Amylyx Pharmaceuticals at H.C. Wainwright: Strategic Advances in Rare Diseases

On Wednesday, 10 September 2025, Amylyx Pharmaceuticals (NYSE:AMLX) presented at the H.C. Wainwright 27th Annual Global Investment Conference, offering a strategic overview of its clinical programs. The company highlighted its focus on avexitide for post-bariatric hypoglycemia and advances in treatments for Wolfram syndrome and ALS. While optimistic about its pipeline, Amylyx also addressed ongoing FDA discussions and financial strategies.

Key Takeaways

• Amylyx is advancing avexitide in a Phase 3 trial for post-bariatric hypoglycemia, with enrollment completion expected by the end of 2025.
• The company is exploring a long-acting formulation of avexitide with Gubra.
• Amylyx completed a $175 million financing, extending its financial runway into 2027.
• In Wolfram syndrome, discussions with the FDA are ongoing, with a report expected by year-end.
• Initial data from the ALS program using AMX0114 is anticipated by the end of this year.

Financial Results

• Amylyx reported a cash position of $180 million as of June 30th.
• The recent $175 million financing bolsters their financial runway through 2027.
• Detailed financial guidance will be provided at a later date.

Operational Updates

• Avexitide (Post-Bariatric Hypoglycemia):

- The Phase 3 LUCIDITY study began in April, with data expected in the first half of 2026.

- The study is a 16-week, randomized, double-blind, placebo-controlled trial involving 75 participants across 21 US sites.

- Amylyx is targeting over 160,000 US patients affected by hypoglycemia post-bariatric surgery.

• AMX0035 (Wolfram Syndrome):

- A 48-week study in 12 patients has shown positive trends in markers like C-peptide and HbA1c levels.

- Ongoing FDA discussions aim to design an efficient study for this rare disease affecting 3,000 to 3,500 individuals in the US.

• AMX0114 (ALS):

- The focus is on axonal degeneration by targeting Calpain 2, with data from the first patient cohort expected by year-end.

- Dose ranging is being conducted to assess safety and biomarker analysis.

Future Outlook

• Avexitide:

- Amylyx aims to complete the Phase 3 LUCIDITY study, potentially bringing the first treatment for post-bariatric hypoglycemia to market.

• Wolfram Syndrome:

- The company is committed to designing a clear study in consultation with the FDA to address this rare disease.

• ALS:

- The program aims to assess safety and biomarkers, focusing on Calpain 2 inhibition.

For more detailed insights, readers are encouraged to refer to the full transcript below.

Full transcript - H.C. Wainwright 27th Annual Global Investment Conference:

Li Chen, Equity Research Associate, HC Wainwright: Welcome everyone to the Investment Global Conference. My name is Li Chen. I’m an Equity Research Associate at HC Wainwright. Our next speaker is Mr. Jim Frates, CFO of Amylyx Pharmaceuticals. Amylyx is a clinical-stage biotech focusing on developing novel therapies across several neurodegenerative and endocrine diseases.

Jim Frates, CFO, Amylyx Pharmaceuticals: Thank you very much. Good morning, everybody, both here in the room at the HC Wainwright Conference and the folks tuning in online. It’s really a pleasure to be here. We’ve been here a number of years, and I’ve been at Amylyx Pharmaceuticals for four years as the CFO. I want to provide an update on some of our exciting programs. We work in the rare endocrine space, as well as in neurodegeneration as well. Let’s jump right in. Before getting started, of course, I will make forward-looking statements this morning. Pretty hard to do that when you’re working in biotech and not think about the future. That’s why we’re all here and at the business. I would recommend that you read all the risk factors in our SEC filings. Those can be accessed through our website or, of course, through the SEC website.

We do spend a lot of time, and there’s obviously a lot of risks in developing clinical-stage assets in biotech. Thank you for that. Getting into the pipeline, we have three assets that people are focused on, but most of the attention is on our late-stage asset avexitide. Excuse me. We are focused on the next nine months on executing on an important Phase 3 LUCIDITY study that we’re talking about, and we’re very excited about that. It’s in post-bariatric hypoglycemia or PBH, and the Phase 3 is really undergoing right now. We continue to expect enrollment completion by the end of this year and data in the first half of 2026. We’ll get more into the details of that and the mechanism and the clinical background, but that’s where investors are most focused.

We also, importantly, are working on a long-acting formulation with our partners at Gubra, and that was a program we announced late in 2024. We’re in the early stages of that, but we’re excited about that development. We’re working with AMX0035 in Wolfram syndrome, which has completed a 48-week study in 12 patients, and we’re working through our next steps with the FDA. We hope to report that out by the end of this year. We also have an exciting new program in ALS with an antisense oligonucleotide called AMX0114, and we’re going to have data from our first cohort of patients, people living with ALS, by the end of this year as well. For a small company, we’re pretty busy, and we’re very excited about the work with avexitide.

