Checking this one. What's that? Can you hear me? I'll just talk louder. Well, good morning, everybody, and thanks for joining us for today's another fireside discussion here at Guggenheim's Healthcare Innovation Conference. Really pleased to have the team from Amylyx here with us today, Co-CEOs Josh Cohen and Justin Klee. That went sequentially to my left. But really thrilled. Amylyx has actually been a really gratifying story for the Guggenheim team. We picked up coverage, I think, in June of last year before kind of an epic run of successes. I'll turn it over to Josh and Justin to really give us a little bit of the lay of the land of where you see Amylyx headed from here in the wake of the very positive LUCIDITY data.
Sure. Yes, we had a really exciting year. We had the phase III readout from LUCIDITY where we met our pre-specified primary endpoint with a p-value of 0.000003, which we're incredibly excited about. That measured the rate of Level 2 and Level 3 hypoglycemia. These are severe hypoglycemic events. Level 3 is basically when somebody's rendered so incapacitated that they need kind of third-party assistance. Level 2 is a level that's been picked by the ADA where your brain is at a severe lack of sugar and you start to have major problems. We met that pre-specified primary endpoint. We also met all of the secondary endpoints with a kind of consistent and highly statistically significant result across those two, with a favorable safety profile as well.
With that in hand, we're now working towards our NDA submission by the end of the year, planning for a launch, if approved, in 2027. I think just the more we've dug into the PBH market, the more excited we've gotten. About 90% of people who have PBH describe themselves as disabled. When you have this condition, it really takes over your whole life. It's really hard to live with and manage. I think in line with that, both from physicians and patients, we hear an incredible excitement for the potential of a therapy. As we've continued to do claims-based work and dig into the market, we estimate there are about 160,000 people living with PBH, and today there's no therapy for them. We're very excited about this.
We had a big year this year, but I hope we have an even bigger year next year.
Yeah. Before we drill more deeply into LUCIDITY and what's coming next week at ObesityWeek, which I am sure you will have limited ability to talk about specifics, from a commercial perspective, Amylyx has a history of having launched a product previously. That always is one of the big questions for any biotech. What are you doing from a commercial prep perspective to really land in this market effectively?
Well, thanks, and I appreciate the nod to our prior launch. We are very proud of the work we did there, but of course, there are always lessons learned, so we hope to do even better this time. That being said, each market is different, and so we are approaching this with the right level of diligence. I think first and foremost, it always starts with people. I think you really need the right leadership on down, especially as you are building a new market, as we are with PBH. Huge unmet need, but there has never been an FDA-approved treatment for people with PBH. So, this is new. There is a lot of education needed. I think on the people side, given the strength of the prior results going into LUCIDITY, we started to build that leadership team both on the medical affairs and commercial side.
We have a really strong leadership in medical affairs and commercial in place. They have been doing great work. I think this past year, we spent a lot of time really understanding the market, understanding the patient journey, going through multiple different claims analyses to recognize where people are, how are they treated, who is treating them, figuring out what future call points and those things will be. So really getting a sense of the landscape. I think right now there is a lot of focus on disease education. We have an ongoing campaign both for people with PBH as well as for healthcare professionals, and those efforts will continue to ramp up as we go into anticipated launch next year. I think overall, the way we are approaching this is a rare disease, but of course, it is a large rare disease.
We estimate there are about 160,000 people in the United States. And so, I think generally what we have seen so far is that the concentration in the market is similar to what you might see in other rare diseases, but the overall numbers are just higher, given the size of the population. That we are doing a lot of payer preparation work now. We're starting to work on our various campaigns that we will have. So we are in full launch preparation mode, but I think it is going to be really important that while this is a high unmet need, there are well-educated centers, and we need to make sure we are partnering with them. There is also a market to build, and so I think we are really trying to make sure we get both of those aspects right.
Perfect. Let's talk about LUCIDITY and just what you are excited to educate the market on next week in particular. We have the August top-line results, but what would you just want investors and patients and physicians to really focus on coming out of the meeting?
Yeah. I think I touched on a little bit, but I think first, just the meaningfulness of these outcomes. When you think of Level 2 and Level 3 hypoglycemia, these are severe, dramatic events for patients, and being able to reduce them is just a very, very big deal for this disease. I' d also add just the consistency of data, the consistency of data between this trial and the previous trials, as well as the consistency of the data within this trial. Not only did we hit our composite of Level 2 and Level 3, but we hit Level 2 and Level 3 individually. We also hit Level 2, whether you measured it by finger stick or by continuous glucose monitoring.
