If you have any questions, please reach out to your Morgan Stanley sales representative. Good afternoon, Justin and Camille.
Good afternoon.
Great to have you here.
Thanks so much for having us.
So much has happened over the past year at Amylyx. You've got four clinical trials ongoing, and so there's a lot to talk about today, so congratulations on all that, and I guess most recently, you in-licensed a product called avexitide, so it'd be great to hear a little bit about that.
Sure, yeah, very happy to. Well, thank you. So, yeah, so we're very excited about our pipeline. We have AMX35, which is a combination small molecule in two clinical programs, one in PSP. We'll have data, interim results on that, mid-next year. And in Wolfram syndrome, we announced interim data, earlier this year, which was quite encouraging, and we have further data in October. And then our antisense oligonucleotide in ALS, we're working to get first participants enrolled by the end of the year, and we'll have our first cohort-level data, next year on biomarkers such as neurofilament light chain. But then to your point, this summer, we're very excited to acquire avexitide, which is a first-in-class GLP-1 antagonist, first for the treatment of post-bariatric hypoglycemia.
Post-bariatric hypoglycemia is a condition that affects, we estimate, about one hundred and sixty thousand people in the U.S., and grows over time with bariatric procedures. It's basically a condition that happens in a rare group of people, roughly one to three years after, so avexitide has breakthrough status for post-bariatric hypoglycemia. There have been five trials supporting its use in raising the glucose nadir and thereby helping with hypoglycemia. It's really phase III ready, so we're working to get that trial up and running in the first quarter, and we figured then data in 2026 and hopefully commercialization in 2027.
So we're super excited about the asset, and the fact that it's a first-in-class GLP-1 antagonist, we think is really exciting too, 'cause we've seen how much power there is in targeting the GLP-1 receptor, but this would be the first antagonist as opposed to the many agonists.
Maybe we'll get into a little bit more detail on that, so people understand the differences between antagonism-
Yeah.
- and agonism. But, you know, maybe stepping back, because I think I'm not sure if anyone can close the door there, please. Thank you. You set out some very important criteria in terms of products to in-license, and I think avexitide really fits the bill in terms of that, and it does provide the context in terms of the profile that you've just delineated. So maybe we can touch on that first, because I think it does speak to, obviously, the excitement associated with the product.
Yeah, absolutely. Well, happy to start and then pass to-
Certainly
... Camille, who has a wealth of experience in these areas, so we've had a long process of looking for opportunities to complement our existing pipeline, and I think we've learned that there's no shortcuts. I think you have to do deep diligence to really see, you know, many assets maybe look good on the surface, and then you dig in and, you know, they can be more challenging. Avexitide, really, the more we learned, the more we got excited, so at first, you know, on the surface, the clinical trials looked really good, so every clinical trial showed reductions in insulin, raising of the glucose nadir, and hypoglycemia. That's what led to the breakthrough status from FDA. In fact, avexitide has two breakthrough statuses.
Also, it has breakthrough status in congenital hyperinsulinism. I think that speaks to the pharmacology as well. We understand GLP-1 fairly well. We know that antagonism of the receptor lowers insulin. It prevents insulin secretion and thereby raises the glucose nadir, so of course, helps with hypoglycemia. I think critically for us as well, I think it really, they'd done a nice job with their manufacturing scale-up, their toxicology program, some of the things that maybe can trip up development programs, so it's really phase III ready, and I think critically as well, PBH is an orphan disease, a really high unmet need, so this is a persistent, progressive form of hypoglycemia, where people are often afraid to leave their homes.
They're afraid to be alone, and it's because they experience often multiple hypoglycemic events a week.
Mm-hmm.
And hypoglycemic events really are that the brain's not working the way that it's supposed to. They're generally characterized as neuroglycopenia, and it's because our brains are perhaps the highest glucose utilizers in our bodies. And so when we don't have enough glucose, our brains don't function, so it's anything from lack of focus and tingling and those sorts of things to loss of consciousness and seizures. So if you're constantly in fear of these, you know, oftentimes people have their driver's licenses taken away. They often have to live with family members. They can't work.
