Amylyx Pharmaceuticals at Baird Global Healthcare Conference: Advancing Rare Disease Treatments

On Tuesday, 09 September 2025, Amylyx Pharmaceuticals (NYSE:AMLX) presented at the Baird Global Healthcare Conference 2025, outlining strategic developments in its treatment pipeline. The focus was on their promising drug avexitide for post-bariatric hypoglycemia (PBH), alongside updates on treatments for Wolfram syndrome and ALS. The company aims to address high unmet medical needs, signaling both challenges and opportunities ahead.

Key Takeaways

• Amylyx Pharmaceuticals is advancing avexitide for PBH, with potential commercialization in 2027.
• The Phase III LUCIDITY trial for avexitide targets completion of enrollment by the end of 2025.
• The company is exploring avexitide’s application in other conditions like congenital hyperinsulinism.
• Amylyx is working on treatments for Wolfram syndrome and ALS, with updates expected later this year.
• The estimated PBH market size in the U.S. is about 160,000 patients.

Operational Updates

• Phase III LUCIDITY Trial (Avexitide for PBH):

- Enrollment is expected to be completed by the end of the year.

- Topline data is anticipated in the first half of next year.

- 19 out of 21 centers are currently active and enrolling participants.

- The trial is a 16-week double-blind placebo-controlled study targeting people with Roux-en-Y gastric bypass PBH.

• Wolfram Syndrome (AMX0035):

- Ongoing discussions with the FDA about the Phase III trial design.

- Plans to update on the Phase III design by the end of the year.

• ALS (AMX0114):

- Early cohort data focusing on safety and biomarkers is expected by the end of this year.

Future Outlook

• Avexitide:

- The company is targeting commercialization in 2027.

- There is potential for avexitide to treat other conditions like congenital hyperinsulinism and gastrectomy-induced hypoglycemia.

• Wolfram Syndrome:

- An update on the Phase III trial design is expected later this year.

• General Focus:

- Amylyx is committed to addressing high unmet medical needs and rare diseases through efficient clinical development.

Q&A Highlights

• Market Size for PBH:

- Estimated at 160,000 patients in the U.S., supported by literature and independent analysis.

• Awareness of PBH:

- Increasing among endocrinologists and within the medical community.

- Educational efforts are planned to further raise awareness among patients and healthcare providers.

• LUCIDITY Trial Design:

- The trial focuses on level II and level III hypoglycemic events.

- Patients are prompted to check blood glucose levels during symptomatic events or meals.

• Safety of Avexitide:

- Trials and animal studies show no evidence of hyperglycemia or weight gain.

- The aim is to help patients achieve better glycemic control and improve their lifestyle.

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

Full transcript - Baird Global Healthcare Conference 2025:

Chris Chen, Research Associate, Baird: Is this on? OK. Thank you all for coming today. My name is Chris Chen. I’m a Research Associate here at Baird. It’s my pleasure today to be joined by one of the CEOs of Amylyx Pharmaceuticals, Justin Klee, and probably more importantly, new father. Congratulations on that.

Justin Klee, Co-CEO and Co-Founder, Amylyx Pharmaceuticals: Thank you very much.

Chris Chen, Research Associate, Baird: That’s so cool. Thank you for joining us today. I just thought it’d be best to maybe take a moment to introduce yourself and provide some high-level background on the Amylyx Pharmaceuticals story before we get into the Q&A.

Justin Klee, Co-CEO and Co-Founder, Amylyx Pharmaceuticals: Sure. First of all, thank you so much for having us here today. We really appreciate it. As Chris was mentioning, I’m Justin Klee, one of the two Co-CEOs and Co-Founders at Amylyx Pharmaceuticals. We have three different assets that we’re working across three different indications. Our lead asset is avexitide, which is a competitive inhibitor of the GLP-1 receptor. It competes with endogenous GLP-1. Whereas the GLP-1 receptor agonists lower blood glucose, this raises blood glucose. We’re evaluating it in conditions of hyperinsulinemic hypoglycemia. In particular, we are in a phase III pivotal study for post-bariatric hypoglycemia, which is a very significant unmet need, where it’s a rare consequence of bariatric surgery. In the years following, people develop this very persistent symptomatic hypoglycemia, and there are no treatments available for it. While I mentioned it was rare, there have been millions of bariatric surgeries.

