Thanks for joining us here at the Goldman Sachs Annual Healthcare Conference. Thrilled to be joined today by the co-CEOs of Amylyx. Maybe you guys could just start with an overview. The company's changed a lot in the past year, really, since the last time we were standing on the stage. Maybe we can talk about the complexion of Amylyx today, and where you see some of the key value drivers.
Yeah, thanks so much for having us. Thrilled to be here. We have three different assets and four ongoing clinical trials. Our lead asset is Avexitide. It's a GLP-1 receptor antagonist, so it lowers insulin and raises glucose. We are running a pivotal study in post-bariatric hypoglycemia. This is the sixth study. There were five prior studies of Avexitide and PBH that supported FDA Breakthrough Therapy designation. We dosed the first study participant in April, and we are targeting completion of enrollment by the end of this year and have the pivotal data in the first half of next year. Very excited about our lead program. We then have AMX0035, which is our small molecule targeting stress and mitochondrial dysfunction, in two trials: Wolfram syndrome, which is a rare neuroendocrine disease, as well as PSP, which is a progressive supranuclear palsy. It's a really devastating neurodegenerative disease.
Wolfram syndrome, we announced positive data from our first study a few weeks ago, that's the HELIOS trial, looking out over 48 weeks. Now we see C-peptide increasing over time, which is a direct measure of insulin production and therefore beta cell health. And then, in PSP, we'll have data from the phase II readout next quarter. And then, last, we have AMX0114, which is our antisense oligonucleotide targeting calpain- 2, for ALS and potentially other neurodegenerative diseases. We just started our first study in people with ALS. That's a dose-escalating placebo-controlled study. We dosed the first study participant a couple months ago, and we should have our first safety and early biomarker data by the end of this year. A lot going on, quite a few exciting milestones this year and hopefully more to come.
Yeah, very exciting. All right, let's start with Avexitide. You acquired this asset last summer for the treatment of post-bariatric surgery hypoglycemia. What have you learned since taking on the development of this drug with respect to that market?
Yeah, it's a great question. I think this has been, you know, an asset that as we did the diligence to acquire it, and even as we've continued to own it, we've just continued to kind of like it more and more. You know, as we've dug in, you know, Avexitide has FDA Breakthrough Therapy designation, lots of strong previous trials. We've also now been able to spend a lot of time talking to doctors who care for people living with PBH, talk to a number of people living with PBH. And what just comes across again and again is just how difficult and disruptive this disease is for people's lives. You know, endocrinologists describe it as, these are some of the most fragile patients. I'm kind of constantly, you know, trying to get ahead of their symptoms, but I'm still getting calls at midnight, and everything like that.
When you talk on the patient side, it just becomes incredibly limiting. You know, at any point they could have one of these hypoglycemic drops, most commonly after a meal, but it can also happen due to stress, exercise, sometimes out of the blue without any obvious cause. When they happen, it can mean, you know, dizziness, it can mean loss of consciousness, it can mean confusion. To have that possibly happening at any point of any day is just really tough for people. Usually they cannot drive. They like to have people around them to rescue them if they are in a tough spot. You know, really, really excited, you know, to be advancing Avexitide for these individuals.
Yeah. PBH is kind of a new market for a lot of people, although I think it's become a bit, since you guys bought the asset, people understand it a little bit better. Maybe help us understand the underlying assumptions. You've talked about 160,000 patients who are addressable. What does that embed with respect to the number of patients that exist and who are inadequately managed by the current standard of care?
Yeah, it's a very important question. So, you know, the first thing we did is we looked through the literature, and I would say that there are pretty good studies, both prospective and retrospective, looking at patient cohorts of thousands of people over time. And the estimates are, you know, it's always a range, but it's about 8% of people who get bariatric surgery will develop PBH in the future. Now on average, it takes one to three years for symptoms to manifest. So it takes time. But it's been pretty consistent from study to study that that's the estimate of how many people will get PBH. So if you back into how many surgeries there have been over the past, even just decade, there's been well over 2 million bariatric surgeries. You get to about 160,000 people who would have PBH today.
