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Good morning. My name is Jenny, and I will be your conference operator today. At this time, I would like to welcome everyone to the Amylyx Pharmaceuticals Fourth Quarter and Full Year 2023 Earnings Conference Call. All participants will be in a listen-only mode. After today's presentation, there will be an opportunity to ask questions. [Operator Instructions] I would now like to turn the call over to Lindsey Allen, Head, Investor Relations and Communications. Please proceed.

Good morning, and thank you for joining us today to discuss our fourth quarter and full year 2023 earnings. With me on the call are Josh Cohen and Justin Klee, our Co-CEOs; Jim Frates, our Chief Financial Officer; and Dr. Camille Bedrosian, our Chief Medical 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 made 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 RELYVRIO, also known as ALBRIO

Thank you, Lindsey, and good morning. 2023 was a transformational year for Amylyx. It was the first full year that our commercial product RELYVRIO, also known as ALBRIO

Thanks, Justin, and good morning. As mentioned, 2023 was a transformational year for Amylyx. We delivered a strong launch for people living with ALS and we've become a profitable business. In addition, we're developing a significant pipeline to neurodegenerative disease and preparing for long-term growth. Now, let me turn to the financial results for the quarter. Net product revenues were $108.4 million for the fourth quarter compared to net product revenue of $102.7 million for the third quarter of 2023 and $21.9 million for the fourth quarter of 2022. The increase from Q3 to Q4 was primarily driven by an increase in net product revenues in international markets, including revenues generated in Canada and through early access pathways in Europe. In the US, which represents the vast majority of our revenue, our net product revenue in Q4 were slightly ahead of our revenues in Q3. For the full year, net product revenues were $380.8 million. Gross to net adjustments were approximately 14% in the quarter and 12% for the full year, in line with our expected gross to net range. They were higher in Q4 as a greater proportion of our revenue came from outside the United States. Going forward, we continue to expect gross to net adjustments to be in the range of 12% to 15% until more significant revenues begin to accrue from outside the United States. Channel inventory levels at quarter end were as expected, with approximately two weeks of inventory in the channel at specialty pharmacies similar to what we've seen in previous quarters. Cost of sales were $9.4 million for the quarter and $25.4 million for the full year, representing roughly 9% and 7% of net product revenues for the quarter and year, respectively due to slightly higher write-offs in the quarter. We continue to expect COGS to be in a range of 5% to 10% of sales. In terms of free goods, roughly the same number of people in the United States received RELYVRIO for free in Q4 as they did in Q3, through either our interim access program or patient assistance program. Going forward, we expect free drug to remain in the range of 10% to 15% of total US prescriptions. Research and development expenses were $44.9 million for the quarter and $128.2 million for the full year. The increase in the fourth quarter was primarily driven by increases in personnel expenses, our global Phase 3 trial in PSP, which was initiated in December of 2023, the open label extension of PHOENIX, and spend related to the advancement of other programs in our portfolio. We expect quarterly R&D expenses to grow modestly quarter by quarter as we enroll patients in our ORION study and continue to build out our preclinical portfolio. Selling, general and administrative expenses, or SG&A, were $52.2 million for the quarter and $188.4 million for the full year. The increase was mainly driven by increases in personnel and marketing expenses. Again, we expect SG&A to grow modestly as we roll out additional growth initiatives for RELYVRIO in the United States and prepare for additional growth internationally should the PHOENIX study be supportive. Our work this year led to a strong bottom line with $49.3 million in net income for the full year. This represents our first full year of profitability and is a testament to the demand that we see both near and long-term for an efficacious treatment at ALS. Supported by our operating profits, we ended the year with a strong balance sheet, we had $371.4 million in cash and short-term investments and zero debt. Finally, before I turn the call over to Camille, I'd like to take a moment to reflect on our first full year of launch. We're proud that RELYVRIO has already been prescribed to thousands of people with ALS in the United States and Canada, and our therapy is having a transformative effect on the way people with ALS are treated. We believe we have significant growth opportunities ahead of us as we work to bring our treatment to many more thousands of people. We're focused on delivering for people living with ALS, expanding the use of RELYVRIO and other neurodegenerative diseases, and expanding our research into new mechanisms even as we deliver on our bottom line. We're in a unique and exciting position as we enter 2024. I'll now turn the call over to Camille.

