All righty. I think we're gonna go ahead and get started. Hi, everyone in the room and online. Thank you for joining us at day two of TD Cowen's 46th Annual Healthcare Conference. I'm Joe Thome, one of the senior biotech analysts here on the team at TD Cowen, and it is my pleasure to have with me today, we have co-CEOs, Josh Cohen and Justin Klee. Thank you both for joining us. Maybe before we dive into the individual programs and specific questions, if you wanna just kick things off with a brief state of the company, and maybe what investors should be looking for in 2026. Obviously, you had your update this morning.
Thanks so much for having us. We believe 2026 will be a transformative year for the company. We're very excited. Probably first and foremost, in 2025, we kicked off the LUCIDITY phase III trial of our lead asset of avexitide for the treatment of post-bariatric hypoglycemia. That's the sixth study of avexitide in PBH. First five, very statistically significant, clinically meaningful reductions in hypoglycemia, hypoglycemic events, which supported FDA Breakthrough Therapy designation. In 2026, we announced just this morning that the screening phase of the trial is now complete. We expect to complete enrollment this month, meaning, you know, randomizations will be complete this month. We anticipate data for top-line results in the third quarter.
We're very excited with positive results that would support an NDA submission, and then commercialization in 2027. We're hard at work right now on the NDA as we wanna get as much done in advance of the trial results as possible. Then, of course, alongside all of that will be our commercial preparation as well. I'd say our market research just continues to reiterate that there are about 160,000 people in the country today who have PBH. It's really an unmet need. You know, each one of these hypoglycemic events has the potential to be a catastrophe. It's a medical emergency, and the ADA and others very clearly state that.
These are people who are frequently having medical emergencies, and there's no treatments available for them. We have our other products in development as well. AMX0114 for ALS is in a dose-escalating study. We're very excited about that. AMX0035 for Wolfram syndrome. We have a long-acting GLP-1 receptor antagonist that we announced earlier this year. That's in IND-enabling studies now. That would then follow avexitide. Avexitide, we're very excited about the profile. It's a once daily subcutaneous injection. The long-acting, we'd be aiming for long-acting, potentially once a week or better, but still in early development. Lot going on, but probably first and foremost, top-line results in Q3.
Great. Maybe ahead of those top-line results for people that maybe aren't as familiar with the PBH market, obviously, you know, indicated the patient number. I guess how well diagnosed is PBH? Can you kinda walk us through the timeline of a patient actually presenting? Cause they have the surgery, obviously the actual, you know, PBH tends to present a little bit later. How is that patient found and sort of diagnosed?
Yeah, great question. PBH appears in the years following bariatric surgery. On average, it's one to three years following bariatric surgery. How that usually presents is patients will start having the symptoms of hypoglycemia. Patients may begin getting very sweaty, very dizzy, very shaky. They may get more severe symptoms such as loss of consciousness, seizures, possibly even coma in, you know, particularly severe cases. Then that will get worked up. People will start thinking about what could be causing this hypoglycemia, and usually, you know, endocrinologists have had growing awareness of this. It's now on the Endocrinology Board Exam. You know, there's been lots of discussions at the recent ENDO conference. You know, there's work ongoing with the physician community to potentially have an ICD-10 code this year.
With all of that, people suspect when they see somebody with bariatric surgery and recurrent instances of low blood sugar that it might be PBH. What it means when somebody has this, PBH is really a hyperreactive state. Patients, you know, when they have meals or other, you know, daily events that change their blood sugar, their body can hyperreact to it, resulting in a, you know, huge outpouring of insulin and then a, you know, precipitous drop in blood sugar. What this means for patients is they get very nervous, you know, when they eat. Sometimes we've heard described from some patients that, you know, they may be able to have one bite of food, but by the second or third bite of food, that might precipitate, you know, an event.
Patients will also describe having events when they get psychologically stressed, when they have things like caffeine, exercise, alcohol, all manner of things like that can, you know, precipitate an event. Patients really find themselves in a state where despite all of their best efforts, they're continuing to have these drops, which can be quite dangerous. Usually means they can't drive, can be hard to hold a job. Very likely they wanna have a caregiver nearby so that if there's a severe event, there's somebody who can rescue them or get them to the hospital or otherwise. It really ends up taking over their whole lives.
You indicated at the beginning there's nothing really approved for management of these patients. It seems like they try to manage with diet alone. What does that mean? I guess, what proportion of patients can be managed by diet alone? Are they really managed, or do they have breakthroughs? Kinda how do you think about that?
