Amylyx Pharmaceuticals, Inc.

Good morning. My name is Alan, and I will be your conference operator today. At this time, I would like to welcome everyone to the Amelinks Pharmaceuticals Third Quarter 2024 Earnings Conference Call. All participants will be in listen-only mode. After today's presentation, there will be an opportunity to ask questions. To ask a question, please press star 1 in your telephone keypad. To withdraw your question, please press star two. Please limit your questions to one with one follow-up. If you have additional questions, you may rejoin the queue. Please be advised that this call is being recorded at the company's request. I would now like to turn the call over to Lindsay Allen, Head, Investor Relations and Communications. Please proceed.

Good morning, and thank you all for joining us today to discuss our third quarter 2024 financial results. With me on the call today are Josh Cohen and Justin Klee, our co-CEOs, Dr. Camille Bedrosian, our chief medical officer, and Jim Fradies, our chief financial officer. Before we begin, I would like to remind everyone that any statements we make or information presented on this call that are not historical facts are forward-looking statements. that are based on our current beliefs, plans, and expectations, and are made pursuant to the safe harbor provisions of the Private Securities Litigation Reform Act of 1995. These statements include, but are not limited to, our expectations with respect to Avexotide, AMX 35, and AMX 114, statements regarding regulatory and , the impact thereof, and the expected timing thereof, and statements regarding our cash runway. 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 AMELEX 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 all for joining us. The last few months have been productive in advancing our late-stage pipeline in the effort to fulfill our mission to bring new potential treatments to communities with high unmet needs in neurodegenerative diseases and endocrine conditions. We continue to progress our lead asset of Exatide, a GLP-1 receptor antagonist with both FDA breakthrough therapy and orphan drug designations in diseases with no approved treatment options. We remain on track to initiate our Phase III trial in post-bariatric hypoglycemia, or PBH, in the first quarter of 2025. which Camille will discuss a little later. We have also significantly increased our interactions with the endocrine and PBH communities and are excited for the potential of this therapy. In mid-October, we reported positive top-line data from our open-label Phase II Helios trial of AMX35 in 12 participants living with Wolfram syndrome. People treated with AMX35 showed improvement in pancreatic function, as measured by the primary endpoint of C-peptide response at 24 weeks. We also saw similar overall improvements or stabilization across all secondary endpoints. Additionally, the longer-term data being collected demonstrated sustained improvement over time. With these positive data in hand, we plan to meet with the FDA and other stakeholders to inform a Phase III program. Our Orion trial of AMX35 in PSP is recruiting well, and we continue to expect data from an interim analysis mid next year. And we are looking forward to initiating our phase one clinical trial of AMX114, our antisense oligonucleotide targeting CalPain2 in people with ALS. We are in a strong financial position and continue to expect our cash runway to take us into 2026. Our pipeline strategy is focused on addressing orphan conditions and well-defined mechanistic rationales, clear and measurable biomarkers, and is built on rigorous preclinical data. Our progress this quarter, including the positive data we reported in Wolfram Syndrome, supports this strategy. Our team remains focused on progressing our pipeline and delivering on our key milestones ahead. I will now turn the call over to Camille.

