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

Good morning. My name is Kat, and I will be your conference operator today. At this time, I would like to welcome everyone to the Amylyx Pharmaceuticals Phase III LUCIDITY Topline 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 call over to Lindsey Allen, Vice President, Investor Relations and Communications.

Good morning, and thank you all for joining us today to discuss the top line results from the Phase III LUCIDITY trial of Avexitide in Post-Bariatric Hypoglycemia or PBH. The slide deck accompanying our remarks this morning will be available on the Investors section of our website for your reference following the conclusion of the call. With me on the call today are Josh Cohen and Justin Klee, our Co-CEOs; Dr. Camille Bedrosian, our Chief Medical Officer; Dr. Marilyn Tan, Principal Investigator of the LUCIDITY clinical trial and Clinical Professor of Medicine at Stanford University School of Medicine; Jim Frates, our Chief Financial Officer; and Dan Monahan, our Chief Commercial 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, the therapeutic potential and safety of Avexitide as a treatment for PBH, expectations regarding the timing for NDA submission with the FDA, the potential benefits of regulatory designations held with the FDA, the plan to present data at an upcoming medical meeting and expectations regarding the timing and preparations for potential commercialization of Avexitide if approved. 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 Camille.

Thank you, Lindsey, and thank you all for joining us this morning. It is with great enthusiasm that we share the positive top line results from the Phase III LUCIDITY trial of our lead asset, Avexitide, an investigational first-in-class GLP-1 receptor antagonist in post-bariatric hypoglycemia or PBH, following Roux-en-Y gastric bypass surgery. LUCIDITY met its FDA agreed upon primary endpoint, demonstrating a 55% reduction in the composite rate of Level 2 and Level 3 hypoglycemic events compared to placebo p-value of 0.000003. The trial also met all secondary endpoints, demonstrating consistent reductions in both Level 2 by self-monitoring blood glucose, or SMBG, and continuous glucose monitoring, or CGM, and Level 3 hypoglycemic events versus placebo. And importantly, Avexitide was generally well tolerated through the double-blind study period with a favorable safety profile. LUCIDITY is the sixth clinical trial of Avexitide to generate statistically significant results in PBH and the largest and longest study conducted to date. Taken together, these findings support the potential for Avexitide to become the first FDA-approved therapy for PBH, a condition with a profound unmet medical need. I would like to briefly recap the design of the Phase III LUCIDITY trial. LUCIDITY is a multicenter, randomized, double-blind, placebo-controlled trial evaluating the efficacy and safety of Avexitide in adults with PBH following Roux-en-Y gastric bypass surgery. The prespecified primary endpoint was the composite rate of Level 2 and Level 3 hypoglycemic events compared to placebo through week 16. In addition, we evaluated secondary endpoints of Level 2 hypoglycemic events as measured by SMBG and by blinded CGM and Level 3 hypoglycemic events. Level 2 events are defined as glucose levels below 54 milligrams per deciliter, an established threshold for clinically significant hypoglycemia and Level 3 events are defined by significant cognitive or physical impairment requiring assistance from another person. These endpoints capture hypoglycemic events that matter to patients and can have meaningful consequences for safety and day-to-day functioning. In a few moments, Dr. Tan will speak about the day-to-day impact of PBH on those living with this condition. In the trial, 78 participants were randomized 3:2 to receive either Avexitide 90 milligrams once daily or placebo. The treatment groups were generally well balanced. More than 90% of the participants completed the 16-week double-blind treatment period and all eligible participants entered the ongoing open-label extension portion of the trial. Avexitide met the primary endpoint, demonstrating a 55% reduction in the composite rate of Level 2 and Level 3 hypoglycemic events compared to placebo through week 16 with a p-value of 0.000003. It is important to note that these results are on top of current standard of care medical nutrition therapy. We are deeply inspired by these results and the potential to address a long-standing unmet need for people living with Post-Bariatric Hypoglycemia. In addition, LUCIDITY met all secondary endpoints, demonstrating consistent, highly statistically significant and clinically meaningful reductions in Level 2 hypoglycemic events by SMBG, Level 2 hypoglycemic events by CGM and Level 3 hypoglycemic events compared to placebo. Taken alone, each of the prespecified primary and secondary endpoints yielded highly statistically significant and clinically meaningful results. Taken together, these efficacy findings demonstrate a compelling body of evidence for Avexitide in PBH. Avexitide was generally well tolerated in the double-blind portion of LUCIDITY with a safety profile consistent with that observed across all PBH clinical trials completed to date. The majority of adverse events were mild to moderate, and there were no serious adverse events deemed related to Avexitide treatment. The most common adverse events were diarrhea, injection site redness or erythema and injection site bruising. Furthermore, there were no changes in body weight observed in either the Avexitide or placebo group over the 16-week double-blind period. To close, the LUCIDITY results demonstrated highly statistically significant and clinically meaningful reductions in hypoglycemic events together with a favorable safety profile. Based on these positive data, we believe that Avexitide has the potential to be the first ever FDA-approved therapy for PBH. I want to thank the PBH community for their collaboration and participation in the study, including the 21 LUCIDITY sites, investigators, study coordinators and importantly, the participants. I also want to acknowledge our outstanding Amylyx team for their unwavering dedication to running such a robust and high-quality trial. Now I would like to turn over to Dr. Tan, principal investigator of the LUCIDITY clinical trial to give an overview of PBH and what these trial results mean to the PBH community.