I think it just, the kind of strength of the data comes from the fact that no matter how you look at it, sort of no matter how you slice it, you see a strong and consistent benefit that also matches what we have seen in prior trials.
I would add too, I think, is we have had a few opportunities to have ad boards show the data to different key opinion leaders. The totality of the data, I think, has been really important for physicians, both from an efficacy perspective, as Josh was talking about, but the safety and tolerability as well. The profile is very consistent with what we have seen in prior trials. We did not see any evidence of weight gain or sort of things that people could be concerned about mechanistically. We never thought that that might be a concern, but again, nice to see the 16-week data to support that.
I really think it is that totality of data that physicians have found very encouraging, because again, there has never been an FDA-approved treatment for people with PBH before, and I think it is that totality of data that has physicians very excited that they may finally have something to offer their patients.
Great. Then, just without obviously going into specifics, just what you observed in the placebo arm, I know there is still some confusion around that, but it seems like the primary emphasis is to kind of go back to the official phase II data and utilize that as a point of education. How consistent would you say those data were as you went from four weeks to 16 weeks? That was probably one of the sort of uncertainties that we had heading into the phase III data.
Yeah, I would say data, as we have said, that were quite consistent. It was really an incredible thing to see just how consistent the data has been trial to trial. Obviously, I cannot give specific data from ObesityWeek before ObesityWeek, but I just mentioned, as we have presented this data at advisory boards, as we have shared it with some of our clinician advisors, there is just great excitement. Really, it is the type of data, the more we dig into it, just the more excited we get.
Great. Again, no specifics, but in terms of just this perception of Level 3 events having more value to prevent than the Level 2 event, can you talk a little bit more about that and sort of the dynamics of, or maybe the wrongness of that mentality?
Yeah. I'd say when you talk to endocrinologists, they're very familiar with Level 2 hypoglycemic events, they're very familiar with Level 3 hypoglycemic events. I think they're both telling you really important things about what's going on with the individual as well as, of course, the population. Level 2 is telling you what's happening in the blood. The level of hypoglycemia we're talking about with Level 2, this is not your run-of-the-mill sort of low blood sugar. This is a medical emergency. This means that your brain is starved for glucose. The medical term is neuroglycopenia. Physicians are very, very worried about that. If someone in the hospital, for example, for any indication, has blood glucose less than 54 mg/dL , it's like all hands on deck. I mean, it's a big, big deal, because people know the consequences that can occur with that level of hypoglycemia.
That's a really important measure. Level 3, as Josh was indicating, means that the person can't help themselves. They need independent rescue. It means you've had the manifestation of that neuroglycopenia. You need help. Both are really important, and again, I think the strength of the dataset here is you can look at either, avexitide clearly showed very strong reductions on both. I think, again, that's why the physicians we shared the data with are very excited, because whichever way you look at it's telling you the same story.
Got it. Experts like Marilyn Tan, who've been sort of leading the space from 2016 on, are outliers, I think, to some degree, in terms of that level of expertise. As you look at the awareness from endocrinologists, where does that sit today, and how do you sort of see ObesityWeek as kind of a starting opportunity for building that awareness?
Yeah, I'd say there's decent awareness among the endocrinology community. It's not uncommon you hear from endocrinologists, even the ones that are not the Marilyn Tans of the world, that they see a number of these patients, that they have a number of these patients under their care. I think what they really struggle with, though, is in most endocrinological conditions, we have drugs, we have treatment pathways, we have ways to manage. This is a condition we really don't today. So you hear from a lot of physicians this sense of kind of helplessness, that I really, I have these patients, but I have sort of nothing for them. I really want to have a therapy for them.
I think we observed at ENDO earlier this year just an incredible interest of people coming to our booth, speaking with our team, wanting to learn more about avexitide. I anticipate that continuing at ObesityWeek as well. I would say for our team, it is also a great opportunity to do a bunch of one-on-ones, to meet with a bunch of the physicians, just to give them more information, answer their questions, et cetera. But I think there is a tremendous excitement. There has really been nothing in this space, and I think the endocrinologists really recognize that they need something. I will say as well, we are also working right now with our disease state education campaign, Uncover the mystery of PBH.
What we have seen there is also a lot of engagement directly with the materials we are putting out to help educate people on how to recognize and observe PBH. We have actually even heard directly stories of people being diagnosed through the campaign, as well. I think there is good awareness. I think there could still be even better awareness, and that is what we are working to do.
Great. In terms of the participation in the open-label extension, the strong rollover, can you talk a little bit about that, and how the expanded access program actually operates? I think there may be a little bit of confusion there that this is just an unlock and patients are just going to be piling right into it. I may be guilty of thinking that way also. But help us understand how the EAP is structured.