Thanks, Justin. I will briefly review each of our four programs, Avexatide and hyperinsulinemic hypoglycemia, including post-bariatric hypoglycemia, or PBH, AMX35 in Wolfram syndrome and in progressive supranuclear palsy, or PSP, and AMX114, our CALPANE2 ASO in ALS. First, I'll provide an update on our lead program, Avexatide, for the treatment of PBH. We are actively planning and are on track to initiate a pivotal phase three program in PBH in Q1 of next year. We expect to share the trial design once finalized and prior to the initiation of the trial. We expect top line data from the program in 2026. Let me touch a bit further on PBH and the mechanism of action. PBH is a debilitating condition that affects an estimated 8% or approximately 160,000 of the more than 2 million people on bariatric surgery in the last decade. TBH is thought to be caused by an excessive GLP-1 response leading to persistent and, in some cases, progressive hypoglycemia. Avexetide is designed to bind to the GLP-1 receptor on pancreatic islet beta cells and block the effect of GLP-1 to mitigate hypoglycemia by decreasing insulin secretion and stabilizing glucose levels. Avexatide has been studied in five clinical trials in PBH. Data from these trials demonstrated highly significant reductions in hypoglycemia events. Most notably, the 90 milligram dose, which we intend to study in phase three, showed a 66% reduction in level three hypoglycemia events in a phase 2B trial with a p-value of 0.0003. and a 53% reduction in level 2 hypoglycemia events with p-value of 0.004. For context, level 2 hypoglycemia events occur when blood glucose levels drop below 54 milligrams per deciliter. At these levels, symptoms can include tremors, dizziness, and risk of losing consciousness. Level 3 events are defined clinically as requiring third-party rescue. The primary efficacy outcome of our Phase III program will be the reduction in the composite of Level 2 and Level 3 hypoglycemia events. FDA has agreed on this primary efficacy outcome. We look forward to initiating the Phase III program expected in Q1 of next year and top-line data anticipated in 2026. Turning now to the Wolfram Syndrome Program. As Justin mentioned, we were pleased to present positive top-line data for all 12 participants in the phase 2 Helios trial at week 24, including longer-term data available for participants who reach their week 36 or week 48 visits. These results are encouraging because they suggest treatment with AMX 35 may result in meaningful improvements across multiple measures of disease progression in an otherwise progressive fatal disease with no approved treatment option. The 24-week data showed improvement or stabilization in all disease measures in the study, including pancreatic function as measured by C-peptide primary endpoint, as well as additional measures of glycemic control, visual acuity, and overall symptom burden from the patient and clinician perspective. In addition, longer-term data for participants who completed week 36 and week 48 assessments showed sustained improvement over time. With these 24-week and longer-term data in hand, we plan to meet with the FDA and other stakeholders to inform the phase three program and expect to provide an update in 2025. Now, turning to the Orion PSP program. Enrollment in the study is going well. As we have described previously and as planned, we are on track to conduct an interim analysis of Orion and share data in mid-2025. This will be an unblinded analysis of top line data for the first part of our phase 2B3 study with approximately 100 people living with PSP through week 24. We also plan to analyze the available data on participants who have proceeded beyond 24 weeks. This analysis will inform a go, no-go decision on this program. In ALS, we are pleased to share that we received clearance from Health Canada for our clinical trial application for AMX114 in people living with ALS. We plan to begin the phase one multiple ascending dose placebo-controlled trial called Lumina in Canada in the coming months. We plan to evaluate safety and the biological activity in approximately 48 adults living with ALS and evaluate four dose levels starting with 12.5 milligrams. We were pleased to present our plans for the study at the Northeast ALS Consortium Annual Meeting last month. We also submitted an investigational new drug application to the FDA for AMX-114. The FDA restricted dosing to an amount that is lower than our proposed starting dose of 12.5 milligrams and requested additional information, which resulted in a clinical hold in the U.S. Toxicology data from studies showed a greater than 10x safety margin at the starting dose of 12.5 milligrams based on the no observed adverse effect level or NOAEL observed by independent toxicology firms. We are working to address FDA comments. We believe the trial can be completed outside of the US if needed. We continue to expect early cohort data from Lumina in 2025. We are encouraged by our progress this quarter and remain on track to achieve our key expected milestones for our pipeline. I will now turn over the call to Jim. Jim? Thanks, Camille.

Financially, Q3 turned out as we expected. After the closing hour of Exatide acquisition in July, we ended Q3 with $234.4 million in cash and investments. Importantly, we continue to expect our cash runway to take us into 2026, as we work to manage the company through expected meaningful clinical data readouts, namely the interim readout from our PSP program, early cohort data from our AMX 114 program, and the readout of top-line data from the Avexotide Phase III program. Now, turning to our financial results. Net product revenues were $400,000 for the third quarter, and cost of sales were $800,000. both related to true-ups and trailing rebates from our now-discontinued commercial sales of Relivrio and Albreoza. Research and development expenses were $21.2 million for the quarter, compared to $30 million for the same period in 2023. The decrease was primarily due to a decline in clinical expense following the top-line data from the Phoenix trial and a decrease in payroll and personnel-related costs as a result of our restructuring. Selling general and administrative expenses were $17.8 million for Q3, compared to $48.7 million for the same period in 2023. The decrease was primarily due to a decline in payroll and personnel-related costs and a decrease in consulting and professional services. Our restructuring plan is now complete, and we do not expect to record any material amount of restructuring expense going forward. We recorded $36.2 million of expense related to our acquisition of Avexatide during Q3, comprised of the $35.1 million purchase price and related transaction costs. Consistent with our prior expectations, as we move into 2025, we expect total combined spend on R&D and SG&A, excluding stock-based compensation, to be in the range of $30 to $40 million per quarter. Finally, in the third quarter, we recorded a net loss of $72.7 million, or $1.7 per share. Overall, we believe we're in a solid financial position and believe in our ability to deliver on the critical milestones ahead. I'll now turn the call over to Josh to provide some closing remarks.

