Good afternoon. My name is Debbie, and I will be your conference operator today. At this time, I would like to welcome everyone to the Amylyx Pharmaceuticals First Quarter 2023 Earnings Conference Call. [Operator Instructions] Please be advised that this call is being recorded at the company's request. I would now turn the call over to Lindsey Allen, Head, Investor Relations and Communications. Please proceed.

Good afternoon, and thank you for joining us today to discuss our first quarter 2023 earnings. With me on the call are Josh Cohen and Justin Klee, our co-CEOs; Margaret Olinger, our Chief Commercial Officer; and Jim Frates, our Chief Financial Officer. Before we begin, I would like to remind everyone that any statements we make are 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 pertinent 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 results to RELYVRIO and ALBRIOZA, statements regarding regulatory developments and the expected timing thereof, our business strategy and outlook and our expected financial performance. 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 good afternoon. As everyone on this call knows, there is an enormous unmet need in ALS and other relentlessly progressive and fatal neurodegenerative diseases. It is our mission at Amylyx, to one day end the suffering caused by these diseases. Our treatment RELYVRIO enables us to make meaningful advances toward and continued investment in our mission. During the first quarter, we generated $71.4 million in net product revenues, reflecting the significant progress we continue to make toward our goal of ensuring every eligible person living with ALS has access to RELYVRIO. RELYVRIO is the first and only approved treatment for ALS that in a randomized placebo-controlled trial both met its prespecified primary outcomes, demonstrating a statistically significant benefit and function and showed a benefit on survival in a longer-term post-hoc analysis. These data suggest that ALS can, in fact, be treated. The full approval of RELYVRIO is an important step toward ALS, one day being a manageable disease. The ALS community has been waiting for meaningful treatment option since the disease was first characterized over 150 years ago, and we believe that RELYVRIO will eventually be a foundational therapy for ALS. In the first quarter, we saw a continued high level of interest from the ALS community in RELYVRIO, broadened insurance coverage and high levels of engagement with our Amylyx Care Team, also known as ACT. Just 2 quarters into launch, over 10% of the approximately 29,000 people living with ALS in the U.S., are now on RELYVRIO. Even with that success in our first 6 months, we have more to do. There remain many more thousands of people living with ALS in the U.S. and at least 200,000 people living with ALS globally. We are still in the early stages of our journey, and our team remains hard at work. Shifting to our plans internationally. We are diligently preparing to help bring our medicine to all eligible people living with ALS around the world. The regulatory review process in Europe remains ongoing, and we continue to expect an opinion from CHMP midyear and a decision at the earliest in Q3. Overall, we believe we have a strong scientific position that is supported broadly by the ALS medical and advocacy community and a capable team who is leading our process. We continue to prepare to execute a successful launch in the EU if approved. We are proud of our team's progress on advancing our mission. And now I'll turn the call over to Margaret to share a commercial update.

Thank you, Justin. As we enter the seventh month since our U.S. launch, we remain focused on 3 key priorities. The first is our effort to drive awareness and education about RELYVRIO among people living with ALS and clinicians. This includes educating that RELYVRIO is the first approved drug for adults with ALS to demonstrate a statistically significant benefit and function in a clinical trial as well as a benefit on survival in a longer-term post-hoc analysis. Our efforts to drive awareness are yielding strong results. We are seeing continued interest and demand for RELYVRIO. As of March 31, there were roughly 3,000 people on RELYVRIO in the U.S., more than double the number of people on RELYVRIO at the start of the quarter. We are pleased that this many people have gained access to our important treatment. I think it's worth spending a minute to provide some additional context on the strength of our launch. While we knew there was pent-up demand, the fourth quarter and first quarter were still well ahead of our expectations. The rate of net patient adds has begun to moderate as expected. However, we still see significant demand from people living with ALS and physicians alike. Importantly, we still have plenty of room for growth, both at the top ALS Centers and the broader neurology community. Now let me run through a few metrics that show our progress but also the growth opportunities ahead of us. By the end of the first quarter, approximately 65% of the top 500 U.S. prescribers and approximately 95% of key ALS Centers have prescribed RELYVRIO to at least one person since launch. Prescribing remains fairly concentrated with roughly 80 prescribers mostly at major ALS Centers, representing approximately half of all RELYVRIO prescriptions during the quarter. While we are…