Yeah, it's a critical piece of the unmet need here. I'll maybe walk through a bit of a funnel, if I hope that's helpful for people. Post-bariatric hypoglycemia occurs in roughly 8% of people who have bariatric surgery. Now, as you were saying, it doesn't happen immediately. On average, it's about one to three years after the surgery the symptoms will start to manifest, but it can be longer than that. We've heard from people five, seven, eight years later is when they start to exhibit the hypoglycemic symptoms. Now, if you look at the portion of people following bariatric surgery who have any hypoglycemia, it's a much larger number. It's about 40% or so.
You look over the past decade, there's been over 2 million bariatric procedures that have occurred in the U.S. You know, if you take the 30%-40% of people who have any hypoglycemia, you know, you're looking at 500,000+ people. With PBH, what characterizes it is that despite any sort of dietary intervention or anything else, people continue to have these severe hypoglycemic events, and that is roughly 8% of the population. If you take the 8% of the about 2 million bariatric procedures, that's probably the simplest way that you end up with about 160,000 people in the country today.
We've since also gone into the claims databases and looked ourselves and again, sort of everything is triangulated to this rough 160,000 number. The team out of Stanford who did a lot of the seminal work on avexitide also did their own independent work looking at the overall prevalence of the U.S. population of PBH, and they came to very similar estimates, I think about 167,000 people with PBH. Everything is triangulated to this.
Again, today, the only sort of intervention that it really exists is medical nutrition therapy, which basically means avoid simple carbs, eat as frequently as you can, eat very small meals, try to keep your glycemic control as best as possible, and PBH has characterized that even with that, they continue to have these events. We believe that's 'cause the body has such an exaggerated GLP-1 response, and GLP-1's very strong, right? We certainly know that. If your body is producing 10 to 20 times the normal levels of GLP-1, no matter what you do, your blood glucose is gonna plummet, and that's what we see in PBH.
Maybe last question on the population itself, but obviously the other side of the GLP-1 mechanism is being used for weight loss. We're seeing those drugs take off. I guess, how do you think that impacts the number of bariatric surgeries? I could see that some may see that it's not as needed anymore, but then others might use the GLP-1 to get to the weight where they then could safely do a surgery. I guess what are you seeing in your numbers, and how do you think that's gonna change going forward?
Good question. The bariatric surgery numbers have actually been quite robust. When you look since Wegovy was approved, actually, the bariatric surgery numbers have net gone up since the initial approval. I think that comes down to bariatric surgery is still really the gold standard for people who have, you know, severe obesity and need substantial weight loss. It's not uncommon when we talk to people with PBH and they talk about their bariatric surgery experience, that they lost 100, 150 pounds in six months following the surgery, which is a very different outcome than what you see with the GLP-1 agonists, you know, for example.
Often the patients who are going for bariatric surgery are doing it not just for weight loss, but they also may have, you know, be worrying about, you know, the downstream consequences of weight loss. Not uncommon that these patients have, you know, severe hypertension, you know, very high blood pressure. Not uncommon, they have very high cholesterol. They're really when bariatric surgery is being conducted, it's usually looked at as kind of a life-saving, life-altering type of intervention, you know, for people less so, you know, for cosmetic or other reasons. Maybe I'd just add to that, too, PBH is a lifelong condition. You know, once the gut has been altered, it doesn't unalter. We've interacted with many PBH patients who have the disease 10, 15, 20 years.
When we're talking about the continuing bariatric surgery, it's actually only the growth rate of the disease. You know, the disease is here to stay, and the question is, how fast it continues to grow from here on out.
Maybe turning to avexitide itself, can you walk us through sort of the early you know, kinda phase I, phase II data that got you excited to start the LUCIDITY trial? Kind of what are you seeing in terms of, you know, reduction in events?
Yeah. I think it was a really elegant development program. There were three phase I's and then two phase II's, and then that supported the FDA Breakthrough Therapy designation for PBH, and now we're on the sixth trial. There were also three trials in congenital hyperinsulinism, also looked very positive, supported a separate FDA Breakthrough Therapy designation. We'll focus on PBH 'cause that's really our primary indication. I think the first phase one, I think, was kinda the eureka moment, if you will. The investigators at Stanford brought people in with PBH, and they had them fast, and they gave them Glucola. Glucola is, you know, essentially what it sounds like. It's basically a liquid sugar.
To a person, they're with the administration of Glucola, they became hyperglycemic and then hypoglycemic, and then they rescued them in the clinic with avexitide on board. At that time, it was dosed IV because it was the first trial. To a person, it prevented 100% of the hypoglycemia. So it really suggested, I think, actually going back to the '80s, in fact, some of the seminal work discovering GLP-1 was discovered around this surgery-induced hypoglycemia. So I think it was well assumed that in post-bariatric hypoglycemia, it was GLP-1 that was driving this insulin spike in hypoglycemia.
