Amylyx Pharmaceuticals, Inc. (AMLX) Earnings Call Transcript & Summary

Good morning. My name is Drew, and I will be your conference operator today. At this time, I would like to welcome everyone to the Amylyx Pharmaceuticals PHOENIX Top Line Data Conference Call. [Operator Instructions] Please be advised that this call is being recorded at the company's request. I would now like to turn the conference over to Lindsey Allen, Head, Investor Relations and Communications. Please proceed.

Good morning, and thank you for joining us today to discuss the top line data from our PHOENIX Phase III trial. With me on the call are Josh Cohen and Justin Klee, our co-CEOs; Dr. Camille Bedrosian, our Chief Medical Officer; and Jim Frates, our Chief Financial Officer, will join us for the Q&A portion of the call. 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 plans and expectations with respect to RELYVRIO and ALBRIOZA, statements regarding our current and planned clinical trials and regulatory developments and the expected timing thereof, and our business and marketing strategy and outlook. Actual events and results could differ materially from those expressed or implied by any forward-looking statements as a result of various risks uncertainties and other factors, including those set forth in our most recent filings with the SEC and any other future filings that we may make with the SEC. 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.

Thank you, Lindsey, and thank you all for joining us this morning. Earlier today, we announced that the PHOENIX trial of AMX0035 and people living with ALS, did not meet its primary endpoint of reaching statistical significance as measured by the revised Amyotrophic Lateral Sclerosis Functional Rating Scale, or ALSFRS-R. The study also showed no statistical significance and secondary endpoints or in participants who met the criteria of our CENTAUR clinical trial. The trial did reinforce in a larger and broader population to people living with ALS, that AMX0035 is generally safe and well tolerated. We know how difficult this must be for a community who had hoped for a different outcome. This outcome comes as a surprise and disappointment to all of us at Amylyx. And while we continue to assess the data, it brings with it meaningful implications for our go-forward strategy. As we consider our plans, we will be led by 2 key principles, doing what is right for people living with ALS, informed by regulatory authorities in the ALS community and doing what the science tells us. This will take some time. Our team will meet with FDA, Health Canada and others, as well as the ALS community to share top line data within the next 8 weeks and make informed decisions, which may include voluntarily withdrawing RELYVRIO, also known as ALBRIOZA, from the market. At this time, RELYVRIO will continue to be available in the U.S., and ALBRIOZA will continue to be available in Canada. Our patient support services will also remain in place. Amylyx has voluntarily decided to pause promoting the medication during this time. To review the history, the first trial of AMX0035 that we ran in ALS was called CENTAUR. CENTAUR was a 24-week, randomized, placebo-controlled Phase II trial with 137 participants. CENTAUR met its prespecified primary end point of reducing functional decline, as measured by the ALSFRS-R and extended overall survival in a post-hoc analysis. These results were published in the New England Journal of Medicine and supported FDA approval and approval with conditions by Health Canada. The findings from CENTAUR led to our Phase III PHOENIX study. PHOENIX was a 48-week randomized, placebo-controlled global Phase III trial that enrolled 664 people living with ALS, designed with input from global regulatory agencies, with somewhat broader inclusion and exclusion criteria than CENTAUR. Trial participants were randomized three-to-two to receive either AMX0035 or placebo, with both treatment groups able to receive standard of care. European participants that completed the 48-week randomized phase had the option to enroll in an open-label extension of the trial for up to 2 years, and this part of the trial remains ongoing. The outcome of PHOENIX reinforces how heterogeneous of the disease ALS really is. With data collected from 664 participants, we are sure that there will be important learnings that will help inform future ALS research. We plan to submit the data from PHOENIX to a peer review publication and present the data at an upcoming medical meeting. On behalf of Amylyx, we offer our sincerest thanks to the people living with ALS who participated in our trials, along with their caregivers and families. We are also grateful for the trial investigators, healthcare professionals, nurses, patient coordinators, the entire Amylyx team, as well as our investors for all their help and support. The ALS community inspires and motivates us in everything we do, and we are fully committed to achieving our mission to end the suffering of people living with neurodegenerative diseases like ALS. I will now turn the call to Josh.