We then started looking in different claims, analysis, data sets, and we found very similar numbers, around that 160,000 estimate. There's actually at the ENDO Conference next month, the Stanford group, who are actually the ones who invented Avexitide, have done their own prevalence work using different methodology and come out with quite similar numbers, actually a little, little higher than the estimates of what we've found. Now in terms of, you know, who's diagnosed, who's being regularly seen at clinics, you know, that's work that we're still doing now. I can say that we've talked to, you know, quite a few clinics who have hundreds of people under their care. And there are a lot of clinics who might have tens of patients under their care.
So, there are definitely many people who are being followed up with regularly, and participating as much as they can in sort of, you know, active medical care. And I think we see in the future that, you know, that might be a sort of first target population for us when we commercialize, you know, of course, given positive data. But that's all work that, you know, our commercial team and medical affairs teams are doing now to really zone in on, you know, what do we think that first target population would be. But in terms of people who need a treatment, who have not responded to diet, it's the 160,000 people. So it sounds like a lot, but it's really just because there have been so many bariatric surgeries over the past decade or so.
Where are these patients being seen? Are they primarily in like the endocrinologist's office, community academic, by the surgeons? Who's kind of catching this and helping manage their symptoms?
Yeah, so the symptoms are primarily managed by adult endocrinologists. And, you know, as Justin said, speaking to adult endocrinologists, there are, you know, a number of them who see hundreds of these patients, you know, many who see tens of these patients as well. In terms of their journey to get there, so they'll have the surgery and usually, a surgeon will follow them post-op, maybe six, nine months, possibly a year. And, but the symptoms for PBH usually don't appear for a year to three years. So it's rarely the surgeon, who will be caring for this or, or seeing it. Then often as they start to have symptoms, you know, maybe they're getting dizziness or they've lost consciousness or confusion, they'll get kind of triaged through the healthcare system, you know, to an endocrinologist who will kind of take over their ongoing care.
I think to Josh's point, you know, sometimes with rare disease, it can be a sort of amalgamation of symptoms. This is very clearly hypoglycemia, and endocrinologists are very, very experienced at recognizing signs and symptoms of hypoglycemia. I think what we found often is that when people get to an adult endocrinologist, you know, one, they pretty quickly recognize the person's had bariatric surgery, they have hypoglycemia, they try to rule out other causes, but it's a pretty straightforward diagnosis.
To that end, is this an indication where you think there's going to be education required to kind of bolster diagnosis, or do you feel like this patient population is well identified? It's more a matter of breeding treatments.
Yeah, I, you know, I think a little bit of both. I think there's certainly a population who's, you know, at the experts, you know, well, you know, seen very frequently, et cetera, who I think, you know, there, I don't think there will be an immense amount of education required. I think as you get out further and further from that, you know, to kind of have a faster diagnosis, to have this high on the index of suspicion, you know, I see somebody lose consciousness and they've had a bariatric surgery. This should be right at near the top of my list. There is education to do on that.
While we do think that, you know, many of these patients do get diagnosed, we have talked to patients who had, you know, bounced around the healthcare system for some time before somebody ultimately said, okay, this is, this is PBH.
You mentioned originally that there's a lot of clinical data supporting the drug's activity in this indication and others. Maybe you just run us through the phase twos that are available.
Yeah, very, very happy to. So, there have been five prior trials of Avexitide in post-bariatric hypoglycemia. The first three were phase ones looking at dose, changing from IV to sub- Q. What's first very striking is that you can see the effect of the drug with a single dose. So, very quickly the drug lowers insulin and raises glucose. The phase twos were then looking kind of more in the real world setting, so to speak. They were 28-day crossover studies. The first phase II was a placebo period, running period, placebo period, and then 28-day crossover. The phase II- B was a running period and then crossover. In those studies, they were looking at level 2 and level 3 hypoglycemic events.
These are medical events that have been defined by the American Diabetes Association and other groups for quite a few decades now. Level 2 is defined by a blood glucose that is less than 54 mg/dL. The reason that is important is that is the blood level where neuroglycopenia starts to occur. Neuroglycopenia, as you might imagine from the name, is where the brain is starved of glucose. People start to have very significant symptoms, severe confusion, maybe loss of consciousness, et cetera. A level 3 event is independent of blood glucose. It means that the person needs independent rescue. They have had such symptoms that they need somebody to help them. A clear example, of course, would be loss of consciousness. There are other situations, you know, maybe someone is so severely confused, they do not know where they are and they need someone to help them.
