All right, great. We'll get started with the next session. Happy to be here with Amylyx Pharmaceuticals. I have Co-CEO Josh Cohen and Chief Commercial Officer Dan Monahan. Thanks, guys, for coming. Congrats on all the success this year. Obviously, a super interesting time for you guys. Maybe Josh or Dan, if you want to just kind of kick it off with a brief kind of recap of the avexitide data and just sort of the setup from here in terms of catalysts and the regulatory path going forward.
Sure. We're super excited. We had great data earlier this year. Met our pre-specified primary endpoint with a P-value of 0.000003 on our pre-specified primary outcome, which was the rate of level 2 and level 3 hypoglycemia in people living with PBH. To remind, level 2 is when your blood sugar goes below 54. That's often considered a level where neuroglycopenic symptoms or kind of severe neurological symptoms can begin. It was a composite outcome with level 3, which is when hypoglycemia has become so severe that you sort of require or it warrants independent rescue.
We also met all of our secondary outcomes, had a favorable safety profile, so we're incredibly excited about those data. I think we had high expectations going in, but the data even exceeded our own expectations. Based on that data, we're now presenting at ObesityWeek this coming weekend. We're excited about that.
I think we've already shared most of the headlines from the data, but I think there is a certain magic to getting all the figures and tables and whatnot out there as well. For the rest of the year, we're working towards submitting our NDA before year-end. We're on track to do that, which preps us for a commercial launch in 2027. It's been sort of an incredibly exciting, I'd say, sort of a milestone year for Amylyx, and I think we're set up for the next year as well.
Yeah, definitely. Maybe just to level set on the data this weekend at ObesityWeek, just in terms of the breadth of data that we are going to get, is this the full sort of detailed data? Maybe it would just be helpful to understand if there is one or two key things you think is especially important for docs that maybe you have not kind of disclosed already.
Yeah.
Granted, you have been pretty disclosing already.
Yeah, I think I would answer yes, this is the full data. All that being said, we like to continue to have presentations as time goes on. Wall Street does a good job, I think, of reading press releases. The medical community may not always get information when it comes out by press release or otherwise. So it is really important to be at medical conferences, speaking, sharing the information, doing one-on-ones with doctors, all those sorts of things.
So, at ObesityWeek, we will present the double-blind placebo-controlled data. We will be excited to present the open-label extension data at a future time point. But again, I think as we have dug into this data, we just get more and more excited. I mean, it sort of goes with having such a strong P-value. You can sort of cut the data any which way, and you kind of get the same result.
I mean, it is a very clear and strong effect that we are seeing here. I do not know that I would flag anything in specific. I think there is something cool about seeing the data in full with kind of tables and figures and everything like that.
Yep. I think you guys have mentioned it's consistent with sort of the prior data, especially on the safety side as it relates to, I think the most common AEs were GI stuff, injection site reactions. Is that right that it's kind of consistent with the phase II is kind of where we should be thinking about?
Yeah. Safety's been generally consistent with past trials. As well, tolerability was good. We had more than 90% of people complete the study. More than 90% of people enter the open-label extension. So people, good persistence as well in the study.
Yeah. Makes sense. Great. So, looking ahead, you mentioned NDA end of this year. I think there's obviously, this is a sort of like established endpoint in terms of it's in the guidelines, very statistically significant. I think maybe one of the more important questions or questions people have as it relates to the regulatory dynamic is the label, and whether it's going to be Roux-en-Y specifically, more broad beyond just Roux-en-Y and kind of covering all PBH. Maybe just kind of help us understand what your latest kind of thinking there is and where people's heads should be at.
Yeah. I think probably first and foremost, we don't think it's a particularly It won't change the commercial market all that much either way. We believe that approximately 120,000 of the 160,000 people living with PBH had Roux-en-Y gastric bypass. Whether the initial label kind of contemplates Roux-en-Y or contemplates more surgical types, it's maybe 120,000 versus 160,000, not that big of a difference. What I'd say is we do have data. Our phase IIb study was sort of a basket study.
Yeah.
Included multiple different surgical types. We recently published the phase IIb, and when you look at the surgical types one by one, which is sort of done in the publication, the effect seems very similar across surgical types. We believe we have clinical data that also supports that there is not really differences here. It also sort of stands to reason medically. The body does not quite know why you conducted surgery on the gut, whether that was due to bariatric surgery, whether that was due to cancer, whether that was due to other reasons why you might do surgery on the gut.
At the end of the day, you are getting the same sort of fast nutrient flow, the same GLP-1 spike, the same hypoglycemia. So we believe there is a good medical argument that these should all be treated the same. Of course, FDA may accept those arguments, they may not. If they do not, I think launching into a 120,000 market is also excellent. If we did find ourselves in that situation, we would look to quickly generate the evidence to be back to the 160.
