Justin, welcome. Thanks so much for spending time with us coming down here. Before we delve into Q&A, why don't you just kick things off with any opening comments, summary of the business?
Yeah, sure. Thanks so much for having us. Very glad to be here. Thanks for joining us this morning. I'm Justin, one of the two Co-CEOs and Co-Founders at Amylyx. We have an exciting pipeline ongoing. My guess is we'll talk the most about Avexitide, which is our competitive inhibitor of the GLP-1 receptor that is in a phase three pivotal study right now for post-bariatric hypoglycemia. That's following five quite successful prior studies of Avexitide and PBH that ultimately supported FDA Breakthrough Therapy Designation. We're looking at completing enrollment in the first quarter of next year and top line results in Q3 of next year. I'm guessing we'll spend a decent amount of time on that program given its stage of development. We have two other assets in clinical development right now as well. We have AMX0035 in Wolfram syndrome.
We had positive results from our phase II-A study announced earlier this year. We are working on phase III design now, pending alignment with FDA. We also have an antisense oligonucleotide targeting Calpain-2 for the proposed treatment of ALS. That is in a phase I study right now, but in people with ALS. We will have safety and tolerability data at an upcoming medical conference in ALS and biomarker data in the first half of next year. Exciting clinical pipeline. We also recently did a financing that gives us cash runway into 2028. We are very excited with our programs and happy to dive in.
Great. A lot to unpack here, but let's just focus on obviously the main focus of Avexitide for PBH. Just given the prevalence of bariatric surgical procedures for the past 30 years, why would you say PBH still remains a relatively untapped market where current therapies consist of dietary modifications and suboptimal off-label treatments? How do you see the space evolving over the next couple of years?
Yeah, it's a really important question. I would say those were definitely our first questions as we started to evaluate Avexitide early last year is we estimate that there are about 160,000 people with PBH in the U.S. today, and that number is only growing. Wow, that's a lot of people. It's a rare disease, but it's kind of large, rare disease. How come this isn't more, there's more awareness of this? To your point, bariatric surgery has been prevalent for some time now. I would say, I think as you start to dive in, you understand why maybe historically there wasn't as much focus on PBH, but I think there's growing focus on PBH. I'll share a little more on that. Bariatric surgery really started to ramp up in the early 2000s.
PBH, post-bariatric hypoglycemia, takes on average about one to three years to manifest. It can be even longer than that. If you think about those dynamics, it kind of takes over time that you start to have this much more substantial population where you get to the numbers like you have today. The other thing is that I think the presentation of the disease can feel a bit nebulous. People have bouts of severe confusion. They have bouts of losing consciousness. They become terribly shaky. There are things like that that again, I think an expert endocrinologist would say, okay, those are clearly signs of hypoglycemia. If you've had bariatric surgery, okay, this must be post-bariatric hypoglycemia, but it takes a little time to define that. In fact, the term PBH in the United States was really first written about in 2008.
It is still relatively recent. However, what do we see today? Even independent of our efforts, there is a lot going on with awareness of PBH. At this year's ENDO meeting, there were several posters and presentations on PBH independent of our work. They are now on the endocrine board exams. There are questions on post-bariatric hypoglycemia as well. There was recently a presentation to the CDC recommending an ICD-10 code for PBH. There is a lot of work ongoing, and that is before we even start our marketing efforts. What I would say is that historically, yes, I think PBH may be under-recognized, underdiagnosed. I think where we are today, in the endocrinology world, you talk to just your general endo or certainly an academic, I think they are much more familiar with it. It is often because they have a lot of patients under their care.
Got it. Got it. When you speak to endocrinologists and other thought leaders in the field, Justin, just with the ramp up of GLP-1s and the continued white hotness of the space, so to speak, where you have agents that could cause one to potentially lose 30% or more of their body weight, how might that impact the addressable market of PBH?
Yeah, I think what we've, so first, I think you're starting with a very large prevalent pool, right? I think, and all evidence suggests that once someone has PBH, it doesn't go away. Starting with 160,000 people, that's already a lot. The question is really how much does the market grow from there? So far, we haven't seen changes in the rates of bariatric surgery. The running rate's been about 270,000 procedures annually. I think what we've heard from weight management clinics is they still view bariatric surgery as the gold standard for people who need to lose, let's say, 150 lbs, 200 lbs. We're not there yet with the weight loss drugs. I think the way weight management clinics view it from what we've heard is these are all tools in the toolkit.
People who maybe want to lose 30 lbs-40 lbs, yeah, we have great treatments for you. People who need to lose 150 lbs-200 lbs, they may be better candidates for surgery. We are still talking about 10,000,000 maybe 100,000,000 of people. I think it is a long way of saying we do not see it yet impacting the market. Maybe it will over time, but I think what we are talking about is what is the growth rate of the PBH market as opposed to the actual total market.