So in the phase II trial, they were looking at 30 mg twice daily or 60 mg once daily. Again, significant reductions in level 2 and level 3 hypoglycemic events. In the phase II-B, they were looking at 45 mg twice daily or 90 mg once daily. Again, looking at level 2 and level 3 hypoglycemic events. In the 90 mg once daily dose, which is what we'll be taking forward to the phase III , there was a 53% reduction in level 2 events with a p-value of 0.004 and a 66% reduction in level 3 events with a p-value of 0.0003. Very statistically significant, very strong reduction. I think this is what supported FDA Breakthrough Therapy designation.
Yeah. So you've now disclosed the phase III trial design. You mentioned you've initiated the study. I guess talk to us about the key parameters for the trial. How did the phase II inform it, et cetera?
Sure. So overall, the goal was to keep as many things the same, from phase II to phase III as we possibly could. Probably the most important inclusion criteria in these studies is the, you know, essentially the severity, the rate of events that you're having. So in the previous studies, you had to have, you know, an event a week, level 2 or level 3 event a week, to be enrolled in the study, in a run-in period. We're doing the same in the phase III. So you have to be having an event a week. Our run-in period's three weeks, first two weeks. We did that just to get a little bit more experience with all the technology because the study does have CGM, finger-sticks, diaries, things like that.
We wanted to make sure before they get into the main study, they're really good, you know, at all of this technology. And then, you know, I think probably other main elements, previous studies were four weeks. The phase III will be 16 weeks. It is longer. But, you know, by and large, tried to keep as much the same as we could, essentially same endpoints, you know, similar severity, you know, with the running criteria and everything like that as well.
What is the study powered to show in terms of the difference versus placebo, and what is the underlying placebo expectation?
Sure. So we, so maybe just as a reminder, as Justin said too, previous study, 53% effect on level 2, 66% on level 3. This study is looking at the composite of level 2 and level 3, which actually gives you even a little more power because you're getting both of the types of events contributing to the primary outcome. We have 90% power to see as little as a 35% effect. You know, again, that's conservative compared to the 53% and 66% effects that we saw in the phase II-B. And, in that modeling, we put pretty conservative assumptions around standard deviation, around placebo. We modeled as high as a 50% placebo effect. So when I'm describing that 90% power at 35% effect, that includes, you know, a 50% placebo effect as well. All that being said, we don't really expect a placebo effect in this indication.
We did not see one in the phase II, and also, patients really do not want to be having these events. Just because a placebo patient starts, you know, injecting saline or otherwise, there is not really a great opportunity for them to, you know, kind of miraculously substantially reduce their event rate. We conservatively powered with a 50% placebo effect rate. We do not really expect that it will actually come to be.
Okay. You also did extend the trial. You mentioned that already, but how, what gives you comfort in extending to 16 weeks, both on the efficacy and the safety side?
Yeah. So, I think, on the efficacy side, there's nothing we've seen that would suggest a waning of effect, in either the preclinical studies or the clinical studies thus far. So nothing like tactical axis or neutralizing antibodies, you know, ADAs, that sort of thing. The molecule itself also is a truncated exenatide. So, there, you know, I think can be some read-through from the experience with exenatide where they did not see any of that as well. And that was used in tens of thousands, if not hundreds of thousands of people. So, I think, you know, and then I'd probably say on the GLP-1 agonist side as well, I think it's been shown that you can engage the receptor over time and continue to have consistent effects. So, you know, ultimately the important thing is to, you know, run the study and see the results.
Going into it, there's nothing that would suggest that you'd see a waning of effect.
You've dosed the first patient. You're now enrolling. Can you give us any update in terms of site activations, patient enrollment as you progress towards year-end completion?
Yeah. So, as you said, we're targeting completing enrollment by the end of the year. Expect data in the first half of 2026. You know, we've activated 13 sites, and continuing to activate at a good clip. And, you know, the engagement, eagerness from the sites, I think has been very strong. So we're, you know, remain, you know, on track or, you know, towards that, you know, target of year-end enrollment.
Okay. And then in terms of just the approvability of this trial, I guess what's your level of confidence that this will be sufficient to support regulatory approval?