Yeah.
Josh mentioned it, but from a commercialization perspective, it does not change our plans. Our launch plans and our preparation for launch remain the same in terms of the call point of the endocrinologists as well as some of the bariatric surgeons.
Yeah. Makes sense. Anything else to keep in mind, label-related, regulatory-related?
Nothing I'd flag in particular. We do have Breakthrough Therapy Designation, which we're excited about. Yeah, on track to submit by year end.
Yeah. Makes sense. You kind of alluded to some of the market research work you've done, triangulating around this 160,000 number. I've said, I think there's probably more data supporting that than in a lot of rare disease contexts. Maybe kind of walk through some of that data and just the more work you've done as you get closer to launch, your confidence in that kind of epidemiology.
Sure. I'm happy to start and maybe-
Sure
...pass to you, Dan, as well. We sort of started when we were diligencing the asset looking at the literature, and there have been a number of good prospective cohort studies, many of them several years in duration and large cohorts of patients that have followed patients who had bariatric surgery to look at what the outcomes are over long term. Those studies helped us triangulate that about 8% of people following bariatric surgery go on to have persistent, unacceptable hypoglycemic symptoms despite their best efforts to manage that.
That contrasts to, for example, if somebody just wears a CGM, who has bariatric surgery, you will see much higher rates. You might see 40% or more people having some hypoglycemia. But with the 8%, we are really talking about that group who is having persistent, unacceptable symptoms despite their best efforts to manage it. When you take 8% times roughly two million, a little more than two million bariatric surgeries over the last decade, you get about 160,000 people living with PBH. We then followed that up with claims-based analysis.
So we looked at people in the claims who had had bariatric surgery who went on to have hypoglycemia codes. Hypoglycemia codes mean they have interacted with a healthcare provider to seek treatment for hypoglycemia. And we tried to exclude anybody who might have a hypoglycemia code for a different reason. For example, if they were on insulin or they were on some other glucose-modifying drug. When we did that claims-based work, we got, again, about 160,000 patients.
I would add we also followed that up doing survey-based work where we, in doing market research, would talk to a large number of sites, ask them a number of questions, included among them, "How many patients does your particular site see?" And then on the back end, we compared that to our claims data. So, for example, if we asked a site, "How many patients do you see?" And they say, "I see 40 patients," we would look at our claims data to see if the claims data also said they see 40 patients. We found those to be quite concordant.
I would say all of these things together give us good confidence that not only is the 160,000, I think, a good estimate, but also that our claims data are accurately sort of tracking where these patients are, which is helpful as we start thinking about commercial targeting and how do we deploy to the field as well. I do not know if any other-
I think you covered it all. The only other thing I would add is that our medical affairs colleagues are out there now in the marketplace engaging in the scientific dialogue with our KOLs, and they are also validating the size of the population with them as well. From the claims analysis, from the surveys, and then from one-on-one conversations and the medical team, again, is validated, and we feel very confident in that size.
Yeah. No, makes total sense. And I think people look at that as obviously a very big rare disease and try and think through what is maybe lower hanging fruit. And I think in sort of the claims data, one number that kind of has come up a few times is this sort of critical PBH number that is still very sizable. It is 30,000 patients, I think, for that Stanford work.
And again, I think the sort of investor view and from a positive perspective is like, "Oh, that is like low-hanging fruit." Is that sort of the right way to characterize maybe what is kind of like low-hanging fruit in the most severe end of these patients, or is it more all of these patients are really kind of like in that severe bucket?
Yeah. So, maybe just to kind of drill into the Stanford analysis as well. So the Stanford analysis defined medically important PBH, which they estimated at about 167,000 patients. These were patients basically based on their criteria, had PBH that was sort of important to treat. They also created a bucket of what they called critical PBH, which was people who had sought emergency care for PBH.
That is a hard analysis to do because often when people seek emergency care, the reason tied to that can be different. For example, if somebody has severe hypoglycemia, it may not say severe hypoglycemia. It may say loss of consciousness. It may say motor vehicle accident. It may say fall, fracture, et cetera. So one, I would say that 30,000 probably underestimates how many people are actually going to the hospital and seeking emergency care due to PBH.
Kind of separate question of sort of what is the low-hanging fruit. I would say as we have cut the market in different ways, we have not found a completely obvious answer to that question. When we ask endocrinologists, they generally say, "If I have a patient who is having severe hypoglycemia, I want to treat that." This is a dangerous thing. When you look in diabetic populations or otherwise, it can be associated with greater mortality, greater really kind of dire long-term outcomes.