You’ll also notice too, I should probably mention for folks, we had an announcement last night that we completed the financing, which I’ll touch on at the end as well. We’re well capitalized as we move through these milestones. Let me get started with avexitide, which is a first-in-class GLP-1 receptor antagonist with FDA Breakthrough Therapy Designation in two areas, actually. The first one is for post-bariatric hypoglycemia. You’ll see here the mechanism outlined in this slide. When the major resection for bariatric surgery, this is for folks who are dealing with obesity, tends to be people with BMIs over 35 or 40. These are folks that are, you know, as a result of bariatric surgery, losing in the order of 100 to 150 pounds, right? Obviously very major surgery, but they also have major medical issues with obesity.

Oftentimes what happens in this surgery is that GLP-1 gets overproduced, and they have, in a small number of people, that secretion causes after meals and also after, you know, exertion, exercise, stress, other things that might drive blood glucose normal elevations, right? It gets magnified because these folks have an overproduction of GLP-1. That’s the theory. If we block GLP-1, you block the production of insulin. If you block or lower the production of insulin, really lower the production of insulin, you can lower the incidence of hypoglycemia because this is sort of a hypoglycemia that’s caused by hyperinsulinemia, it’s called, basically the overproduction of insulin. You’ll have to excuse my, you know, my scientific knowledge is only so deep given that I’m the finance person, but obviously a lot of references here, and we try and make sure all the references are available. The goal is fairly simple.

An important endocrine pathway, we block the GLP-1 receptor with some effectiveness. You lower that pathway’s normal response, i.e., more GLP-1, you produce more insulin. You know, and it’s logical, right? The first GLP-1 agonists were approved for type 2 diabetes, right? Because you want to lower hyperglycemia, you produce more insulin, and therefore you deal with the hyperglycemia. In cases where folks are dealing with hypoglycemia, right, hyperinsulinemia, you want to lower the production of insulin, and then that hopefully solves the issue of the hypoglycemia. Again, first-in-class approach to this, and here’s some of the early data. What we really like about this program, which we acquired last year, avexitide was developed by physicians at Stanford and CHOP. It was licensed to another company. We acquired that asset last year and have been really working to extend the Phase 3 program and into commercialization.

From the very first Phase 1 studies, in a single dose, you see this happening not only in healthy volunteers, but also in people that have post-bariatric hypoglycemia. Here we’re showing what happens to insulin, both in the presence of an insulin challenge. Obviously, you’d expect with high glucose, one of those drinks that they do, what is it called? Glucola, right? Pure sugar, basically. You have people fast overnight. You give them a high amount of sugar. Their insulin’s going to go way up. In the case of a patient dealing with this, their blood glucose then is going to drop. In controlled environments, these folks are rescued so they don’t have dangerous levels of hypoglycemia that you can see on the right. We can also test with avexitide. When avexitide’s on board, again, in this Phase 1 study, folks didn’t have the massive drop.

We are seeing that lower production of insulin, which you’d like to see. Very solid results in Phase 1. They also developed a very nice program over time. Five clinical studies over time. These are listed here. Single ascending dose, multiple ascending dose, and then two Phase 2 programs where people were actually at home in more regular, let’s say real-world settings. Very nice p-values and very consistent data that one might expect from a very clear mechanism. We’re happy to see that. That’s what gives confidence to move into a Phase 3. Just to describe some of the Phase 2 programs in more detail, I don’t have a lot of time here, but there was also some nice dose ranging that was done, right? 30 milligrams. I’ll point you to the left-hand graph. 30 milligrams twice a day, 60 milligrams once a day.

In a second Phase 2 study, the Phase 2b study tested at 45 milligrams twice a day and once a day of 90 milligrams. We’re seeing fairly solid results, in the high 50s and 60% reduction in overall rates. These are average rates of what are called level 2 and level 3 hypoglycemic events. That’s very important. These are guidelines outlined by the ADA. They’re recognized around the world and commonly used. This is also recognized in FDA guidance as well as what the appropriate measures are for measuring hypoglycemic events over time. Just to remind you, normal glucose levels for us are between 90 and 110 milligrams per deciliter. Again, when you eat, your glucose goes up. It could go to the high 100s. It could go over 200 if you might have, you know, and that’s what we worry about with type 2 diabetes, right?

Your glucose levels go too high. That’s where you need the insulin response and the GLP-1 agonist to keep those insulin levels, those blood glucose levels, not to go high, hyperglycemia. In hypoglycemia, a level one event is when you have your blood glucose below 70, right? We’d all feel that. A level two event is when your blood glucose goes below 54 milligrams per deciliter, right? That’s a medical emergency according to the ADA. This is when neuroglycopenia starts. What does that mean? That means your brain isn’t getting enough sugar. Of course, that can lead to seizures, to disorientation. It can lead to, ultimately, if it’s not treated, it leads to coma and death. It’s a medical emergency that needs to be dealt with. That’s a level two measured by, you know, the gold standard is a finger stick with a glucometer.