Thank you, Jim. In closing, we are excited about our four pipeline programs, upcoming milestones, and path ahead. Our lead asset, Avexitide, has both FDA breakthrough therapy designation and orphan drug designation, and is on track to advance into Phase III development in PBH beginning in the first quarter of 2025. In Wolfram Syndrome, with our positive Phase II top-line Helios results in hand, we plan to engage with the FDA and other stakeholders as we look to inform our Phase III program with the expectation of providing an update in 2025. The Orion trial of AMX35 in PSP is recruiting well, and we continue to expect data from the interim analysis mid-next year. And we are working towards initiating our phase one clinical trial of AMX114 in ALS by the end of the year or early next year and sharing early cohort data study in 2025. We look forward to keeping you updated as we build upon our critical work in orphan neurodegenerative diseases and endocrine conditions with high unmet need.

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

Thank you. Ladies and gentlemen, we will now begin the question and answer session. To ask a question, please press star one on your telephone keypad. To withdraw your question, please press star two. Please limit your questions to one with one follow-up. If you have additional questions, you may rejoin the queue. At this time, we will pause momentarily to assemble our roster. Thank you.

Your first question comes from Michael DeFiore, sorry, Kareem Johnson of Goldman Sachs.

Your line is already open.

Thank you. This is Omari on for Corinne.

So I have a couple questions. How should we think about the market size for PBH patients that are insufficiently managed by existing therapy?

And then what are the gating factors initiating the phase three PBH study? Sure.

So in terms of the market, we estimate there are roughly 160,000 people living with PBH.

This comes from literature that suggests that between 20% and 40% of people who have a bariatric surgery will ultimately show in mixed meal tolerance testing or in continuous glucose monitoring abnormal glycemic control. Some of those folks are able to be managed by available therapy. So when you account for that, about 8% of people continue to have persistent PBH And 8% of roughly 2 million surgeries in the last decade gets you to an estimated 160,000 people living with PBH. In terms of the phase three and getting factors, I'll say we're on track, and I'll pass over to Camille to provide any more detail.

Sure. Hi. Thank you very much for the question. Yes, so we are actively working with clinical sites, and our clinical team is doing what's needed to initiate and stand up the trial for initiation first quarter of 2025. We're going, it's going very well. There's a lot of enthusiasm.

So we're looking forward. Thank you.

Your next question comes from Charlie Yang of Bank of America. Your line is already open.

Great. Thanks for taking the questions. I wanted to touch on PBH as well. You know, just given what we know about the Iger's kind of previous agreement with the FDA on this, you know, trial design, what are the other factors that kind of you are contemplating with, you know, in terms of design? And is there a potential to have readout earlier in 2026? Thank you.

Yep. Thank you very much for the question. So, just as a reminder, we don't With vexatide having breakthrough therapy and PBH, there have been a number of interactions with the FDA, and as we read the minutes, we believe agreement with the agency on a trial design. I'll summarize those as Iger put it, and we're just refining around the edges, and we'll provide the details prior to initiation. The study will use 90 milligrams per day as the dose with the primary endpoint of composite level 2 and level 3 hypoglycemia. And as a reminder, the phase 2 and 2B studies conducted already in PBH with Avexatide showed highly statistically significant and meaningful improvements and reductions in the hypoglycemia events, both level 2 and level 3. notably at the 90 milligram dose level. So we're quite pleased about that aspect. Furthermore, level 2 and level 3 hypoglycemia are the endpoints that the trials in diabetes used to evaluate hypoglycemia in that population, and that information is in the guidances for studying antidiabetic drugs. So 90 milligram dose composite endpoint level two and level three. Hypoglycemia is the primary endpoint. As Iger described it, they had proposed a 90 participant study for 12 weeks. Again, randomized placebo controlled parallel arm study. So, you know, and as I said, we'll be around, you know, that's a good benchmark. We'll be refining it a bit and proceed from there. You know, we will be beginning as soon as possible in Q1 of 2025 for the study and expect by the end of the year to have the concluded enrollment at any rate and then data in 2025. I'm sorry, 2026. Yeah, apologies. Yes, 2026. Thank you. You're welcome.

Your next question comes from Michael DeFiore of Evercore. Your line is already open.

