Amylyx Pharmaceuticals, Inc. ($AMLX)

Presenter at the BofA Annual Healthcare Conference. My name is Jason Gerberry. I cover pharma and biotech, and I'm pleased to be introducing Amylyx Pharmaceutical and Joshua Cohen, Co-Chief Executive Officer; This is an interesting time for Amylyx on the cusp of pivotal Phase III data expected in the third quarter, a transformational event. So I imagine a lot of our discussion is going to be focused on the lead program for PBH. So Josh, thanks for joining us.

Yes. Thank you so much for having us.

So fresh off of 3Q and I guess ahead of the Pivotal Lucidity trial. Maybe if you can just talk a little bit about the trial design, some of the questions that did answer -- and if successful, how this could be an advancement for patients with PBH, sort of frame and then we'll go from there.

Sure. So we're very excited about the Phase III read. I expected next quarter. Avexatide, our lead asset has been through 5 prior trials all of which showed highly statistically significant effects on glucose and insulin and then in the Phase II and Phase IIb, we studied the rate of Level 2 and Level 3 hypoglycemia which showed quite a strong effect as well. So under that backdrop for the Phase III, our goal is to try to keep as much consistent as we possibly could. So very similar inclusion exclusion criteria, looking at the endpoints in the same way, you try to replicate that success we saw previously. To your point about meaningfulness as well, -- this is a patient population that's completely underserved. There are no approved therapies for PH the disease consists of having these frequent recurrent dramatic blood sugar drops, sometimes following a meal, but sometimes more out of the blue, maybe after exercise or stress or otherwise. And when these occur, people can become very busy, they can lose consciousness, -- and most patients on the describing themselves is disabled because they can't drive. They may want somebody with them at all times in case they lose consciousness or otherwise. So to have potentially the first and only therapy that can impact that disease would be transformational for these patients.

Okay. And I think you've framed on your recent earnings call that Stating result would be a win on the primary endpoint. What does that mean to treatment options like 8 carbons that are used by doctors when you talk to them and they cite this as something that they're giving patients. Is there any ability to kind of tease out what sort of benefit patients get from existing modalities even if they're not FDA approved.

Yes. So there have been some small trials of CARBO. I'd say what happens in PH is sort of what happens in a number of rare diseases where there's no available options. People try what they can, even if it's not particularly effective. So acarbose is an alpha glycoside inhibitor. It basically makes it harder for your body to break down complex carbs. -- that doesn't really treat the underlying disease. People continue to have events. And the other thing is when you cannot break down complex carbs, they end up getting broken down by the bacteria very late got so you get severe gas and kind of gastrointestinal side effects, not uncommon that people have trouble being on Acarbosfor more than a couple of weeks. But -- so we don't see -- as we've talked to KOLs and otherwise, we really don't see much eagerness excitement. It's sort of what they have, but it doesn't really prevent the events and very hard drug to take. This would really be the first drug targeting what we see as the underlying mechanism. -- in PBH, people have faster nutrient transit, which leads to a dramatically increased GLP-1 response. So after meals, patients with PBH, MACI 10x normal sometimes 20x or 30x normal GLP-1 responses. So with AveXis, we have a GLP-1 antagonist. We're going at what we believe is kind of the core of the condition, which is unique. There's nothing else like that.

Yes. So to maybe summarize, it sounds like, hey, we're the first with the positive RCT with the drug where mechanistically, there's a lot of sensible rationale in the eyes of HCPs, and that's going to be enough to be kind of enough for physicians to want to use this most of their patients. Is that a fair summary?

I think it is, and maybe I'd just add just characterizing the burden that these patients go through. They're having frequent severe hypoglycemic events. The ADA defines a single Level 2 or Level 3 hypoglycemic event is a medical emergency. And it's true. I mean, we've spoken to endocrinologists who have described patients passing away in their sleep. -- due to severe hypoglycemia, patients can have falls, car accidents, all matter things -- and it also is just dramatic and scary. When you suddenly lose consciousness you may need somebody rescue, you wake up, you don't quite know where you are. These are really, really severe things for patients. And there's nothing available today that's been proven to do anything. -- to these hypoglycemic events. So to potentially have a therapeutic that could impact that as we've done market research, the intent to treat does seem high. They're really looking for an option for their patients.

Okay. Can you talk about Phase II to Phase III, imagine to try to keep as many things consistent as possible. But what are some of the -- maybe the risks of a Phase II to Phase III effect-size compression? Is it more heterogeneous population, which is oftentimes the case in a lot of studies? Is it the slightly longer endpoint? What are some of the key variables from Phase II to Phase III translatability.

