Amylix Pharmaceuticals at Leerink Global Healthcare Conference: Strategic Pipeline Insights

On Monday, 10 March 2025, Amylix Pharmaceuticals (NYSE: AMLX) presented at the Leerink Global Healthcare Conference 2025, offering a strategic overview of its pipeline developments. The company showcased optimism about its future, highlighting potential breakthroughs in treating neurodegenerative and rare diseases, while also acknowledging the challenges ahead.

Key Takeaways

• Amylix is advancing Avexitide for post-bariatric hypoglycemia, with Phase 3 trial results expected in 2026.
• The company is conducting a Phase 2b/3 trial for AMX-35 in progressive supranuclear palsy, with interim data anticipated in the third quarter.
• AMX-35 is also being studied for Wolfram syndrome, with promising early results.
• CALPANE-2 is in development for ALS, with initial data expected by the end of the year.
• Amylix focuses on unmet needs in neurodegenerative and rare diseases, leveraging a data-driven approach and targeted commercial strategies.

Operational Updates

Amylix’s Co-CEOs, Josh Cohen and Justin Klee, emphasized the company’s commitment to addressing unmet medical needs through its innovative pipeline. The company’s strategy includes:

• Targeted commercial efforts in orphan disease markets, utilizing specialty pharmacy distribution and orphan pricing.
• Data-driven decision-making to advance its programs.
• Research collaborations, such as with Gubra, to develop long-acting GLP-1 antagonists.

Future Outlook

The company remains optimistic about its future, with several key developments on the horizon:

• Avexitide (PBH): A Phase 3 trial is underway, with results expected in the first half of 2026. The target market includes 160,000 PBH patients, with a focus on adult endocrinologists and weight management clinics.
• AMX-35 (PSP): Interim results from the Phase 2b/3 trial are expected in the third quarter. The trial aims for a 30% improvement in the PSP Rating Scale.
• AMX-35 (Wolfram Syndrome): Early data shows stabilization or improvement in key outcomes, with final results due soon.
• CALPANE-2 (ALS): Initial data from an ongoing trial is anticipated by year-end, focusing on safety and biomarkers.

Q&A Highlights

During the conference call, the Co-CEOs shared insights into their strategic vision:

• Justin Klee remarked on the company’s origins and enduring focus on neurodegenerative diseases.
• Josh Cohen highlighted the surprising stabilization of outcomes in Wolfram syndrome, contrary to the disease’s typical progression.
• Both leaders emphasized the importance of a targeted approach in orphan diseases, leveraging specialty pharmacy and orphan pricing strategies.

In conclusion, Amylix Pharmaceuticals continues to make strides in its pipeline development, positioning itself as a key player in the treatment of neurodegenerative and rare diseases. For more details, readers are encouraged to refer to the full transcript.

Full transcript - Leerink Global Healthcare Conference 2025:

Mark: Alright. Great. Thanks, everybody. Alright. Well, welcome back for another session.

We have, the Amylix Pharmaceuticals co CEOs, Josh Cohen and Justin Klee. Thank you for joining us guys. And, maybe what makes sense is just a quick sixty second, two minutes on how we got here. You know what I mean? Just make sure everybody understands the company, where we came from, and and what we’re doing.

And and you don’t need to get into each of the programs that you’re working on right now because we’re gonna get through those. So just just a very quick update on the founding of the company and where we are.

Justin Klee, Co CEO, Co Founder, Amylix Pharmaceuticals: Very happy to. Well, first, thanks so much for having us. Thanks to the Leerink team. And good to see some familiar faces too. So Mark was saying Justin, Co CEO, Co Founder alongside Josh, Fellow Co CEO and Co Founder.

So we started Amlex about twelve years ago. We were very focused in neurodegenerative disease. We still are. I think with that focus, we’ve maybe broadened to say more rare disease. I think we focus exclusively though on areas that are very high on that need.

So right now, as Mark said, we’ll get into, we have programs in ALS progressive supranuclear palsy on the neurodegenerative side, Wolfram syndrome on the neuroendocrine side and then Avexotide in PBH. Our history as a company, our first drug was for ALS. We brought that through FDA approval and commercial launch, had a very successful orphan drug launch. We ran a confirmatory study that was not as successful. So we would do that from the market, but that same core team is still here today.

