Great. Excited to get into the next session here with the Amylyx Pharmaceuticals team. I have Co-CEOs Justin Klee and Josh Cohen. Obviously, a super exciting time for Amylyx. I think everyone knows the story well, but maybe we can just start off with a quick overview of your data recently. Any key highlights, key takeaways from investor or clinician conversations, and then we can jump into some more specific Q&A.
Sure. So maybe just to start for those possibly newer to the story, we are focused with avexitide on treating post-bariatric hypoglycemia. Post-bariatric hypoglycemia, or PBH, is a disease that people get in the years following bariatric surgery. We estimate about 8% of people following bariatric surgery, or roughly 160,000 people in the U.S. And when people get PBH, it sort of takes over their whole life. It is characterized by frequent recurrent hypoglycemic episodes, often after meals, but not only after meals. Sometimes people will experience these during stress. They will experience these during exercise. Sometimes they will experience them out of the blue, with no precipitating cause. And they can get very deep very fast, with people potentially losing consciousness, having seizures, becoming very dizzy, confused, et cetera, resulting in about 90% of people describing themselves as disabled due to PBH.
We just recently completed a phase III trial of avexitide in PBH. I would say we had high expectations, but it even exceeded those, meeting the pre-specified primary outcome, which was tracking people's Level 2 and Level 3 hypoglycemia. These are basically really significant hypoglycemic events characterized by the American Diabetes Association. Each event characterized as a medical emergency. But we showed a 55% reduction with a P value of 0.000003. We had consistent results across the secondary outcomes. We met every secondary outcome also all with high statistical significance. And those included looking at Level 2 events individually, looking at Level 3 events, which are basically when people have had the severe loss of consciousness or severe confusion or otherwise. And then also looking by CGM as well, also met with high statistical significance. Drug was safe and well-tolerated, generally consistent with the prior trials as well.
We are quite excited. Disease with significant unmet need, and our team had already been hard at work on the NDA prior to receiving the study results, given our excitement about avexitide overall. So we expect to submit before the end of the year, and are already hard at work prepping for a potential launch in 2027. And maybe last thing I will say, and then maybe pass it over as well, is I think the more time we have spent in this space, we have just seen what a significant unmet need it is. I was pretty struck at this year's ENDO conference, where we had a disease state education booth educating on the signs and symptoms that might trigger a physician to know that what they are seeing is PBH.
Our booth was just constantly incredibly well-attended by different physicians telling us a really consistent story, that they have many of these patients, that despite their best efforts to manage them, these patients remain incredibly debilitated by this condition, and really their excitement for any potential new science, new approaches that might come out. We're all systems go, and excited to talk today.
Yeah. That's awesome. I think it seems like the data are pretty unequivocal. There's five zeros in that P value on the primary. Maybe just to get a little bit color on the secondaries, is there one or two that you think is most important for docs? Again, it seems like you're saying everything is consistent, but curious if there's one data point or so that is really important for docs.
Yeah. I think the beauty of this data set is that it all looks good, right? It hit with similar effect size and significance across all of those outcomes. I think that's what so far we presented to our steering committee. We're working hard on the medical presentation publication as well. I think, again, speaking to the steering committee reaction, I think their first thought was, "Wow, that primary outcome tells you everything." I think also is the totality of the data. The fact that each secondary outcome tells you something slightly different. Level 2 events by self-monitored blood glucose is the most accurate, but CGM is continuous, right? Both hit with high significance. Level 3 events, which of course is someone's had the clinical manifestations of hypoglycemia such that they need rescue. That hit.
Each component is telling you something slightly different, but each way you look at it's a very strong signal. I think that's really the feedback that we've gotten from physicians, that the primary speaks for itself, but it's really the totality of the data, of course, combined with the safety profile that is so encouraging.
Yeah. If I remember correctly, you mentioned all eligible patients rolled into the OLE, which I think is really obviously encouraging from both an efficacy and safety perspective. I do want to focus most of the conversation on commercial, just because I think that's a lot of where investor focus is. Maybe just help us understand for the full data, if you have a sense yet of when we may see that. But two, if there's anything specifically to keep an eye out for or anything you think clinicians are specifically interested in seeing.
Yeah, I don't think anything specific to keep an eye out for. We tried to get the most important data out, the primary endpoint, the secondary endpoints, the safety. Our team's hard at work to try to get a presentation, and potentially a publication, as quickly as possible. I think we'd love to do it before the end of the year. The reason for that is, we think when there's important medical data, it's really good to get it in front of the medical community as quickly as possible. That's certainly what we attempt to do here. Certainly trying to get it in as high profile a setting as we possibly can, which I think is, again, really important when you have, in our view, hopefully practice-changing types of data.