Mm-hmm.
So it's a really severe condition, and very sadly, there's nothing for PBH right now. endocrinologists and doctors who care for people with PBH try to manage it with diet intervention. There's glucagon rescue, but that has its own challenges, so it's a really unmet need. And I think what we've shown is that we have a team that's very good at developing assets in the orphan space, and then if they work, making sure that they get to people effectively. So those are the things that really attracted us. And, Camille, I'll maybe pass to you to just
Sure, absolutely. I would say as well, stepping back a bit, understanding that the driver of the disease, excess GLP-1, and because of the change in the anatomy, food is seen coming through to the small intestine, releasing GLP-1. The food, the amount of food is seen as excessive to what is actually ingested, and so excess GLP-1 is secreted up to 10 times as much as would be appropriate for the size of the meal, and that fact then has taught us more generally that that's the driver of the disease process. And avexitide is addressing that driver of the disease, namely blocking the excess GLP-1 at the beta cell level so that excess insulin then is not secreted, and when Justin speaks of the phase III-ready nature of the study, it's absolutely true.
We did deep diligence on the regulatory meeting minutes that Eiger had had, and of course, because of breakthrough therapy designation, there were multiple iterations and meetings and minutes. It was clear that the most recent iteration with a proposed phase III trial design was finally agreed to by the agency, namely, primary endpoint, composite Level 2, Level 3 hypoglycemia, and we can go into those definitions in a moment. The dose, 90 milligrams daily, where in the phase IIb study, we saw a 66% reduction in the hypoglycemia Level 3 events, which is so meaningful because those are the events that require assistance by another person. Also, they agreed to the nature of the trial design, randomized placebo-controlled trial, and Eiger had proposed a 90-participant, 12-week trial.
Now, we have our own biometrics team at Amylyx, which is a luxury, and it's great and very important, actually. Now, they're doing their analysis so that and we're refining around the edges the details of the trial. But we wanna be sure that inclusion/exclusion criteria, the patients who we ultimately enroll are those that recapitulate what was done in phase II, as well as addressing those individuals who are most severely impacted by PBH.
So there was a lot of content in there, Camille. So, I mean, maybe, like, peeling back, so-
Sure.
Five clinical trials-
Yes
underpinning the product.
Correct.
And we now know what the phase III clinical trial design is. Maybe you can just dissect the clinical underpinnings and then the read-through from those to what you're-
Of course
Anticipating for that phase III trial.
Yes, absolutely. Absolutely.
Okay.
So the first three studies were a single-dose IV, which showed very clearly a reduction in insulin production and an increase in the glucose nadir, statistically significant. The second was a single ascending dose study, subQ. Third, multiple ascending dose study, subQ. Those all were used glucose tolerance test to look at the insulin production and the glucose levels. The phase II PREVENT study, which has been published-
Mm-hmm
... looked at two doses, two dose regimens, actually. 60 milligrams once a day, 30 milligrams twice per day, and did also use mixed meal tolerance test to show the reduction in insulin production and the rise in the glucose nadir, statistically significant, by the way. And there was a double crossover study with a run-in, placebo run-in, to ensure individuals had a certain level, certain incidence Level 2, Level 3 hypoglycemia. So those are-
And you had Level 3 before, you defined it. Level 2?
Level 2 is based on a glucose level of less than 54 milligrams per deciliter, and these studies use CGM, continuous glucose monitoring-
Mm
to signal when glucose levels were going low. Justin mentioned individuals with this condition have low glucose anyway.
Mm-hmm.
In this instance, the glucose going below 50, 54, you know, we would not be able to function with those glucose levels. These individuals have a lower set point, but even at that, they, you know, individuals start to have the autonomic symptoms and some of the neurological consequences. The glucose monitor has an alarm. Alarm goes off, they do a finger stick and confirm the low glucose. So that is a Level 2.
Okay.
