Participants

Lindsey Allen; IR Contact Officer; Amylyx Pharmaceuticals Inc

Justin Klee; Co-Chief Executive Officer, Director; Amylyx Pharmaceuticals Inc

Camille L. Bedrosian; Chief Medical Officer; Amylyx Pharmaceuticals Inc

James Frates; Chief Financial Officer; Amylyx Pharmaceuticals Corp

Joshua Cohen; Co-Chief Executive Officer, Director; Amylyx Pharmaceuticals Inc

Charlie Yang; Analyst; Bank of America

Michael DiFiore; Analyst; Evercore

Graig Suvannavejh; Analyst; Mizuho Securities

Ananda Ghosh; Analyst; HC Wainwright

Joel Beatty; Anlayst; RW Baird

Presentation

Operator

Good morning. My name is Allen and I will be your conference operator today. At this time, I would like to welcome everyone to the Amylyx Pharmaceuticals third quarter, 2024 earnings conference call. (Operator instruction). Please be advised that this call is being recorded at the company's request. I would now like to turn the call over to Lindsey Allen, Head, Investor Relations and Communications. Please proceed.

Lindsey Allen

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 Frates, 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 exit AMX0035 and AMX0114 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 Amylyx disclaims any obligation to update such statements unless required by law.
Now, I will turn the call over to Justin.

Justin Klee

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 avexitide, a GLP-1 receptor antagonist with both FDA breakthrough therapy and orphan drug designations and diseases with no approved treatment options. We remain on track to initiate our phase ||| 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 || HELIOS trial of AMX0035 and 12 participants living with Wolfram syndrome, people treated with AMX0035 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 end points.
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 ||| program.
Our ORION trial of AMX0035 and 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 | clinical trial of AMX114 our antisense oligonucleotide Calpain-2 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 of 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.

Camille L. Bedrosian

Thanks, Justin. Now I will briefly review each of our 4 programs, avexitide and hyperinsulinemic hypoglycemia including post-bariatric hypoglycemia or PBH, AMX0035 in Wolfram syndrome and in progressive supranuclear palsy or PSP, and AMX0114 in ALS. First, I'll provide an update on our lead program of exit for the treatment of PBH.
We are actively planning and are on track to initiate a pivotal phase ||| 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.
PBH is thought to be caused by an excessive GLP-1 response leading to persistent and in some cases, progressive hypoglycemia aide is designed to bind to the GLP-1 receptor on pancreatic island beta cells and block the effect of GLP-1 to mitigate hypoglycemia by decreasing insulin secretion and stabilizing glucose levels of avexitide has been studied in five clinical trials in PBH. Data from these trials demonstrated highly significant reductions in hypoglycemia events. Most notably the 90mg dose which we intend to study in phase ||| showed a 66% reduction in level three hypoglycemia events. And a phase || B trial with AP value of 0.0003 and a 53% reduction in level || hypoglycemia events with P value of 0.004.
For context level ||, hypoglycemia events occur when blood glucose levels drop below 54mg per deciliter, at these levels' symptoms can include tremors, dizziness and risk of losing consciousness.
Level ||| events are defined clinically as requiring third party rescue. The primary efficacy outcome of our phase ||| program will be the reduction in the composite of level || and level ||| hypoglycemia. Then FDA has agreed on this primary efficacy outcome. We look forward to initiating the AC 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 II HELIOS trial at week 24 including longer term data available for participants to reach their week 36 or week 48 visit.
These results are encouraging because they suggest treatment with AMX0035 may result in meaningful improvements across multiple measures of disease progression and an otherwise progressive fatal disease with no approved treatment options.
The 24-week data showed improvement or stabilization in all disease measures in the study including pancreatic function as measured by C peptide primary end point, 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 A 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 II B three 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 AMX0114. And 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 12.5mg.
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 AMEX0114, the FDA restricted dosing to an amount that is lower than our proposed starting dose of 12.5 mg and requested additional information which resulted in a clinical hold in the US. Toxicology data from studies showed a greater than 10 X safety margin at the starting dose of 12.5mg based on the no observed adverse effect level or NOAL 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.

James Frates

Thanks Camille. Financially Q3 turned out as we expected, after the closing of of avexitide 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 AMX0114 program and the readout of topline data from the avexitide phase ||| 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 RELYVRIO and ALBRIOZA. Research and development expenses were $21.2 million for this 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 avexitide during Q3 comp 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 $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.