Yeah. Makes sense. Great. NDA submission by the end of this year. Maybe as it relates to the label, this sort of gets into the commercial conversation. I think obviously there's a strong argument for why you should have sort of a broad PBH label, but just curious your sort of latest thinking there, and how you're thinking about what your base case looks like as it relates to a label.
Yeah, I really appreciate that. Just to back up for people who are maybe less familiar, seemingly any gastric surgery, certainly bariatric surgery for weight loss can lead to this condition. As we're defining it, post-bariatric hypoglycemia, we're so far talking about bariatric surgery for weight loss leading to this chronic severe hypoglycemic condition. There historically have been two major surgeries that surgeons perform for weight loss. The first is Roux-en-Y gastric bypass. The second is sleeve gastrectomy. Roux-en-Y gastric bypass historically was what was used most. Probably in the last maybe 15 years, 10, 15 years, sleeve gastrectomy has become the more prevalent surgery.
That being said, I'd say we've heard from many surgeons and weight management clinics that I think Roux-en-Y gastric bypass is starting to be used more frequently again, just given that it has a higher degree of weight loss than a sleeve gastrectomy, but both are very effective. I think it depends a lot on the clinic. Each of these surgeries can lead to the same condition, post-bariatric hypoglycemia. Again, it's pretty rare. Most people do not develop this condition. I think the question is, when we ultimately get to the indication statement from FDA, will the label say Roux-en-Y gastric bypass PBH? Because that's the population that we studied in the phase III trial. Or will it say PBH, meaning for any surgery that led to this hypoglycemic condition? Obviously, it's early. We don't know yet. We're far from those discussions.
I'd say to your point, we think there's a strong rationale that we believe the pathophysiology is the same, regardless of the surgery that led to PBH. I think most endocrinologists would say, "Look, PBH is PBH. The surgery that led to it happened some time ago." I think, again, there are no treatments today for PBH, and I think endocrinologists want a treatment for PBH. So we think there's a strong, rational argument from our earlier phase II-B trial. Avexitide was also studied in people with a variety of different surgeries leading to this condition, and avexitide appeared to work just as well, regardless of the surgery that led to PBH. All that being said, the phase III trial inclusion criteria was Roux-en-Y gastric bypass leading to PBH. That's why I think we really don't know yet.
If we end up in the scenario where the label is Roux-en-Y gastric bypass PBH, our current estimates is that about 120,000 of the 160,000 people with PBH in the U.S. today had Roux-en-Y gastric bypass surgery, so still a very substantial population and part of the population. Then, we feel pretty confident we could run an efficient trial to show that avexitide works regardless of the surgery leading to PBH. I think in either scenario, we feel quite confident in our plans going forward, and we'll wait to see what FDA says.
Yeah. Makes sense. Like you said, either way, 120,000, 160,000, these numbers as it relates to a rare disease are really meaningful. Obviously you guys have done a lot of work kind of triangulating around those numbers. Maybe just speak a little bit more to your confidence in sort of those numbers being sort of the right sort of overall market, and just as we've gotten closer to a potential launch.
Sure. Yeah. I'd say when initially, we started with the literature. One thing that's very nice in the bariatric surgery space, is that there's been a number of long-term outcome studies, many of which are prospective as well. Looking at studies that have looked prospectively five years or longer, in people who have had bariatric surgery, that's how you start zeroing in initially on that 8% number or roughly 160,000, given the more than two million surgeries that have happened in the past decade. We then followed that up with claims-based analysis. We looked in claims for people who had had bariatric surgery, went on to have hypoglycemia claims that couldn't be explained by any other medical condition. You similarly got to approximately 160,000 with that approach.
We then followed up the claims analysis doing survey work where we would do surveys with various sites, and ask them how many people with PBH are under your care. We also asked a number of other questions just to really characterize their PBH population as well. We then back compared what the clinics would say unaided compared to our claims data, and those were quite concordant as well. It seemed that our claims data wasn't picking up something different than what the clinics are actually seeing in day-to-day practice. I'd say maybe having multiple different approaches all arrive at the roughly 160,000 gives us good confidence that that is the patient population of people with basically PBH that cannot be managed by any other means.
