Amylyx Pharmaceuticals, Inc. Price & Performance (AMLX)

Actual events and results could differ materially from those expressed or implied by any forward looking statements. You are cautioned not to place any undue reliance on these forward looking statements and AMOLED disclaims any obligation to update such statements unless required by law. Now, I will turn the call over to Justin.

Good morning, and thank you for joining us. As we look to 2025 and 2026, we're entering a pivotal stage for Amylyx, with key milestones across three assets in four ongoing clinical trials. All targeting orphan diseases with few or no treatment options. We are excited that started the pivotal study of Vivek and anticipate top line results in the first half of next year We also recently completed a financing raising approximately $65,500,000 to begin commercial preparations for vaxitide and to extend our cash runway through the end of twenty twenty six. Over the next twelve to fifteen months, we are focused on execution as we look forward to three key data readouts. Our lead asset of exotyme is an investigational GLP-one receptor antagonist with FDA breakthrough therapy designation in post bariatric hypoglycemia or PBH as well as orphan drug designation. PBH is a debilitating condition that leads to persistent and often progressive hypoglycemia, There are no treatments approved for the approximately one hundred and sixty thousand people living with PBH in The U. S. Today. Avexitide has already been studied in five clinical trials of PBH that showed consistent dose dependent statistically significant reductions in hypoglycemia. We started recruiting lucidity our pivotal sixteen week Phase three clinical trial in mid February and expect that the first study participant will be dosed in March or April.

We expect to complete recruitment of the approximately 75 participants by the end of this year and anticipate top line data in the first half of twenty twenty six. Next in our pipeline is AMX-thirty five, a combination small molecule that is designed to target endoplasmic reticulum or ER stress, and mitochondrial dysfunction. AMX-thirty five is currently being evaluated in Wolfram syndrome and progressive supranuclear palsy or PSP two diseases characterized by ER stress and mitochondrial dysfunction. Wolfram syndrome is a rare, fatal, monogenic, progressive diabetic and neurodegenerative disease affecting an estimated three thousand people in The U. S. There are no approved treatments. Like many childhood onset monogenic diseases, the pathophysiology of Wolfram syndrome is well characterized. Our program is focused on people who carry mutations in the WFS gene. Which encodes a protein called Wolfframan. That spans the membrane of the endoplasmic reticulum. These mutations in wolframin directly cause ER stress and mitochondrial dysfunction. Last year, we reported our first data in people with Wolfram syndrome, In our 12 person Phase two open label HELIO study, participants showed improvement or stabilization across all measured outcomes We are continuing to follow participants in the ongoing HELIOS trial. And expect to share the week forty eight data in the coming months.

These data along with regulatory interactions will inform the design of a Phase three trial. We are also anticipating an interim readout of our Phase 2b3 ORION trial evaluating AMX-thirty five and PSP in the third quarter twenty twenty five. PSP is a rare progressive fatal neurodegenerative disease that affects an estimated twenty three thousand people in The U. S. At any one time. And has no currently approved treatments. PSP is the most well characterized pure tauopathy because all people with PSP have tau protein build up in the brain genetics and model systems show that this abnormal tau buildup causes a characteristic brain degeneration and presentation observed in the disease AMX-thirty five previously demonstrated that it reduced tau measured in the cerebral spinal fluid of people with Alzheimer's disease we believe AMX-thirty five is the first brain and cell penetrant agent that has previously shown significant how protein reduction in CSF to be tested in PSP. The Phase 2b portion of our Phase 2b3 ORION trial evaluating AMX-thirty five and PSP was fully enrolled in January with a total of 139 participants randomized We expect safety and efficacy data from an unblinded interim analysis in the third quarter of this year.