Joshua Cohen

Thank you, Jim. In closing, we are excited about our four pipeline programs, upcoming milestones and path ahead. Our lead asset of Avexitide has both FDA breakthrough therapy designation and orphan drug designation and is on track to advance into phase ||| development in PBH beginning in the first quarter of 2025. In Wolfram Syndrome with our positive phase || line HELIOS results in hand. We plan to engage with the FDA and other stakeholders as we look to inform our phase ||| program with the expectation of providing an update in 2025. the ORION trial with AMX0035 and PSP is recruiting well, and we expect it and we continue to expect data from the interim analysis mid next year.
And we are working towards initiating our phase | clinical trial AMX0114 in ALS by the end of the year or early next year and sharing early cohort 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.

Question and Answer Session

Operator

Thank you, ladies and gentlemen, we will now begin the question-and-answer session to ask a question. (Operator instrcution). Your first question comes from Michael de Fiore. Sorry Corinne Jenkins of Goldman Sachs.

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 officially managed by existing therapy? And then what are the gating factors to initiating the phase ||| PBH study?

Joshua Cohen

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% to 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, you know, account for that, about 8% of people continue to have persistent PBH, an 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 doctors will say we're on track and I'll pass over to you to provide any more detail.

Camille L. Bedrosian

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.

Operator

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

Charlie Yang

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

Camille L. Bedrosian

Yeah. Thank you very much for the question. So just as a reminder, we with avexitide 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 I put it and we're just refining around the edges, and we'll provide the details prior to initiation. The study will we use 90 mg per day as the dose with the, the primary end point of composite level two and level three hypoglycemia.
And as a reminder, the phase || and || B studies conducted already in PBH with of avexitide showed highly statistically significant and meaningful improvements or, and reductions in the hypoglycemia events, both level || and level ||, notably at the 90mg dose level. So, we're quite pleased about that aspect. Furthermore, level || and level || hypoglycemia are the end points that the trials in diabetes used to evaluate hypoglycemia and that population, and that information is in the guidance's for studying anti diabetic drugs. So 90mg dose composite end point level || and level ||| hypoglycemia is the primary end point.
As I 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 that's a good benchmark. We'll be refining it a bit and proceed from there. 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 date in 2025.
I'm sorry. 2026. Yeah, apologies. 2026.

Charlie Yang

Thank you.

Camille L. Bedrosian

You're welcome.

Operator

Your next question comes from Michael DiFiore from Evercore.

Michael DiFiore

Hey guys, thanks so much for taking my questions. Two for me. The first one is on an avexitide. Just kind of curious on how you think about the risk of hyperglycemia since the GOP one antagonist don't address this this happening. It could lead to lots of undesirable, sequently. So just kind of wanted 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 mg dose to be too high. Like assuming the trial just runs in Canada and, and safety seems fine. Do you think the FDA will be amenable to allowing future trials to be run in the US? Just thinking on whether this, asset could even be commercialized in the US? If the FDA still deems that, that, that starting dose too high? Thank you.

Camille L. Bedrosian

Sure. So, first your question about of avexitide as a reminder of avexitide is GLP one 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 hypoglycemia hyperglycemia in that setting. Furthermore, we have not observed hypoglycemia hyperglycemia. Sorry, I'm used to saying hypoglycemia glycemia either in the toxicology program that was conducted prior to starting the clinical work nor in the clinical trials of PBH.
So, 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.

Justin Klee

And, 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, injection site reactions, those sorts of things, but it's been quite well tolerated generally as well.

Camille L. Bedrosian

Yes. And then with regard to 114, I'll begin and Josh may, may want to have additional comments. So, the FDA we will have some interactions with the FDA to address their questions and understand more of their thinking. Given that the independent toxicologist who reviewed the data, believe that 12.5mg and determined. In fact, the 12.5mg is 10 X 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 regard to whether we can go in the US. Yes, we're confident that ultimately we will be able to.

Joshua Cohen

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

Michael DiFiore

Very helpful. Thank you.

Operator

Your next question comes from Graig Suvannavejh of Mizuho Securities.

Graig Suvannavejh

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 || trial design for avexitide and PBH I think Camille and the team you are proposing that you go with a primary end point that is the composite of level || and level |||. And I just want to get thoughts around maybe a clarification as to why in PBH you've chosen to include level ||, I believe had previously proposed focusing just on level || and there was, concurrence around that. So just trying to maybe get a sense of, of whether including level || hypoglycemia. What that does around giving increased confidence on trial success? Thanks.