Yeah. No, makes total sense. I think in some ways there's a lot more data supporting that number than in a lot of rare diseases that people are typically looking into. I guess, obviously a really big number. What's the best estimate or your perspective on how many of those are diagnosed today and under active care for their PBH? In that context, is this disease concentrated at certain larger centers, or is it really disparate?
Yeah. It's a very important question. As we get closer toward our potential launch, we'll work on more of our go-to-market strategies and what concentration there is where. I can speak at a fairly high level right now. First, the 160,000 population is the population, as Josh was saying, we see through our claims data as well. It sounds like a really big number. It's actually a subset. The subset is you have millions of people who have had bariatric surgery. This is a small fraction of that overall population who continue to have recurrent severe hypoglycemia.
It gets to be a large number, or has gotten to be a large number over the years, simply as a subset of just the many, many bariatric procedures that have been performed now over decades in the U.S., because PBH does not appear to go away once someone has it. We regularly work with people who have had PBH for 15, 20 years. That's sort of the backdrop. I'd say as well, there's a surprisingly high awareness among adult endocrinologists of PBH. I think for us, we'd done all of our market research, talked with many different physicians, but being at ENDO this past summer really drove it home for us. We just heard from so many different endocrinologists who said they have large populations of people with PBH under their care, and they really have very little to offer them right now.
It's essentially trying to counsel on diet. But for people who have had PBH for years, they're very well into their routines. They know their bodies, they know their regimens, and yet they continue to have these frequent medical emergencies. I think what we heard again and again at sort of the highest level is endocrinologists have a quite severe condition under their care, very little to offer their patients, and I think they're very eager to have a treatment to offer them. Also, just given the severity of these events, these events, by definition, are medical emergencies. I think a long way of saying we think there's quite high awareness of PBH. We see the 160,000 population even through our claims research. I think the work that we're doing now is how do we approach this as we plan for our launch.
Our intention really is to approach this as a rare disease, but it's a large rare disease, and that's everything that we're working towards now.
Yeah. Makes sense. I think as it relates to sort of the claims data, I think one data point some investors have kind of looked to is this 30,000 critical PBH number as maybe sort of a proxy for maybe the most severe patients, and those who are maybe the highest motivated or most near-term easily addressable. Is that a fair proxy in terms of how to think about those data and maybe those patients being lower-hanging fruit in terms of them being more near-term accessible? How do you think about that?
Yeah. I'd say I don't really think so. I think that number comes out of a paper from Dr. Colleen Craig, where she tried to characterize ER visits with people with PBH. I'll also say, even when you do the claims data on ER visits, it's quite hard because sometimes the ER visit will say hypoglycemia, but sometimes it will say syncope or loss of consciousness or broken bone or car crash, and it's not always clear that you attribute that to hypoglycemia or not. So one, our guess is that the number likely far underestimates what the total number of ER visits are. But maybe just kind of characterizing and from our conversations with endocrinologists as well, any one of these events could lead to a complete crisis. Almost every endocrinologist we speak to has anecdotes they share about car crashes, broken bones, falling down stairs, things like that.
I think the most extreme I've heard as well is somebody passing away in their sleep from hypoglycemia as well, which you certainly hear not infrequently in Type 1 diabetes, for example. So I think the endocrinologists really view if a patient is having frequent hypoglycemia this is a very concerning sort of medical condition. Even if they weren't in the ER three months ago, it's still something you very much want to treat because any next event could be that event that has sort of dire consequences. We didn't really find, in our market research, much subsetting among the physicians when you ask them, "Well, what if they had an event every day? What if they had an event every week?
What if they had an event every month?" I think their view was, "I want to bring these events as low as I can, so I'm going to intervene as much as I can to try to reduce their event rate as best as I possibly can.
Yeah. Just to underscore those last points, I think as we've continued to work with the community, with the healthcare professionals, just the severity of this condition just comes through again and again. We're trying to help bring that to life and provide better education through our disease state education campaign. But just sort of as one sort of way of looking at this, the American Diabetes Association, in all of their materials, very clearly say severe hypoglycemia is a medical emergency. If you talk with people who have Type 1 diabetes or family members who do, almost to a person, they will tell you the one case or the two cases where they or their loved one had a severe hypoglycemic event. People with PBH may be having these weekly.
It just gives a sense of how significant and debilitating this condition is, and I think therefore why endocrinologists are so eager to have a reduction in these severe events.