And now we have four ongoing clinical trials, one with a pivotal readout next year. And so we’re very much looking forward to hopefully taking advantage of that development and commercial capability soon as soon as 2027. So excited to get into that.

Mark: And that underlying molecule is one of the assets that’s moving forward in the program, which we’ll get into in a second. But let’s start with Avexitide. Tell us what is this product and talk about the proof of concept data so far?

Josh Cohen, Co CEO, Co Founder, Amylix Pharmaceuticals: Yes. So Avexitide is a GLP-one receptor antagonist. So people are probably very familiar with the GLP-one receptor agonists such as Ozempic and otherwise. And part of why those work is they increase your insulin response, decrease your blood sugar. One of the reasons they were approved for diabetes and otherwise.

With a GLP-one receptor antagonist, you blunt the insulin response and increase blood glucose, which can be very important in diseases where we have too much insulin and where we have resultant hypoglycemia or drops in blood sugar. So Avexotide, our lead indication we’re focused on is PBH or post bariatric hypoglycemia. It has FDA breakthrough therapy designation for the treatment of PBH. And that’s really built on five previous studies in people living with PBH. There’s also been studies in healthy volunteers, which have shown a blunting of the insulin response, an increase in the post meal glucose and then over time, a reduction in the rate of people having significant hypoglycemic events.

People with PBH will have their blood sugar drop, leading to them becoming dizzy, unconscious, confused, fatigued, etcetera. So being able to reduce those events is really meaningful for patients.

Mark: And the dosing, just somebody understands, is what?

Josh Cohen, Co CEO, Co Founder, Amylix Pharmaceuticals: So it’s once daily sub Q and ninety mgs once daily sub Q. And that’s also what we’re studying in the Phase three, which, you know, as Justin mentioned as well, we’re actively recruiting the Phase three trial, expect readout in the first half of twenty twenty six and then filing and hopefully commercialization.

Mark: So the underlying cost of PBH is what?

Justin Klee, Co CEO, Co Founder, Amylix Pharmaceuticals: Yes. So I’ll say it’s a newer condition. The term was only coined for the first time in 02/2008. And it’s a rare subset of people who get bariatric surgery. We estimate about eight percent of people who get bariatric surgery will develop post bariatric hypoglycemia, which as Josh was saying is really characterized by these treatment resistant, persistent hypoglycemic drops.

So people’s blood glucose just drops often in reaction to a meal, but it can be sometimes without a trigger or to other triggers as well. What really pops out of the literature is that it seems that people with PBH, their bodies are overproducing and secreting GLP-one. So people may have as high as 10 times normal levels of GLP-one and this happens particularly in response to a meal or other triggers. So we really think that this is a GLP-one driven condition, which makes sense as you think about it. People are trying everything they can to control their diet and yet they’re still having these very strong blood glucose drops.

Well, if you’re having too much GLP-one, then kind of no matter what you’re going to do, your blood glucose is going to drop. So that’s where we also think an antagonist of the GLP-one receptor makes a lot of sense. You prevent GLP-one from interacting with the receptor, so you don’t get those drops and you raise the overall glucose level.

Mark: So describe to us the Phase three study.

Josh Cohen, Co CEO, Co Founder, Amylix Pharmaceuticals: Sure. So it’s a randomized placebo controlled study in seventy five people living with PBH. The primary endpoint is the composite of Level two and Level three hypoglycemic events. To kind of dive into that, a Level two event is when your blood sugar drops below 54 mgdl. A Level three event is when you’re so incapacitated that somebody has to rescue you.

And there were statistical significance on both Level two and Level three events in the Phase two and in the Phase 2b study, Probably most notably with the dose we’re using ninety mgs in the Phase 2b, there was a fifty three percent reduction in level two events and a sixty six percent reduction in level three events in the Phase 2b with high statistical significance. So as we go into this Phase three, we’re looking at endpoints that have previously shown evidence of effect with Avexetide. Study sixteen weeks with an open label extension. So the idea is to see a difference in event rate between active and placebo over that sixteen weeks.