So endocrinologists usually take the view, "If my patient is having severe hypoglycemia, I want to treat that." And so when you ask them, "Well, what if the patient went to the ER?" "Well, sure, I want to treat that." "What if the patient is having severe hypoglycemia, but they did not go to the ER?" They still want to treat that. We haven't really perceived in kind of the market research that there's too stark of a divide between those populations as well.
We've also looked at maybe denser settings of care compared to more community endo. I'll say, for example, at conferences we've been to, looking at the endocrinologists who've come to our booth or otherwise, major academic endos come to our booth. We also have folks who are maybe from smaller, more community-based centers who come and seek us out as well. I don't know that there'll be a sort of obvious low-hanging fruit.
What I will say is, like many markets, especially new markets, there are patients and physicians who are very actively managing their patients, very actively thinking about this disease on a day-to-day basis, who may activate very quick. There's also going to be a sort of long-term benefit of education as we sort of educate through the referral networks and everything like that. I do think this is the type of launch where there's patients to address early on. Also kind of a continued growth as you continue investing and educating deeper and deeper into the market.
Yeah. No, makes total sense. That was going to be my sort of follow-up question is in terms of how concentrated sort of these patients are today in terms of that 160,000, what proportion are maybe in centers of excellence and at sort of these key KOLs centers versus the percentage that are kind of outside and maybe like more in the community? Do you have like a rough sense? I know you probably can't be specific, but just like, is it half these patients are under like academic care, or is there a way to sort of like quantify like?
I can start maybe with just painting a picture a little bit of the patient journey. We know the patient had bariatric surgery. They stay in the care setting of the bariatric surgeon's office for usually up to nine months, sometimes up to 12, and then they are out into the primary care physician for their care. With post-bariatric hypoglycemia surfacing one to three years on average following surgery, they are in their primary care setting, and then these patients are likely routed back to an endocrinologist. In some cases, that community endo could be treating the patient.
Oftentimes, because there has not been an approved therapy for these patients, they are routed to the local hypoglycemic expert. Oftentimes, that's in an academic center. Sometimes it's in a larger group practice where a physician is that particular expert in the local market. It's really around the local dynamic. That patient journey is going to vary a little bit within each of the local care settings. As we uncover that, we'll also see where the concentration of patients are being treated.
I'd say yes, there is a concentration in some of these larger academic centers because these are really difficult to treat patients. They take up a lot of time and resources within your local community practice, so they're transitioned to that expert. Based on the claims analyses that Josh has alluded to, we know where those settings are.
Yep. Makes total sense. I think it was interesting when you try and find these docs to talk to, and it's not hard to find some that are treating dozens, 50+ patients, which is always interesting. As it relates to this kind of broader market and building just broader disease awareness, you guys have talked about how this is on ENDO boards now, PBH coding. Maybe talk about some of the other sort of dynamics that are going on in this space and just how the awareness for this disease is evolving within the endocrinology and more broadly community.
Sure. I will maybe start and then pass to you a little bit to talk to our disease state education campaign as well. I think as we have continued to educate, we do just kind of see the awareness growing as well. As some examples, actually just today, we had an investor come speak who took an endocrinology course recently and shared with us that the professor talked to them quite a bit about post-bariatric hypoglycemia.
So, clearly a kind of important element of education that is occurring in endocrinology as well. I would also say, we recently had the ICD-10 code. That is a kind of sign of this disease state maturing, and it is a pretty new disease state. I mean, if you think about it, bariatric surgeries only became popular in the 1990s, early 2000s in the U.S. So, you only started seeing large numbers of people with PBH in the years following that. So, it is pretty new.
Some of the things like guidelines, ICD-10 codes, all that sort of stuff is sort of coming as a kind of wave following this kind of number of patients that have sort of come through the funnel. I would also say there is clearly pent-up interest as well. When we are at conferences, when we have booths, things like that, our people basically are in constant demand by physicians. Literally, for example, at the ENDO conference earlier this year, we had hundreds of physicians coming to talk to our team, and the story was pretty consistent, endocrinologist, "I have a lot of these patients.
I have nothing for them, and please keep me updated on avexitide and everything because I want to know, and I want to be able to help these patients." I think we have seen with endocrinologists too, they are used to having something for their patients. Most endocrinology diseases have at least one effective drug approved and available. It is very frustrating for the endocrinologist when the patient comes in, says, "I am having these significant events." They say, "Here is this incredibly hard to follow, incredibly difficult diet."