Thanks, Justin. I first want to echo what Justin said. This result comes as a surprise to us, given the positive results seen in CENTAUR. We are deeply feeling the impact this will cause for the ALS community. ALS and other neurodegenerative diseases remain urgent, with terrible unmet needs, and we remain fully committed to our mission despite the setback. We believe we have the financial resources to make meaningful progress towards our goals, with about $370 million in cash as of December 31. We are reviewing our business plan and adjusting it as necessary, to ensure those resources are directed towards efforts that most rapidly advance our products, and we do believe we have several compelling programs to advance. While this study did not meet our expectations, we remain confident in the scientific rationale underlying AMX0035's potential. AMX0035 has been shown to reduce neuronal cell death by simultaneously mitigating ER stress and mitochondrial dysfunction in multiple preclinical models. It has also been shown to reduce markers associated with neurodegenerative diseases, including a reduction of tau, a key protein aggregate shared across neurodegenerative diseases, in a clinical study. Outside of ALS, we are conducting 2 key studies based on strong preclinical and mechanistic rationales. The first study is the ongoing 12-participant open-label Phase II HELIOS clinical study of AMX0035 in Wolfram syndrome, which is an inherited condition that is typically associated with childhood onset, insulin-dependent diabetes, progressive optic atrophy and premature mortality. The HELIOS study is fully recruited, and we plan to present preliminary data from it in the second quarter of this year. Open-label data to date are demonstrating evidence of clinical activity of AMX0035 and people living with Wolfram syndrome. The second is our global randomized, double-blind, placebo-controlled Phase III ORION clinical study of AMX0035 in progressive supranuclear palsy, a rare neurodegenerative disorder that affects body movements such as walking, balance and eye function. PSP is characterized as a tauopathy, with genetic and pathological findings supporting a primary role for tau in this disease. Based on the mechanism and the tau reduction we have seen in our Phase II placebo-controlled Alzheimer's disease clinical trial, we are pursuing this indication. The first participant in the study was dosed in December 2023, and we continue to expect top line results from the full population in 2025 or 2026. In the meantime, we are planning to conduct an interim analysis to evaluate the data earlier than the top line results. We also remain focused on investigating other therapies, including AMX0114, our antisense oligonucleotide targeting Calpain-2. Calpain-2 is considered an essential protein in the process of axonal degeneration, and has been repeatedly linked to neurofilament biology in published studies. In our experimentation with AMX0114 and in multiple independent published studies of calpain inhibitors, inhibition of Calpain-2 has reduced cell death and degeneration and decreased neurofilament levels. We have nearly completed all the toxicology studies and CMC work that we believe is necessary to advance to an IND. And we hope to have AMX0114 in clinic during the second half of this year, pending regulatory authorization to proceed. So to reiterate, the outcome of the PHOENIX trial comes as a surprise and disappointment to us, particularly in light of the positive results we saw in CENTAUR. We plan to take swift action to understand the significance of this outcome with regulators and members of the ALS community. We will act in accordance with the best interest of people living with ALS, informed by regulatory authorities and the clinical community, and we will take steps to focus our organization on those projects most essential to fulfilling our mission to end the suffering of people living with neurodegenerative diseases. We'll take your questions for the remainder of the call. Operator, please open the call up to Q&A.

[Operator Instructions] The first question comes from Neena Bitritto-Garg with Deutsche Bank.

I just wanted to ask a little bit more about the factors that are going into your decision to potentially withdraw drug from market and how you're thinking about really what you need to hear from the discussions that you're having over the next 8 weeks from regulators and the ALS community in order to make that determination? And then also if you can give us some clarity on potentially when we could see that sort of determination made? I know it's still early and hard to determine that, but anything that you could share would be helpful.

Thank you, Neena. And yes, I mean, it's why we're sharing the top line results today. We wanted to make it clear that the primary outcome was not met. The secondary outcomes were not statistically significant. Those are the top line results. Obviously, this has significant implications both for Amylyx and the ALS community. So we'll spend the next 8 weeks or, I guess, within 8 weeks engaging with regulatory authorities and the ALS community to share the top line data. In the meantime, we voluntarily decided to pause promotion. And in brief, we'll follow the science, and we'll do what's right for the community, which may include voluntarily removing the products from the market.