Yes. I mean, maybe highlighting your first point, we are trying to keep as much consistent as we possibly can. Probably the key inclusion criteria in these studies is the event rate of people coming into the study. So we do have a run-in period during the Phase II and Phase IIb, People are required to have at least 2 severe hypoglycemic events in 2 weeks in the Phase II, we're requiring at least 3 severe hypoglycemic events in 3 weeks. So it's an event a week to get into the study, you have to be having at least an event a week. So we kept that consistent -- in terms of the elements that are different, the Phase II and Phase IIb were 4 weeks in the Phase III is 16 weeks. We don't really expect that to change treatment effect or otherwise, we haven't seen on the reverse side with the agonist a real attenuation over time. So we don't think with the antagonist, you'll see in attenuation. We don't see ADAs of any particular nature with this drug either. So nothing that would really lead us to believe that the effect changes there. And then in terms of sites and otherwise to -- we tried to keep the sites quite consistent. So the Phase II was 5 centers the Phase IIb was a single center trial. The Phase III includes just about all of those sites, and it is a U.S.-only trial at kind of expert endocrinology centers and expert clinical trial centers. So it's all it's all groups that we think were kind of handpicked and we believe can give them on a quality study.

Okay. So correct me if my details are wrong. I think it was Citi 90% power to detect 35% effect size placebo response, 50% is sort of the statistical assumptions here.

I'd say that we are powered to that. I'd say we don't -- we try to be conservative in our statistical assumptions -- so I'd say we don't think there'll be a 50% placebo effect. Patients with PBH are already doing everything they possibly can not to have these events. So we don't think, for example, they enter a trial and they suddenly become much more successful at not having events. So I'd say we don't anticipate too much in terms of placebo effect. And similarly, with effect size, we powered to see a 35% relative rate reduction. But in Phase II, we saw 55% Phase IIb at 64% -- so I'd say we were conservative in all the statistical assumptions in part because this is the first Phase III, we've conducted with the compound, and we believe we have an active compound. So we want to make sure we have more than enough power to detect that back.

Okay. Yes, because I think the 2 things that come up most commonly with the Amylyx story is placebo rate risk and market size. So maybe if we could just dig in a little bit more on placebo. I agree when we talk to physicians, they all tell us that they wouldn't expect much placebo response in this population. So echoing what you said. I do wonder what you learned from like the run-in period of the -- when you assess that. How much can be gleaned from natural history with this population as you think about that? And some people talk about Resolute's CHI study and the placebo response there as maybe an analog population where there was a higher-than-expected placebo response. So how do you kind of -- what's the rebuttal on some of those points? Or just how would you contextualize that?

Yes. Maybe I'd first underscore your first point from the -- this is really a condition where people do everything they possibly can not to have these events. If you think about it, if having 1 of these events meant that you're going to become unconscious, is going to feel incredibly bad, be incredibly confused you really try actively not to have them. So patients are already really doing everything they possibly can. We don't expect that, that's going to change all that much when they enter a trial setting. Additionally, there have been other trials in the space, including a trial of dasiglucagon in PBH there wasn't a placebo effect observed there either. So I'd say, again, we don't -- we were conservative in our powering. We have enough power even if there is a placebo effect. -- but I think we don't expect too much medically. You also mentioned Resolute and CHI. And maybe, Mark, that they're very different conditions. is primarily a fasting hypoglycemia. So you're basically -- people with CHI basically bleb out insulin somewhat constantly. So if they don't eat very frequently, their blood sugar will drop, particularly a problem externally, the blood trigger can drop because, of course, you're not eating during the course of the night. But you can prevent most of the hypoglycemia and CHI if you just eat frequently and need very slow burn in carbs like cornstarch or otherwise. That's very different than PBH. PBH is a triggered hypoglycemia. So it occurs following a meal, it gets triggered. And sometimes it's triggered out of the blue, such as from exercise stress or otherwise. So there's not really -- you can't just eat and not have the hypoglycemia like you may be able to in CHI.

Okay. and CHI. Yes. Okay. And if data are positive, what are the outstanding work streams, operational work streams that are most critical just to enable a rapid NDA submission?

Yes. I mean we have the benefit of having a very experienced team on this. It won't be the first NDA that Amylyx has submitted. So we took the action of trying to get as much done as we possibly can ahead of the data. So that it's really a process of sort of dropping in the data once the trial reads out compared to starting the NDA after the trial reads out -- everything is kind of proceeding and locks up with that, too. So there's not like a big CMC or otherwise thing that we have to wait on after the trial runs out to be able to cement -- it is still a big document. NDAs are not infrequently hundreds of thousands or even millions of pages. So it's a big document, and you want to do it right. But our intention will be to submit as fast as possible following data to enable a 2027 launch. And we do a breakthrough therapy designation. So we'd expect the kind of 2-month filing period and the 6-month review, that priority review that you get with breakthrough.

Yes. Can you speak to regulatory interactions that you've had so far? I met you're dealing with the endocrinology division, right? And some investors do flag that division and specifically maybe some more unexpected review outcomes of late. So I don't know, is there anything that you can say to the division and your regulatory actions?

So the division we're in is it's actually sort of a subdivision, it's DDLO that we interact with. -- our interactions have been pretty business as usual. And I'd say, one, we have breakthrough therapy, which I think helps in any FDA interactions. And I think we're also just very down the fairway. Whereas I think some of the cases where there have been maybe more contention with FDA have been open-label trials or external controls or novel end points Here, we have a placebo-controlled study with a very well-established endpoint, hypoglycemia something that's been known for quite some time. And we did have -- we did submit our protocol and it was reviewed prior to initiating our study. So we do believe we're running the study in a way that could support registration.