Thanks, Jim, and I too wish you a good morning. I am pleased to have this opportunity to speak with all of you today. I joined Amylyx just a few months ago at an important inflection point for the company as we near anticipated top line data from the PHOENIX trial. The Amylyx team has made great strides in redefining how people with ALS are treated and in developing innovative therapeutic candidates for the treatment of neurodegenerative diseases more broadly. Prior to Amylyx, I was the Chief Medical Officer at Ultragenyx, Alexion and ARIAD, and now I'm excited to be a part of this mission driven Amylyx team as we work to change the lives of people living with ALS and other neurodegenerative diseases. Many doctors consider ALS one of the worst diagnoses possible to give a person. ALS is a disease of being locked in a body relentlessly losing its ability to function independently, while also being conscious of what is going on. Every day, people living with ALS wake up in the morning and discover they will never again independently button their shirt, put in their contact lenses, brush their teeth, or speak with their families. They lose the ability to eat, to hug a loved one, and to walk. Knowing that the next loss is just around the corner, people living with ALS and their families live in a perpetual state of uncertainty and loss. We have shown the trajectory of ALS can be meaningfully changed. RELYVRIO is the first and only ALS therapy to help slow disease progression, maintain functional independence, and extend overall survival in the same trial called CENTAUR. With CENTAUR, we completed a randomized, placebo-controlled study that met its pre-specified primary endpoint. This result led to regulatory approvals in the US and Canada, publications in the New England Journal of Medicine, the Journal of Neurology, Neurosurgery and Psychiatry, and several other peer reviewed journals. The PHOENIX trial will provide additional efficacy and safety data and a larger population of people living with ALS and build on the robust and positive results observed in the CENTAUR trial. PHOENIX enrolled 664 people living with ALS and will evaluate function over 48 weeks using the same primary endpoint as CENTAUR, the ALS Functional Rating Scale Revised, or ALSFRS-R, which is the gold standard measure of disability progression in ALS. Baseline characteristics show the population enrolled in PHOENIX has substantial overlap with CENTAUR, as was presented at ENCALS in July 2023. The PHOENIX population is within one point of CENTAUR on the baseline ALSFRS-R score and within one month of CENTAUR on baseline times and symptom onset. PHOENIX has the potential to be the largest Phase 3 study in ALS to demonstrate a treatment benefit, which would make RELYVRIO the first and only therapy in ALS to generate positive data in two different trials. This would be an achievement never before seen in ALS, and we are enthusiastic about what supportive data from PHOENIX might mean for people living with this disease. Moving to our R&D pipeline, we are advancing several important programs and have a number of expected milestones coming up in 2024. We believe targeting neuronal death with RELYVRIO also known as AMX0035, may have applicability across other neurodegenerative diseases. A multinational Phase 3 ORION trial of AMX0035 in Progressive Supranuclear Palsy, or PSP, was initiated in December 2023 and we anticipate top line results in 2025 or 2026. We shared the scientific rationale on AMX0035 for the treatment of PSP in detail in a webinar posted on our website in July 2023. Turning now to our Phase 2 HELIOS trial of AMX0035 and Wolfram syndrome. The trial is now fully enrolled and we expect to report results in the second half of this year. Wolfram syndrome is an ultra-rare genetic disease that leads to multisystem failure resulting in blindness, deafness, diabetes, ataxia, neurodegeneration, and typically death by early adulthood. There are no approved therapies for Wolfram syndrome. Our R&D team has been collaborating with Washington University for many years to conduct research, which led to our decision to conduct the Phase 2 trial. We are looking forward to what the data from HELIOS would mean for people with Wolfram syndrome, a community where the unmet need is incredibly high. We are also advancing AMX0114, our antisense oligonucleotide candidate targeting calpain-2, through IND-enabling studies and expect to enter the clinic by year end. Calpain-2 is a critical effector of axonal degeneration, which is implicated in the pathogenesis of ALS. Again, I am very excited to be part of Amylyx and look forward to meeting many of you. I will now turn over the call to Josh.