These data will inform our decision whether or not to move into Phase three portion of the trial. Powering analyses published in the 80% power to detect a 30% slowing the rate of decline of PSPRS with the sample size. Our fourth clinical program is evaluating AMX-one hundred and fourteen for the treatment of ALS. AMX-one hundred and fourteen is an antisense oligonucleotide that knocks [indiscernible] one of the key proteases driving axonal degeneration. Last month, the Phase one multiple ascending dose LUMINA trial of AMS recruiting in Canada. We are working diligently to open additional sites in Canada and The U. S. We started recruiting Lumina and expect the first participant dosed in March or April. We look forward to early cohort data from our Phase one LUMINA trial in expected later this year We're also actively working to build our pipeline in PBH and other rare diseases that may benefit from GLP-one antagonism. Of particular note, at the end of last year, we announced a collaboration to develop a novel long acting GLP-one receptor antagonist with GUBA, GUBRA is an industry leader in peptide based drug discovery. We will continue to focus on clinical execution as we look forward to milestones in each of our programs over the next twelve to fifteen months.

I will now pass to Camille to speak further on our Phase III lucidity clinical trial of vivaxitide in PVH.

Thanks, Justin. We are very excited about the potential of Avexitide. Become the first approved treatment for people living with PBH. [indiscernible] This debilitating condition is believed to result from an excessive GLP-one response following bariatric surgery leading to persistent recurrent and debilitating hypoglycemic events that take a profound toll on a person's quality of life. There are no approved treatments for PBH. Despite dietary modifications and rescue measures, such as Gookagam, people with PBH still experience persistent symptoms with no sustainable management options. And a potential first in class GLP-one receptor antagonist of exotide is designed to bind to the GLP-one receptor on pancreatic islet beta cells and inhibit the effects of excessive GLP-one and PBH, mitigating hypoglycemia by decreasing insulin secretion and stabilizing blood glucose levels. In December 2024, we presented evaluating of exetide in participants with PBH following Roux on Y gastric bypass surgery. In February of this year, we started recruiting lucidity and expect to dose the first participant in March or April. [indiscernible] The Phase three study is designed to have similar inclusion and exclusion criteria to the previous successful Phase two prevent trial that led to breakthrough therapy status and the subsequent Phase IIb trial of avexotide in PBH.

Lucidity will evaluate the FDA agreed upon primary outcome of a reduction in the composite of level two and level three hypoglycemic events. We believe there are many contributing factors for overall optimism for the study. We are encouraged by the engagement of the sites as they are activated. As well as the responsiveness of potential participants. The study team is fully engaged with carefully chosen sites as they provide comprehensive training materials and facilitate site activation. Furthermore, the study has a number of blinded touch points and monitoring elements that will serve to support the study site staff and by extension the participants throughout the study.

The strength of the substantial clinical data generated to date for VENEXA TIDE underpins our confidence in the potential of this program.

Across five clinical trials of avexitide in people with PBH, there have been consistent dose dependent effects that we believe support its potential to become the first approved treatment In multiple early stage trials in PBH and in healthy volunteers, evesitide had a clear pharmacodynamic effect Avexitide showed a rapid statistically significant decrease in post meal insulin levels in and stabilization in plasma glucose nadir Data from two Phase II trials of vivexitide demonstrated statistically significant and clinically meaningful reductions in hypoglycemic events and improvements in glucose control and PBH following Roux and Y gastric bypass surgery. In the Phase 2b trial, participants received ninety milligrams once daily of obexetide, the dose we are evaluating in our pivotal Phase three lucidity trial. Most notably, treatment with ninety milligrams of Avexitide led to a statistically significant reduction in hypoglycemic events. Specifically, a fifty three percent reduction in level two events with the P value of 0.004 a 66% reduction in level three events with a P value of 0.0003. [indiscernible] ninety milligrams once daily of evexotide also has demonstrated [indiscernible] exposure in the therapeutic range through twenty four hours supporting daily dosing. This property translated to a similar meaningful improvements in nadir glucose levels as measured by CGM both during the day and overnight.