Right. Obviously this disease, the severity exists on a spectrum. Maybe talk about how your internal market research has corroborated the independent claims research that was recently presented at ENDO.
Yeah. I think it's the way we tend to think about it as a funnel. You start with how many bariatric surgeries have there been? If you just look at the past decade alone, there's been over 2 million surgeries. If you look at the past 30 years, there's been many millions of bariatric procedures that have happened. I'd say roughly 1/3 of people will develop some hypoglycemia. Again, you're still talking hundreds of thousands, maybe even over a million people. We're defining PBH as the people who have continued persistent hypoglycemia despite any dietary or other intervention. We get to about 8% of the total population. Dr.
Colleen Craig from Stanford presented at ENDO that for Roux-en-Y specifically, she thinks it's closer to about 11% of people who will develop this very persistent symptomatic PBH who are on that quite significant severe end of the spectrum, as you were saying. That's how you get to about the 160,000 total population. We've done our own independent claims analysis now on multiple claims databases. I'd say that kind of regardless of methodology, we get to very similar numbers no matter how we're looking. We're quite confident in that as the general population. It sounds like a big number, but it's actually a rare complication of a big population. You just get to a large number, but it's actually still ultimately rare.
Got it. No, that's very helpful. When you think about the patient journey, Justin, of maybe they get bariatric surgery and then it could take a year or two to really kind of just finalize a diagnosis of PBH. Among these 160,000 patients that are really severe, what will be the key drivers for adoption here? What's going to take to open up this market, would you say?
Yeah, I think we're doing all of our sort of market insights work now, as you might expect, and working with our medical affairs teams as we get into the field. I think what we're coming to realize is if you think about a population of 160,000 people across the country with PBH, I'd say there's quite a large population of people who are actively managed right now, particularly at the large centers. As we've been in the field, it's not uncommon for us to come across a clinic that might have 100+ people under their care. There are some centers that have really a lot of people.
I think though over time, we'll want to sort of build into the market as well, raising suspicion as you get into more community endos at this sort of quote unquote front end with surgeons starting to build that educational knowledge that, hey, if someone exhibits these signs and symptoms, they should go see an endocrinologist. Because at the end of the day, it's not that difficult of a diagnosis. They have signs and symptoms of hypoglycemia. They've had bariatric surgery and there's no other reason for the hypoglycemia. It is fairly straightforward, especially now with the tools we have to measure blood glucose. I think it's much more just an educational piece. That's why we're doing all of our insights work now so that we can build into that next year and then in 2027 as we hopefully move to launch.
Okay. Two quick more commercial questions and we'll dive into the phase III. You mentioned that there's currently, at least at these academic centers, a lot of patients kind of under care. Assuming approval, should we kind of expect kind of a bolus effect of initial patients, kind of a warehousing effect, which will kind of take time to work through and then a typical S-shaped launch curve? Any thoughts on that?
Yeah, I think it's probably a little early, but I would say there's certainly great enthusiasm at the academic sites. I think particularly the people enrolling at the trial. I would say the sort of general awareness, as I was saying, of PBH. It's in part because it's a particularly severe condition. I'd say patients are very frequently calling the clinic because they're having events. They're going to the emergency room. It's highly debilitating and they're having these events very frequently. I also think there's going to be a big educational component as well. I think there's going to be kind of both aspects of the market where I do think that there are people who are very, very actively managed under care today, potentially seeking treatment if there's one available. I also think that there's an educational component.
I think there's going to be both pieces to the launch.
Got it. Final commercial question. I know the CDC has until April to make a decision on the ICD-10 code. Any reason why the CDC wouldn't grant this code or is it pretty much accept that that's going to happen?
Yeah, I'd say maybe to state the obvious, I can't quite speak for the CDC. I do think that first, maybe to state, I think the ICD-10 code in this case is kind of a nice to have and not a need to have. What I mean by that is for a treatment perspective, one, I think there are already good definitions of PBH. Two, it'd be covered under a pharmacy benefit. Payers, hospital systems, et cetera, don't need the code in order to reimburse or have a payer reimburse for PBH. From the definition perspective that then leads to the ICD-10 code, I do think that it's a case where you have clear evidence that this is a condition with clear guidelines. It's different than other conditions. There's a substantial population.
My understanding is that those are the things the CDC tends to look for if they designate a new ICD-10 code. We'll have to see what the CDC ultimately decides next year.