Thank you, Camille. It is my pleasure to be here today to discuss these exciting results and how they can make a difference for this underserved population. PBH is a rare chronic metabolic condition believed to be caused by an exaggerated GLP-1 response primarily after food intake, resulting in recurrent and often debilitating hypoglycemia. These episodes can lead to Neuroglycopenic symptoms, including cognitive impairment, loss of consciousness and in some cases, seizures or even worse. Patients frequently describe living with PBH as a constant cycle of highs and lows with sudden and unpredictable glucose crashes that can be difficult to anticipate and manage. The impact extends far beyond just physical symptoms. The unpredictability of hypoglycemia can affect a person's ability to work, drive, care for family members, participate in social activities or even remain alone safely. As a result, many patients structure their daily lives around the risk of hypoglycemic events, creating a substantial burden both on the patients and their loved ones. This burden is reflected in patient-reported data. In one study, more than 90% of individuals with PBH described themselves as living with a disability. This underscores the profound impact the condition can have on quality of life and day-to-day functioning. Based on a growing body of prospective and retrospective published literature, we estimate that PBH impacts approximately 5% of people who have undergone sleeve gastrectomy and 12% of people who have undergone Roux-en-Y gastric bypass, the two most common types of bariatric surgery. This corresponds to an estimate of approximately 160,000 people living with PBH in the U.S. who require medical management but currently have only the option of medical nutrition therapy and off-label medications, which are usually inadequate. And this is also why I'm so excited about the potential for Avexitide in this disease space. Looking mechanistically, individuals with PBH can present with more than 10x normal physiologic GLP-1 activity. By binding to the GLP-1 receptor on pancreatic islet beta cells, Avexitide is designed to reduce this exaggerated GLP-1 response and restore activity towards more physiologic levels. Today's positive results support the hypothesis that a GLP-1 receptor antagonist targets a central pathway of PBH pathophysiology. The top line results show that Avexitide significantly reduced both SMBG and CGM Level 2 and Level 3 hypoglycemic events, which can each be medical emergencies. Based on my clinical experience treating people living with PBH, they want more than anything to reduce the number of hypoglycemia events so that they can live independently without the fear of hypoglycemia. This is our hope for the approximately 160,000 people with PBH in the U.S. alone who face a significant unmet need for treatment. Importantly, Avexitide was generally well tolerated with a favorable safety profile. Overall, these results build on positive results from five prior clinical trials of Avexitide in PBH. Today marks a significant moment for the PBH community who have a high unmet need for an FDA-approved treatment. PBH is a lifelong journey, and I believe that Avexitide has the potential to be a first-in-class treatment for patients that will make a meaningful difference in their lives. Now I would like to turn it back over to Josh, Co-CEO of Amylyx.