And then if I can just ask one more follow-up. Just in terms of the decision that you've made to kind of pause promotional product right now, I guess, is there anything that you can share kind of on the benefit risk that you saw in the study? I know that you did say that the safety look and tolerability looks acceptable. But just curious, what went into that decision? Was there something specific, I guess, in the data set that you saw that kind of led to that decision?

Yes. Maybe one to reiterate, the safety profile in the study was strong. The drug was generally safe and well tolerated. We did not observe any safety signals of concern or otherwise. But I think what went into that decision was what Justin said. The trial list, it's prespecified primary outcome as well as the key secondary outcomes and also in the subgroup of people who specifically meet the CENTAUR inclusion exclusion criteria, the study was also not successful. And so I think it was that data that I think we thought it was the prudent thing to do to pause promotion, given that data, as we evaluate it and as we complete the discussions that we're intending to complete. Yes, I think that's what drove the decision.

The next question comes from Corinne Jenkins with Goldman Sachs.

Maybe one from us. What -- can you share what the change in slope in ALSFRS-R was that was observed in the drug and then in the placebo arm? And did you see any change in one versus the other versus, kind of like what you'd expected that drove this result? Did the drug do worse than it had previously or the placebo do better or things like that?

Yes. Great question, Corinne. The data are fresh, so the first thing we just wanted to share the top line results, which is that the trial didn't meet the primary endpoint, the p-value was 0.667, as measured by the revised ALS Functional Rating Scale, nor was there a statistical significance seen in secondary end points. We will continue to analyze the data, and we plan to present at an upcoming medical meeting and as well as publish the results later this year.

The next question comes from Umer Raffat with Evercore ISI.

A couple here, if I may. First, I'm just trying to reconcile your press release versus the release from the [ Italian ] group, which suggest there's a "step forward for medicine." How could it be that maybe there is a signal in that study and absolutely no signal in this one? Or maybe there is no signal in the other study. I'm curious how you think about the totality of the picture. Secondly, are you 1,000% sure there's absolutely no subgroup, which had any trend of activity, which could warrant some sort of follow-up work, be that definite ALS like your prior trial or less than 12 months from diagnosis or [ SPV of both ] 70, Bulbar-onset, any of those? And then finally, Jim, how long is this cash runway, if you actually do withdraw the drug from the market?

Umer. First, in terms of the [ TECA ] trial, that's not our trial, it's not our product, so we can't speak to that. And as far as our trial and subgroups and questions like that, we have a statistical analysis plan for a reason. We're sharing the [ prespecified ] primary outcomes. They were not met. We do think this is a very valuable data set for ALS. I mean I think what this speaks to is, one, ALS is a really tough disease and two, it's heterogeneous, and there's a lot we still have to learn. And so the data are fresh, the top line results are clear. So that's why we tried to share what we know now. As we said, as hard as this is for us, I can't even imagine what it must be like for the ALS community, especially people living with ALS in their families. But we're trying to share the results as we have them. And then, as I said, we'll plan to present the results at upcoming medical meeting as well as publishing.

Yes. Umer, I very much appreciate your question. I think what we're prepared to say this morning, right, because we still have to do some of that analysis that Josh and Justin said. But I think if we're in the worst-case scenario, we'll take swift action, and we'll be very focused on what the business looks like going forward. So I think with $371 million of cash and you can kind of look back historically about what we spent before we were really growing the company to market the drug, and that will give you a sense that I think we have resources, as Josh said earlier, to be able to focus on some of our earlier stage programs. But it would clearly be under a very different structure. And I do just want to be mindful of everybody at the company and everybody in the community. We'll talk about that very soon, but I don't think this morning is the right time we give you clear plans.

The next question comes from Charlie Yang with Bank of America.

I just wanted to maybe just get a little more details regarding kind of the 2025 or 2026 [ count ] expectation there? Like what can we actually expect, results-wise, given what we have seen today? And could that have any potential change in terms of how you'll be thinking about the direction of RELYVRIO? And maybe if you can just clarify the interim analysis that you referred to earlier in terms of when can we expect to see those analysis?