Got it. Got it. Now we'll delve into the eventual TIDE phase III study. It's been designed to replicate the successful phase II trials as much as possible. I think the biggest difference is the treatment period. In phase II was four weeks, but in phase III, it's 16 weeks. Is there any risk here in treating longer, maybe in terms of tachyphylaxis? And what was the decision made? Why was the decision made to increase the treatment period 4X versus phase II?
I would say in terms of the decision, the goal of the trial is to support an approval. I think with breakthrough status, it's nice to get a lot of back and forth with the FDA. I think the FDA reviewed the protocol and the protocols that exist today. The goal is to support approval if successful. There has been no evidence of tachyphylaxis or anything like that that would suggest a kind of waning of effect. I think if we look at the opposite side on the GLP-1 receptor agonist, we've seen continued effect over long periods of time, both in trials and the real-world setting. There's no reason we believe that there should be a difference over time between four weeks and 16 weeks.
Yes, you're right that that's probably the main difference between the phase IIs and now this phase III trial.
What would you say, what aspects of the trial design are just most critical to ensure consistency with the prior phase II studies?
I think probably the couple of most important things that come to mind. First, how we're measuring the outcomes, we're doing exactly the same as was done in the phase IIs. For the primary outcome, it's a composite of level two and level three hypoglycemic events. Level two hypoglycemic event is blood glucose value less than 54 mg per dL. In the primary outcome, that's measured by a fingerstick blood glucose, which is the same as what was done in the phase II trials. The level three event is defined by you need independent rescue. You've had such significant complications of hypoglycemia that you need help, basically. That is done by a kind of eDiary dropdown menu. It is adjudicated by an independent expert endocrinology committee. We're using the same firm that was used in the phase IIs.
We have a charter to define, I'd say these are well defined, but we have a charter that's been reviewed by FDA as well. I think the first most important thing is the primary outcome. We're measuring the events the same way as was done in the phase IIs. This is an outcome that is in FDA guidance as well as an acceptable outcome. I think the second is making sure that we're enrolling the right participants in the study. In the phase II, they had a run-in portion where they were looking for two hypoglycemic events in two weeks. In this trial, we're looking for three events in three weeks. Same event rate.
One of which has to be level two.
One of which has to be a level three. That's correct. The reason that's important is you're making sure that you have people who are sort of on the right end of the severity spectrum. You have people who are frequently measuring their events. Ultimately, that's what gives you the powering as you go into the phase III as well. Because if people are having very consistent events, you get a lot of events and it gives you quite good powering for the study.
Got it. Okay. Missing data. I mean, have you been able to, are you able to disclose how missing data will be handled?
I'd say probably a couple of things. One, I think going to the number of events, because I think you have so many events in the study, it's a very well-powered study. If you just add up 75 participants x an event per week x 16 weeks, that would get you to 1,200 events. One is just if you have a lot of events, you have a lot of powering, which I think helps substantially. I'd say two, looking at the prior trials, there's very strong effect size as well. Using the exact statistical model that we're using in the phase III, if you did that in the phase II-B , there was a 64% reduction in the composite. I'd say long way of saying, I think it's quite a robust design.
Got it. Got it. Just in the interest of time, maybe just rapid fire in terms of the other pipeline. But other areas for GLP-1 antagonism, I mean, what else do you see this mechanism, where else do you see this mechanism having impact potentially?
Yeah. I think we're very focused right now on the lucidity trial, of course. We do think that there's great potential for this mechanism in other areas as well. It's been long known that really any upper GI surgery appears to be able to cause this persistent hypoglycemia, whether that's gastrectomy for gastric cancer or esophagectomy for esophageal cancer. There are many different reasons that someone may present with this. I think that is a whole other area. Avexitide has an independent breakthrough status from FDA for congenital hyperinsulinism. We're not pursuing that at the time, but I think it speaks to the fact that this mechanism is very powerful. There are other causes of hyperinsulinemic hypoglycemia as well.
I think long way of saying, we think this is a mechanism we're very excited about, which is also why we're excited about our research partnership with Gubra to try to develop a long-acting inhibitor of the GLP-1 receptor as well. That's coming along really nicely.
Got it. Real quick, two final questions. Wolfram syndrome, remind us of the timelines and how big the market could be.
Yeah. We estimate about 3,000 people with Wolfram syndrome in the U.S., substantially more ex-U.S.. We're working on the phase III design right now. Pending alignment with FDA, it'd be second half of next year we'd start the trial.
Got it. The Calpain-2 ASO for ALS, the phase I MAD first cohort is completed. Data is still expected later this year?
Yes. I would say safety and tolerability data later this year and then biomarkers first half of next year.
Excellent. That is about time, Justin. This has been immensely helpful. Lots to look forward to in the year to come. Thank you for being with us.
Yeah. Thanks so much.
Take care.