, is to be as consistent as possible. Probably the key criteria, the first is the number of events per week that someone needs to qualify for the study. As you might imagine, the event rate is what ultimately leads to the powering. In the prior phase II studies, it was required to have at least one event per week. We're doing the same in the phase III trial. They had a two-week run-in. We're having a three-week run-in. We're requiring three events in three weeks. They had two events in two weeks. The event rate is the same. In terms of surgery type, while we believe PBH is PBH, it doesn't matter what surgery led to it. We have the most data on Roux-en-Y gastric bypass leading to post-bariatric hypoglycemia. That's what was studied in the phase II.
The phase II-B, they allowed people with a variety of different surgeries. In the phase III, we are allowing only Roux-en-Y gastric bypass PBH, which, again, as we go forward, as we have discussions, future discussions with FDA on label, we think there's a strong case to say PBH is PBH. We have data on people from a variety of different surgeries leading to PBH, and that avexitide is effective, and the pathophysiology is the same. For the phase III, we want to make sure we're trying to control all the variables we can.
Makes sense. I'd imagine reducing level two, level three events are meaningful already. Presumably, you're capturing other endpoints, outcome measures, I don't know, symptoms, quality of life measures. Maybe talk us through what you're capturing to eventually strengthen the totality of data to convince payers to pay for this drug.
Yeah. So I mean, first, I'd say maybe reiterating your first point, level two and level three hypoglycemic events are already a very big deal for people. Level three, in particular, to highlight, this is people becoming completely incapacitated. If you're preventing people becoming completely incapacitated, that's a big deal. We are also guided in part, too, by some of the past work that had been done on the asset, including structured patient interviews. There had been work to do structured interviews with patients after they had finished the trials to assess what their perception was of being on avexitide, of being on the drug. Patients reported, when they were asked to rate the drug on a scale of 1- 10, all but one of the interviewed patients rated it a 10. The other one rated it a nine, was a tough grader.
When asked why, why did you give it that rating, a lot of them kind of described that it was like a fog had lifted, that they had a lot more energy, that fatigue was quite a lot less, of course, that they felt protected by the fact that they were having fewer events. As we thought about quality of life in the phase III, we thought about incorporating some measures that might be helpful for that as well. We do have some measures related to hypoglycemia fear. We have some measures related to fatigue. We are also looking at kind of generalized quality of life measures. I'd come back to the start. Level two and level three are already very robust for seeing a clinically meaningful treatment effect.
Right. And so again, you started, you've actually dosed a patient, it sounded like, and then you complete enrollment later this year. Is that right?
That's exactly right.
Data and for sure.
Yeah. Yeah. Those are exactly the milestones.
Do you need ICH six-month, one-year long-term follow-up data before you file?
You're saying for clinical?
Mm-hmm.
This is the pivotal study. The FDA reviewed the protocol, 16-week placebo-controlled trial. This is what would support approval.
Oh, wow. That's great. You can file right after in the marketplace 2027.
The.
Or late 2027.
Yeah. Top-line results, first half of 2026. Our team will work as fast as we can with positive data, of course, to submit. That would mean commercialization in 2027.
Are there any other peripheral studies you need to do in the meantime to support this submission?
I'd say nothing material. There's always work that you do and kind of boxes you check leading up to a potential NDA submission. There's nothing that the clinical trial is the main element.
Yeah. I'd add to we're very proud of our team. And this was a team that got an orphan drug approved. We had a very successful orphan drug launch. So this is a very experienced team. They're already working towards what would be required for the NDA submission next year. We're starting to look at things like you were mentioning, market access, which is critical to support access for people if the drug is approved. The engine's going. But first things first, we're focused on execution on the trial.
Yep. Maybe a couple of questions on competition, then talk about why you think you're differentiated from others working on the same indication.
Yeah. So we're not aware of any other drug that's shown any efficacy in this space. I think our view is there's a lot of hurdles before we have competition.
Yep. I don't know if this is misinformed, but when I think about GLP-1s, is that something that can shrink the market for you?
We don't believe so. I think the reason is a few-fold. First, the people who are looking to get a bariatric surgery as opposed to use a GLP-1 agonist for weight loss, it's a very different population. People who get bariatric surgery are morbidly obese. There are people who need to lose 100, 150 lbs. Getting a surgery, that's quite a significant undertaking. People are doing it for their health. That's still a very substantial population in the United States. It's about 9% of people who have a BMI of 40 or greater. So far, we haven't seen the number of bariatric procedures decrease. As I mentioned, with PBH, once someone has PBH, it does not appear to go away. We think that those numbers will only increase.