There are probably, we estimate, about 160,000 people who have this. Avexitide has FDA Breakthrough Therapy Designation for post-bariatric hypoglycemia. We’re targeting completion of enrollment by the end of this year in that phase III study and data in the first half of next year. I’m guessing we’ll spend a decent amount of time on that program. We’re very excited about it. We also have a small molecule program targeting stress and mitochondrial dysfunction in Wolfram syndrome, which is a rare monogenic neuroendocrine disorder where the gene mutations cause stress and downstream mitochondrial dysfunction. We had positive phase II clinical data earlier this year, and now we’re working towards a phase III trial. We have an antisense oligonucleotide targeting CALPANE2, which is a key actor in axon degeneration for the proposed treatment of ALS.

We’ll have our first cohort data, primarily safety, but also looking at biomarkers by roughly the end of this year. We have a lot going on, very focused in high unmet medical needs, rare diseases, and very pleased to get to share more about that today.

Chris Chen, Research Associate, Baird: Definitely. That’s a great background. We do want to focus on avexitide. I feel most people may be up to speed, but for those who aren’t, just taking kind of a step back, do you mind just kind of walking us through a bit the decision to focus on avexitide in neuroendocrine and that process? I know you acquired it from another pharmaceutical. What stood out to you in terms of avexitide, and why did you decide to go forward with that?

Justin Klee, Co-CEO and Co-Founder, Amylyx Pharmaceuticals: Yeah, thank you. We have always had a process at looking at promising assets in license. I think our vision has always been to be a great developer in areas of high unmet medical need. When we came across avexitide, we really saw a significant unmet need and opportunity. Avexitide is a first-in-class inhibitor of the GLP-1 receptor. Now, why would that be important? It turns out that there are conditions where the body significantly upregulates GLP-1 levels. In particular, the area we’re studying the most is post-bariatric hypoglycemia. People have bariatric surgery, and some people in the years following develop this very symptomatic persistent hypoglycemia. That is due to the body pretty dramatically upregulating this production and secretion of GLP-1. GLP-1 controls insulin, which therefore controls glucose. What happens is people’s bodies become hyperreactive, certainly in responses to meals, but it can be due to stress.

It can be due to exercise. People get severe hypoglycemia. Severe hypoglycemia, as the American Diabetes Association says, is a medical emergency. The reason is because our brains are the highest glucose utilizers in the body. When your brain doesn’t get enough glucose, like in severe hypoglycemia, then it basically starts to shut down. People get bouts of severe confusion to the point where they don’t know where they are. They may lose consciousness. Other people can have seizures. As you might imagine, there’s many visits. It’s really a debilitating condition. When we came across avexitide, we felt like, wow, what great pharmacology. You have a competitive inhibitor of the receptor in a condition that is driven by too much GLP-1. The real proof is in the data.

There have been five prior trials of avexitide in post-bariatric hypoglycemia, and you can see the effect of it in a single dose. In a single dose, by outcompeting this excess GLP-1, it prevents people from becoming hypoglycemic. Really compelling data. I think one sign of that is the FDA Breakthrough Therapy Designation, highlighting the unmet need for PBH, but also the data supporting avexitide. I think for us, the opportunity to work in an area where there are no treatments, high unmet medical need, we have quite long experience in the rare endocrine space from our work in Wolfram syndrome. The opportunity to do really, hopefully, efficient clinical development with this phase III trial and then get to people in need is, I think, a really wonderful opportunity for us.

We felt very fortunate to be in the position we were and to have the opportunity now to hopefully bring this forward for patients.

Chris Chen, Research Associate, Baird: That’s great. Before we delve into the phase III in avexitide, I did want to talk a little bit about the market for avexitide. I know you mentioned the 160,000 patient number. Can you talk a little bit more about the process in coming up with that number? I think there are some questions about diagnosis and the process with that. Can you just expand a little bit more on the market for PBH?