That, if unmanaged, people can often go level 3, where they are unable to assist themselves. It's less about glucose levels and more about the clinical condition of the individual.
Right.
So they need somebody to be there to make sure they don't fall in the shower or fall in a Walmart, and I use these examples because that's what we heard from the participants.
Mm
- in the study.
Okay.
And often, that also means, you know, some assistance and rescue potentially.
And then two phase II studies supporting it. In the second phase II, again, they tested two dose levels, 45 mg twice a day or 90 mg once per day. The 90 mg once per day, we think has the best efficacy as well as patient friendliness. So that's the dose we're gonna take going forward. But high level, there have already been two phase 2 studies.
Mm-hmm.
That hit the exact endpoint that we're now taking into phase 3, which is this Level 2 Level 3 hypoglycemic events, which has been agreed to with FDA. In fact, it's in the FDA guidance when you're running trials for hypoglycemia, that a Level 2 Level 3 events is an acceptable primary outcome. So the reason I think we have such confidence going into the phase 3 and what attracted us to the asset as well is two phase 2s that already hit this endpoint with breakthrough status, now going into a phase 3, again, for a very unmet need. So we think it's quite clinically de-risked as far as development goes.
I'll make one other relatively small point, but it might be implied, but I'll explicitly state, the FDA agreed to one clinical trial.
Right.
-as well.
Yeah.
Yeah.
Fantastic. Great. And so the specific plans in terms of initiating the pivotal trial?
Yes, so we are on track very much to initiate the trial first quarter 2025, and by initiate, I mean enrolling participants in the study, and we anticipate that we'll have data readout by 2026.
Great.
Yeah.
Fantastic. And maybe just touch on the IP position of the product.
Yeah. So, great IP position, again, something we did a lot of diligence on, as you might imagine. So 11 issued patents. The base case we're saying for the composition of matter patent goes to 2037. That's without patent term extensions. The patent term extension may be a few years past that, but very solid, IP as well, and of course, you know, orphan designation, as well.
Great. And maybe just thinking about the competitive landscape, are there other drugs in development addressing this area? And I guess just with respect to the advent of GLP-1s-
Mm.
How are you thinking about the market opportunity?
Yeah, so I would say, you know, currently, really unmet need, there's nothing approved specifically for the treatment of PBH. Physicians will use medical nutrition, acarbose, but again, still very high unmet. Those are really not specifically for PBH. In terms of the landscape, there's a company, MBX-
Mm-hmm
... that has a GLP-1 antagonist for the treatment of PBH in early development. It's just in phase I now. And, but, aside from that, there have been, you know, several other companies looking at various mechanisms around insulin glucose in PBH. But as Camille was saying, we really think GLP-1 antagonism gets to the, to the-
Heart
heart of the disease. And again, I think that's why, you know, for example, in the phase 2b with a ninety mg dose, there's a 66% reduction Level 3 events, and the p-value is point zero zero zero three. So, you know, very highly significant and clinically significant results.
Right. And I think you whizzed by the stats, but a hundred and sixty... Maybe just go over the target patient population.
Mm.
This is a rare disease, but it's a large rare disease.
That's right. Maybe to back up, over the past decade or so, there's been well over two million bariatric procedures-
Wow!
-that have been performed in the United States. Of those, roughly one in three people will experience hypoglycemia. Those can often be managed through nutrition and other interventions. We estimate that about 8% develop this very persistent significant often progressive form of hypoglycemia that is resistant to such things as nutrition. Because it's 8% of a very large number, it's about 160,000 people who have post-bariatric hypoglycemia in the United States today. With the bariatric procedures that happen annually, we estimate there's probably roughly an additional 16,000 cases new cases every year of PBH. So it's been quite enlightening talking with endocrinologists. Many of them will say, "You know, yes, I have many patients who have PBH.
You know, I don't have much to offer them," and they'll often tell us, "You know, these are some of the most fragile patients that I have. They're afraid to travel from their home to my clinic.
Mm.