Thank you, Dr. Tan. Our mission at Amylyx is to deliver novel therapies for communities with high unmet needs, and today's results are an important step forward towards achieving this goal. With these results in hand, we are acting with urgency to bring this potential treatment to the PBH community. We have been advancing NDA readiness and regulatory preparations so we can move rapidly now that we have positive top line data. Avexitide has received breakthrough therapy designation from FDA, and we are working expeditiously towards an NDA submission by the end of this year. Following the top line data readout, we are also focused on presenting the LUCIDITY results through congress presentations and publications and deepening our understanding of PBH via expert engagement. We continue to execute against a comprehensive launch readiness road map to ensure we are fully prepared for commercialization of Avexitide if approved in 2027. As part of our launch readiness efforts, we are continuing to build our understanding of the PBH market and making key hires in our medical affairs and commercial organizations. Additionally, we recently activated our disease state education campaign, Uncover the Mystery of Post-Bariatric Hypoglycemia to address the educational need among HCPs and the PBH community. As part of this initiative, we launched uncoverpbh.com. This platform provides educational resources for both health care professionals and the PBH community. With over $250 million in cash on hand at the end of Q2, we believe we are well positioned to execute on the next stages of our launch plans. We are excited about today's results and the potential to bring Avexitide to people living with PBH as the first approved therapy of its kind. I'll now turn the call over to Justin for concluding remarks.

Thank you, Josh. At the start of the year, we outlined three primary objectives for Avexitide to deliver top line data from the LUCIDITY trial, advance NDA readiness to support a potential submission and strengthen our commercial launch preparations. With strong top line data in hand, we have achieved our first objective. We are well on our way to achieving our further objectives as we diligently prepare to advance Avexitide through the regulatory process and ultimately, if approved, deliver this potential treatment to the PBH community. This is a remarkable moment for people living with PBH, their loved ones and for Amylyx, and we are deeply grateful for everyone's support. I would like to once again thank the PBH community, investigators and our team for their collective efforts. Now I would like to open it up for Q&A.

[Operator Instructions] And your first question comes from the line of Seamus Fernandez with Guggenheim Securities.

Congratulations on the data. Maybe just one confirming question. As I look at the data and the way that it's presented, I think the most simplistic way to look at this without knowing the exact placebo response may be to kind of draw us back to the Phase II results where we saw a 55% to 60% absolute reduction in the events. Is that the right way to think about the data? It's just we haven't seen slides posted yet. And so it's a little bit challenging to draw conclusions there. So if you could tell us the placebo response, that would be very helpful. But if it is the right way to think about it, just go back to the Phase II because you're preserving these results for publication and for a major medical meeting, that would be super helpful, I think, to everybody on the line. And then separately, we have this outstanding question, and this is a question for the team and for Dr. Tan as well. Is there any reason to think that Roux-en-Y versus all other types of PBH or hypoglycemia brought on by a bariatric surgery or even a gastric surgery would have a meaningfully different result than what we saw in this Roux patient population. I asked that question just because it seems like there is a broader potential opportunity should the agency take a more flexible approach to the results that were just published.

Yes, possibly, I'm happy to maybe take the first one and Dr. Tan, and I'll pass to you right after that if it works. So maybe kind of confirming on your first question about the placebo. Yes, I think you're thinking about it right. And probably overall, our goal in LUCIDITY was to be as consistent with the prior trials as possible. And I think we're quite excited to have seen that the results appear quite consistent with what we've seen in prior trials. So yes, the 55% is relative to placebo, very similar to the 55% reduction we saw in the composite relative to placebo in PREVENT, the Phase II trial. And then yes, on your question about Roux-en-Y versus other surgical types, I'll pass to Dr. Tan.

Thank you. As mentioned, the data from Phase IIb in particular, we had reanalyzed looking at a similar endpoint. And so we're very excited for the results compared to placebo. And as you know, this study was in patients with Roux-en-Y gastric bypass. And increasingly, we are seeing more vertical sleeve gastrectomy. However, there is still a very prevalent population of those with Roux-en-Y gastric bypass. And in my personal practice, I have many patients actually with other subtypes of surgery as well, which you alluded to. Many patients who have had total gastrectomies for gastric cancer, Nissen fundoplication, other upper GI surgeries. And while this study only included patients with Roux-en-Y gastric bypass, the Phase IIb study did include patients with other surgical subtypes. And when we separated out the VSG and gastrectomy patients, their response to Avexitide was just as robust for reducing Level 2 and Level 3 events. We know that there is an exaggerated GLP-1 response in those patients as well. So I'm excited to have this option available. And I am fairly certain that most health care providers who are treating these patients would use it in PBH patients who have other surgical subtypes.