Mark: So in Phase two, how long was the study? Four weeks. Four weeks. So we know that and the numbers that you were quoting, just to repeat them again, was fifty three percent and sixty six percent. Okay.

So that’s level two.

Justin Klee, Co CEO, Co Founder, Amylix Pharmaceuticals: Yes, level three. And level three.

Mark: Okay. What about level one? What is level one and why are we excluding them now?

Justin Klee, Co CEO, Co Founder, Amylix Pharmaceuticals: Yes, yes. No, so good question. So maybe starting with why do we measure blood glucose generally? The main outcome is our whole body needs glucose to function. But in particular, our brains are the highest glucose utilizers in the body.

And so what was recognized quite some time ago, originally studying in diabetes but then other indications, was that as blood glucose dropped to particular levels, the brain stops functioning the way that it should. So the technical term is called neuroglycopenia, which is just a fancy term for your brain needs more glucose. It was recognized that when the blood glucose drops below 54 milligrams per deciliter, that’s really when your brain starts not functioning the way it’s supposed to. So that’s what’s level two. Level one is above that.

Level one is sort of like you’re getting into that range. We all probably know the signs and symptoms and feelings of you skipped a meal or something like that. You maybe start to dip into the level one range there. Level two is where it really starts to be dangerous. And so that’s why the ADA and other groups agreed on saying, okay, level one matters.

And in fact, in the Avexotide data, level one. It worked. Absolutely. Yes, it worked on level one. But it’s really level two and level three where things start to get serious.

And so the FDA guidance for hypoglycemia is that having a composite of level two and level three events, that’s an acceptable primary outcome because it’s viewed as this is when things are getting really bad. And so that’s what we’re also using as our primary outcome.

Mark: So at Phase II though, those numbers you’re recording us were at four weeks? Correct. What do they look like at sixteen weeks, for instance, because the Phase III is at sixteen weeks?

Justin Klee, Co CEO, Co Founder, Amylix Pharmaceuticals: Yes. I mean, that’s exactly why we’re running the study. But I think our hope would be to have similar effect size to what we saw in the Phase II. And sort of putting this in context, when I say your brain is not functioning the way that it’s supposed to, people get severe confusion. Neurological manifestations.

So these fifty three percent reduction in level II, sixty six percent reduction in level three. This is really a big deal. And in fact, in the exit interviews in the trial, people said, Oh, my gosh, I feel so much better. It makes sense. If you’re constantly in fear of having these sorts of events, it’s highly, highly debilitative.

Mark: So in the Phase II, were the patients followed past four weeks?

Justin Klee, Co CEO, Co Founder, Amylix Pharmaceuticals: So they weren’t. So that’s probably the key difference between Phase II and Phase III is the duration of dosing. Now the nonclinical studies, the preclinical studies all went

Josh Cohen, Co CEO, Co Founder, Amylix Pharmaceuticals: substantially longer than that.

Justin Klee, Co CEO, Co Founder, Amylix Pharmaceuticals: So there’s no a waning of effect. That’s

Mark: what I was going to ask you

Josh Cohen, Co CEO, Co Founder, Amylix Pharmaceuticals: about waning of effect at all.

Justin Klee, Co CEO, Co Founder, Amylix Pharmaceuticals: Yes, exactly. We don’t think so. But the longest dosing clinically so far has been eight days.

Josh Cohen, Co CEO, Co Founder, Amylix Pharmaceuticals: I’ll also add this pathway doesn’t show any evidence of waning of effect. It’s the GLP-one pathway. Probably people are familiar. People taking, for example, on the agonist side continues working for months, maybe even years. So we don’t have any anticipation that four weeks and sixteen weeks are going to be so different.

Mark: Let’s talk about just commercial opportunity for a second. And what’s the patient journey like here? What are they doing? What are they currently on? What’s their standard of care?

Yeah.

Justin Klee, Co CEO, Co Founder, Amylix Pharmaceuticals: So I’ll say before we acquired Avexotide, this was a new area for us. But gosh, the more we learned about it, the more we realized this is a real unmet need and hopefully an area we can help. So patient journey right now, so people get bariatric surgery. Most people will not develop PBH. Bariatric surgery is very effective for huge So I think particularly in people who are severely obese, maybe morbidly obese, bariatric surgery can be a great option.