Patient follows the diet and is still having events, and they are sort of left with, "I have nothing else for you." So, there is quite a lot of excitement about the endocrinologist for the potential to have an option, something to be able to help these patients who, to date, they really have not had much. I do not know if you want to touch on DSE.
Sure. So, we launched our disease ed campaign, uncoverpbh.com, in June at the ENDO conference, and it has been well received on the HCP side. We have seen strong engagement from endocrinologists, from bariatric surgeons, as well as from primary care physicians. On the patient side, we have also seen significant engagement on the platform and downloads of various resources.
What we are trying to uncover is really an engagement around the signs and symptoms of post-bariatric hypoglycemia, but then in the long run, really a productive conversation between a patient and a physician around those signs and symptoms to accelerate diagnosis.
Yep, makes sense. Then just in terms of the current treatment landscape, I think it is pretty well understood the existing options aren't great. But maybe one thing that has come up with investors, or at least a few more investors recently, is just the use of GLP-1 agonists in this space, and just there are some anecdotes out there from docs. Maybe just kind of share your perspectives on those drugs in this disease, managing this disease. We can talk about kind of the market later, but just how you think about their role in this treatment paradigm, if any.
Yeah, great question. So maybe first I would say, based on our kind of claims work, market analysis, this is a fairly uncommon practice. In this disease. But you could ask why might somebody use a GLP-1 agonist in post-bariatric hypoglycemia? The two things that kind of come up in research are, one, this sort of potential of treating the hypoglycemia with the GLP-1 agonist, which doesn't make all that much sense. I mean, these drugs were approved for diabetes to lower your blood sugar. It would be quite surprising for them to raise your blood sugar.
And in fact, there have been three controlled studies, and those did not show any benefits on hypoglycemia. So, we don't think there is much evidence to support that these actually do help with hypoglycemia. The one other case you might think about is if somebody wants to lose some residual weight. Most people who have had a bariatric surgery have either reached their goal weight or are pretty close.
So again, we think a pretty uncommon practice, and hypoglycemia is probably going to take precedence over losing the last 10 pounds, so to speak, as well. I am forgetting if there is a second part of the question.
No, that was really it. I think that makes sense. All the other options, like acarbose, these patients are typically refractory to those options.
Well, I think it speaks to the frustration of the endocrinologist. They have nothing for these patients, so they do, from time to time, try certain kind of off-label medications. Those medications have been generally disappointing. The small studies that have been done with acarbose or some of the other agents have both shown a difficult tolerability as well as pretty modest, if any, sort of benefit. But I think this is what you sort of see in a rare disease that has no available therapies. The physician tries to do what they can, but would much prefer to have an effective FDA-approved option.
Yeah. Makes sense. So yeah, I guess in terms of the size of this patient population, the unmet need, what is the right way to think about pricing for this drug? If there are analogs, just curious how we should be thinking about that right now.
Yeah, I would say probably pretty early to speculate too much on price. We are still doing a lot of that research, not something we really finalize until closer to the launch. I would say we continue to study the rare endocrinology space, rare disease space. We do believe we are bringing quite a lot of value here. About 90% of people, there is a study that found that about 90% of people with PBH describe themselves as disabled due to the condition.
So, this is a condition that really upends people's lives, and we do believe we have the potential with avexitide to have a meaningful impact. All that being said, probably early to give a final number or anything like that.
Yeah.
The only thing I would add is within the last two to three years, there have been a fair amount of analogs that we can look at that can help us look at some benchmarking as to what the pricing looks like specifically for rare endocrinology.
Yeah. No, definitely. I think there are a lot of compelling comps. Maybe just on the point of analogs, there is never a perfect analog as it relates to what a launch may look like, but I think obviously investors typically try to point to analogs. So, in the context of some of these rare endo launches that we have seen, or just rare disease in general, is there kind of a good analog here for what this launch may look like? Do you guys have, just curious if you have a perspective there, if there is a good analog.
Yeah, I think, again, I don't know that we want to just point to one specifically or otherwise. I think, again, we continue to look at the rare disease space probably early ahead of launch to kind of zero people in too precisely, let's say.
Yeah. No, totally makes sense. So yeah, great. Maybe just other commercial dynamics here from a payer perspective, just in general, what those conversations have looked like and-
We've hired our national account team. They're in training right now, and they'll start educating and engaging with the payer community at the beginning of the year. They'll have their payer information exchange conversations, first to educate on what is PBH. It's not a disease state that payers are really familiar with at the moment. So, that's the first part, is just go out there with our medical colleagues and have the productive conversations around what is it, what's the size of the population within their membership.
That would be the first. Then we'll start to get into a little bit more specifics. But payers are not going to tell us what their prior auth or step edits may look like or make formulary decisions until after we have a label. So, we've got some time to educate the market, but more to come as the engagements continue.