If you’re below 54, very clear you have a level two event. A level three event is defined clinically. That’s where an independent person needs to rescue you. You’ve had such a medical emergency that you can’t take care of yourself anymore, and you have to be rescued. The other component of this disease, which is also very important, sorry, I’ll just go back, is because this happens persistently in post-bariatric hypoglycemia, we’re talking about people who are having an event a week. They’re having multiple events, much more than you would see in your typical, say, type 1 or type 2 diabetes where you might have hypoglycemic events less frequently. This is what’s the hallmark of PBH, is this persistent and difficult to treat and repeated hypoglycemia. That’s why we got breakthrough status, one might imagine, from the FDA because of the medical importance of this scenario.

Now, just to touch on some data we presented at Endo, because the Phase 3 design, which I’ll get to next, we’re looking at the composite of number. Basically, that’s adding up the number of level two events and the number of level three events because they’re both serious. It’s the composite. You simply add them up together, and we’re going to compare what happens in the placebo group over time and what happens in the active group over time. That will be the primary endpoint. Again, well-established primary endpoint. Just in our Phase 2 study we presented at Endo, we saw a 64% reduction in that in level three events, a 53% reduction in level two events. In the composite, we saw a 64% reduction, you might imagine, right in the middle of those two if you’re adding them both together, with a p-value of 0.0031.

That’s one of the reasons why we’re excited about this program with its solid data. Of course, we have to talk about side effects when we’re talking about potential efficacy as well. The side effects were generally well tolerated with a favorable safety profile across both Phase 2 studies. They were mild to moderate, mild to moderate injection site reactions, which weren’t terribly different, excuse me, from placebo. Most of the side effects were transient. No patients discontinued in the studies because of the side effects. That’s important. Also, I should talk about the dosing. We’ll talk about that in a moment, but it’s an injectable product, and it would be a daily injectable product. That’s another important thing to note. We are going to end up spending most of our time on avexitide, but that’s appropriate because that’s where most of the questions come from.

Just quickly on the Phase 3 design, that’s the box on the bottom. The top two are the Phase 2 designs. The bottom one is the Phase 3 design. Sixteen-week randomized double-blind placebo-controlled Phase 3 study in 75 individuals across 21 sites in the U.S. It’s important also, our whole supply chain is in the U.S., so that’s important. We have U.S. manufacturers and sources, and that’ll hopefully come into play later if we can think about commercialization. What we tried to do was keep the Phase 3 as close as possible as we could to the Phase 2s that were done previously. Here’s a table that you can look at, and you should look at more deeply about what the changes are.

Probably the most specific one is we decided on that 90 milligram once-a-day dose, even though that had been studied, you know, to recapitulate what we saw in the Phase 2b. It’s over a longer period of time. We’re studying it over 16 weeks instead of four weeks. The primary endpoint, again, is the composite, which is what the FDA likes to look at, as opposed to either level one, excuse me, level two or level three events. That’s really just adding them together. Interestingly, it gives you more statistical power because you can push both together. That’s important. Let me also, we’ll sort of wrap up on avexitide here, which is also a lot of the questions we get are about the commercial market. What’s interesting is they’re actually, while it’s a market that may not be aware to everybody, right? It’s a rare disease.

We think there’s over 160,000 people in the U.S. that are living with this medically meaningful, again, and persistent hypoglycemia after bariatric surgeries. That seems like a large number, but it is a small percentage of what is a very large pool of people. It was interesting for us to learn as we started to look at this program over a year ago. There’s been over 2 million bariatric surgeries in the U.S. over the last decade. Roughly 8% is where we come on when we look at the data. People have this persistence. That’s where we get to the 160,000. That’s the top half of the slide. Over in the box on the right is really a lot of the references from the number of papers. There’s been quite a few papers, actually, where people are trying to understand what the incidence is.

We can talk a little bit more about that, and you can delve in. Interestingly, again, at Endo this year, the Endocrine Society meeting that was out in San Francisco in July, Dr. Colleen Craig, who is one of the experts, person who really identified or was important in identifying that it was GLP-1 overexpression that was likely the root cause of this persistent hypoglycemia we were seeing. She’s also done a very deep and detailed persistence work. You see that work in reference in the bottom in that square, on the, excuse me, rectangle on the right. She came to a very interesting, you know, 168,000 patients in the U.S. So it’s hard to get, of course, precise down to the individual patient. We are confident, and as the more work we do, the more confident we become. This is a real condition.