Thanks, Camille. As we eagerly await the PHOENIX top line results, we are developing updated clinician engagement and marketing program and believe supportive data would help in all aspects of our launch. And of course, our plan in the event of supportive data will be to re-engage global regulatory agencies, including in Europe, in support of our goal to help more people access the benefits of RELYVRIO as quickly as possible. And to preempt a question that may be on many of your minds, there's no early look into the PHOENIX data and we do not yet know the outcome of PHOENIX today. In addition, we are continually striving to transform and improve the way ALS is treated. And to this end, we are working to accelerate the time it takes to diagnose ALS. Current data suggest that diagnosis takes about a year from symptom onset and is not a straightforward path. Many people with ALS are misdiagnosed initially and see several specialists before they are accurately diagnosed with ALS, valuable time that could be spent on a therapy that slows neuronal death. To accomplish this, we are developing a novel biomarker panel to assist in diagnosing ALS earlier and we intend to provide results from initial experimentation this year. Lastly, in addition to Camille and Dan, we are thrilled that Linda Arsenault recently joined us as our new Chief Human Resources Officer. She brings over 30 years of leadership and experience, including most recently from Sunovion where she was the Chief Human Resources Officer. We are excited to welcome her to our team. In closing, we are proud of the achievements we made in 2023. We had a strong start to our launch of RELYVRIO and have reached many thousands of people living with ALS. In 2024, we are planning for PHOENIX top line data anticipated during the second quarter or before, which we believe if supportive will be instrumental to our growth trajectory. We are a profitable company, which enables us to self-fund our R&D pipeline and evaluate RELYVRIO in other neurodegenerative diseases. We have a substantial opportunity ahead of us, both with our commercial launch in the US and globally and with our pipeline. We are intently building a differentiated long-term franchise focused on developing and delivering innovative and impactful treatments for people living with neurodegenerative diseases around the world. Now, we'd be happy to take your questions. Operator, please open the call up to Q&A.

We will now begin the question-and-answer session. [Operator Instructions] Your first question is from Geoff Meacham from Bank of America. Please ask your question.

Great. This is Charlie Young on for Geoff. Thanks for taking the question. I guess, for this year, given this Part D redesign, can you just talk about what's the potential kind of gross projection for this coming year? And secondly, can you also tell us about what's the net patient ad for the fourth quarter compared to prior quarter? Thank you.

Yes. Maybe I'll start on the Part D benefit redesign and I could pass to Justin on the net patients as well. So in the Part D benefit redesign kind of happens in two steps. There's some degree of the redesign that happens this year and then it goes into full implementation at the start of 2025. The big change this year is that the copay during the catastrophic phase of Part D is no longer in effect for patients. So I think we view that generally as positive for patients. But of course, we already had robust programs to provide financial assistance or free drug when necessary. So we don't think it's going to be a major impact on the business. And I'll pass to Justin on net patients.

Yeah. In our prepared remarks, we said net patients on therapy were stable to Q3, meaning it was approximately the same level as what we reported in the third quarter.

Thank you. Your next question is from Neena Bitritto-Garg from Deutsche Bank Canada. Please ask your question.

Hey, guys, thanks for taking my question. I was just wondering if you could talk a little bit more about some of the gross to net dynamics that impacted the numbers specifically in the US. I know you did take a gross price increase in the US. I was just wondering if that was offset. And then if you could maybe explain a little bit more about the magnitude of the ex-US sales and how that compares to prior quarters and how we should think about that contribution moving forward. Thanks.

Sure. Hey, thanks, Neena. And I didn't realize you were part of Deutsche Bank Canada, but that's good.

Me neither.