Yeah. I'd say, you know, first, of course, the FDA always likes to reserve the right to review the data when they get it. That being said, I think one, Breakthrough status helps a lot. It suggests that FDA thinks that there's a real unmet need and that the data supports that this is substantial, substantial improvement over standard of care. I think that already helps. What Breakthrough status also allows is much more frequent interactions with FDA. With the previous owner and with us, we've had, you know, quite a lot of engagement with FDA, including on trial design. They've reviewed the phase III protocol, and so, you know, we believe this is the pivotal study to support approval, of course, along with the very strong data from the phase twos and phase ones as well.
Yeah. Okay. Can you talk about like pricing in this market? Obviously, with a registrational study ongoing, you have to start thinking about the commercial piece. What are the analogs you think are appropriate and how does the size of the patient population factor into that?
Yeah, great question. You know, of course, we haven't priced the drug yet. You know, we'll wait on the phase III data and everything like that. But I'd say we have been, you know, keeping an eye on some of the other rare endocrine launches that have been happening, whether that's, you know, for Soleno, whether that's for Ascendis, Rhythm, you know, others, [Chronicity], you know, others as well. You know, I think it does depend a little bit as we continue doing market research, who is that, you know, best target population that we'll go after at launch. I think what we are seeing is that, you know, this does have Orphan Drug designation. It is a rare disease.
what we are seeing is that, you know, there is a significant, you know, ability to, you know, create strong markets in rare endocrine conditions.
Okay. I think our experience too with payers is that, for rare disease, they really want to understand, is this a real unmet need? Clearly is. In fact, I think this is a population that are very high healthcare utilizers. I think that'll be particularly interesting to payers. Ultimately, do you have data to support the use of this treatment? Again, if we show, you know, anything like what we've seen in the phase twos, I think that's a very strong data package to bring to payers. At that point, I think, you know, payers understand rare disease. They understand Orphan Drug pricing. I think we're in a nice pair, especially when unfortunately for people, there are no approved treatments for PBH today.
Very good. Maybe remind us the intellectual property surrounding this agent.
Base case is 2037. We have both method of use and kind of formulation composition, type patents as well. You know, Orphan Drug designation on top of that as well.
Okay. You also have a collaboration with Gubra to develop a long-acting GLP-1 receptor antagonist. Maybe talk about that, the structure around that partnership and how that fits into the broader strategy.
Yeah. I think we, you know, we're very excited at the potential of a GLP-1 receptor antagonist. We think it makes a lot of sense in PBH. We think there are other areas as well that it could be a really impactful candidate. You know, we feel like when you believe in a target like that, you want to invest for the future. Avexitide has a very nice profile as we go into the phase III trial. I think if efficacy, safety, et cetera, were all equal, it would be great to have a longer acting version. We're very excited to be partnering with Gubra. They're one of the world leaders in peptide drug development, including in taking peptides and making them long-acting. We started that research partnership. We announced it at the end of last year.
We're moving along at a really nice clip. Still a little early to say, timelines for, you know, when that would be an IND enabling in clinic. But we're making really nice progress. I think our hope would be that, as we continue with Avexitide, as hopefully that's commercial as soon as 2027, and, you know, we show what an impact this may have for people with PBH, then we can come with something even better.
Very cool. Maybe you can tell us a little bit more about the target product profile for that. How, like, long of a dosing interval do you think it would be useful? And you mentioned that there are other indications. So maybe, like, quickly overview the other hypoglycemia indications you're interested in.
Yeah, maybe I'm happy to, take it in reverse if you don't mind. And, I think, there are some areas that we think are probably, I hate to say almost obvious to, to start with. First, there are other surgeries that can cause the same persistent hypoglycemia. For example, gastrectomy, which is indicated for gastric cancer. It's a big deal here in Asian countries such as Japan and Korea and China. It's one of the leading causes of death. There are many, many gastrectomies. It appears that any significant upper GI surgery, whether bariatric or gastrectomy or esophagectomy, can cause this same persistent symptomatic hypoglycemia. In the phase II-B trial of Avexitide, it was used in people who had different surgeries that caused hypoglycemia and the drug appeared very effective for those people as well.