In a subset of people again, we estimate about eight percent in the years following bariatric surgery, average one to three, but it can be even longer, people start to get these events where suddenly they’re very confused, these events where suddenly they’re very confused, suddenly they feel terrible, suddenly they lose consciousness. Generally they go to their PCP. Their PCP tries to help them out. They refer them to an adult endocrinologist. The adult endocrinologist is often the person who makes the connection and tests their blood glucose and says this is hypoglycemia.

Standard of care right now is medical nutrition therapy, which is again a fancy way of saying eat every two hours, don’t eat carbs, eat small meals, and try to keep your blood glucose as stable as possible. Now medical nutrition therapy by itself I think helps people manage. But first of all, it’s pretty draconian, right? It’s not exactly a good way to lead your life. And the second is that for many people, they still have hypoglycemic events despite this medical nutrition therapy.

Now some people ask us, well, with diet, was that going to affect the type of events you see? Well generally, because I hate to put it this way people have such a strong negative feedback, right? They have a diet excursion. They feel it, and it’s really terrible. So people are pretty careful to stick to their diet.

Besides that, there are no treatments approved for PBH right now.

Mark: So the drugs are what what drugs are they?

Josh Cohen, Co CEO, Co Founder, Amylix Pharmaceuticals: Are they There’s nothing approved specifically. Right.

Mark: But what are they using?

Josh Cohen, Co CEO, Co Founder, Amylix Pharmaceuticals: So people will use a couple off label drugs known to kind of raise blood sugar, such as a carbo’s octreotide, you know, and some others. But one, those drugs, you know, have kind of mixed results when you talk to clinicians and in the literature and they have side effects. So there’s no specific drug for PBH. And the ones that they try off label are kind of met with mixed success.

Mark: So how many patients have this? You said eight percent is what?

Justin Klee, Co CEO, Co Founder, Amylix Pharmaceuticals: So we estimate about one hundred and sixty thousand.

Mark: So how many of the one hundred and sixty thousand are on one of these two drugs, for instance?

Justin Klee, Co CEO, Co Founder, Amylix Pharmaceuticals: Instance? From our research, people blow through them pretty quickly. So very few.

Mark: So maybe all one hundred and sixty tried it, but you’re saying there’s very few that actually stay on it or very few ever even try it?

Josh Cohen, Co CEO, Co Founder, Amylix Pharmaceuticals: Yeah. I would say we haven’t kind of put out kind of exact numbers there yet. But if I were to guess, I’d say probably actually not that many. You know, PBH is only so well known and only so many people are going to kind of reach for an off label medication to try to treat this. So I think our experience is that most expert, most KOL individuals do use these compounds.

Those who are maybe a little less close to PBH may very well not.

Mark: Let’s talk about the indication that you would receive if this works. And is it important that it’s broad versus the bariatric surgery because there’s different types of surgeries. So I guess where I’m going with this is, if you get approved, will it just be across the board for any surgery? And how often do the other surgeries have the same problems?

Justin Klee, Co CEO, Co Founder, Amylix Pharmaceuticals: Yes, it’s a great point. So maybe giving the landscape a bit. So there are from what we can tell, any upper GI, any significant upper GI surgery can lead to this persistent hypoglycemia. And that can be for weight loss, that can be for gastric cancer, that can be for GERD, that can be for all sorts of things. For bariatric surgery specifically, the two main surgeries that are used today are vertical sleeve gastrectomy or Roux en Y gastric bypass.

Vertical sleeve gastrectomy is the most commonly used, but Roux en Y is used quite substantially as well. Over the past several years, Roux en Y gastric bypass has actually been sort of increasing in prevalence because it has higher weight loss than vertical sleeve. But historically, vertical sleeve is used more prevalently. Between those two surgeries, we get to well over 200,000 procedures annually has been the run rate for the past five to seven years. So in this trial, in phase III, we are enrolling only people who had Roux en Y gastric bypass PBH.

And we are not allowing people with ESG PBH. Now pathophysiology, we think it’s the same. We don’t think there’s any difference. But I think cardinal rule in your Phase III trial is try to maximize success and try to replicate

Mark: That was your decision, that was at FDA guidance. That was our decision. As far as you know, the FDA would give you a label for post bariatric surgery.