Justin Klee, Co-CEO and Co-Founder, Amylyx Pharmaceuticals: Yeah, absolutely. I think anyone who’s worked in rare disease knows one of the big questions is always like, how many people have this given rare disease? I would say with PBH, there are quite good literature studies looking at just that question. Both prospective and retrospective studies looking at hundreds, sometimes over 1,000 patients and tracking how many people after bariatric surgery, and it’s usually in the years following. It’s not immediate, but it’s on average about one to three years after the surgery, develop this very persistent symptomatic hypoglycemia. I think what’s nice in this case is that hypoglycemia has been well defined, largely thanks to work in diabetes. We can measure what does severe hypoglycemia really mean. I’d say first is based off the literature estimates.

We estimate that about 8% of people, and the literature ranges from maybe roughly 5% to 13% of people, will develop post-bariatric hypoglycemia. With that, plus the fact that there have been over 2 million bariatric surgeries just looking at the past 10 years alone, you get to an overall prevalence of about 160,000. We wanted to go into the claims databases. We’ve now looked at three different claims databases, and all of those analyses have corroborated the same numbers. Now there’s not an ICD-10 code for PBH right now. However, we know that everyone’s had a bariatric surgery. We know that they have hypoglycemia, and there are codes for hypoglycemia. We know they should have symptoms associated with severe hypoglycemia, like syncope. I’d say all three claims databases came out to very similar numbers.

On top of all of that, most recently at this year’s ENDO meeting, independent work from us out of Stanford, one of the co-inventors of avexitide, Dr. Colleen Craig, did her own prevalence work, really looking back over many years at how many people have presented with PBH. She estimates about 167,000 people in the U.S. today have post-bariatric hypoglycemia. I would say rare disease is always tough to get at exactly these numbers, but the fact that we had multiple literature sources, plus three different claims databases, now with Dr. Colleen Craig’s work, all showing very similar numbers, gives us confidence that these numbers we think are pretty good.

Chris Chen, Research Associate, Baird: That’s great color there. At the ENDO event, there was also mention about kind of these potential patients who might have kind of fallen through the cracks. You mentioned sometimes symptoms are years, sometimes even decades after the surgery. Are you doing any kind of outreach efforts or work with ENDOs? Along those lines too, the awareness of actually having PBH, even among ENDOs, is kind of relatively low. Are you doing outreach efforts to build that awareness among patients, among ENDOs, about just the existence of PBH?

Justin Klee, Co-CEO and Co-Founder, Amylyx Pharmaceuticals: Totally. I would say, I think as we’ve, I think this year, if all goes according to plan, commercialization in 2027. Right now, we’re focused a lot on our market insights, as well as starting to develop what may be the marketing approaches. We’ll continue that work into next year. I would say as we’ve been getting into the market, there are really, I’d talk about almost two populations. One, there are a lot of people who are diagnosed at key centers seeking treatment. Fortunately, there are really no treatments for PBH right now. As you might imagine from the 160,000 number, there are many, many people who are in that category. I think for them and for that population, it’ll be more about, frankly, the trial data. The phase II trials have been very strong. Of course, the phase III will be critically important.

To your point, there’s also, I think, a broad group of people who maybe know they have PBH but don’t know what to do about it, or they have the signs and symptoms, but they haven’t quite gotten the right diagnosis yet. I think there is really to use almost classic rare disease education approaches to try to educate people about post-bariatric hypoglycemia. What’s also been encouraging for us is that even since the time that we acquired avexitide, there’s been quite a groundswell of awareness for post-bariatric hypoglycemia, really independent of us. On the endocrinology board exams, there are now questions on post-bariatric hypoglycemia. Recently, there was a group of physicians who sent a petition to CMS to get continuous glucose monitoring coverage for post-bariatric hypoglycemia. At this year’s ENDO meeting, there was quite a lot of information on PBH as well.

I think it’s becoming a much more recognized area, as you might expect, as I’m describing the unmet need in the population. I think our efforts will very much dovetail with the efforts that are ongoing in the medical community right now.

Chris Chen, Research Associate, Baird: Great. Turning to LUCIDITY, the phase III in avexitide, I know you mentioned top line is expected first half this year, enrollment on track for end of this year. Can you just maybe provide the 10,000-foot view of the trial, trial design, and then maybe just speak a little bit on what you’re hearing from site managers about how enrollment is going?