I think that experiment really showed that it was clearly GLP-1 was at least the strongest driver, if not the primary driver of hypoglycemia, because when you blocked it, you blocked the hypoglycemia. Looking at the other two phase I studies, they had multiple ascending dose, they moved to sub-Q formulation. In the phase II, they tested two different doses, and in each trial, they split it either two times a day or one time a day. In both of those trials, the first phase II, they had a placebo period and then a crossover study design. The second, they went straight to the crossover design because there was no placebo effect. There was no difference in event rate.
In those trials, what they were looking at were level two and level three hypoglycemic events. Level two is a study participant checks their blood glucose by finger stick, and it's less than 54 milligrams per deciliter. Level 3, they fill out a diary, and they've had basically the manifestations of a severe hypoglycemic event. That's adjudicated by an independent committee. An obvious one would be loss of consciousness. It basically means somebody needs independent rescue. Both of those trials, very significant reductions in hypoglycemic events in the phase IIB using the dose that we're now carrying forward to the phase III.
They had 52% reduction in level 2 events, 66% reduction in level 3 events, with a very high level statistical significance. All of that supported FDA Breakthrough Therapy designation, and then we really tried to take change as little as possible going into the phase III. Probably the key difference is it's longer. Those were 4-week trials, and this is a 16-week trial. They were crossover, and this is a parallel group. Aside from that, the inclusion criteria, the way that we're measuring the outcomes, the outcomes that we're looking at, et cetera, we've kept consistent from the successful phase IIs to the phase III.
That was gonna be my next question, was kind of on the inclusion criteria. Obviously, you mentioned this morning, the progress on the screening and kinda completing that. I guess, do you anticipate releasing the baseline characteristics before we see the final data? Or I guess any commentary on sort of are you happy with the type of patients that you're finding in the study as it relates to the phase II?
Yeah. I'd say, yes, we are happy with the patients we're enrolling. You know, we do take very seriously, you know, trying to make the quality of the study as high as it possibly can be. In the LUCIDITY trial, there is a run-in period, so patients have to have at least an event a week during a three-week run-in before they're able to be eligible for the study. We also do a kinda central sign-off. You know, Amylyx has to sign off on every participant entering the study. Again, we do that to make sure that these are good study participants that are gonna, you know, be good for the LUCIDITY study. In terms of baseline characteristics, it's a good question. We haven't, you know, decided yet.
There is a pretty quick turnaround, though, on this study, right? It's a 16-week study. You know, you may end up in a situation by the time you put out baseline characteristics, you might be putting out data. We're kind of evaluating if that's useful for people or, you know, if it's better to just put out data and not, you know, create confusion. Yeah, I'd say we're quite excited about the study. You know, I think as Justin said, you know, building off of five prior trials, all of which showed high significance on, you know, glucose, insulin, you know, hypoglycemic events, these outcomes, you know, we certainly go in, you know, feeling good about, you know, about the readout.
Obviously, you mentioned that the phase III study is a little bit longer than the phase IIs. I guess, can you kinda walk through that a little bit and why that was the case? You know, sometimes in trials like this where diet does play a role in kind of patient symptoms, if a patient's feeling good on your drug, which hopefully that's the goal, you know, they might not be as disciplined in kind of what they're eating as time goes on. I guess anything in the study to make sure that doesn't happen.
I'll probably just underscore a lot of the points that Josh was just making. With the prior successful studies, the goal here is to change as little as possible and to be very consistent in the study conduct. You know, included in those trials were, you know, diet, dietary management, and there are still the very statistically significant and clinically meaningful reductions in hypoglycemia. It speaks to also why historically there hasn't really been a placebo effect in PBH. You know, in some areas of medicine, you know, for example, diabetes, you know, dietary management can be difficult because people don't really know, you know, their blood glucose is elevated fine, but like, you know, to what degree. This is very symptomatic.
If people have dietary excursions, they have severe traumatic events, so they're very unlikely to deviate too much from their general lifestyle practices. Now we still train at the start of the study. We retrain at every study visit on the medical nutrition therapy. It's, you know, something that we definitely pay close attention to. But people coming into the study generally are already on the diet. They're already kinda in their routines, exactly. That's why I would say, you know, the probably most important point that we don't expect too much in the way of excursions.
Going back to the first phase I study, the kind of eureka moment, as I was saying, even with a very strong trigger, you know, 75 grams of sugar, avexitide was still able to prevent hypoglycemic events. I think it also speaks to, we really believe that the mechanism of PBH is this GLP-1 bolus. If you can block that GLP-1 bolus, then you'll prevent this sort of hyperreactive hypoglycemia.