Josh Cohen, Co CEO, Co Founder, Amylix Pharmaceuticals: That’s certainly what we’ll pursue. And we do have some data as well in the Phase 2b. A broad set of surgeries were included and the data was comparable across surgeries. So we do think we have a good argument both mechanistically as well as with some clinical data. So that’s what we’ll pursue.

If we need to at some point generate additional data, we will. But we think we already have a pretty good argument for a broader

Mark: I know. I would think so

Justin Klee, Co CEO, Co Founder, Amylix Pharmaceuticals: too. Yes. To your point, we believe BBH is BBH.

Mark: Yes. And let’s go back to the call point and what kind of commercial organization you think you need for this product.

Josh Cohen, Co CEO, Co Founder, Amylix Pharmaceuticals: Yes. I’d say we’re still doing research. This is definitely a year where we’re, in theory, two years out from launch where you start to gather a lot of insights and really build your knowledge on exactly what you’re going to need for the best possible launch. You know, I think the most clear call point is the adult endocrinologist. You know, people end up getting referred over to their endocrinologist, who usually does the ongoing care for this indication.

I think questions we have as well is, you know, how important is the bariatric surgeon in this whole approach as well? If you think all these patients were initially at a bariatric surgeon, some years after they come down with the condition, usually at a point where they’re beyond post operative care. So they might no longer be followed by the bariatric surgeon. And then they find their way back into the healthcare system as they’re having events and they’re maybe going to a PCP and eventually to an endo. You could imagine in the future having a pathway where after bariatric surgery, there’s some sort of regular glycemic testing, possibly coordinated through the bariatric surgeon or otherwise.

But so I’d say in terms of physicians, there definitely are some sites that have serious expertise in this area, have large numbers of patients. There are almost definitely some sites that have less than a handful of patients as well. But we’ll have to figure out the degree to which we do it personally versus non personally. How much is it digital? How much is it sales reps?

We don’t anticipate we’re going to build a massive footprint to Maybe

Mark: 100 people or something.

Justin Klee, Co CEO, Co Founder, Amylix Pharmaceuticals: Well, I think to your point, as we were looking at assets to acquire, we looked at what have we been, I think, good at historically. I think it’s development and then then commercialization in orphan disease. And so this is really orphan disease, I hate to put this away, the orphan disease playbook, right? This would I think we should plan on specialty pharmacy, orphan pricing, targeted commercial efforts.

Mark: And it does seem like it should be the endo. I mean, I would think some of these bariatric places like centers where there’s probably endo and there’s bariatric those would be obvious areas too.

Josh Cohen, Co CEO, Co Founder, Amylix Pharmaceuticals: Yes, I think so. And one interesting thing we’ve started seeing pop up, I think, especially in the age of the GLP-one agonist is this concept of a weight management clinic. Exactly. Yeah. So sometimes actually the bariatric surgeon and the endo are somewhat partnered.

Sometimes even with primary care or nutrition or some other specialties as well. So that weight management clinic may end up being an essential part of the launch as well.

Justin Klee, Co CEO, Co Founder, Amylix Pharmaceuticals: And I think it’s really exciting for both groups and for the whole weight management clinic to your point, because right now we have quite a few agents to help deal with hyperglycemia, too much glucose. We really don’t have much or effective, well tolerated treatments for hypoglycemia, which is just the other side of the same equation. So we’ve heard a lot of excitement from all people sort of involved in this type of care.

Mark: So just to go back, this is a dosing, it’s a daily subcu, but we’re going to try to change that over time. Talk about the partnership you have and what the goals are.

Justin Klee, Co CEO, Co Founder, Amylix Pharmaceuticals: Yeah, absolutely. So we think this is a really exciting mechanism. Our primary focus right now is PBH, but we think there’s great promise beyond PBH as well. For example, I mentioned other surgeries that can lead to this form of persistent hypoglycemia. One that definitely comes to mind is gastrectomy for gastric cancer, gastric cancer being one of the leading causes of death in major Asian countries.