Hey, guys. Thanks so much for taking my questions. Two for me. The first one is on Avexatide. Just kind of curious on how you think about the risk of hyperglycemia since GLP-1 antagonists don't address this happening. It could lead to lots of undesirable sequelae. So just kind of want to see how you're thinking about that. And then separately, with regard to AMX0014, any color on why the FDA deems a 12.5 milligram dose to be too high? Like assuming the trial just runs in Canada and safety seems fine, do you think the FDA will be amenable to allowing future trials be run in the U.S.? Just thinking on whether this asset could even be commercialized in the U.S., if the FDA still deems that starting dose too high. Thank you.

Sure, sure. So first, your question about Avexatide. As a reminder, Avexatide is a GLP-1 receptor antagonist, and it's blocking the ability of excess GLP-1 in the case of PBH to activate the receptor. It's not turning off or reversing the function of the receptor. So it really is returning the glycemic control insulin glucose access to homeostasis. So we don't anticipate hyperglycemia in that setting. Furthermore, we have not observed hyperglycemia either in the toxicology program that was conducted prior to starting the clinical work, nor in the clinical trials of PBA. So, you know, we do, you know, that is something we looked at. And given the mechanism of action and the pathophysiology of PBH, we do not see that as an issue.

And I would just add, too, in terms of side effects and profile generally, it's been quite well tolerated. The principal side effects are ones that you often see with injectable peptides, you know, injection site reactions, those sorts of things. But it's been quite well well-tolerated generally as well.

Yep. And then with regard to 114, I'll begin, and Josh may want to have additional comments. So the FDA, you know, we will have some interactions with the FDA to address their questions and understand more of their thinking, given that the independent toxicologists who reviewed the data believe that 12.5 milligrams and determined, in fact, that 12.5 milligrams is 10x below the NOAEL observed in the non-clinical toxicology program. So we're very confident in the overall safety profile of 114, and certainly Health Canada has given us the green light to proceed, which we are going to do with all speed. With regard to whether we can go in the U.S., Yes, we're confident that ultimately we will be able to.

Yeah, and I'll just add, you know, Mike, you've probably seen as well, I think with several RNA therapeutics, there's been kind of, you know, a move to, you know, do kind of first trials outside of the U.S., often for, you know, very similar, you know, dose level reasons as we're encountering here.

Very helpful. Thank you.

Your next question comes from Greg Zavadovich of Mizuho Securities. Please go ahead.

Okay, thank you very much. Thanks for taking my question and congrats on the continued progress. I did want to go back to the proposed phase three trial design for vexatide and PBH. I think Camille and and the team, you are proposing that you go with a primary endpoint that is the composite of Level 2 and Level 3, and I just want to get thoughts around maybe a clarification as to why in PBH you've chosen to include Level 2. I believe Iger had previously proposed focusing just on Level 3, and there was, you know, concurrence around that, so just trying to maybe get her sense of whether including level 2 hypoglycemia, what that does around giving increased confidence on trial success. Thanks.

Yeah, sure. So I don't recall specifically that Iger wanted to limit to level 3. The phase 2 and 2B study at level 2 and level 3 hypoglycemia events and the reduction in those hypoglycemia events And the composite of level two and level three actually, as the diabetes world knows well, is a well-established endpoint for antidiabetic drugs to see if there are problems with hypoglycemia in that setting. The composite just gives us an opportunity as well to capture all the events that might be occurring that are clinically meaningful The level two, of course, is based on a blood glucose level, starting with a CGM and then a finger stick if the blood glucose by CGM goes below a certain level and alarms. And the level three is a clinical one where the individual is just unable to rescue themselves from the dire consequences, and one can precipitously

uh drop so go from level two to level three before even realize and only other comments add on the top two um in the phase two and phase two b you know strong effects were seen on both the level two and level three um you know so you know we see the drug to be um promising against you know both of those you know not not distinct to either one great thank you and then um maybe just my

follow-up with respect to your PSP trial and the interim readout. I apologize if I may have asked this in the past, but with regards to a go-no-go decision in PSP, could you just remind us what you're looking for and what would be considered to be good enough to feel comfortable with moving forward with the Phase 3 portion? Thank you.

Sure. Thank you, Greg. So, at a high level, we'll be looking at the interim data to demonstrate that AMX35 shows clear clinical activity in PSP. The primary endpoint is change from baseline in PSP-RS, the rating scale for progression of function and decline in function in PSP from baseline. And there is, that is an established endpoint, and there are very strong placebo data that are recapitulated over a number of previous trials in PSP. So we, you know, we'll have a benchmark against which to compare. And we will be doing an unblinded look, so we also will be comparing against placebo. We'll be looking at biomarker data and also information out beyond 24 weeks as well. So, based on those data and how they all line up, we'll be able to make a decision regarding the potential of AMEX 35 and PSP.