Obviously, you mentioned the phase II, you're seeing, you know, fifties and sixties levels of reductions of level 2 and level 3 events. I guess, what's clinically meaningful for patients based on your KOL discussions, and maybe how did that factor into the powering of the phase III study?
Yeah, good question. As we've spoken to the endocrinologists, really they've shared that they view these hypoglycemic events as quite a big deal. You know, when you look at the American Diabetes Association guidelines, they have in kind of big red letters, there's actually, like, an ambulance on the that webpage from them, where they say severe hypoglycemia is a medical emergency. It's true. People die, you know, frequently of severe hypoglycemia. It causes motor vehicle accidents. It causes fractured hips. It causes people falling down stairs. Severe hypoglycemia can be life-limiting, life-altering, et cetera.
As we've spoken to physicians, and, you know, every physician we speak to shares their anecdotes too, of my patient who got in a motor vehicle crash with somebody else in the car, or, you know, my patient who, you know, fell down the stairs and, you know, had a broken hip or whatever it might be. The physicians really say any significant reduction for my patients is a big deal. You know, even one event could be that event that, you know, kind of changes their life forever. You know, we really don't. Yeah, I think our view is a statistically significant reduction is clinically meaningful here.
In terms of the powering, you know, given that we do believe based on the prior data that we have a very likely to be effective drug here, we, you know, wanted to make sure that we were conservative, you know, as we designed the powering. So we expect to have about a 90% power to detect a 35% treatment effect relative to placebo. You know, that gives us a quite a nice margin, compared to what's been seen in the prior studies as well. I think we were conservative really in all of the assumptions we put in that powering too, in terms of variability and all that kind of stuff as well.
You know, we really wanted to go into the study very, very well powered, and we definitely think we are.
Great. In terms of what will be needed for a filing after the data, I guess, is the data kind of the last thing? Do you need anything from a safety database or CMC perspective? I guess, just overall timelines after the trial reads out, when could you submit the package?
Yeah. We're Thanks for asking. We're working on all those things now. We do believe that the LUCIDITY data will be sort of the key set to then include in the NDA. Of course, there's a lot else that goes into the NDA, as you're mentioning. CMC, you know, we have our registration batches up on stability, the non-clinical work, et cetera. But from a clinical point of view, we really believe the LUCIDITY trial is what we need. FDA reviewed the protocol ahead of starting the study. We have Breakthrough Therapy designation, which facilitates far more frequent interactions than a typical program. That's why we're working on all of that NDA now in anticipation of the top line results.
The goal would be commercialization next year.
Great. If the data are positive, obviously, you mentioned congenital hyperinsulinemia, and some of our doctors have brought up gastrectomy related to various you know, tumors or cancer diagnoses. I guess, what's the appetite for the company to go into some of these other indications if it looks to be working in PBH?
Great question. We do believe that there are a lot of other conditions that precipitate hyperinsulinemic hypoglycemia. You know, in particular, as you mentioned, we are quite interested in the other surgeries that can lead to this. You know, people may get surgery on their, you know, upper GI tract to lose weight through bariatric surgery, but there are also a number of surgeries done for gastric cancer to kinda remove the cancer essentially, for esophageal cancer. People with severe GERD, basically acid reflux, can have surgeries to kinda alter the anatomy for that. All of these have been shown in the literature pretty strongly and in our, you know, discussions with physicians to precipitate hypoglycemic events.
you know, I'd say both in the U.S., but also even when you think internationally as well, in several Asian countries, you know, gastric cancer is the leading cause of cancer death, and there are quite a number of gastrectomies, you know, conducted per year. I'd say, first and foremost, our focus is on, you know, being successful with avexitide in the U.S., but we do see this as being a product that has a lot of opportunity to expand, as you said, both into, you know, additional surgeries, but possibly, you know, also into additional geographies as well.
I'll add as well, that's also why we're investing for even a next generation candidate now. We established a collaboration with Gubra last year. They're one of the world experts in peptide drug development. They've over the years developed a really impressive peptide platform. So we partnered with them to develop a potential long-acting GLP-1 receptor antagonist. We're very pleased with the collaboration. At the start of the year, we announced a lead candidate from those efforts. We had several molecules that met our criteria for drug-like properties, but also PK to support potential long-acting, and that's in IND-enabling studies now.
The reason that we're investing in that is because, as Josh was saying, we believe we have a really substantial unmet need and opportunity just with PBH in the U.S., but we think there's even more to do beyond that. We wanna invest for the future.