Yeah. No, that makes sense. And maybe one other question here. In terms of an early access program, can you maybe kind of talk about what that looks like for you guys and what that may mean or look like in terms of those patients becoming commercial patients eventually?
Yeah, good question. I'd say we always try to be a little careful just because early access is for access, not for pre-approval promotion or anything like that. But definitely, there's a lot of excitement for people to have access to avexitide. I think as we see at various conferences, endocrinologists are seeking us out to understand more about avexitide, potentially to get access to avexitide. So, it's a program we're quite excited about, but really it's for getting people access compared to the launch.
Yeah. Yep. And how big is it? Have you guys disclosed that?
Currently, the program's up to 200
Yeah
people. But we haven't given, we probably won't give kind of
Yeah
day-to-day numbers or things like that.
Yeah, totally. Makes sense. Great. Maybe just sort of at a higher level here too, in terms of PBH, I think naturally the other question that comes up with folks is, what's going to happen to bariatric surgery now with GLP-1s? Maybe just sort of comment on your perspectives there and kind of what the longer-term trajectory for this market may look like.
Yeah, great question. I'd say first and foremost, PBH is a chronic disease. We've interacted with PBH patients who've had the disease more than 20 years. As we talk to endocrinologists, they describe it as chronic as well. Once people have PBH, they, in our view, have it for life. When we think of the population itself, again, it starts with this is a sort of new disease. Bariatric surgery got more popular in the 90s, early 2000s, et cetera, and the average age to get a bariatric surgery is about 40 years old. So you have a prevalent population that's pretty young.
As we go continue to have bariatric surgeries, those are only adding to the prevalent population. There's not too many people who are maybe old to the point where they may no longer be part- of the prevalent population as well. In terms of the actual dynamics of the surgeries, what we hear is for deep and durable weight loss, bariatric surgery is still the gold standard. Typically, people who get bariatric surgery have BMI over 40, so this is often a population looking to lose quite significant weight. When you hear the stories from people, it's quite incredible.
You hear stories from people over six months or 12 months losing 150, 200 pounds, and it's that fast as well. I think for people looking for that sort of outcome, there's nothing else that quite delivers that. When we talk to bariatric surgeons, they're still, bariatric surgery does not seem to be going away.
Yeah. No, that makes sense. Great. Maybe, you have your long-acting injectable. Before we get to that, anything else to specifically highlight on sort of the commercial dynamics here as you get closer to a filing and potential approval?
Just excitement.
Yeah.
I think it's a significant condition. It's a large, rare disease, and we're really excited about the opportunity ahead. I think the LUCIDITY results, you'll see a lot more of that this weekend when the data's released. From a commercial perspective, we're really, really excited about the opportunity, not only to educate, but to bring potentially the first approved solution to patients with PBH.
Yeah. I was going to ask just sort of the next steps and timing on your long-acting injectable, GLP-1 antagonist.
Yeah, absolutely. So maybe just as background to start. We worked to develop as optimized a GLP-1 antagonist as we could. This is with Gubra. We picked Gubra because they are, in our view, one of the top firms for peptide chemistry, really strong peptide experts. We worked with them over more than a year to screen a large number of peptides to try to find the best possible peptide in terms of in vitro potency, in vivo efficacy, half-life extension, everything like that, with the goal of making an injectable that would be once weekly or even less common when administered.
That is now in IND-enabling studies, which are going well. We expect to submit the IND next year. I will say this disease naturally lends itself to efficient clinical development. Given that with avexitide, for example, we could see differences on a single dose. We would expect to be able to see differences relatively quickly with a long-acting as well.
Overall, I would say that given this kind of severity of this disease and how significant having level 2 and level 3 hypoglycemic events is, we do not think that this population is going to have a particular issue with a daily injectable, but we believe in this market, and so it makes sense to continue investing in a better and better presentation, including doing the kind of long-acting.
Yeah. That was going to be my question, just like how important that is to the commercial opportunity in the context of the daily injectable. But as you mentioned, you guys seem confident there that is not going to be an issue in the real world.
Yeah
the daily injectable.
We don't think so, but I think it kind of goes with our mission as well. We want to serve the patient populations we serve as best as we possibly can. It makes sense to kind of continue investing there. I'd add too, not only is it long, do we expect it to be long-acting, but we also tried to optimize every property we possibly could.
Yeah.
We'll just be very excited to see how the molecule performs in the clinic.
Yep. Makes sense. Awesome. We're right up on time, so thanks guys for joining and thanks for everyone listening in.
Thank you so much.