Probably a few things there. First on the open-label extension. Greater than 90% of people completed the study, and then all the eligible people went into the open-label extension. Eligible meaning they made it into the study and with compliance, and then went into the open-label extension. Very, very good continuation, and I think that presents us further data presentation opportunities as well, which we are really excited about. On the expanded access program particularly, I would say first at a high level, FDA has made it very clear that these programs are about access. I think that is very much where we are focused as well. There are different types of EAPs, but this is the type where you have something that is promising, has phase III data, looks like it is headed toward a near-term approval marketing authorization, and so this is to provide access.
Now, the way that actually works is that you have a protocol, and then different physician centers reach out to ask about, they have people they would like to enroll in the expanded access program, and that starts the whole cascade. It is unlike a clinical trial where it is very prescribed and you have these set number of centers and you get the whole enrollment engine going. Expanded access is much more driven by the physicians. Now we have the protocol, we have the setup, et cetera, but again, it has to do, the operations has to do with the access side. That being said, there has been such excitement around avexitide, both from the physician standpoint, as well as people with PBH.
I would say generally as a company, we are enthusiastic about expanded access programs because I think they provide a great humanitarian benefit for people and has long-term follow-up as well. So that is why we initiated the program even ahead of the phase III trial, and we will continue.
Great.
Yeah, and I just add too, to your point of like, is it just turning a key, so to speak? You still need to do budgets, there are still IRBs, there are still protocols. So there is still work that goes into setting up and standing up an EAP at every individual site that you do that. But exactly as Justin said, there has been a lot of excitement about this program.
Hopefully it does not take the seven months that we keep hearing it takes to like establish a phase I program in the United States. Anyway, outside of that, beyond the EAP, you have got your regulatory path. I think one of the things that we have talked about is just frustration to some degree is to watch large pharma companies execute a program from phase III data, and within six months you have got the product filed and ready to go. You are absolute outliers in that regard with the rest of biotech in my experience. So, how are you doing it? And how far along are you? And it seems like you have very high conviction to be able to execute and deliver.
Yeah, so we're on track to submit by year end. I think it's a lot of pre-planning and work at risk. Even ahead of the phase III readout, we were already doing tremendous work to prepare the NDA. I think that started from having a lot of confidence in the drug. With five prior trials, gave us a lot of confidence going into the phase III. It is still hard work. These are big documents. All that being said, we did all the kind of forward planning. We mapped everything out so that we'd be able to submit by year end.
I'd add too, as I mentioned with the commercial, the same goes for regulatory and medical. I mean, we have just a world-class team. Our regulatory team, whether at Amylyx or at other organizations, have overseen multiple NDAs, BLAs, marketing authorizations, not even just in the U.S. but globally. Same with our clinical team, our CMC team, et cetera. So we have a really experienced team that's been working on these things. So I think that's the other advantage we have, is that this is not their first rodeo. They've done this a lot, and so that's why I think we're in the very strong position we're in today.
From a manufacturing perspective, can you just help us understand what needs to be completed, executed to initiate the NDA, and then, or are you pretty far down that path at this point?
Yeah, we're on track, so we don't see any issues there in terms of submission or otherwise. I'd say similarly to everything else, we believe this is a big market, so tried to get quite ahead of things on the manufacturing side as well.
Got it. What will the commercial dose be and what is being used in the OLE?
The commercial dose, the intention is to have the 90 mg dose single injection. To be just very, very specific, in the 16-week LUCIDITY trial, the dose was the same as was done in the phase II-B, which was a back-to-back injection of two 45 mg doses. So total 90 mg back-to-back, two injections. In the open-label extension, we manufactured our own material, single 90 mg dose, and that is what we intend to use commercially. We do not believe there should be any difference between doing back-to-back injections or a single injection, and of course, far more convenient for people to have that single injection.
Perfect. The ICD-10 code, can you maybe talk a little bit about how that can benefit the company, and really sort of benefit patients in the disease state?
Yeah. Just to kind of level set too, ICD-10 codes are more tracking codes. They are not reimbursement codes, so not something we need for reimbursement. We are quite excited that there is now a dedicated ICD-10 code for PBH. There was not prior, and I think it represents kind of the increasing knowledge, interest, excitement about PBH as well. These things take a little bit to kind of flow through the healthcare system and into people's Epics and Cerner and everything like that. We do believe it will provide kind of another tool to continue tracking people with PBH, both for us, but also for sites. If they want to call all their patients with PBH, for example, it is nice if they can track in their system with an ICD-10 code. On balance, I think, beneficial. Not something we required, but beneficial as we build this market.