Justin Klee, Co-CEO and Co-Founder, Amylyx Pharmaceuticals: Sure. I would say the trial is a 16-week double-blind placebo-controlled study in people with Roux-en-Y gastric bypass PBH, which is one of the two most common surgeries leading to post-bariatric hypoglycemia. I think the first thing is that our goal is really to be as consistent with the phase IIs as possible. Very strong reductions in hypoglycemic events in the phase II trials. In particular, the primary outcome of the phase III study is the composite of level II and level III hypoglycemic events, which is also in FDA guidance as an acceptable outcome. On that outcome, in the phase IIb at the dose we are now using in the phase III, there was a 64% reduction in level II and level III events with a p-value of 0.003. Very strong reductions in hypoglycemic events and very statistically significant.

Now going into the details a bit, level II, level III hypoglycemic events, what are those? Level II hypoglycemia is defined by a blood glucose less than 54 milligrams per deciliter. That’s the range where the body starts to get into neuroglycopenia. That’s where really your brain is being starved of glucose. As the American Diabetes Association says, it is a medical emergency. This is not your sort of run-of-the-mill, you know, I skipped a meal. This is really a medical issue. Level III means that the person has had the clinical event. It means that they’ve had the event due to hypoglycemia to the point where they need independent rescue. They need someone to help them. An obvious one would be loss of consciousness. There are others as well where someone is so hypoglycemic that they can’t help themselves. We will be tracking level II, level III events.

Level II is measured by fingerstick blood glucose. Level III is measured by eDiary in the lucidity trial. These are the outcomes that were looked at in the phase II and the phase IIb trial as well, with very significant reductions. The study is a parallel group. One arm active, one arm placebo. As you mentioned, we’re targeting completion of enrollment by the end of this year. Seventy-five participants, 21 centers. We have 19 of the 21 centers active and enrolling. I’d say there’s a lot of excitement around the trial, as you might imagine. We’re very pleased with the progress. I think we have a really excellent clinical operations team who, as always, has their finger on the pulse to make sure that we execute on it.

Chris Chen, Research Associate, Baird: Excellent. Going more a little into the level II and level III events, I’m just trying to get a better picture of how those might look during the experimental arm. Say I have a level II event, I’m a patient. Typically, kind of in the real world, when these patients have these events, there’s some type of rescue protocol where they’ll maybe eat some starch or some, you know, some rescue protocol. How are you kind of integrating that rescue protocol into the experimental arm? Do you foresee the possibility that those on avexitide might respond better to that rescue treatment during the trial?

Justin Klee, Co-CEO and Co-Founder, Amylyx Pharmaceuticals: Yeah. I would say it’ll probably be a theme you hear from me. The first is just to be as consistent as possible with the phase IIs. Again, very strong results. Our goal is to be very consistent with those. I would say the way that it’s being done in the trials, which is the same way that it was done in the phase IIs, is also in line with how people are supposed to manage their condition. The people are prompted to take their blood glucose by fingerstick for a few reasons. The first is when they’re feeling symptomatic. When they feel like they’re going low, they’re supposed to check their blood glucose. For some people, there are particular triggers. For example, two hours after a meal can be a typical time that someone can start to go low.

That may be another time where people frequently check their blood sugar levels. Also, in the trial, while the primary outcome is based off of the fingerstick, everyone also has a blinded continuous glucose monitor on. That CGM will alarm when it gets into the neuroglycopenic range. That’s another prompt for somebody to check their fingerstick blood glucose. What I would say in terms of rescue is that what people with PBH are told by their physicians is you really want to check that you’re in the hypoglycemic range before rescuing. The reason is that rescue in PBH is quite difficult. People’s bodies are hyperreactive. They’ve often lost a lot of their counterregulatory processes in their bodies. When they rescue, if they take too much glucose, for example, they’ll shoot up. Their GLP-1 levels will spike. Their insulin will spike. They’ll shoot right back down.