So they really -- I mean, I think the gross to net, you see sort of typical local fluctuations, and as I pointed out in the remarks, most of the change, sort of the upward trend in Q4, really came from actually the European and Canadian revenue that we saw growing. So those have higher gross to nets than we do in the United States. And so in the United States, we did take a modest price increase. It was less than the inflation rate, actually, and really didn't impact gross to nets at all. So those remain stable and we're not doing any contracting with insurers. That hasn't changed. And we think our access is actually really excellent in the US. So related to the European and Canadian sales, we announced our early access program in France in October. There are other managed access programs across Europe, some free, some paid. That's a far cry from obviously a full approval and the access that we want. But of course, post a successful PHOENIX, as Josh mentioned, we'll be back and looking for broader global approvals as quickly as is appropriate should the database be supportive. But we did point out that the revenue in the United States was quite stable. It did grow slightly quarter-over-quarter, but the majority of our growth came from those programs ex-US. And I think it does point to a global opportunity for us as we move forward, right? We retain rights around the world for this product. ALS is a disease that unfortunately strikes people equally in all regions of the world. And there's a major opportunity, as I think all of you know, in rare disease treatments for the global contribution to be quite significant over time. Obviously, we'll have to wait and see how PHOENIX goes, but I think it's portends wells for the future.

Awesome. Thank you so much.

You're welcome.

Thank you. Your next question is from Corinne Jenkins from Goldman Sachs. Please ask your question.

Thanks and good morning. Maybe from me, can you just provide an update on the duration of therapy you're seeing in the US and talk to us about some of the specific strategies you're deploying to improve that duration of therapy? And then maybe as a follow-on, like, when do you expect those to potentially translate into real benefit as measured by revenue?

Hi, Corinne. Yeah, thank you for the question. So you know, our -- we've been reporting on our six-month persistence rate and it's held steady. So in the US, we're still seeing approximately 60% of people still on RELYVRIO six months after initiating treatment. And in Canada, that number is roughly 80% at six months. So I think the first thing is that we're taking learnings from Canada and applying those to the US. And I think what we found is that when you look doctor by doctor, some doctors have much, much higher persistence rates than others. And I think what we've learned from Canada, as well as looking at those individual doctors, is that it comes down to education. If people know that this is -- they're being prescribed this treatment, because it'll slow down their ALS, it'll keep them alive longer, then they're much more likely to stay on treatment. There are also very practical strategies for mitigating any potential side effects. Again, we're trying to transform ALS from a disease that has historically focused mostly on symptom management to one that focuses or we're trying to focus on intervention. And so part of that is, as things come up, how do we manage them. And there are very practical ways that we can do that. And so I think in terms of when that will translate to revenue, we've, I think, made these recognitions recently, we've put many initiatives in place. We now have Dan Monahan leading our US commercial efforts as well. So we expect all of these things to build throughout the year.

Thank you.

Thank you. Your next question is from Michael DiFiore from Evercore ISI. Please ask your question.

Hi guys, thanks so much for taking my question. Two for me. Number one, how is the campaign of taking learning from Canada and applying it to the US prescribers? What's the reception been like so far? I realize it's pretty early. And my follow-up is, any thoughts or any color you could add on when you may lift the restriction on prescription reporting data, when might we expect that to happen? Thank you.

Yeah, thank you. And I'll certainly take the first one. So, I agree. So it's early, but I think the learnings from Canada, the initiatives now that we're advancing the US, we've had very positive feedback. I think, again, if you try to think about what does it mean to transform a disease that historically is focused on symptom management, because that's largely the tools that have been available, I think that, in short, it's education. So, for example, saying that this is not a cure, but it may slow down your ALS and keep you alive longer. That's a big deal. And that changes how one even talks about the disease, focusing on mitigation of any potential side effects. Again, in the past, if one has not had to manage side effects, then those things can be uncertain. But again, it just comes down to education. And I think that the doctors and nurses and therapists who care for people with ALS, I mean, first of all, they're just amazing people. And second, I think they're very, very excited at the opportunity to see this sort of transformation. But I think it's important that we and not just we, but all of our partners provide the right education on these things as well. So I would say that I think the reception has been excellent. As I was saying in the previous questions, I think that the impact long-term on revenue, we'll see continue to build throughout the year.