And I'll just, Greg, I know you know this well, but reminding everyone too that the rationale for the PSP trial was based off of our prior study with AMEX 35 in a trial of about 100 participants with Alzheimer's disease. And in that study, there were very strong reductions in both total tau and phosphatau-181 measured in CSF, both by ELISA as well as with some proteomics work that we did, and we published that earlier this year as well.

Thank you. Next question comes from Mark Goodman of Learing Partners.

Please go ahead.

Hi. Good morning. This is Basma on for Mark. Thank you for taking our question. Can we – we have another question about the OREON study. You said you're going to be measuring the p tau and the total tau. So is it only going to be CSF-based biomarker data, or are you also planning to look at the tau PET in order to make your decision for the biomarker? Also, we have a follow-up about .

Great. So, for the PSP study, we'll primarily be looking at the CSF compared to baseline. And as Justin just indicated, we saw a very strong signal in the Alzheimer's disease study that was recently published in, you know, dramatic reductions in both tau and phospho tau in the CSF.

Great. Thank you. Regarding the C3 vexatide, are you planning to include an active R in the standard of care or is it only against placebo? Thank you.

Yeah, so really there are no approved therapies for PBH. What is used as a, you know, throughout the management of people with PBH is a medical nutrition therapy, which is actually quite a draconian diet eating small meals every couple of hours, restricting the type of food that's eaten, high protein, complex carbs, no sugar, et cetera, and can be very, very difficult for people to follow, although that's certainly what they strive to do. Other medications or drugs are used, but with very little effect. And the people that we are studying and for which vexatide has been studied so far are those who've tried these other approaches with little, no success. So people will continue their medical nutrition therapy, and it will be placebo versus a vexatide.

Thank you.

Your next question comes from Anandam Ghosh of H.C. Wainwright. Please go ahead. Hey, hi, guys.

Good morning. I just have one question on avixotide. Can you briefly talk about the pharmacokinetic profile for the 90 milligram dose of avixotide with respect to the hypoglycemic events? That is, how fast, you know, those symptoms occur post the events and how fast avixotide counters them based on their PK?

Yeah, so...

So, vexatilide pharmacodynamically, and I guess also pharmacokinetically, you know, reaches, you know, therapeutic range at about an hour post-dosing. It remains in therapeutic range for about a complete day, you know, or about 24 hours, or you're just short of that. So, we do get coverage, you know, over the course of the day with a 90-meg dose. In terms of pharmacodynamically, You know, there have been PKPD modeling, which do, you know, suggest that, you know, the onset of this is pretty quick. And in fact, some of the earliest studies of the drug were single-dose crossover studies and, you know, met statistical significance on glucose and insulin with a single dose. Again, suggesting that, you know, the onset of effect is pretty clear and fast. And, you know, I think it also makes sense in the context of the receptor where, you know, you're competing with endogenous GLP-1, which, you know, essentially happens instantaneously.

Great. Thanks. Your next question comes from Joel Beattie of Baird.

Please go ahead.

Hey, thanks for the update. How do you think about balancing kind of remaining cash among, say, your lead program of Exatide, the other programs which, you know, may potentially have a lower probability of success, as well as the potential for business development? Yeah. Hey, Joel. It's Jim Fraze. Thanks for a financial question.

I was getting a little lonely here at the table talking all about the science. Well, I think as we've made clear since, at least as we've hopefully made clear since we acquired Vexatide, we view that as our lead asset. The clinical data that we've seen, the safety profile, the opportunity in the market, its late stage of development, clearly make it the most valuable and potentially impactful for patients in the near term. That said, our other three major programs all have very, you know, important scientific validation work already done. And, you know, we're quite far along in the development of each of those where we're close to important milestones. So we'll be making sure that our cache runway gets us through the Phase 3 data on Avexotide, most importantly. And if we have to tighten our belt to other places, we can do that. But I think with our current plans, as we've outlined, I think we're on track with the data that we've seen in each of the programs.

But it's something we work on every day. Thank you. You're welcome.

There are no further questions at this time. I'll turn the call back to Mr. Klee. Please go ahead.

Thank you for joining us on today's call to discuss our third quarter 2024 financial results. Have a great day.

Ladies and gentlemen, this concludes today's conference call. Thank you for your participation and you may now disconnect.