Thanks, Margaret. We are very pleased with how quickly we are bringing our important new treatment to people with ALS. Our top focus day-to-day remains the success of our commercial launches. These efforts enable the continued investment needed to bring RELYVRIO to more people living with ALS worldwide. They also enable the research and development needed to advance our pipeline in support of our mission. There's tremendous scientific interest among the neurodegenerative community to further investigate AMX0035 in other diseases. We have a positive randomized clinical trial data in ALS, encouraging biomarker data from the randomized Phase II PEGASUS study in Alzheimer's disease and a wealth of preclinical models demonstrating the effects of AMX0035 in reducing neuronal death. To prioritize which diseases to focus on, we look at the following criteria: clear unmet need, strong scientific rationale, existing and robust understanding of the natural history of disease, biomarkers to track treatment effects, adjacencies and synergies with ALS, potential to move directly into a Phase III pivotal study and interest and support from KOLs. We are excited to announce today our plans to initiate a global pivotal Phase III study with AMX0035 in progressive supranuclear palsy or PSP, a disease which meets all of these criteria. For those of you who may not be familiar with PSP, it is a rare, progressive and fatal neurodegenerative disorder that affects body movements, walking with imbalance, speech and swallowing and eye movement. It is typically fatal within just 5 to 8 years. The estimated prevalence is 5 to 7 in 100,000 people worldwide, translating to between roughly 15,000 to 20,000 people in the United States. There are currently no disease-modifying treatments for PSP. In addition to PSP meeting our criteria for a significant unmet need with a well-characterized natural history, there is also a…

Thanks, Josh. We're encouraged by the strong interest and demand we continue to see from the ALS community. From a financial point of view, our business is strong. Net product revenue was $71.4 million for the quarter, compared to net product revenue of $21.9 million for the fourth quarter of 2022, with the vast majority of that revenue from the United States. Gross to net adjustments were approximately 16% in the quarter, consistent with our expectations in the 15% to 20% range. Inventory levels at the quarter end were as expected, with approximately 2 weeks of inventory in the channel at specialty pharmacies. Cost of sales were $5.3 million for the quarter and in the range of our expectations as sales volume grow. And for modeling purposes, keep in mind that roughly 10% of the people on RELYVRIO are receiving it for free through either our Interim Access Program or Patient Assistance Program. Research and development expenses were $24.2 million for the quarter compared to $21.5 million for the same period in 2022. These costs were primarily driven by our Phase III PHOENIX study and added personnel as we support our programs. Starting in the second quarter, we expect R&D expenses will increase as we incur meaningful expenses to initiate our Phase III pivotal study in PSP. You should expect R&D expenses to increase this year in a range of $30 million to $40 million per quarter as we move through the remainder of the year. Selling, general and administrative expenses, or SG&A, were $44 million for the quarter compared to $26.3 million for the same period in 2022. We're investing in SG&A to support our strong commercial launch and expect our spend to settle in around $45 million per quarter for the remainder of the year. Overall, we're very…

Thanks, Jim, and thank you to everyone for joining us today. We covered a lot of exciting news. Our commercial ramp in the U.S. and Canada is proceeding very well, and we will know more on Europe later this year. We are expanding our clinical pipeline into PSP, a market that is likely as large as ALS with a product that has already been shown to have a favorable safety profile in another disease and that has a demonstrated effect on relevant biomarkers. And we achieved our first quarter of profitability in just the second quarter of our commercial launch in the U.S. We remain committed to our goal to help additional people with ALS and other relentlessly progressive neurodegenerative diseases, gain access to new therapies. Now we'd be happy to take your questions. Operator, please open the call up to Q&A.

[Operator Instructions] The first question comes from [indiscernible] with Bank of America.

Great. This is [indiscernible] on for Geoffrey Meacham. So I have 2 questions, please. The first one is, you mentioned that the rate of the pace has moderated [indiscernible] going to perhaps the second quarter. Can you just provide more clarity on that? And my second question, just can you provide little more details with regard the payer discussions that you have and kind of what's your expectation for the remainder of the year?