We think that's a clear area for us to look into in the future. Avexitide also has a breakthrough status in congenital hyperinsulinism. I think it's just suggesting that targeting or having an antagonist of the GLP-1 receptor is very powerful and I think, you know, may lend itself to being an important treatment in other areas. Now, first and foremost, you know, we have a pivotal study ongoing in PBH, so that's where our focus is, but we're very excited about those future programs too.
Yes, TPP with Gubra. It's early to, you know, be too definitive, I think, but, you know, the target is to make it longer acting. If there are other, you know, probably at least weekly, you know, if there are other things we can continue to, you know, if we can make it even longer, great. I think the goal is just to make something even more convenient, if that makes sense.
Perfect. Maybe we'll switch gears to Wolfram syndrome for a few minutes. At a high level, maybe just give us the, like, quick lay of the land. What is Wolfram syndrome and what is a therapeutic agent in this trying to accomplish?
Sure. Wolfram is a monogenic disease that, you know, it's a monogenic form of diabetes. It's recently come to light that, you know, classically diabetes was Type one, Type two, but in fact, there are a number of forms of diabetes that are genetic, of which, you know, Wolfram is one of those. It starts by looking like type one diabetes. People usually, or children usually present with diabetes between six and nine years old, but as they get older, it becomes clear that it's not just diabetes. Usually in early adolescence, they'll start going blind, becoming usually fully blind in adulthood. They start showing other symptoms like deafness, walking difficulties, breathing difficulties, swallowing difficulties, and it, you know, kind of transitions from a diabetic disease to a neurodegenerative disease as the patients get older.
It's caused by mutations in a gene called WFS1, which makes it nice from a preclinical modeling perspective as well. All of our preclinical models were WFS1, you know, models where we showed quite strong differences with the drug as opposed to vehicle or otherwise. I'll say it's also a progressive disease. People get worse both on the diabetes and all the neurodegenerative markers as they get older, typically passing away in early thirties, mainly due to complications of the breathing and swallowing challenges that the patients have.
Okay. I think, what's nice is, I think, we've been working on Wolfram syndrome for about eight years now, and I think it's becoming more and more recognized, which is nice for people and their families. There are now genetic panels for diabetes and the Wolfram syndrome mutations are on those. I think people are recognizing now, you know, if you see early onset diabetes and start the progressive vision loss, you know, maybe this is Wolfram syndrome. There's even a patient listening session at FDA last month focused on Wolfram syndrome. I think it's nice to see it start to be recognized because these people and families really, really need better options.
Okay. You recently published clinical data on a 48-week study. Maybe what were some of the key takeaways for that trial?
I think what we've seen, we're quite excited about, so the primary things we were looking at were measures of glycemic control. People with Wolfram syndrome, their pancreatic beta cells become dysfunctional and degenerate, which means their bodies can't produce insulin the way that they're supposed to. We saw not just a slowing of that loss of insulin production, but we actually saw an overall increase in the amount of insulin production produced by the pancreatic beta cells, as well as a faster time to produce that because you want the insulin to happen in response to a meal. We saw both earlier and more insulin production. It's the first time in any trial of diabetes we're aware of that has seen that. We are very excited at what that means. We think what it means is that the patient's beta cells are functioning better.
We saw concomitant changes in the other glycemic measures as well. Hemoglobin A1c went down, time in target glucose range went up. Then we looked at other measures of function impacted by Wolfram syndrome. Visual acuity, we saw stabilization or even improvement in a couple of people. We saw overall changes in things like clinician and patient reported impression of change. In short, every outcome we looked at went in the right direction, which in a progressive disease is very exciting.
Yeah. You're now planning to meet with regulators on a phase III trial design. What are some of the key things you want to establish with the regulators as you think about the length of the study, the right endpoints, whether it's controlled? Talk to us about that.
Yeah, great question. So, you know, similar as we discussed with Avexitide as well, we try to keep as much similar as we can phase II to phase III. And, you know, in our phase II, our primary outcome was a C-peptide. We then had other glycemic measures. We also had visual acuity and various measures of, you know, global change as well. I think, you know, to the extent, you know, those outcomes can be central to our next trial, I think that would be to our benefit, given that we've already seen, you know, effects there. In terms of duration, you know, we did see continued change, as we went out to 48 weeks.