So I think just one example, the drug also has breakthrough therapy in congenital hyperinsulinism. So I think it’s a really powerful mechanism that we’re targeting. Based off of that, we think it makes sense to invest for the future. So at the end of the year, we started a research collaboration with Gubra. Gubra, one of the world leaders in peptide drug development, and the goal there would be to try to develop a long acting GLP-one antagonist.

So early days, we’ve just started that collaboration, but they’re super strong. And I think our goal, we think of Exotide as a great profile to bring to market, but is to keep researching and then try to develop along acting.

Mark: Let’s switch gears. PSP, you wanted to define it for us and help us understand what the proof of concept data so far is and why you’re pursuing this?

Josh Cohen, Co CEO, Co Founder, Amylix Pharmaceuticals: Sure. So PSP is a tauopathy. It’s a neurodegenerative disease. People progress over time. It starts by looking like Parkinson’s.

People have gait disturbance, but people do not respond to dopamine therapy, which is one of the signs that it’s PSP. They also start having other symptoms, such as the inability to look up and down and kind of an abducted arm posture and some balance difficulties. It will eventually progress such that they have swallowing and breathing difficulties, usually six to eight year survival after the diagnosis. So again, it’s a tauopathy. There’s both strong genetic data implicating tau in the disease, as well as strong post mortem and CSF data implicating tau in the disease.

So with AMX thirty five in a past trial, actually in people with Alzheimer’s disease, randomized placebo controlled study, we saw a highly statistically significant reduction in CSF total tau and phospho tau. And that led us to be interested in, you know, where might we study this in tauopathy. PSV being kind of the prototypical tauopathy, opathy, you know, became quite exciting for us. This will also be the first compound that gets both across the blood brain barrier and into cells that reduces tau to be studied in PSP. So we kind of view it as us testing the hypothesis that will a tau reducing agent be effective in this disease.

Mark: And you know the molecule. Yes. It’s the same.

Justin Klee, Co CEO, Co Founder, Amylix Pharmaceuticals: It’s the same exactly. This is the treatment that we developed for ALS. We think this is even closer to the mechanism here because PSP, we know it’s a tau driven neurodegenerative disease, ER stress and mitochondrial dysfunction are central. And to Josh’s point, we have tau lowering data from a prior Alzheimer’s study.

Mark: Yeah, yeah, yeah. Okay. So let’s talk about the Phase III study and what are the expected outcomes. What are we looking at here?

Josh Cohen, Co CEO, Co Founder, Amylix Pharmaceuticals: Yeah. So it’s a seamless Phase IIb3, which could be confusing. So to kind of break it down, we’re basically reading out the Phase IIb portion and that’s going to serve as a go no go whether we go into Phase three or, you know, if the results are less strong, whether we reprioritize resources elsewhere. So we randomized 139 patients to the Phase 2b portion. It will look at several outcomes, the primary of which is the PSP rating scale.

We expect we have about 80% power to see a 30% effect on the PSP rating scale with the sample size. So, you know, we do think it’s possible we’ll see some clinical changes in this study. We also have several other rating scales as secondary outcomes, some biomarkers, some imaging outcomes as well. So we’ll look at it’s an unblinded analysis. So we’ll look at everything at that time and ultimately make Now I’d say in our view, we have very exciting programs.

So we’re going to have a high bar. Certainly, what we need to see are some strong data to support investing forward into the Phase three when we get that result.

Mark: So when will we get some data here?

Justin Klee, Co CEO, Co Founder, Amylix Pharmaceuticals: Third quarter of this year. So third quarter, we’ll have an unblinded look. And to Josh’s point, we’ll That’s

Mark: the interim.

Justin Klee, Co CEO, Co Founder, Amylix Pharmaceuticals: That’s the interim, exactly.

Mark: And you chose to do that because why?

Justin Klee, Co CEO, Co Founder, Amylix Pharmaceuticals: So we want to be confident before enrolling for a large Phase three study. And I think with PSP, the scale appears to be quite linear and it’s also been quite consistent trial to trial. And so based off of that, as Josh was saying, we have quite good power, 80% power to see a 30% therapeutic effect with the population we have. So we’ll be looking at one hundred and thirty nine people through at least six months treatment. For people who have had longer treatment, we’ll use all available data.