Great. Maybe we'll jump to a couple of the other programs. Maybe we'll start with Wolfram. If you could just give us a little bit of an update on kinda where you stand with the FDA in terms of next steps here. You know, is the company committed to running a study? What would the endpoints kinda be? Any sort of update on that would be great.
Sure. Maybe just as background, you know, we continue excited about Wolfram. You know, part of what got us into the space as well was, Wolfram is often considered a prototypical disease of ER stress. AMX0035, you know, the compounds that make up AMX0035 have been studied, you know, for decades really in ER stress models, which led to a lot of excitement in this space. We had strong preclinical data, later strong, you know, initial clinical data that, you know, certainly, you know, excited us there. Wolfram is a complex disease. You know, there are multiple different organ systems involved. There are multiple different symptoms that patients experience, ranging from, you know, essentially type one diabetes, to visual loss, hearing loss, you know, speech and swallowing difficulties, ataxia.
We are still working with the FDA on what does a appropriate phase III trial look like. I think probably makes sense for, you know, for any company, our focus will be on doing something that's feasible, that's efficient, and we're still working towards, you know, what exactly that might look like.
How large is the opportunity for Wolfram for a therapy kinda overall?
We estimate about 3,000 people with Wolfram syndrome in the U.S., and there's substantially more internationally as well.
Then maybe jumping over to 0114 for ALS, can you just give us a little bit of background on why calpain-2 makes sense as a target for ALS and when we can expect some of the initial data?
Yeah. I guess kind of at a fundamental level, ALS is a disease of axonal degeneration or thought to be. Some of the long neurons that reach down to, you know, key skeletal muscles, degenerate and die. There's been studies for over 150 years on a pathway called Wallerian degeneration, basically how long axons degenerate and die, and calpain-2 has been implicated as one of the key players in that process. The hope is if you can inhibit calpain-2, you will result in less axonal degeneration and hopefully, you know, longer function, you know, for neurons in people living with ALS. You know, as you mentioned too, we're currently in a multiple ascending dose placebo-controlled study in people living with ALS. We've shared the safety data from the first cohort, which was quite safe and well-tolerated.
We expect to share biomarker data in the first half of this year at a medical meeting. We also expect complete enrollment of the second cohort this month. You know, I'll say the first cohort is our lowest dose. We may see pharmacological activity there, we may not, you know, as we get our biomarker data, but we'll, you know, continue to, you know, share the data as we keep moving up and keep, you know, escalating the dose. You know, we do believe calpain's a, you know, important pathway activated in ALS.
Maybe what are the most important biomarkers that you're gonna be looking at to kind of continually dose escalate and move forward with this program? Is it CSF, NFL, anything else that we should be kind of looking at here?
I'd say probably the most important thing in the dose escalation is safety and tolerability. All of our data suggests that the more you knock down calpain-2, the better. I think that's largely what we'll be looking for in our in our continued escalation. On the biomarker side as well, I think what is exciting is that because calpain is a protease, it cleaves many things, and so you can look at a variety of different measures. There are. We'll of course be looking for calpain, but also calpain activity. There are particular what are called spectrin breakdown products, which are signatures of calpain activity.
There's early evidence that those spectrin breakdown products are actually elevated in people with ALS, which we think is a signal that calpain is overactive in ALS. Calpain also cleaves neurofilaments. It cleaves the sort of parts of the axon, as Josh was saying. We believe that depending on how you measure the neurofilaments, it can be both a measure of ALS, but it can progression, but it can also be a measure of calpain activity, and so we'll be looking at a variety of things in that regard as well. Then we'll be, you know, looking at some other more exploratory markers. There's, you know, quite a lot to look at in ALS with calpain-2 inhibition, so we're very excited about that program.
Maybe last question, obviously the company has transformed really well on the back of, you know, the BD for avexitide and a lot of focus on getting this program across the finish line. What's the company's appetite, you know, now or looking forward 12 months into kind of additional BD deals, similar to that? Any area of the company that you want to kind of transform again?
Yeah. I'd say we always keep. You know, we always have an active process. We're always looking at things, you know, that we may want to add to our pipeline. I'd say assets like avexitide are rare. They don't come along in our experience all that often. If we come across something that looks like avexitide, that would of course be very exciting. I'd say overall right now we're excited about what we have in avexitide. Our focus is on, you know, the phase III, LUCIDITY readout, and then the NDA and, you know, hopeful launch thereafter.
Yeah. I'll add to that, especially with cash runway into 2028, we expect commercialization of avexitide in 2027. We're very excited for this year and next.
Awesome. Well, good luck and we'll see the data soon. Thank you very much.
Thank you.
Thank you so much.