It’s very difficult for people to live with this condition. It’s really been hiding in plain sight as people don’t really have medicines to be able to deal with it. Ours, if we’re successful in our Phase 3 and the regulatory process, would be the first drug to come to market to treat this disorder. We’re excited to help this patient population. Here’s just the timeline. Again, really key issues for us executing on that clinical study. We started enrolling patients in April, and our guidance has remained consistent through the year, which is completing enrollment by the end of this year. With the 16-week study, that would leave us for data in the first half of 2026. Just to touch on patents, important, we have patent rights through 2037, licensed from Stanford and CHOP, and we’re also developing our own patent portfolio.

Importantly, we’ve been granted orphan designation for this indication, for these indications. We expect that we’ll have NCE exclusivity as well. Let me just touch briefly on our two remaining programs. One is Wolfram syndrome, which is a rare disease, a monogenic disease, in fact, that’s sadly fatal and progressive. Folks are diagnosed. This is just an explanation of how Wolfram syndrome manifests over time. Interestingly, patients present generally with the first cells that unfortunately are affected, the insulin-producing cells in and around the pancreas and that whole system. This is an interesting insight too, right? We were working in Wolfram syndrome for over seven years. Understanding the endocrine endpoints here as we look at measuring how people deal with too low levels of insulin, actually, right? We’re looking at C-peptide. We’re looking at HbA1c. The neurological degeneration company that’s looking at Wolfram syndrome understands the endocrine pathway.

As we were looking at avexitide, we recognize the power of that data in their early clinical studies because of our work in Wolfram syndrome. Some serendipity there. These folks generally present as young children with type 1 diabetes, right? You replace their insulin and they seem like they’re a type 1 diabetic. Ultimately, sadly, what happens is their next day, their optical nerves are starting to degenerate and their hearing and their kidneys and they start to go through a progression. It is a very difficult disease with so far, again, no treatment. Here we’re using AMX0035, which is working in the endoplasmic reticulum with stress in that area. Wolfram syndrome is actually thought of to be a prototypical disease of endoplasmic reticulum stress. Studying it there makes a lot of sense.

In the open label Phase 2, we saw a number of, over 48 weeks, we’ve seen a number of these markers move in the right direction: C-peptide, A1C, HbA1c levels, excuse me, and also optical degeneration. We are slowing and even in some ways seem to be improving outcomes in some of these areas. Where are we now? I’ll put up the safety slide too. Where are we now? We’re in discussions with the FDA because no study has ever been done in Wolfram syndrome. It’s very important for us and it involves many organ systems as I’ve outlined. It’s very important for us to be able to design a clear study, a study that we can hopefully execute efficiently and one that doesn’t put too much burden on the patient population. In that sense, we estimate this is much more of a rare disease.

We estimate that in the U.S., there’s somewhere between 3,000 and 3,500 people living with Wolfram syndrome. That’s another program we hope to move forward. Finally, I’ll just briefly touch on our program in ALS. We’re still focused there. We’re very excited that we’ve gotten into the clinic with AMX0114, which is targeted at axonal degeneration by looking at the Calpain 2 target. Calpain is a very common and well thought of, it’s a target that a lot of people think about. The problem is there’s a number of different calpains. If you block calpain too broadly, you can lead to a lot of side effects. Actually using an antisense oligonucleotide requires an intrathecal injection. For ALS, as we’ve seen, and other sort of rare and deadly neurodegenerative disorders, an antisense oligonucleotide in the intrathecal space is viable and has been successful in other drugs.

Using an antisense oligonucleotide where we can exquisitely target Calpain 2 as opposed to the other calpain enzymes, we think is an exciting opportunity. We’re studying it in, let’s just get that study design up. Excuse me, sorry, hitting the wrong forward button. We’re studying it in a number of patients. As you might imagine, doing dose ranging, most important to look at safety, but we’ll also be looking at important biomarkers, things like NFL. There are also particular cleavage remnants that we can look at for CalPAN2 so we can know if we’re getting target engagement and hopefully having an impact in some of the biomarkers. Obviously, safety is important and we’ll be escalating that dose, but we hope to have the first readout of the first group of patients by the end of this year. For a small company, I think we have a lot going on.

Just again, recently, yesterday, we announced we raised $175 million. That will extend our runway well into 2027. We’ll have more detailed guidance on that. It’s obviously hot off the presses, but we had $180 million in cash on the balance sheet as of June 30th. With this $175 million, we have a lot of flexibility to be able to invest and continue to prepare in avexitide, but also to have a longer runway so we can make sure that we’re doing our best for patients. Thanks so much for the interest. There’s a lot of unmet need here. We’re going after large unmet markets and doing that hard work in science. Really just hats off and thank you to the patients and doctors who work with us and all my colleagues back in Cambridge doing the work every day to try and make these discoveries turn into medicines.

Thanks for your attention and look forward to chatting with you in the future.

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