And maybe just to talk about the label itself, and the sort of opportunities for the label. One big question is, I do not think there is any reason to believe that a Roux-en-Y PBH would be different from gastric sleeve, which would be different from a gastrectomy or gastric surgery. But the agency may take a different view. Can you just help us understand, what are you putting in front of the agency, and what is the focus of the breakthrough designation in particular?
Yeah. It is a great question, so I will try to give the lay of the land. Starting with your point, which we very much agree with, we believe that PBH is PBH, meaning post-bariatric hypoglycemia, and even further, any gastric surgery can lead to the same condition, and the pathophysiology is the same. This has been studied for many decades now. If you talk to surgeons who do gastric surgeries, they will say, "yeah, we have seen this for a long time." We believe that it is the same pathway, which is you have this increased nutrient transit, which causes a GLP-1 sort of exaggerated response, which causes hyperinsulinemic hypoglycemia. So we think the pathophysiology is the same. In terms of what we will be putting forward in our submission, the prior five trials leading up to LUCIDITY were mostly in people who had PBH following Roux-en-Y gastric bypass surgery.
In the phase II-B, they allowed any gastric surgery, including sleeve gastrectomy, leading to hypoglycemia, and avexitide appeared to work regardless of the surgery that led to the condition. LUCIDITY was in people who had PBH following Roux-en-Y gastric bypass. So, the agency, we will make the case that we believe the pathophysiology is the same here. We believe avexitide appears to work regardless of the surgery leading to the condition. The agency could take the stance that the phase III trial was in people with Roux-en-Y gastric bypass and who now have PBH. So, I think it is very much a sort of education question, right? This will be the first time there is an application for post-bariatric hypoglycemia before the agency.
If we find ourselves in the situation where the indication statement is for just people who had PBH following Roux-en-Y gastric bypass surgery, first, that is about 120,000 out of the estimated 160,000 people in the U.S. today. So still, the majority of the population, very sizable population. And it would just mean that we have some additional clinical work to do to show these things are comparable. So, I think we will be prepared for whatever the scenario is, but in the long term, we do not think it should make much of an impact.
Great. I think, one of the things that investors kind of struggle with to some degree, is how do you launch into a market opportunity that is rare disease pricing, rare disease state, but not so rare patient population? Is there kind of a low-hanging fruit approach that makes sense, or is this kind of an all-comers type launch opportunity as you see it?
Yeah, I probably wouldn't draw too stark of a line between kind of low-hanging fruit, as you said, or others. I think certainly the intensity of our efforts will differ at the sites that, for example, have more patients as compared to the sites that have less. But we do believe, if people have PBH, we want to serve them, we want to help them. So we won't necessarily have no efforts, let's say, for those who maybe are at less dense sites or otherwise. I think that's where you can also really lean on things like digital tools, ways to reach many people without necessarily having a rep physically in the door. I think where reps can have a really high leverage is in those sites that have quite a number of patients.
Not just to meet the doctor, but we often call it a total office call to meet the doctor, the nurse, the back office, et cetera. All the care team that come together to help in an endocrinology clinic, to help with somebody living with PBH. So, I'd say I probably wouldn't starkly divide a kind of low-hanging fruit compared to a broader group. But definitely, at launch, we will put extra efforts towards those sites that have quite a number of patients.
Great.
I'll underscore too, this is of course informed by our market research. One of the things we looked at early on and subsequently as well is, if you try to segment the population based on severity of their condition, does the endocrinologist see it differently? For example, if someone is frequently going to the ER, going to the hospital, versus someone who's not, who's having these events, but they're having them at home. Endocrinologists really view these as both are, we need treatments for. Because the type of hypoglycemia we're talking about is very dangerous. While yes, of course, a physician is very worried about the person going to the hospital, they're still very worried about the person having hypoglycemia at home because that next event could land them in the hospital. So there's a, just generally, there's a very high intent to treat in this population.
And of course, today, there has not been a treatment for people with PBH. We really do think this may be an opportunity to fundamentally change the practice of PBH.
Great. And maybe just as a final comment, maybe remind everybody, there's a lot of education to go on here. 25 minutes is never really enough. Just the timing of your event and the availability on Sunday.
Yes. We will have both a presentation, kind of live on-stage presentation at ObesityWeek, as well as an investor event. I should know the exact time of day, but it is posted kind of on our website, and we put out a press release—
Please reach out to our investor relations team as well for further information on that.
Great. Thanks so much, and good luck this weekend, and look forward to a very eventful December and 2027.
Excellent. Thank you so much.
Thank you so much.