You know, so there's some trade-off in terms of how long do you want the study to be, et cetera, but it does seem like the separation grows over time, you know, and so that certainly factors into the thinking, you know, as we go forward, you know, towards a potential phase III trial. I'd also say overall, this would be the first pivotal study ever run in Wolfram. You know, we do want to make sure as we interact with FDA that we've kind of cleared up the necessary questions and that, you know, hopefully if we have a successful study that, you know, we're clearly moving towards a registration approval, things like that.
Okay, great. Maybe we can spend a minute on the progressive supranuclear palsy. Phase III interim data is expected in the third quarter. Remind us what exactly we're going to see with that result.
We're running this phase II-B trial to basically serve as the go/no-go point to determine if we enroll in a phase III. We've randomized 139 people, three to two, active to placebo. We're following them over time. The analysis point we're using is that everyone will have at least 24 weeks of treatment. For people who have longer treatment, we'll use all available data. PSP, as I mentioned, is a really tough neurodegenerative disease. Sadly, there's nothing approved for PSP. It's a progressive movement disorder disease that's ultimately fatal within generally six to eight years. The things of note we're going to be looking at in the interim analysis or in the phase II analysis is the PSP rating scale, so pretty well-validated scale.
It's been used in quite a few large studies in PSP. I think that's generally looked at as, you know, kind of the gold standard in the field. We'll be looking at other clinical outcomes as well. People may be familiar with from, you know, Parkinson's or Alzheimer's or other such clinical scales. We'll also be looking at a number of biomarkers, including MRI. There are particular patterns of brain degeneration that one sees in PSP, as well as the sort of typical CSF biomarkers one looks at in neurodegenerative disease. We'll very much be looking at the totality of the data to determine if we go into that phase III portion of the study. That being said, we're going to have a high bar.
If we want, if we plan to embark on a phase III study in PSP, we want to have a high confidence that, you know, this is a good shot on goal.
Okay. Maybe we'll spend one second on the next generation candidate in ALS, AMX0114. Maybe just give us a quick, why is an ASO something you guys felt you should bring into the clinic and what is kind of the goal for this phase I?
Yeah, great question. It started with the target actually. We got very interested in calpain- 2 as a target. You know, in the time we were in ALS, we continued to kind of accumulate, you know, knowledge, information, dug very deep into literature and calpain- 2 emerged as one of our absolute favorite targets, in part because there's decades of evidence linking it to axonal degeneration. It's central in neurofilament processing. This insight of increased neurofilament may be saying something about calpain as well. As we thought about how to target it, there are many calpains in the calpain family. Calpain- 2 seems to be the one that's really central to neurodegeneration and things like ALS. To get that kind of exquisite targeting of just calpain- 2, an ASO made a lot of sense.
I'll say we, you know, worked with others who had, you know, done ASOs before, helped us as we, you know, developed, you know, this ASO. And, you know, now, you know, in clinic, just got fast track designation as well. One other thing I'll mention just at the ENCALS, you know, conference, just recently as well, there was new genetic data presented that actually showed calpain- 2 emerging as a genetically, you know, potentially genetically validated target, in ALS as well, which was kind of nice to see, you know, as kind of further confirmation, also. And maybe last, you know, preclinically we've seen neurofilament reductions, we've seen benefits on axonal degeneration, which was kind of what we, you know, hoped to see based on all the, you know, literature and the science that kind of led us to calpain- 2.
Great. Maybe in our last minute here, you can just give us an update on the cash runway and what activities are embedded in that guidance.
Yeah. I'd say we ended last quarter with $204 million. We have no debt. That gives us cash runway through the end of 2026. Essentially everything that we've been talking about is included in that cash runway guidance, probably most notably, in the first half of next year, the pivotal Avexitide PBH study readout. The one thing not in that runway would be the phase III PSP trial. I think our feeling is if we have very positive data in PSP, there are a number of options we can, you know, consider to progress into a phase III trial. We're very excited because we have, I think, you know, genuine exciting milestones in the coming, you know, 12-14 months. We're, yeah, we're excited to keep progressing across all of our programs.
Perfect. Thanks so much for joining me, guys.
Excellent. Thanks so much.
Thank you so much.