So it's a really unmet need, and to your point, it's orphan, but it's quite a significant orphan condition. And maybe the last thing I'll say, too, is that while we're you know we're studying for people who had had weight loss surgery and then developed this, there are other surgeries and other reasons that people can develop this form of hypoglycemia as well. Such as in gastric cancer, gastrectomy is often standard of care. It's one of the leading killers in many Asian countries. And again, with gastrectomy, as Camille was saying, when you alter the gut, some people can develop this form of GLP-1 really driven hypoglycemia. So we think that there's probably many, many people who are in need of help.
Again, having a first-in-class GLP-1 antagonist, you know, we feel like we may have a real opportunity to change their lives.
Mm-hmm.
I know, Kathleen, you had asked about with GLP-1, what does that mean?
Mm-hmm.
Right? And that is something that we consider also. But in speaking with the endocrinologist and speaking also with bariatric surgeons, it's not going away, for sure. And then we can't really predict, you know, whether it's the use of bariatric surgery will increase or decrease or how or by how much, either way.
Mm-hmm.
What we are reasonably confident is it's not going away completely, for sure, and the sample size, the population is already quite large. So if it's reduced by 10%, even 20%-
Mm-hmm.
You know, that's good for people who have obesity. There's increased awareness of obesity.
Mm-hmm.
9+% of the population in the U.S. have elevated BMI above 30 and/or 40. Those are individuals for whom weight loss is a major problem, and maybe the GLPs, maybe combinations will help, but it's not necessarily for everyone. There will always be a need for something more, a different approach because of all of the consequences of being morbidly obese.
Mm-hmm. Mm-hmm.
So...
Yeah, I think the last point is that obviously this is a rare disease, but the identification of these patients is absolutely right in front of you in terms of the-
Yes
... people who have undertaken the procedures versus having to put all the metrics in place and in terms of identifying-
Right.
A simple glucose level will tell you.
Exactly, and again, in our discussions with endocrinologists, you know, many of them have even set up multidisciplinary clinics for people with PBH. They'll have a dietician, a nurse, social support. So, this is a well-known issue in endocrinology, and again, hopefully, being able to provide a tool to really help people get their lives back is really exciting.
Great. Any questions on avexitide? No? Okay, well, I think, then, we'll move on to AMX0035 , and you've got two indications ongoing. Perhaps you'd like to describe Wolfram's disease, and then we can move on to PSP.
I would. Thank you, Jessica. So the Wolfram syndrome, so this is a program we've been working on for over seven years now. So Wolfram syndrome is a monogenic disease caused by mutations in WFS1. WFS1 is an ER transmembrane protein that helps—that's very close to what's called the mitochondrial-associated ER membrane. And so deficits in this cause both ER stress and mitochondrial dysfunction. And what we see is that in cell types that have high expression of WFS1, and/or, you know, are only so resistant to this form of cellular stress, you see cell dysfunction and cell death. And so it's the same pathophysiology from cell type to cell type. It first presents in the beta cells of the pancreas.
And so, it's the disease first presents as what looks like early-onset diabetes. So, kids aged six, seven, eight, nine, have what looks like early-onset diabetes. What then I think makes it clear that it's not just early-onset diabetes is, kids get progressive vision loss, and then progressive hearing loss, ataxia, and early mortality. It's a really tough condition. And again, it's the same pathophysiology, this ER stress and mitochondrial dysfunction from cell type to cell type to cell type.
Mm-hmm.
There are no approved treatments currently for Wolfram syndrome. We estimate there's about three thousand people in the United States who have this. It is indeed a global disease. There are people who have WFS1 mutations globally, and as you might expect, with a small molecule or combination of small molecules, one that targets ER stress and one that targets mitochondrial dysfunction, it's almost tailor-made for Wolfram syndrome. So we had done years of preclinical experiments with one of the world experts, Dr. Fumihiko Urano, at WashU, looking first in cellular cultures, in beta cells, in iPSC neurons derived from people with Wolfram syndrome, and showed quite encouraging results. Then we had an in vivo model of Wolfram syndrome, and now, just recently, we announced our interim clinical-
Mm-hmm
... Results in Wolfram syndrome, which were very encouraging, and we can talk a bit more about that. But seeing increases in C-peptide, which is very different than what one would expect. So our Wolfram program, we're quite excited about, and as we said as well, in October, we'll have further data from that program.