Yes. And I'll just add -- just to give a little more context from our perspective and a bit on the landscape. So I think the best current prevalence estimates come from the work from the team from Stanford, which found that the current U.S. prevalence of PBH is about 160,000 people. And of that group, the estimate is about 120,000 of the 160,000 had Roux-en-Y gastric bypass leading to their PBH. As Dr. Tan said, though, there are many different surgeries that can lead to this condition. I'd say from an FDA perspective, obviously, it's early. We have yet to even submit our NDA. Our position is that PBH is PBH, and we have evidence that Avexitide appears to work regardless of the surgical intervention. But FDA can also take the stance that the Phase III population was Roux-en-Y gastric bypass PBH. And so we'll see as we get into the NDA. But again, our belief is that PBH is PBH. However, if we need to run an additional study to show that comparability, we think we can do that in a pretty efficient manner, given that we can see the effect of Avexitide in a single dose.

And your next question comes from the line of Joseph Thome with TD Cowen.

Congratulations on the data. Maybe one for Dr. Tan. Can you talk a little bit, assuming a broad label here, how quickly this would be adopted into your practice? Maybe sort of what proportion of your PBH patients would you recommend the therapy to upon approval? And then one for the company. Is there anything left on the sort of pivotal path to the NDA submission related to CMC? Or is it mostly just kind of getting this data into the NDA now? Anything you can highlight there?

My patients and I are extremely excited. I mean, the patients who have been on prior studies, the patients who are following this on the Facebook group, are asking me -- I literally had two asked me yesterday in clinic, when can I be on this drug. So there is a lot of excitement despite it being a new therapy, people are ready for it. So I don't think that there will be any hesitation. There is robust evidence in the PBH population. And more importantly, there is just no other effective treatment for these patients. And so to actually have a dedicated treatment targeted for this disease that actually targets the underlying pathophysiology is extremely exciting.

Yes. And as far as your second question on the NDA submission. So we've been working on the NDA this entire year, given the confidence in the five prior trials in anticipation of these results, although I'll say these results exceeded even our high expectations, which is really exciting with both the significant primary outcome and also the consistency across the secondary outcomes. But as far as the NDA submission goes, our goal was really to be in a position where the sort of last piece would be the Phase III data and all of the writing associated with that. And so that's the position we're in today. We're in a very strong position with our NDA. The goal is to submit by year-end. We have a breakthrough therapy designation for Avexitide, which makes the product eligible for priority review. And so with that, that's how we are planning for a potential launch of Avexitide if approved next year in 2027.

And your next question comes from the line of Michael DiFiore with Evercore ISI.

Huge congrats on the data, very well deserved. Two questions for me. Would you be able to provide the mean and median absolute composite event rates for Avexitide and placebo as well as for the 3-week run-in? And my second question is, what was the percent of Avexitide patients with 0 Level 2 or Level 3 events over the 16 weeks? I think your Phase IIb showed that they were -- this proportion was greater than 50% who were event-free.

Yes. Thanks, Mike. So yes, here, we're presenting the primary outcome, which to remind, we saw a 55% reduction with a p-value of 0.000003 which we're incredibly excited about. So that's our primary outcome here. I think as Seamus brought up a little bit earlier, we do want to preserve some results for publication. So we haven't given every nitty-gritty detail at this point. But what we have seen is kind of consistent and strong results across, including hitting every single one of our secondary outcomes with high statistical significance. And then yes, I think probably the same answer on the question of percent with 0, but I think you can probably tell from the p-value, the placebo and active groups are quite separated.

And your next question comes from the line of Jeff Meka with Citigroup.

This is Jarwei on for Jeff. Just wanted to add our congratulations on the strength of the data as well. Maybe first for Dr. Tan, just a question on Level 2 versus Level 3 differences given the -- it's very clear that the placebo response and the Avexitide response are quite separated. But at the end of the day, does it really matter the differences between Level 2 and Level 3? Or does the totality of the composite is just so compelling that it would be broadly applicable to patients living with PBH. And then for the Amylyx team, just thinking about the data that you guys generated, can it be utilized to maybe generate some pharmacoeconomic estimates? Just thinking about from a reimbursement perspective.