Bevexitide was generally well tolerated. With a favorable safety profile replicated across the clinical trial. In summary, we are executing this important Phase three trial supported by compelling and consistent evexotide data and a dedicated study team. I will now turn over the call to Jim. Jim? Thanks, Camille. We ended 2024 on a solid cash position. With $176,500,000 which does not include the approximately $65,500,000 in net proceeds from our public offering, which closed on 01/13/2025. With these resources, we expect our cash runway to take through 2026. Now turning to the financial results for the quarter. Total operating expenses for Q4 were $39,900,000 down 62% from the same period in 2023. Research and development expenses were $22,900,000 compared to $44,900,000 in Q4 twenty twenty three We primarily due to a decrease in spending on AMX-thirty five for the treatment of ALS payroll and personnel related costs, and a decrease in preclinical development activities. Selling, general and administrative expenses were $17,100,000 compared to $52,200,000 in Q4 twenty twenty three. Primarily due to a decrease in payroll and personnel related costs, and a decrease in consulting and professional services. During the quarter, our ongoing operating In addition, we used roughly $31,000,000 in cash for previously recognized items, related to our voluntary discontinuation of Relibrio Albriosa in April of last year.

These included payments for product returns and rebates, and the final settlements of previous purchase commitments for MX35 for commercial production. Going forward, we have approximately $7,800,000 of these obligations remaining. Which we expect will be paid through 2025. Looking ahead, we believe we have the necessary cash to support our progress and to deliver on our planned clinical milestones through the end of twenty twenty six. These milestones are data from the Phase three lucidity trial of obexetide in PD data at week 48, from the ongoing HELIOS trial in Wolfram syndrome the unblinded interim analysis of the Phase 2b portion of our ORION trial [indiscernible] and data from our Phase one LUMINA trial of AMX114 in ALS. Along with commercial preparations, for the potential first to market launch of evexitide in PBH. With that, I'll turn the call over to Josh to provide some closing remarks. Thank you, Jim. We are entering this year with strong momentum.

We are focused on executing our clinical trials and making meaningful progress on preparing for a potential commercial launch of a GLP-one receptor antagonist. At the start of the year, we appointed Dan Monahan, Chief Commercial Officer. Dan is leading our commercialization strategy across our portfolio beginning with evexitide. He brings more than two decades of commercial leadership experience launching industry leading medicines at Otsuka, Novartis and Sanofi. With a proven commercial and medical team in place, we believe we are well positioned for a potential first of evexitide in PBH. We estimate based on our projections from published literature and claims based work that there are about 160,000 people in The United States are living with PBH today. Who have persistent symptoms despite dietary modifications and who face a significant unmet need There is a new slide with these details in our updated corporate deck. [indiscernible] The condition doesn't happen to most of the millions of people who undergo bariatric surgery. And PBH does not present immediately. On average, symptoms appear approximately one to three years following bariatric surgery. Once people have PBH, the condition is chronic debilitating and often progressive. It can mean loss of work, inability to drive, and a state of disability.

Bariatric surgery remains standard of care.

For addressing obesity. Particularly for people who require significant and sustained weight loss meaning the unmet need in PBH is only expected to continue to grow. We are preparing diligently ahead of the Abexitide Phase three top line data expected in the first half of next year and if approved, we anticipate commercial launch in twenty twenty seven. In addition to avexitide and PBH, we have exciting milestones ahead this year. That have the potential to make a meaningful positive impact on the other communities that we aim to serve. For 35 and PSP, we expect top line data from an unblinded interim analysis of the Phase 2b portion of the ORION trial in the third quarter of this year. For AMX-thirty five and Wolfram syndrome, we are continuing to follow participants in the ongoing Phase two HELIOS trial and expect to share week 48 data in the coming months. These data along with regulatory interactions will inform the design of a Phase three trial. And we expect early cohort data from our Phase one LUMINA ALS trial in 2025. We appreciate your continued support and look forward to keeping you updated on our progress toward developing novel therapies for people living with serious and fatal neurodegenerative diseases and endocrine conditions.

Now, I would like to open the call up for questions.

Question and answer session. At this time, we will pause momentarily to assemble our roster. Your first question is from Michael DiPietro from Evercore ISI. Your line is now open. Hi, guys. Thanks so much for taking my question.

And congrats on the progress. Two from me. One on the PBH Phase three, why limit the entry criteria to just Roux and wide gastric bypass procedures and not include sleeve gastrectomy, especially when considering the greater prevalence of sleeve procedures. And my follow-up is on the PSP ORION study. Could you remind us how efficacy will be interpreted [indiscernible] in this study across regions given the use of the 10 item PSP rating scale in The U. S. As a primary and the 28 item PSP rating scales in ex U. S. Jurisdictions? Thank you.