Right. Well, maybe, I don't know, Camille-
Sure
... if you want to provide some of the details from the interim analysis.
Certainly, yes.
What the expectations for the data readout were.
Of course, Jessica, certainly. So what we did an interim analysis earlier this year, as mentioned, where we looked at the impact of AMX0035 on the beta cell in particular, namely. And our a priori hypothesis was that the beta cell, we would slow the deterioration and loss of beta cell function, loss of beta cells. And we measured that by using a mixed meal tolerance test to stimulate the pancreas to secrete glucose.
Mm-hmm
... and insulin to help with the diabetes. And the insulin, a measure of insulin, which is independent of exogenous insulin, is C-peptide. That's also produced. It's one of the byproducts of insulin secretion. So we measured C-peptide response in a mixed meal tolerance test. Expecting from baseline, maybe we'd see a slower decline or maybe, you know, a decline in the C-peptide levels. What we actually saw, both at 12 and 24 weeks, was an improvement in the C-peptide response... so that was very exciting, and it's further supported by other measures of glycemic control: hemoglobin A1c, time in range, acceptable glucose range, and other measures as well. So that was very encouraging for us. The other measure we focused on during our interim was the visual acuity.
As Justin mentioned, many of these individuals lose their sight because of optic atrophy. Again, the neurons are dying, and individuals lose their sight. And what we saw was stabilization or maybe even slight improvement in the visual acuity of these individuals, again, in a disease that's otherwise progressive. So we're very encouraged by those results. And in October, we'll be sharing all 12 individuals from the study through 24 weeks, and a subset through 36 and 48 weeks. We'll be looking again at the glycemic control measures, C-peptide response to a mixed meal tolerance test, as well as other measures such as hemoglobin A1c and the visual acuity.
Yeah, and that data will be at a medical conference, the International Society for Pediatric and Adolescent Diabetes.
That's a long one, isn't it?
Yeah.
It's a bit of a mouthful.
Yeah.
But that's been accepted for an oral presentation.
Oh, fantastic.
-which we're very proud about.
Yeah. Excellent. Excellent.
Yeah.
With that data in hand, what would you anticipate the next steps for the program?
The next steps will be to, you know, we already are engaging with a number of stakeholders, including the FDA, to work on a design and finalize a design for a phase III study, which we believe at this point would be the definitive study.
Mm-hmm.
-to, going forward, since this is an orphan drug. It has orphan drug designation. And as Justin said, there's nothing for these individuals, and no one's really studied it either. So this is we're, you know, sort of, you know, at the vanguard of trying to solve this problem.
Right. Fantastic. Any questions on Wolfram? Okay. So on PSP, you expect to read out some interim data in middle of twenty twenty-five, and, as I understand, have a go/no-go decision with respect to that program. So I think it'd be helpful to discuss the parameters on that decision.
Yeah, certainly. Yeah, happy to start. So, first, what drove us into PSP. So, we ran about a hundred-participant Alzheimer's study. We published the data, just about a month ago.
Mm.
We looked at a number of CSF biomarkers in the Alzheimer's study, and what really jumped off the page were the reductions in tau and phospho-tau 181. Very, very highly significant reductions. We were talking with people in the neurodegenerative disease world, and they all said, "PSP." PSP is really considered the purest tauopathy. The genetic association with PSP, tau and PSP is like p to the negative hundred. I mean, it's very clearly a tau-driven neurodegenerative disease. That led us into a trial for PSP. For those who don't know, PSP is another really devastating neurodegenerative disease. People think that it's Parkinson's when it presents, but it's really clearly not Parkinson's.
It eventually leads to people being locked in, and then usually dying within about seven to nine years, and there's nothing approved for PSP. In fact, one of the ways they know it's PSP is 'cause they give dopamine therapy.