I can go first. As you noted, the data are just so compelling, and it was statistically significant for both Level 2 and Level 3. And I would say that from a clinical standpoint, I mean, we make this distinction in research, right? We have to have cutoffs. We have to have a number of cutoffs, and we have to have an adjudication committee to verify that it is a Level 3 event. But in the real world and in clinical practice, any hypoglycemia event can lead to a catastrophic accident or some other bad outcome. And so really any reduction in these significant -- clinically significant episodes of hypoglycemia is meaningful to these patients.

Yes. And I'd just add from a pharmacoeconomic perspective, we're continuing to evaluate and continuing to learn there. We did present a poster at ENDO earlier this year where we began to describe the burden of PBH from a pharmacoeconomic perspective, probably unsurprisingly, given how severe these events are, there is quite a large economic burden to the health care system from PBH. So we do believe a drug that's able to impact that can have quite a significant benefit there as well. But that's something we'll continue to research as we go into our payer interactions.

And I'll just add from a payer perspective as well. First of all, there are no treatments for PBH today. So that's the landscape that we go into. However, payers are very aware of the dangers of hypoglycemia given their long-time coverage of insulin and other drugs that may be associated with hypoglycemia. So I think they're very aware of just how dangerous severe hypoglycemia is for individuals. And I think that gives us a great position as we work toward the hopeful approval of what would be the first approved treatment for people with PBH.

And your next question comes from the line of Marc Goodman with Leerink Partners.

Can you talk about the diarrhea adverse event? Was it relatively mild? Did it occur at the beginning of the 16 weeks? Was it lasting throughout the whole period? Maybe Dr. Tan, was it severe enough that anybody complained about it and you think would prevent anyone from using the drug?

Happy to start, and then we can pass to Dr. Tan. So I'd say, again, obviously, these are the top line results, but I'd say, generally, the safety profile was quite good and Avexitide appeared to be quite well tolerated in line with prior studies. And so generally, events such as diarrhea were mild or occasionally moderate. And I would say, just generally, we had very good compliance continuation in the study. All eligible participants went into the open-label extension. So hopefully, that gives you a sort of population view, and I'll pass to Dr. Tan for her comments on the study as well.

So I can't speak to the exact details of all of the participants, but I can tell you that I did not have any participants discontinue and all of them went on to open-label extension. And just looking back at the prior trials that I've done with Avexitide, there have been four that I was the principal investigator -- or three others that I was the principal investigator on. And I have not had any drug discontinuations and even patients who have had any GI events in the past have asked me repeatedly when they can get back on the drug. So it has not been anything to the point where it discourages a patient from actively seeking out the treatment again.

Can I just ask Dr. Tan, how many patients do you have that would be eligible here for this drug?

The vast majority of my patients, over 90%. I have a more severe patient population, which tends to be more moderate to severe, although I do have a couple of mild ones that I've just kind of incidentally diagnosed in my clinic. But I would say anybody who is having any clinically important hypoglycemia would qualify for this medication. And people are waiting. They're excited. They're ready.

So over 90% of what absolute number.

Well over 100. But I don't focus so much on the number because I personally limit my clinic because I have no meaningful treatment for them. And so more importantly, I'd like to highlight that I literally get 1 or 2 new referrals each week, sometimes more, which I expect there will be more after this week from all over the country and from even outside of the country for PBH patients. So have I actually -- had I actually accepted all of those, I would have probably over 1,000 patients. I've literally had that number of referrals over the last couple of years.

And your next question comes from the line of Rami Katkhuda with LifeSci Capital.

Just wanted to pass along my congrats on the data as well. Fantastic results. I guess, can you touch on how consistent the efficacy was across baseline disease severity? Did patients with the highest event burden drive a similar greater, I guess, relative benefit? And could that influence whether the initial commercial focus is concentrated in more severe PBH patients?

Yes. So one, I'll just remind that everybody in the study was required to have at least an event per week during the run-in. So that was one of the key inclusion criteria of the study. I'd say based on the kind of difference you see here and the strength of the p-value, the groups are quite separated. So no individual or no small set of patients is driving this. The groups are really not overlapping once they're on drug. But yes, we'll continue to share more details as we get towards publications and presentations as well.