Sure. So this is Margaret. Thank you very much for your question. And we continue to be incredibly pleased with our launch to date and more importantly, our ability to bring a new treatment option and hope to the ALS community, especially given that this is the first product to demonstrate in a clinical trial, a statistically significant benefit in both function and survival. So maybe if I could just reiterate a few key points. We ended the quarter with roughly 3,000 patients, again, double what we started with at the beginning of the quarter. And that's about 10% of the 29,000 patients living with ALS. So not surprisingly, our net patient adds can't double forever. So in Q2, we are expecting the number will be lower than what we delivered in Q4 and Q1. I think more importantly, we continue to see significant interest in demand for RELYVRIO, both from patients and HCP, and we have a tremendous opportunity for us to grow both in depth and breath at all the key ALS Centers as well as the broader neurology community. And then the second question was on payers. And again, we're very pleased with the progress we're making with payers with 50% of the covered lives to date, having a published policy, and we expect that to only get better over the first half of the year.

The next question is from Michael DiFiore with Evercore.

Congrats on the quarter. A few for me. The first question I have as a follow-up to the previous one. Now that more commercial payers have come on board and given the fact that you said that the rate of net patient adds is beginning to moderate. Could you perhaps provide any updated views on how big this initial [indiscernible] of patients could be and how long it could last before you achieve a steady-state trajectory of new starts? That's my first question. And the second one is regarding the Phase III PHOENIX trial. You mentioned that the OS data is going to take at least a year more to read out and that it's a critical endpoint. So if we assume conditional approval in the EU based on CENTAUR and the statistically significant benefit on ALSFRS in PHOENIX, are you expecting EMA to still maintain their conditional approval until the OS data finally comes in? And could there be a scenario when full EU approval could be granted based on just positive ALSFRS data alone?

Great. Thank you. This is Margaret again. Thanks for your question. Regarding the bolus, it's really too early to tell when the bolus will finish. But what I can say is that we know in Q4 and in Q1, we did see that high level of demand due to the pent-up demand that we had and they were quite frankly, even ahead of our expectations. So we have begun to see the rate in new patient adds moderate. But again, I want to reiterate, we have a tremendous opportunity for growth because even within the key accounts that we penetrated and just to remind you of some of the metrics, we said 95% of all the key ALS Centers have prescribed for at least one patient. Every account, you see one account, you see one account, right? It's a typical rare disease. So some accounts are highly penetrated and some accounts have a great deal of room ahead of us to penetrate and we really have just started to get out into the broader neurology community. So again, we see tremendous growth ahead of us to serve all the remaining patients that are depending on us.

Yes. Mike, this is Justin. Thanks for the question. So first, just sort of baseline for everyone. So we continue to expect an opinion from the CHMP midyear and decision at the earliest in the third quarter. And in the meantime, our team is preparing for approval and launch. So in terms of the PHOENIX trial and how that could affect the conditional approval, so the way that the EMA -- so first, we won't know if it's a conditional approval or full approval until we get the final decision. But in terms -- but our expectations is on the conditional marketing authorization. So the way that, that works is that you get approval, but with the condition that you do a follow-on study. And in this case, our expectation would be that it would be the PHOENIX trial. And then you have to renew that every single year until you meet the condition. So then the question is, will we meet the condition depending on the ALSFRS functional results or the survival results. And that's really up to the regulators. What I will say, high level, though, is that if we have a functional benefit, if we have a survival benefit, if we have both, it's the best data anyone has seen in ALS. So I think either is a very positive situation. But ultimately, it's up to the CHMP and EMA.

The next question is from Corinne Jenkins with Goldman Sachs.

Maybe a couple from us. I guess, one, with more than 3,000 patients now on drug up from the 1,300, even understanding that there could be some moderation. How long are you thinking it will take you from here to get to the 10,000 patients you had stated as a target for being stable on therapy at steady state? Maybe the second one for me is just given the clinical priorities that will be initiated. Do you expect to maintain profitability through the balance of the year? And then the final one, just could you talk through the rationale of moving straight into a large Phase III program in PSP without doing sort of like an earlier stage Phase II or otherwise, and help us understand the relevant clinical endpoints throughout indication.

Sure, Corinne. So I'll take the first question, and then I'll turn it over to Josh and Justin and probably Jim as well. So just -- we have not provided a time line on how long it will take us to achieve the 10,000 patients. Our goal of getting to the 10,000 patients really reflects our vision that RELYVRIO will become the most commonly used ALS medication, so basically standard of care. And we feel that that's very achievable, given it is the first product to demonstrate a benefit on both function and survival. I will tell you that right now, we are heavily focused on the launch execution with the goal of getting there as quickly as possible because patients are depending on us.

And maybe I'll turn it over to -- yes, go for it, Jim, sorry.