Yeah. Mike, and maybe I'll take the question on the access to the prescription data. I think from our read of the situation, it's not atypical to not have that data available in a rare disease indication. We don't have any plans to change it now. And I think we're really focused on making sure that we can deliver growth, particularly after PHOENIX and internationally. That's going to be where our focus remains.

Thank you.

Welcome.

Thank you. Your next question is from Graig Suvannavejh from Mizuho. Please ask your question.

Thank you. Good morning. Two questions, if I could. One, any insights you could give into how things are progressing early in 2024 given like the changes that you're trying to make from a commercial perspective and whether there's any uptick versus the fourth quarter trends. And then secondly, I'm curious about this novel ALS biomarker panel that you're developing. Also there, could you provide some color on which exact -- what types of biomarkers might be included in that panel would be appreciated. Thanks.

Yeah. Thank you, Graig. So I would say, as I was saying in the previous remarks, I think with the initiatives we've seen, I think great reception from the community and maybe break things out, as I did in the opening remarks, again into sort of two broad categories. I think first is physicians who specialize in ALS. And I think there the educational opportunities we've seen some people who have fundamentally changed their medical practice, others have not. And so I think there, it's about educating on the benefits of RELYVRIO as well as tools, practical tools to mitigate side effects. And then secondly, there's about half of people with ALS don't make it to a specialist or not primarily cared for by a specialist. And for them -- for many of them, their knowledge and awareness of ALS is what they learned in medical school. I mean, it might be 20, 25 years old, so they're very unaware of not just our treatment, but even the general advances that the field has made. So there, I think awareness is really key. And I would highlight as well that I think PHOENIX is a really great opportunity in both of those segments, both to increase confidence for the specialists in the potential benefits of RELYVRIO for their patients, as well as the opportunity to increase awareness more generally in the medical community. And on the diagnostic side, I'll definitely pass to Josh.

Sure. So when we thought about the ALS diagnostic, I think the first thing to note is that when you think about the pathophysiology of ALS, you have the neurons that go from the brain to the spinal cord and then a second set of neurons that go from the spinal cord to the muscle that degenerate in massive quantity over the course of just two or more years. So it stands to reason that at least something, something must be released or measured or measurable when that process occurs. So we've collaborated with several experts in biomarkers and clinically in the ALS space. And what we can tell from looking is there has not really been a serious effort thus far in the field to try to develop a diagnostic in the space. There's many markers that seem to be up or down in ALS, but nobody's taken those together towards a kind of serious effort towards making diagnostics. So we're quite excited about that program. I think there's a lot of low hanging fruit there, but we'll be reporting data on that later this year.

Thank you. Your next question is from Marc Goodman from Leerink Partners. Please ask your question.

Hi, this is Madhu on the line for Marc. Are patients who are starting on RELYVRIO now earlier on in their disease or closer to diagnosis than earlier in the launch? And then secondly, what's your experience been outside of centers of excellence maybe in more community centers? Has engagement with the general neurologists there and patients been high or just curious on your experience there so far? Thanks.

Yeah, great questions. So I think over time, naturally, I think we'll get people who are closer to diagnosis. I think at launch, we're looking at the prevalent population, whereas over time, the expectation is you get people closer and closer to diagnosis. And then I think that changes how you think about your education and persistence efforts as well. And then on the second question -- the experience outside of the centers. Yes. So I think our prescribing remains fairly concentrated still. So roughly 80 doctors account for about half of all prescriptions. And as you might imagine, those are -- the vast majority are ALS specialists. So I think some of our initiatives that we've just started kicking off, and we're very excited to have Dan lead as well are to boost general awareness in the broader medical community. And so we'll continue to do those throughout 2024 and I think then we'll expect to see the prescriber base broaden throughout the year. But I think it's a really nice place to start from where we have people who have fundamentally changed their medical practice. These are the ALS specialists who see the most people with ALS. So I think it's a really nice foundation to have and then we can broaden out from there.

Thank you. Your next question is from Joel Beatty from Baird. Please ask your question.