Yes. So as we shared in the remarks, we expect to release data from the Wolfram trial in the second quarter of this year. So that will be shortly. And then with the PSP trial, we have not given an exact timeline for the interim analysis. It's also dependent to some extent on the speed of recruitment. So we'll probably give a more exact timeline as we get there. And with 0114, we've shared that we expect to be in clinic in the second half of this year.

Yes. And just to underscore a couple of points, Charlie. So the -- one, we remain confident in the scientific rationale. AMX0035 is targeting key pathways in neurodegenerative disease. And we have observed a very good safety profile as well. As Josh mentioned in his remarks, we're seeing evidence of clinical activity in Wolfram syndrome, and we'll be presenting those in the second quarter. And the PSP scientific rationale, I would say, is largely independent of ALS. We saw very significant reductions in tau and Phospho tau in our Alzheimer's study in CSF. And there's a very compelling preclinical rationale for PSP as well. So I think the PSP trial community is very excited about the treatment, given the mechanistic rationale and the biomarker engagement.

And maybe I'll just have one more follow-up just regarding the PHOENIX trial. So are we going to see the overall survival data for PHOENIX [ channel ] or what's the plan? And maybe I missed that earlier.

Yes. So overall survival, as we shared, would not be available at the time of the initial release because survival does take time to accrue. I think as we're going through this upcoming period, we'll determine what the future of that analysis and everything is as well.

The next question comes from Graig Suvannavejh with Mizuho.

[indiscernible] the data. I was just curious as we look on the forward, I think it's important for investors to get a view of whether the company does still have a viable future going forward. And so with that in mind, obviously, with the pipeline that you have now and given the cash that you have now, is there any current view around, perhaps even looking beyond what you have now to perhaps look to add other things to further diversify the company or with what you have right now, perhaps you feel that's the best that you want to kind of present to investors as the opportunity going forward?

Thank you -- first of all, thank you, Graig, for your kind words, where it's obviously deeply saddening for both us and particularly for the ALS community with these results. And that's really the update today. Obviously, the results are new, and so that's what we wanted to share, but we also wanted to share that we think they're clear. As far as the future of the company, first, I think we have strong conviction in our earlier programs. As you probably noted, we shared new information on the Wolfram syndrome program, and we'll look forward to presenting those results. And as far as the future of the company, Jim was saying, I think it's probably not the time to outline a full business strategy right now. But we're very committed to the mission. We're in a good financial position. And I think there's enormous need and opportunity in neurodegenerative diseases broadly. So today's news is obviously very difficult for the ALS community, but our commitment is unwavering, and we will be steadfast to the mission.

The next question comes from Joel Beatty with Baird.

First one is just a clarification on survival. Was that able to be looked at all as part of this analysis? Or is there still some potential that when the final overall survival analysis is able to be looked at there could be a trend or a benefit?

Yes. So I mean survival is event driven. And so I think as we've said many times that survival will not mature until there's been enough events. But I do want to be very clear, and I hope we set this kind of in the tenor of the release and everything as well. This trial missed its primary outcome, it missed its secondary outcomes, and it did not show an effect in the CENTAUR subgroup. So that's the data that we're operating off of and kind of making our decisions off of at this time.

I appreciate that. And then as a follow-up, any hypotheses or the difference in results between CENTAUR and PHOENIX?

Great question. I think it's early. And again, I think this is where it's particularly important to take time to meet with the ALS experts. I think what it speaks to, again, is the heterogeneity of ALS and also the difficulty in ALS and neurodegenerative diseases more in general. And -- but I think it's so imperative that when we all fighting these diseases have even setbacks like this. We learned from them so that we can continue to advance, because I do very strongly believe that we can have meaningful advances for people with neurodegenerative diseases and it's about following the science and continuing to press forward.

There are no further questions at this time. I'll turn the call back to Mr. Justin Klee for closing remarks.

Thank you, operator, and thank you all very much for joining us on our call today and for your support. We hope you have a good day.

The conference has now concluded. Thank you for attending today's presentation. You may now disconnect.