Mm-hmm.
and it doesn't work. So, and it's another very significant unmet need. The estimates currently are there are about 20,000 people in the U.S. who have PSP. It's very underdiagnosed.
Mm-hmm.
There's been recent autopsy studies that find many people who were diagnosed with Parkinson's actually have PSP, so we think twenty thousand is really a low estimate. So we're very excited about running the study. In the interim analysis at mid-next year, we're gonna do a full efficacy analysis. So we're gonna look at biomarkers like tau. There's a particular pattern of brain degeneration you can measure by MRI, so we'll be looking at that. As well as there's quite a reliable rating scale, the PSP Rating Scale. So we'll be looking at you know subset of the you know participants from the study, you know, who make it to the study endpoint in that interim analysis.
And based off of that, we'll decide to expand or not into a larger phase III. But it's a program we're really excited about. AMX35 has already shown reduction in the key biomarker. In many ways, it's the first intracellular agent that can lower tau being tested in this disease. Now the question is, with tau lowering, do you see the associated changes in clinical outcomes as well?
Mm-hmm. Great. And would you expect those biomarkers to be part of the phase III endpoints?
Certainly. I think that's very important, and I think in a disease like PSP, which is maybe a little more homogeneous than other neurodegenerative diseases, where we have a clear biomarker associated with the disease, we have a pretty reliable rating scale, we have a pretty clear idea of how the brain degeneration pattern occurs. I think all of those endpoints are important in assessing efficacy.
Great. And maybe just going back, you'd mentioned there were a number of tauopathies. I mean, would there, depending on the clinical trial results, could this be broader than PSP?
I think there'd be great excitement. You know, I think our goal right now is to focus, you know, specifically on PSP. But I think there's a huge unmet need in tauopathies generally. So I would imagine, with positive results, that people would be excited about the potential in other tauopathies as well.
Fantastic. Great! And I guess the last candidate is AMX0114 . Perhaps we can touch on that.
Yeah, can we?
Yeah, sure. This is a program. Again, we have been very committed to the ALS community and trying to solve for this devastating, you know, fatal disease for a number of years, as you well know, and we continue our crusade to find a solution, and AMX0114 is a 5-10-5 ASO, antisense oligonucleotide, that targets calpain-2, which is a protease that cleaves neurofilament and is involved in axonal degeneration, so of course, there are data in ALS with regard to the degeneration of the neurons due to axonal degeneration. Neurofilament byproducts are seen in ALS as well, elevated significantly in ALS, so we have biomarkers already for, in this instance, and we'll be studying the ASO in ALS.
Intrathecal ASO. It targets very specifically calpain-2, and only calpain-2 based on the sequence, which is very important since there are about 12 other calpains in our body. We'll give it intrathecally, so we'll get it to the neurons where it's really needed. We'll be conducting a multiple ascending dose study in individuals with ALS, with our goal of beginning the phase one multiple ascending dose study end of the year, with data throughout 2025, cohort by cohort.
Fantastic. Well, I can't imagine we're gonna be sitting here next year, and there's gonna be an incredible number of milestones that have been achieved. Maybe, Justin, you'd like to just recap what we can envision-
Yeah.
That's gonna happen over the next twelve months.
Yeah. Thank you, Jessica. Yeah, we're incredibly excited. I mean, I think all of us at Amylyx are very dedicated to try to help people with unmet needs, and we now have that opportunity across all four of our programs. So AMX0035 and Wolfram syndrome will get data in October, presented at ISPAD. Our PSP program will have interim results on that mid-next year. Again, that'll be a full look at efficacy in totality. Our AMX0114 antisense oligonucleotide against calpain-2 that will be going into a clinic, and we'll have our cohort-level data next year. And then our recent acquisition of avexitide will be going into the pivotal study in the first quarter with a readout soon in 2026.
We're really excited about our programs and the opportunity to help many people in need.
Great. Well, thank you very much.
Thank you.
Thank you. Thank you, Jessica. Thank you.