Hi, this is Ben on for Joel Beatty. Thanks so much for taking our question. Could you walk us through what the potential implications for RELYVRIO could be when the TUDCA ALS trial results are announced?

Yeah. So I think first, it's really important to note that these are different products and different trials. So our drug RELYVRIO is a combination of sodium phenylbutyrate and taurursodiol in a proprietary coformulation. So it is not the same product as TUDCA. And additionally, these are very different trials. PHOENIX and CENTAUR were trials designed with all the experts in the field, using some of the most state-of-the-art ways of running these trials in a controlled and rigorous way. I'd say thus far, the TUDCA trial that's been run is quite different in design. It's a smaller trial, primarily with kind of an academic design tilt that was also run during the peak of COVID. So I think probably the broad strokes is we don't really think they're comparable and that there will be read through between the two. So we wouldn't draw those comparisons as that data comes.

And I would just reiterate, too. RELYVRIO is the only FDA approved medication that was shown to slow ALS progression on the ALS Functional Rating Scale, extend overall survival in the same clinical trial, and was published in the New England Journal of Medicine. So I think that's why among the ALS specialists, we've seen such excitement. That's why FDA approved the medication.

Thank you. Your next question is from Ananda Ghosh from HC Wainwright. Please ask your question.

Yeah. Hi, good morning. First of all, congratulations on reaching the milestone for completing the first year of the launch. It has been great seeing the story evolve from the inception and being the last, maybe I have two questions. The first one is related to PHOENIX. The PHOENIX, as the intuition criteria mentions, definite and clinically probable ALS patients. So my question is, how do one define clinically probable ALS patient? What was the rationale behind including that group of patients and how does it change the way the data is analyzed?

Yes. So maybe first, I probably will try not to get too in the weeds, but first, in terms of the definition. So the El Escorial criteria of ALS defines many different potential groups, including suspected, possible or probable lab supported, probable and definite. And the difference between those is essentially how many regions of the body are convincingly affected by ALS with possible being one, probable lab supported being one plus different lab tests, probable -- clinically probable being two, and definite being three or four. The body's divided into four regions on the scale. What's been shown over time is that even people with possible ALS on this criteria have ALS. About 98% of them have ALS. So it's not like -- it's not actually a scale of certainty, it's much more a scale of diffusion, basically, how far across the body ALS has progressed. When we did statistical modeling, going for the probable and definite patients does give you a more consistent and fast progressing group, which is important. And that was one of the rationales for including them in the trial. But I think the most important thing when we compare CENTAUR and PHOENIX on the baseline characteristics is that at baseline the two populations look very similar. They're within a point on the baseline ALSFRS-R and within a month on the baseline times and symptom onset, which are two of the most important measures when we're thinking about how a cohort is likely to progress and to perform.

Got it. Thank you. The second question is related to the rare disease. Yesterday, there was this public discussion on the biomarkers in the rare disease space, where Peter Marks, I think was very positive about using biomarkers for accelerated approval pathway. Now being in the company where you are looking at rare diseases like ALS, Wolfram syndrome, and there was discussions on developing biomarker panels for ALS. Is there a strategy to kind of develop very definite biomarkers, like surrogate biomarkers, that might help get to that accelerated approval pathway for other rare diseases in the pipeline, such as Wolfram?

Yeah. Thank you. This is Camille. Appreciate the question. We actually are very heartened by Dr. Marks’ comments around the possibility of using biomarkers for accelerated approval and rare disease. It will make a tremendous impact giving the opportunity to treat individuals sooner, study the disease process and impact in particular neurodegenerative diseases where there is often a small window of opportunity and therefore have drugs available to those individuals sooner. And we do see opportunities, you heard Josh mention the biomarker profile for diagnosis, which can have an impact. And we're looking at Wolfram syndrome in similar ways as we consider with our initial trial, ways of learning about the clinical biology as well as potential biomarkers there. So stay tuned.

Thank you. There are no further questions at this time. I will now turn the call back to Mr. Klee for the closing remarks.

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