Yeah. No, that all makes total sense, and is really helpful color. I guess in that context, analogs are never perfect, but I think typically people look for them. Just as we're getting closer to a launch here, what do you think is sort of the right analog maybe, or a relevant analog as it relates to just what the launch may look like, but also from a pricing perspective?
Yeah. Again, probably a little early on the pricing perspective. With having just recently gotten the phase III data, we're still doing some of the research around that as well. But certainly, we've been looking at our colleagues in the rare endocrine space and also the broader rare disease space. Of course, there's no perfect analog for any given drug. But we do look to them and certainly take learnings from there as well. Yeah, I think one of the other things we've sort of just learned in the ENDO space as well, they are physicians who are well-educated, well-trained on the process of prescribing rare disease drugs. There have been a number of rare disease drugs that have come out recently in the rare endocrine space, which I think is, you launch into sort of a prepared community as well.
Yeah. Makes total sense. Then I guess just like, I think the other question investors always kind of wonder about ahead of a rare disease launch is, sometimes there may be a lot of initial demand, then it's a little bit harder to find sort of the next rung of patients. Just curious how you think about sort of the, again, I guess the steadiness or cadence of PBH, which is unique in that it's such a big rare disease versus some of these other rare diseases where there's maybe thousands of patients. Just curious how you thought about that, again, as you think about sort of other launches in the rare space and what this may look like.
Yeah. I'd say, obviously we'll know more as we get into launch, but I think speaking about the population today, you're right, it's rare, but it's large rare. There's very high awareness. I don't think we mentioned, for example, PBH is on the endocrinology board exams. So all endocrinologists are trained to recognize PBH. Again, we see the population even through our claims research. So we see really a long and important opportunity here, and I think that's why we want to invest for the potential launch of avexitide next year. We're fortunately well-capitalized to do so. But it's also why we're continuing our investment in the space, with our long-acting GLP-1 receptor antagonist, AMX0318. That's in IND-enabling studies now. Goal to have our IND next year. I would say even further, there are other gastric surgeries that lead to the same condition.
This is not a U.S.-only condition. Anywhere people get gastric surgery, whether it's for cancer, or weight loss, or reflux, or injury, or any number of things, people can develop this condition. So we really think there's a substantial unmet need and opportunity here. We're heavily focused on making sure we can address the U.S. population, given the size and importance of the opportunity. But we think there's a long road ahead here.
Yeah. Makes total sense. We're just about up on time, but you kind of got to it. Obviously, there's a lot more than just PBH. But I think in the context of PBH, one of the other sort of overarching questions here people have is just, what's going to happen with bariatric surgery and all these GLP-1s. Just curious if maybe we can wrap up with sort of your perspectives on what PBH is going to look like as just sort of a disease going forward in terms of bariatric surgery and all of that?
Yeah. Great question. I'd say maybe top line, I'd say we expect PBH to continue growing over time, and maybe just how we get there. One, unlike a lot of diseases that have been around for thousands or tens of thousands of years, bariatric surgery only became popular in the U.S. in recent decades. As a result, people who have PBH still tend to be pretty young. The average age for bariatric surgery is about 40 years old. As bariatric surgeries continue ongoing, and once you have PBH, you have PBH for life. It's a chronic condition. As we continue doing bariatric surgeries, the pool is only sort of growing of people who are experiencing PBH and might want to be treated for PBH. I'd also say bariatric surgery remains the gold standard for kind of deep and durable weight loss.
I think as we talk to bariatric surgeons, they are generally not having trouble filling their surgical slots and otherwise, especially for those, the target for bariatric surgery has always been those generally with BMI over 35 or over 40, where people might be looking to lose 100, 150, maybe even more pounds, which is generally a different patient, let's say, than those who might achieve their weight goals necessarily with a GLP-1 agonist. I think the markets are a little bit distinct, and I think we expect both of them probably to continue growing over time.
Yeah. To put simply, just as I know we're wrapping up, we estimate there's about 160,000 people with PBH in the U.S. today. We expect that only to grow over time. We don't know what the growth rate is, but we expect it to be about 8% of the bariatric surgery volume in any given year, so we expect that to continue to grow. We expect avexitide to be a chronically used treatment because people have chronic hypoglycemia. That's why we're very focused on our launch preparations, but also on investing for the future.
Yeah. Makes total sense. Awesome. Well, thanks Justin and Josh for being here, and obviously congrats on all the success. It's an exciting time for you guys. Thanks everyone for listening in.
Great. Thanks so much for having me.
Great to see you. Thank you.
Good to see you.
Thanks.