Yes. Yes. Sorry, Josh. I'll take the next one on profitability. We decided not to guide at this stage, Corinne.So that will include also not guiding on profitability because essentially, obviously, that's guidance. But I think you all can see the math in terms of the hydraulics in our P&L. And as long as we can go revenue faster than we grow expenses, we'll be able to maintain that profitability. I think importantly for us, longer term, it just really highlights the opportunity we have in this business and how unique the ALS market is. And ultimately, I think we have to recognize it's the need of the patients that's driving this launch and the fact of the matter of the data that we have with RELYVRIO. So we're going to continue to focus on our long-term goals, as I tried to outline in the prepared remarks, making RELYVRIO the #1 ALS therapy, that's first and foremost, driving long-term profitability for our investors, right, because that's how we get to be a sustainable business long term. And I think that's also another thing that differentiates us from a lot of other companies out there. We don't need to continue to go back to the market to fund our business because of how well the launch is going and the interest that we're seeing in the community. But then also, we're going to invest in our pipeline because there's a real need in neurodegenerative diseases. And I think we can do all 3, which is what makes me so excited to be here at Amylyx at this time. Josh, back to you.

Thanks, Jim. And so talking about PSP. So I think the first thing I can share is, over the last several years, we've gone through a process internally to try to select those indications that are highest priority for the company. And I outlined some of the things that we look at for that. But most importantly, PSP met all of the criteria that we were looking at for an indication to prioritize as a company, and we already have shown in a randomized placebo-controlled study data against what is thought to be the primary pathology of progressive supranuclear palsy. And so I think that's part of what's driving our excitement as well as the excitement we're hearing from the KOLs and the community about this indication. And just doesn't add to there's also some preclinical data that's also supporting and making us excited here. But I think it's that constellation of factors that makes us really excited to go into this PSP study.

The next question is from Neena Bitritto-Garg with Citi.

Congrats on the update. So just in terms of trying to figure out this bolus. Can you talk a little bit about what you're seeing in terms of [indiscernible] versus net adds. I'm just curious if you can talk about the trend you're seeing there. And then give us any color on duration of therapy so far or any dropouts that you're seeing, that would be great.

Yes. So we're not providing any guidance on the number of patients for the quarter. Again, I'll just go back to, we think our net patient adds, they can't double forever. So we'll be lower in Q2 than we've been able to deliver in Q4, Q1 because we believe that, that was the initial pent-up demand. Again, we don't know when that bolus will be over, so it's hard for us to really give any guidance on that. In terms of duration of treatment, it's really too early in the launch to give that. I mean the first patients who started on therapy were basically at the end of October, beginning in November. So they really haven't been on therapy long enough for us to give any clarification there. In terms of discontinuation rates, that's sort of similar as well. People just haven't been on therapy long enough. I can tell you that the general trends that we're seeing are kind of in line with what we saw with CENTAUR. Nothing is out of line there. And just as a reminder, with CENTAUR, we're seeing roughly about a 25% discontinuation rate at 6 months. So again, patients haven't really been on therapy for 6 months yet. So we're going to continue to monitor that very closely.

The next question is from Marc Goodman.

Can you talk about the mechanism for AMX0114? And then second, just the data support the Wolfram study and the recent -- the rationale for moving there?

Sure. So first on AMX0114. So AMX0114 is an antisense oligonucleotide targeting calpain-2. So there's a pathway called Wallerian degeneration, that's been around since the 1850s, which is the pathway whereby a neuron will destroy its own axon in response to injury or stress. And that pathway over the last 150 years, the pharmacology has become pretty clear on what proteins need to be activated and otherwise for that axonal degeneration to occur. And what you'll find digging into Wallerian degeneration pathway is that calpain-2 is one of the key proteins involved in that. And then in addition, there's been preclinical studies with both kind of knock-in models and knock-out models that have shown that calpain-2 inhibition can be effective in several animal models of ALS. And then finally, there's a lot of evidence out there linking calpain-2 to different ALS biomarkers, including TDP-43. And then turning to Wolfram. So Wolfram, as we shared in the last conference call, is a space we've done at least 4 years of preclinical work together with Washington University and Dr. Fumihiko Urano there. And broadly, those experiments studied both cellular models of the disease as well as an animal model of the disease. Much of that data is published in the Journal of Clinical Investigation Insight. But broadly, what we saw was some degree of rescue of the phenotype, both in the cellular models as well as in the animal model. So I think that was the data that got us really excited to go forward there.