Yes. Hi, Mike. This is Camille. Thank you for the question. With regard to Rulan Wai in our lucidity trial, we have the most experience with the vectitide and people who have experienced the underlying biology and then develop PDA. Having said that, we recognize that the pathophysiology is consistent across bariatric surgery. To minimize heterogeneity though, we are limiting the [indiscernible] And expect later to for elexigotide to be available for people with PDH. Generally.

Yes. And just going to the market dynamics as well. So I think first just underscoring Camille's point that we think that pathophysiology is the same is really for trial criteria. So we'll have those discussions when appropriate with FDA. But Roux and Y gastric bypass there have been about six hundred thousand people who have gotten Rouin' Y gastric bypass over the past ten years. And there are roughly sixty thousand people each year who get a ruined wide gastric bypass. So with eight percent we estimate about of people who get a bariatric procedure who get who will develop PBH in the years following surgery. That's still a very substantial market. But to say as well, we think the pathophysiology is the same. So our ultimate intention is we think that this should be a treatment that would be used for PBH period.

Yes. And on your question on PSP, about the 10 item versus the 28 item, So different regulators in different regions are interested in different ways of analyzing the PSP rating scale as you mentioned. Our experience however is that these are pretty consistent. It's not a big divergence to kind of look at the PSP-ten item versus the PSP-twenty eight item. So frankly in the study, we'll be looking at both. But again, we expect the results from both to be very similar.

Got it. Thank you.

Thank you. Your next question is from Tim Anderson from Bank of America. Your line is now open. Hi, good morning. This is Susan on for Tim Anderson. Two questions from us. The first one, what is the target profile that you guys are looking to achieve with the long acting GLP-one? And if you can, how does this profile compare to other long GLP-one? Like Amgen's Meritide and Metcera's Met Yes. So maybe I'll kick those in reverse actually. So this is the GLP-one antagonist. Those are GLP-one agonist. So today, abexitide is the only GLP-one antagonist that has consistently shown reductions in insulin raising the glucose nadir reductions in hypoglycemia in people with PVH, And we think that a GLP-one antagonist may have not just application in people with PBH, but potentially other diseases as well. That are either characterized or accelerated by hyperinsulinemic hypoglycemia. Because we're quite excited about the mechanism, we think it makes sense to invest for the future. So that's why we started the research partnership with Gubra to develop a potential long acting GLP-one antagonist. But we also think of exotide has great potential So we really see this as investing for the future.

Okay. And just one more. So on your PBH market sizing, how are you guys forecasting future patient numbers? I guess I'm just trying to understand I think the market will shrink, right, over time given current use of GLP-one. Which would mean that fewer patients probably get bariatric surgery.

Of course, bariatric surgery is a [indiscernible] and done type of procedure.

Yes.

So maybe a couple of things. The first our estimation actually is that the market will continue to grow. Maybe breaking that down So first, bariatric surgery started becoming common in The United States in the early 2000s. And it's typically done in some to to folks who are generally in their early 40s.

So the population who have bariatric surgery in The U. S. Today are generally in their 40s or 50s. PBH is chronic. Once people have PBH, they generally have it for the rest of their life. So all of those folks who have had bariatric surgery and now have PBH will have it for multiple upcoming decades. Then talking about kind of the ongoing bariatric surgeries, one in talking to physicians and bariatric surgeons, we do hear that there continues to be significant demand for bariatric surgeries. A lot of people describe that there is a differentiation that the bariatric surgery is often used for those who are looking for very significant deep weight loss in some cases looking for over 100 pounds of weight loss whereas they might use the GLP-one in cases that maybe are less significant in terms of total weight loss. So one, we hear that this continues to be quite in demand. Which will continue to grow that pool that already exists today and will have it for the rest of their lives.

Yes. And just underscoring that last point, So we estimate there are one hundred and sixty thousand people with postvarious hypoglycemia today PBH does not go away. For example, we're working with someone who's had PBH for eighteen years So PBH is persistent, it doesn't go away. So the market will only continue to grow not shrink.