And I think the goal here will be, do we think we have a real potential treatment for people.

Mark: But the interim is everybody beyond six months minimum. So that’s the critical point. And the endpoint that you’re looking at to make the GoNo go is

Justin Klee, Co CEO, Co Founder, Amylix Pharmaceuticals: The key is the PSP rating scale. So it’s a commonly used scale in PSP that measures the progressive impact of the disease. But we’ll also be looking

Mark: at It’s a functional

Justin Klee, Co CEO, Co Founder, Amylix Pharmaceuticals: scale. Functional scale. Exactly. Functional scale. But we’ll also be looking at associated biomarkers.

For example, there’s a very particular pattern of brain degeneration that happens in PSP, as well as some other scales as well. NFL. NFL. Exactly. So I think the goal here will be, do we have high confidence that this could be a meaningful treatment for PSP?

And maybe just to share for those who haven’t looked at PSP much, it is a tough neurodegenerative disease. It’s progressive, it’s fatal, and there is nothing approved for PSP right now.

Mark: Okay. So six months, patients are all on, take an interim look. Is there some are all on, take an interim look. Is it is there some clinical meaningful bar that you need to hit? Is there is it flat out statistical significance?

Like, what are we looking for to decide the go, no go?

Josh Cohen, Co CEO, Co Founder, Amylix Pharmaceuticals: Yes. I mean, I think we want to be confident. I know that’s kind of a vague answer. But I think we want to be confident, which I think does mean seeing something relatively strong. You know, I probably won’t set the bar exactly at statistical significance, but something relatively strong on the PSPRS with corresponding, you know, concordant outcomes on the secondaries and otherwise.

I don’t think we want to be looking at a needle looking for a needle in the haystack for signal. We want it to be pretty concordant and strong. In terms of meaningfulness, you know, it depends what physician you ask. We’ve heard everything from a single point is meaningful to those who believe that an effect needs to be larger. So, you know One

Mark: point out of how many points?

Josh Cohen, Co CEO, Co Founder, Amylix Pharmaceuticals: It’s a 100 scale, ultimately.

Mark: So one point would be

Josh Cohen, Co CEO, Co Founder, Amylix Pharmaceuticals: We’ve heard that argument. Yeah.

Justin Klee, Co CEO, Co Founder, Amylix Pharmaceuticals: Yeah. Well, I think to the point, even comparing to other neurodegenerative diseases, and this is hard, right? These are some of the worst diseases there are. But you think with Alzheimer’s, with Parkinson’s, with ALS, with Huntington’s, there’s at least something, right? Wholly inadequate, completely inadequate, there’s at least something.

There’s nothing for PSP. So I mean, it’s sad, but for physicians and for people with PSP, anything would be better than what we have today.

Mark: And the interim, was that planned from the very beginning, or you guys added that in?

Justin Klee, Co CEO, Co Founder, Amylix Pharmaceuticals: So we always planned to do an interim analysis. I’d say that as we’ve gotten more certainty around enrollment and around the trial, now we’ve been more specific on the timing and the powering analysis

Mark: to go with that. Got it. Wolfram’s? I don’t know which one. Yeah.

Which one of you want to take Wolfram’s?

Josh Cohen, Co CEO, Co Founder, Amylix Pharmaceuticals: Sure. So we’ve been working Wolfram about actually at this point it’s probably more like eight years. And we started in Wolfram actually through talking with an academic clinician physician researcher at WashU, who’s one of the top Wolfram experts named Doctor. Fumihiko Jurano. And he approached us because Wolfram is often considered the prototypical disease of ER stress.

Throughout all the literature, the WFS WFS1 gene, which causes Wolfram, is associated with, is strongly associated with ER stress. So we proceeded to do several years of preclinical work with him, including inpatient derived neurons, beta cells, ultimately in the mouse model, all of which looked really strong, which is what encouraged us to go towards clinic. Just giving a picture of this disease, it’s a monogenic disease, so it’s caused by mutations in the WFS one gene. Patients start by looking like they’re type one diabetics, so they get insulin dependent diabetes, but they go on to have many other symptoms such as loss of vision, loss of hearing, walking difficulties, eventually breathing and swallowing difficulties that usually lead to their death approximately 30 years old. So in our trial, we, you know, so we we conducted we are conducting a, you know, initial proof of concept study with 12 people living with Wolfram syndrome.