The next question is from Graig Suvannavejh with Mizuho Securities.

Congratulations on the quarterly results. I've got 2 questions, if I could. First is more commercially related, the second pipeline related. So on commercial, do you have any sense in these early days kind of how the drug is being used in patients? And by that, do you have a sense of distribution of its use, whether what percent is in monotherapy versus some combination setting versus a potential triple combination? Any thoughts there would be great. And then on the pipeline, I just had a question on the new Phase III PSP study. And maybe it's a twofold question. First, in light that there have been attempts in PSP in the past, one was with an anti-tau antibody. Is it really just the movement on markers that gives you confidence that it will be able to work in PSP? Is there some other elements? And then maybe the part B of that is, is the strategy more biomarker-driven in terms of kind of the momentum we're seeing in the neurodegenerative space and how FDA seems to be very open and receptive to biomarker-driven strategies?

Yes. So I'll take your first question. I would say that regarding the use whether or not it's monotherapy or combination therapy, it's really a broad mix from single use of RELYVRIO to combination therapy with all 3 available products. And we're really seeing the utilization in a very broad patient population. So we continue to see patients that have been diagnosed with this disease for many years, get prescribed this drug as well as newly diagnosed patients. And we define newly diagnosed patients as patients who have been diagnosed in the last 6 months. I would say from an ease of access perspective, some physicians may start first with riluzole, and then they'll switch to or add RELYVRIO to riluzole just because again, it could take -- it was taking up to 30 days last quarter in Q1 for a patient to get access to the drug from the time to enrollment on average. And again, we expect that to continue to improve as more policies come on board.

And Graig, thanks for the question on PSP. This is Justin. And yes. I mean first, I would say, I think the PSP community and especially the key opinion leaders are really excited about this. I mean in RELYVRIO, we have an oral safe drug that's FDA-approved for another neurodegenerative disease. And then in terms of the rationale for PSP, preclinically, we've shown that AMX0035 protects against neurodegeneration. PSP is a rapidly progressive neurodegenerative disease. And then clinically, we showed the very significant reductions in tau in our Alzheimer's study. And while, yes, there have been antibodies against tau that were unsuccessful in PSP. PSP is still a tauopathy. That's the canonical protein associated with it. In terms of the study design, we're not going to get into that today. But I think it's really all of the above that makes us and probably more importantly, the key opinion leaders so excited about the study in PSP. So we'll continue to share more on that, but we're really excited about starting that study.

The last question comes from Ananda Ghosh with H.C. Wainwright.

Congrats on the quarter. I have 2 questions on PSP. The first one is, how similar is PSP with ALS concerning the downstream degeneration pathway? And the second is, we never got to hear about the mechanism with which AMX0035 impacts the tau in the -- in your Phase II trial, which is CENTAUR. Is there any insights?

Yes. So maybe first on PSP and ALS and their degenerative pathways. So I think for both of these diseases, there's still a lot of research into exactly all the etiology and pathology. I think our view and the literature, there's a lot of literature on this as well is that both diseases see significant cell death related to endoplasmic reticulum and mitochondrial related pathways, which is what we developed AMX0035 to target. And then in terms of the pathways whereby AMX0035 may affect how -- so I think there's a lot of literature on the link between tau and endoplasmic reticulum stress. And so that's something that we've focused on there. But this change in tau, we've seen both in preclinical models, including ones that are published as well as in our Phase II Alzheimer's randomized placebo-controlled study. So we feel that that's a pretty robust and consistent finding.

Thank you. There are no further questions at this time. I'll turn the call back to Mr. Klee for final comments.

Thank you all very much for joining us this afternoon. We covered a lot of exciting news. Our commercial ramp in U.S. and Canada is proceeding really well. We're expanding into another clinical indication, which has a huge unmet need and has a market that is probably likely as large as ALS. And with the product, as we said, that's already been shown to be safe and well tolerated in a neurodegenerative disease as well as show quite significant reductions in tau. And maybe one other thing we only talked on briefly, but we achieved our first quarter of profitability in just the second quarter of commercial launch in the U.S., which we're really excited about. We're a mission-driven company. We have many more people to help and many more people to help around the world, both with ALS and we hope with other neurodegenerative diseases as well. Achieving profitability is what's going to allow us to have a sustainable business to keep moving forward and keep helping more and more people with neurodegenerative diseases. So thank you all very much for joining us and for your support, and we hope you have a great rest of your day.

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