If they really are hypoglycemic, they’ll try to very slowly bring themselves back up. It could be a multi-hour process. They really want to confirm that they are hypoglycemic before attempting rescue. What people are instructed to do is take multiple fingersticks to really confirm that they’re in that hypoglycemic range. That’s how they manage their condition day to day. Therefore, that’s also what we’re capturing in the trial. I’d say, again, going back to the phase IIs, which were done the same way, very substantial reductions in the number of level II hypoglycemic events. The reason we believe is because this condition is really driven by too much GLP-1. If you can stop that GLP-1 bolus effect, you can stop the insulin spike and sort of bring people back to more euglycemia.

Chris Chen, Research Associate, Baird: Great. Just one more on avexitide. I want to talk a little bit about Wolfram. I heard the company that you acquired avexitide from was pursuing the drug in congenital hyperinsulinism. Can you briefly speak on the decision to pursue avexitide in PBH instead of HI? I’ve heard also that there are potential avenues where you’ll pursue maybe not specifically HI, but other similar indications down the line.

Justin Klee, Co-CEO and Co-Founder, Amylyx Pharmaceuticals: Yeah, absolutely. Avexitide was studied in three prior trials of congenital hyperinsulinism with quite strong results. Avexitide has a separate FDA Breakthrough Therapy Designation for congenital hyperinsulinism. The results are quite strong, and congenital hyperinsulinism is a really tough condition. It often presents at birth and is often due to genetic mutations. Infants basically are constantly secreting insulin, and they’re constantly hypoglycemic. When they’re in the hospital, they get IV dextrose to try to maintain their blood sugar levels. It’s a very hard condition where there’s quite a workup. Some people get diazoxide, some people have a partial pancreatectomy, and then there are various challenges as kids grow up too. It’s a really tough indication. I think we had the choice to work first on PBH or first on congenital hyperinsulinism.

We felt like with post-bariatric hypoglycemia, there was just a more straightforward development path and a larger opportunity, so we chose to focus on that first. However, we do think there’s real promise for congenital hyperinsulinism and a community that really needs treatment. We certainly will figure that into our plans. I would also say more generally, we think a competitive inhibitor of the GLP-1 receptor may have benefit in multiple other areas as well. Just one example, there are multiple other surgeries. It appears virtually any upper GI surgery can cause the same hyperinsulinemic hypoglycemia. For example, people get gastrectomy for gastric cancer. Gastric cancer is one of the leading causes of death in most major Asian countries. Avexitide was studied before in people who had gastrectomy-induced hypoglycemia, and they responded very well as well. We think there are many other uses that we may find.

We’re very focused right now on our trial on post-bariatric hypoglycemia, but we think there’s a lot more to do with the asset as well.

Chris Chen, Research Associate, Baird: Great. As you were speaking, I did have just one other question on safety for avexitide. Some question around the fact that you’re lowering insulin levels would increase sugar levels, leading to maybe hyperglycemia. Can you just talk a little bit about the safety there and what data is out there to suggest that these patients won’t kind of hit that high, overcompensate, and hit hyperglycemia?

Justin Klee, Co-CEO and Co-Founder, Amylyx Pharmaceuticals: Yeah, certainly. Certainly something that we looked for. We have not seen evidence of it so far, nor in the toxicology in the animal studies as well, where the GLP-1 receptor is active as well. Our thinking is that it’s not running the receptor in reverse. You’re more just attenuating the GLP-1 effect, being a competitive inhibitor. We think that’s why you’re really dampening down the effect, as opposed to running the receptor in the opposite direction. That’s why we haven’t seen hyperglycemia. We haven’t seen weight gain. Certainly something we’ll look for. My own bias is I think in clinic, if we can help people get to better glycemic control, then hopefully they can do other positive lifestyle interventions as well. People can maybe get back to exercise. They can have more typical diets.

Right now, the way that people have to manage their condition is basically really limit their lives. I think if we can help people get back to more of the life that they hope to have, then I would hope that actually they can be healthier all around. We’ll continue studying that to see that.

Chris Chen, Research Associate, Baird: Great. Turning to Wolfram and AMX0035, I know right now you’re in discussions for potential phase III. Maybe before getting a little into that, just a general background on Wolfram. I know probably a lot of people are probably not too familiar with it. Just general background on Wolfram and the need there.