We focused on glycemic outcomes, diabetic outcomes, such as hemoglobin A1C, C peptide and time and target glucose range. But we also looked at things like visual acuity, and we included some outcomes of, you know, kind of global burden of symptom change, CEGIC and pediatric clinician global impression to change and patient global impression to change. And what we saw or what we’ve seen thus far across those outcomes is all of them have stabilized or improved over time, which again is surprising given that the normal course of this disease is progressive blindness, So right now, we’re collecting data through forty eight weeks. We expect to have that in the coming months. We’re also interacting with FDA and planning our Phase three program.

But we’re quite excited about the data to date, especially in this disease that similarly people do their best to manage the diabetic and other symptoms, but there’s nothing specifically approved for Wolfram.

Mark: So twelve patients out practically a year. We’ll get that data when?

Justin Klee, Co CEO, Co Founder, Amylix Pharmaceuticals: In In the coming months.

Mark: In the coming months. Okay. So good data will be what?

Justin Klee, Co CEO, Co Founder, Amylix Pharmaceuticals: I think what was surprising in a very positive way is that, as Josh was saying first, all of the outcomes, stable or improvement, and particularly C peptide, which is a direct measure of how the beta cells in the pancreas are functioning and producing insulin, we expect over time it to decrease. We saw an increase. And in fact, it seems like that increase has sustained or maybe even improved over time. So I think what we’d like to see is do we still see that sustained increase? To our knowledge, this is the first diabetic trial that has ever shown an overall increase in C peptide.

So that’s particularly exciting alongside all of the other outcomes going in the right direction.

Mark: And the C peptide increases were at what time point?

Justin Klee, Co CEO, Co Founder, Amylix Pharmaceuticals: So we’ve seen it at every time point. So I think to the point, you know, the longer data, the more people out to that time point seeing that sustained increase, that’s really exciting.

Josh Cohen, Co CEO, Co Founder, Amylix Pharmaceuticals: Yeah. And as of the last analysis, all 12 of the participants had made it through twenty four weeks. We only only six of the participants had made it out, you know, forty eight weeks at that time. So at this time point, we’ll have all the people will have crossed the forty eight week time point.

Mark: So that’s the point where you’ll decide, okay, this is we’re going to go into a Phase three study and get this done.

Justin Klee, Co CEO, Co Founder, Amylix Pharmaceuticals: Yes. I think we’re already very excited about the data, which is why we’re planning for the phase three, but more longer data

Mark: patients the whole time.

Justin Klee, Co CEO, Co Founder, Amylix Pharmaceuticals: Yeah. Exactly.

Mark: Kinda know what’s going on.

Justin Klee, Co CEO, Co Founder, Amylix Pharmaceuticals: Well, more longer data is always better.

Mark: Yeah. Yeah. And in our last, like, thirty seconds, the last program, the CALPANE two

Justin Klee, Co CEO, Co Founder, Amylix Pharmaceuticals: Yeah.

Mark: Just a quick

Justin Klee, Co CEO, Co Founder, Amylix Pharmaceuticals: So, CALPANE two, has been researched for decades. It’s a key protein in axon degeneration. We know in ALS and in other neurodegenerative diseases, one of the hallmarks is the axon retracts and degenerates. So with CALPANE two, we’ve shown in our preclinical studies that if you knock that down, you can prevent axon degeneration. This is an antisense oligonucleotide dosed intrathecally, and we are recruiting for a study in ALS patients right now.

So we expect to dose the first patients in that study this month or next. And we should have our first early cohort data by the end of the year, looking first at safety, but also biomarkers like neuro neurofilament given that CALPANE two, cleaves many axon proteins, including neurofilament. So we see that it may be a signal of both disease, but also target engagement.

Mark: Got it. Good. Thank you. Thanks for joining us. Appreciate it.

Thanks so much, Mark.

Josh Cohen, Co CEO, Co Founder, Amylix Pharmaceuticals: Thank you so much, Mark.

Mark: Yep. Good. Great to see

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