I'd say on the efficacy side, GLP-1 agonist, one of the contraindications or risks is hypoglycemia. This is the other side of the equation. This is raising the glucose nadir and preventing hypoglycemia, which is why we think it's a very exciting mechanism. Too much glucose is bad. Too little glucose is bad. We really want good glycemic control.
Okay. It sounds like you're executing. Good luck on that data set. It's coming up shortly. Maybe in the last five minutes, we can talk about your other programs, starting with Wolfram. What data have you shown so far? It seems like you reported some long-term data set. When do you start the phase III trial? How is this going to be powered? What's the primary endpoint?
Yeah. Great questions. We conducted, maybe starting what got us excited about Wolfram. Wolfram is considered a prototypical disease of stress. It is a monogenic disease caused by mutations in the WFS1 gene, which is believed to be a protein that helps the cell to resolve stress. And AMX0035, stress is one of the main things it is thought to target. We did several years of preclinical work, showed highly significant differences in both cell models of the disease as well as the mouse model of the disease, which led to the clinical trial. Wolfram syndrome itself is kind of a half endocrine, half neurodegenerative disease. People initially look like type 1 diabetics. They get progressive diabetes. As time goes on, they get vision loss, hearing loss, walking and movement loss, swallowing loss, and ultimately, usually death through respiratory failure and breathing challenges, usually in their early 30s.
When we designed the trial, we were looking at endocrine and neurodegenerative outcomes. Most specifically, we were looking at various markers of glycemic control, C-peptide, hemoglobin A1c, and CGM markers for blood glucose control, as well as vision, visual acuity. We were looking at that as well. Going into the trial, what we would expect and what has been seen in the natural history of Wolfram is that all these measures get worse over time. It is a progressive disease. What we saw in the trial, initially over 24 weeks, which we presented late last year, and then most recently over 48 weeks, which we just presented, we saw an improvement or stabilization across all those outcomes. The separation continued to increase as we got out to 48 weeks as compared to 24 weeks.
For many of the outcomes, nearly twice as large in effect at 48 weeks compared to 24. We are very excited about that. It is a single-center open label study. I think our kind of base case of the next step is that we will be running a phase III study. We are right now working with FDA on the design of that. I would add, as we go into any phase III study, and Wolfram is no exception, we try to stay as similar to the phase II as we possibly can. While we have no final design, I would say as much as we can stay in terms of endpoints, in terms of population, et cetera, similar to the phase II, I think that is to the advantage for the phase III.
Okay. So that's just pending. Turning to PSP, then talk about the PSP market, why you're excited about it. It sounds like there's a data update in Q3 coming up. What is the go, no-go threshold?
Yeah. So starting with PSP, so PSP, or progressive supranuclear palsy, is a movement disorder. It's often characterized as an atypical Parkinson's. It's a really tough neurodegenerative disease. It's characterized by gait disturbances, challenges with eye movements. People then progressively lose movement functioning and get to a locked-in state. The disease is usually fatal in about six to eight years. It's a really tough, progressive, fatal neurodegenerative disease. There are an estimated about 23,000 people with PSP in the United States. That's definitely underdiagnosed. There have been many autopsy reports of people who had not-so-typical or atypical Parkinson's, and they, in fact, had PSP. You can see that because there's significant tau buildup in the brain, as well as a characteristic mid-brain degeneration that occurs and what causes the clinical manifestations.
Currently, there are no treatments for PSP, not even symptomatic treatments, which is very tough on people and their families. We are studying AMX0035 in PSP, both because of the mechanism and because AMX0035 in a prior trial showed very significant tau lowering. Tau is what drives the degeneration in PSP. Next quarter, we will have the top-line results from the phase II portion of our trial. That will be 139 people randomized through at least 24 weeks of treatment. We will be looking at the PSP rating scale, as well as a number of other clinical and biomarker outcomes. We are going to have a high bar. If we want to go into phase III, we want to have confidence that we may see a real effect in a phase III trial. That being said, there is also nothing for PSP.
I think there's a real unmet need. We'll be excited to have those results in the third quarter.
Okay. Presumably, you'll try to go for accelerated approval, I'm assuming, if you pass the no-go threshold, maybe through a tau biomarker approach, pair it with a PSP score. I don't know.
I think the results will dictate the path forward. We always try to be very transparent about the results. I will say, though, there is nothing for PSP. We will certainly, as I know others will, take that into account. That being said, nothing has worked in PSP. It is a tough field. We hope we'll change that. We will see the results in the third quarter.
All right. Very good. Thank you so much for taking the time to chat with me today. Thank you, everyone, for listening.
Excellent. Thank you for having us.
Thank you so much.