Justin Klee, Co-CEO and Co-Founder, Amylyx Pharmaceuticals: Yeah. Wolfram syndrome is a neuroendocrine disease. It’s caused by mutations in WFS1. WFS1 encodes for the wolframin protein. Wolframin is a transmembrane protein that also spans to the mitochondria. Mutations cause the cell to be less able to deal with stress and downstream mitochondrial dysfunction. We see the same pathophysiology, stress, mitochondrial dysfunction, cell dysfunction, and death. We see that from cell type to cell type to cell type in the body. It starts with the beta cells in the pancreas. Different nerve populations are affected, particularly in the visual cortex and in retinal ganglion cells, and other neuron populations as well. The way the disease manifests is first, people, kids generally six, seven, eight, appear to have early-onset diabetes.

Where doctors start to cue on maybe this isn’t just early-onset diabetes is then often kids get progressive vision loss, then progressive hearing loss, ataxia, and mortality in sort of late 20s, early 30s. Really tough condition. We estimate about 3,000 people in the U.S. who have Wolfram syndrome. As with many of these genetic diseases, there are different pockets around the world where there are higher prevalence rates as well. I’d say this is an area we’ve been working in now for almost eight years. Really, because the mechanism of AMX0035 targeting stress and mitochondrial dysfunction is a great match for the pathophysiology of the disease, a monogenic disease that causes stress and mitochondrial dysfunction.

Chris Chen, Research Associate, Baird: Great. Just briefly on discussions with FDA, can you put some more color around that, maybe in terms of expectations for the phase III and the nature of the status there?

Justin Klee, Co-CEO and Co-Founder, Amylyx Pharmaceuticals: Yeah, absolutely. I’d say plans to update on the phase III design later this year. Really starting from our quite encouraging phase II results. With a monogenic disease, what you hope to see is the same thing in cells, the same thing in mice, and then the same thing in people. Indeed, that translation is what we’ve seen so far. In the clinical study, the primary efficacy outcome we looked at was C-peptide, which is a direct measure of the pancreatic beta cells producing insulin. C-peptide actually increased overall, which is very encouraging. It means the beta cells are functioning better. They’re producing more insulin. Other glycemic measures also went in line with that, A1C, as well as time in target glucose range. We looked at other parameters as well. Vision stabilized, even improved in a couple of people.

We looked at total scores like PGIC and CGIC, as well as a number of other measures of both the diabetes manifestations and the neurodegenerative manifestations. Quite encouraging data. We’re now working on the phase III design. The reason we want to just take our time is because this will be the first phase III trial ever in Wolfram syndrome. While these are well-known outcomes, I think we, and I would imagine FDA, want to make sure that this sets the appropriate bar for what a phase III study should look like in Wolfram syndrome. We’re quite encouraged by the fact that FDA had a patient listening session earlier this year for Wolfram syndrome. I think there’s more and more recognition. We’ve heard from our collaborator, Dr. Irano, that he’s been getting many, many more referrals for Wolfram syndrome diagnosis at his clinic as well.

We’re very excited about the potential of that program.

Chris Chen, Research Associate, Baird: Yeah, excited to hear more about that. I feel that’s kind of under the radar in the avexitide shadow a bit. I look forward to that update and as well with avexitide first half. Just real quick, I know we’re running short on time. Did you have any additional things you wanted to share with investors that we might be missing?

Justin Klee, Co-CEO and Co-Founder, Amylyx Pharmaceuticals: Sure. Just last thing to say is our last program, AMX0114 for ALS, will have our early cohort data later this year. As I mentioned, looking primarily at safety, but also biomarkers. That is placebo-controlled in people with ALS, 12 patients. I think it’ll be exciting data as well.

Chris Chen, Research Associate, Baird: Great. Looking forward to that as well.

Justin Klee, Co-CEO and Co-Founder, Amylyx Pharmaceuticals: Excellent.

Chris Chen, Research Associate, Baird: Thank you so much. Thank you so much, everyone, for attending.

Justin Klee, Co-CEO and Co-Founder, Amylyx Pharmaceuticals: Thanks so much.

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