Camille L. Bedrosian

Yeah, sure. So, I don't recall specifically that I wanted to limit to level ||, the phase || and || B study at level || and level ||| hypoglycemia events and the reduction in those hypoglycemia events and the composite of level || and level ||| actually as the diabetes world knows well is a well-established endpoint for anti-diabetic 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 || of course is based on a blood glucose level starting with ACGM and then a finger stick if the blood glucose by CGM goes below a certain level and alarm. And the level ||| is a clinical one where the individual is just unable to rescue themselves from the dire consequences and one can precipitously drop. So go from level ||to level ||| before even real.

Joshua Cohen

And only other comment out on the top two in the phase || and phase || B, you know, strong effects. We're seeing on both the level || and level |||. So, we see the drug to be, promising against, both of those, not distinct to either one.

Graig Suvannavejh

Great, thank you. And then 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 ||| portion? Thank you.

Camille L. Bedrosian

Sure. Thank you, Greg. So, at a high level, we're, we'll be looking at the interim data to demonstrate that AMX0035 shows clear clinical and PSP, the primary end point is change from baseline and 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'll have a benchmark against which to compare, and we will be doing an unblinded look. So, we also will be comparing against placebo will 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 AMX0035 and PSP.

Justin Klee

And I'll just, Greg, I know, this well, but reminding everyone too that the, the rationale for the PSP trial was based off of our prior study with AMX0035 and in a trial of about 100 participants with Alzheimer's disease. And in that study, there were very strong reductions in both total tow and phosphatate 181 measured in CSF both by Eliza as well as some proteomic work that we did. And we published that earlier this year as well.

Graig Suvannavejh

Thank you.

Operator

Your next question comes from Marc Goodman of Leerink Partners.

Hi, good morning. This is Basma on for Mark. Thank you for taking your question. Can we have another question about the ORION study? You said you're going to be measuring the P pal and the Tau pal?
So, is it only going to be CSF based by marker data or are you also planning to look at the, total PT in order to make your decision for the buy marketer? Also, we have a follow up about avexitide.

Camille L. Bedrosian

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 and dramatic reductions in both tau and phospho tau in the CSF.

Great. Thank you. Regarding the Phase ||| avexitide are you planning to include an active arm with standard of care or is it only against placebo? Thank you.

Camille L. Bedrosian

Yes. So, really there are no approved therapies for PDH, what is used as a, 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, other medications or drugs are used but with very little effect and the people that we are studying and that for which avexitide has been studied so far are those who've tried these other approaches with little no, no success. So, people will continue their medical nutrition therapy and it will be placebo versus of avexitide.

Thank you.

Operator

Your next question comes from Ananda Ghosh of HC Wainwright.

Ananda Ghosh

Hey, hi guys. Good morning. I just have one question on avexitide. Can you briefly talk about the pharmacokinetic profile for the 90mg dose of aide with respect to the hypoglycemic events that is how fast those symptoms occur, post events and how fast a counter them based on their PK.

Joshua Cohen

Yeah. So avexitide pharmaco dynamically and I guess also pharmacokinetically, reaches, therapeutic range at about an hour post dosing. It remains in therapeutic range for about a complete day or about 24 hours or you're just short of that. So, we do get coverage, over the course of the day with the 90 mg dose in terms of pharmacodynamically. 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 met statistical significance on glue an insulin with a single dose. Again suggesting that, you know, the onset of effect is, is pretty clear and fast. And you know, I think it also makes sense in the context of the receptor where you're competing with endogenous GLP one which you know, essentially happens instantaneously.

Ananda Ghosh

All right, great.

Joshua Cohen

Thanks.

Operator

Your next question comes from Joel Beatty of RW Baird.

Joel Beatty

Hey, thanks for the update. How do you think about balancing kind of remaining cash among, say your lead program of avexitide? The other programs which may potentially have a lower probability of success as well as the potential for business development.

James Frates

Yeah. Hey, Joel, it's Jim Frates. 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, as we've hopefully made clear since we acquired of exercise, we view that as our lead asset, the clinical data that we've seen the safety profile, the opportunity in the market, it's late stage of development, you know, clearly make it the most valuable and potentially impactful for patients in the near term.
That said our other, three major programs are all have very you know, important scientific validation work already done. And we're quite far along in the development of each of those where we're close to important milestones. So, we'll be making make sure that our cash runway gets us through the phase ||| data and have exited 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 data that we've seen in each of the programs, but it's something we work on every day.

Joel Beatty

Thank you.

James Frates

You're welcome.final

Operator

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

Justin Klee

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

Operator

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