Thank you.

Thank you. Your next question is from Joe Beatty from Baird. Your line is now open.

Thanks for taking my questions. For the Wolfram syndrome trial, could you discuss what you're looking for in the week forty eight data that will help inform regulatory interactions And then for avaxitide, can you discuss the potential to develop that agent for other indications beyond PBH? Thank you.

Thank you, Joel. This is Camille. Yes, as we described in October of last year, the week 24 data and some individuals out to week 36 and week 48, we saw improvements in C peptide response to a mixed meal which is indicative of improved beta cell function. Which is uncharacteristic for a disease that is neurodegenerative and beta cell degenerative. All other hypoglycemic control measures also moved in the same direction. And we are anticipating and looking forward to the possibility that at week forty eight, we'll see continued sustained improvements in all those measures In addition to which, the visual acuity an indication of retinal ganglia cell health We expect that and look forward to the possibility of seeing stabilization or improvement in visual acuity as well. Recall that these individuals are adults having lived with this genetic disorder all their lives. So, we're looking forward to that possibility. And that should also provide the FDA with continued confidence in the potential of AMX-thirty five. People living with Wolfram. Who have nothing at this time to treat their condition.

And then speaking to vivexitide and other indications, So first, I'll say PBH is already a large and exciting area and a significant unmet need. So certainly, our first focus is in PBH. We do believe though that there are multiple other indications where the mechanism of a GLP-one antagonist could be important, including diseases of hyperinsulinemic and potentially diseases where other elements of the GLP-one pathway may be helpful. But again, our focus for right now is on PBH. Thank you.

Your next question is from Mark Goodman from Leerink. Your line is now open.

Hi, thanks. This is Madhu on the line for Mark. We've heard from some physicians that there are some patients who exhibit PBH without the postpranal hyperinsulinism. So we're curious if you're screening for patients who specifically show a spike in insulin levels post meal. Has your research shown like a specific proportion of patients who show this in PBH? And then also, how should we be thinking of pricing for exotide? We know it's early, but just wanted to get like a ballpark idea.

Sure. So maybe starting with the postprandial hyperinsulinism, So one, I think we have generally seen the hyperinsulinism going through at least our review of the literature see that across quite a number of studies and quite a number of patients. But I think also important to note our inclusion exclusion criteria are very similar, nearly identical what was used in Phase II and Phase IIb. Where we saw large effect size and high statistical significance. So we think we're well positioned for that as we go into the Phase three study. And then on the pricing side, of course, too early to give anything definitive on pricing quite yet before we have our data. But I encourage you to look at other orphan analogs. This is an orphan drug. And additionally, of course, the efficacy will drive things. And I do think it is quite an impact in people's lives to bring their glucose control to a much more normal measure These patients do describe being in kind of an ongoing state of disability and being able to bring that back more near towards normal would be a huge change for these individuals.

Yes. And just going back to the first question as well. So just to talk through pharmacology a little bit. So hypoglycemia can happen certainly as a result after a meal postprandial But it can happen at any time. It can happen for a variety of different triggers. So that's very true. We think that's why it's important that you want to have a molecule that can protect against these hypoglycemic events throughout the day.

And so with ninety mgs ninety mg once daily dosing, we are in the therapeutic range for twenty four hours So preventing those hypoglycemic events for the full day with daily dosing. With PBH though, what we know from a pharmacology perspective is the reason for these very precipitous blood glucose drops is because there's a very strong insulin response that seems to be due to a very strong endogenous GLP-one response. So GLP-one levels can be up to 10 times normal in people with PBH. That causes very significant insulin secretion which then lowers glucose very precipitously. And that's why of course the GLP-one antagonist makes a lot of sense for this indication.

Thanks. Thank you. There are no further questions at this time. I will now turn the call back to Mr. Xue.

Thank you, operator. And thank you all for your time.

We look forward to seeing many of you in the coming weeks and months If you have any follow-up questions, please reach out to Lindsay. I hope you have a great rest of your day. Thank you. Ladies and gentlemen, the conference has now ended. Thank you all for joining. You may all disconnect your lines.