Okay. Maybe let's to commercial and market size here. There's not a lot of great predicates out there, right? Can you look to things like a cabo's utilization or anything in claims data to substantiate. I think you talked about U.S. 160,000 for Epi and then some segmentation factors to that. But anything that we can anchor to get a little higher degree of comfort around who's in the treatment system, who will be accessible. I mean ultimately, I understand that this is kind of a market build.

Yes, sure. So maybe first starting, we do believe there are about 160,000 people in the U.S. today with PBH. That's based both on a lot of literature -- there have been large prospective studies looking at cohorts of people who got bariatric surgery following them over multiple years and those cohorts do find about 8% of people in general with bariatric surgery going on to get PBH and there's been over 2 million procedures in the last decade, which gets you to 160,000. In addition, we've done quite a lot of claims work. And recently, we do expect that the ID 10 code will become available for PBH October this year. But what we've done so far in absence of officialized is looked at those people who had bariatric surgery who went on to have claims for hypoglycemia that couldn't be explained otherwise. That couldn't be explained by diabetes or drugs they're taking or otherwise and that similarly came out to about 160,000 as well. We went to sort of further validate that claims work by doing kind of blinded market research with a number of sites. We're unaided. We ask them -- how many patients do you see with PBH and then we compared that to our claims data to say, is our claims data accurately estimating what these sites actually have. And that came back quite concordant. So we do believe that we're successful in our claims data, identifying the patients. So there's 1 other element of your question.

Yes. I mean just maybe around segmentation, like what proportion do you think are kind of at the bottom of the funnel?

And Yes. I mean we're trying to target the 160,000. Certainly, as with any rare disease launch, our initial focus is going to be on those centers of highest expertise as well as the centers that are most densely serving the patient population but severe hypoglycemia is really, really bad. One, you have the kind of the acute complications of possibly losing conscious in seizures, car crashes, falls. You also have long-term complications. You look in the type 1 diabetes literature, people who have regular hypoglycemia at much increased risk for or challenges for cognitive challenges, et cetera. So these are things that should be treated if they can be treated. And so our goal is to -- for every eligible patient to try to get them on therapy if our drug is successful.

Yes. Is there an aspect of this when you launch where could there be leakage, a loss of patients in the funnel at the referral stage. I imagine not all these patients are in these higher volume centers, so to speak. And so there's going to be an education and then how do you envision that kind of playing out?

Yes. I think it goes to your point, there will be a build here as well. We think there's both a number of patients that are already under very active care who we think will be able to get on therapy quickly, but there will also be some time where we have to educate, continue building the index of suspicion not for all physicians right now, if somebody has had bariatric surgery and they lose consciousness, do they instantly go to, okay, this is probably a blood sugar problem? Or this variable might be a blood sugar problem? There's education we can do to kind of keep building this market and expand out from those more expert centers. So I think it leads to a dynamic where we can keep growing this market year-over-year, which I think is a nice thing to be able to grow into. And I'd add with that too, we also want to keep investing in this market. First and foremost, we have avexatide for PDH in the U.S. That's what we want to launch in 2027. But beyond that, one, there are a number of other surgical types that can cause hypoglycemia, other surgeries that sort of alter the gut and speed nutrient transit. For example, people who get gastric cancer will sometimes have gastrectomy, which can lead to a very similar set of symptoms as what you get in PBH people offer gel cancer can get esophagectomy, people with various gastric reflex disorders, can get various surgeries. So there are quite a lot of ways you can find yourself towards having hypoglycemia. So we see that as sort of an expansion opportunity as well as looking at ex U.S. geographies. We're working on a long-acting version. So I'd say, first and foremost, we want to serve those, the patients with PBH in the U.S. that we can get to immediately, but we also see this as kind of a multiyear expansion beyond that.

Okay. Is that education both on the patient side and the doctor side, i.e., do you feel like a lot of patients might be out there and they need to kind of elevate what they're at risk of or dealing with or just not aware of what they're dealing with and need a physician interaction. How does that dynamic look to you?

Yes. I think it is education on both the patient and the physician side. On the patient side, right now, physicians really don't have much to offer their patients. So there are some patients who have maybe gone to the endocrinologist several times sort of heard the same advice every time and may be less prone to go back to the endocrinologist at this point because they don't have something new to be told. So there may be some patients we sort of have to reactivate now that there's a -- now that there may be a new treatment available for them. But there are also those patients who are very actively under care today. So I think we'll see both in the market.

Okay. So your expanded access protocol, if I understand right, is larger than the Lucidity enrollment. What are the criteria to get into the EAP? And I just wonder -- is this at all an indicator at all of the market overall, right, a faster enrollment.

Yes. I wouldn't say it's an indicator of the market. We do expanded access programs, mainly to provide free early access to drug, redecline diseases that are very severe. If we're able to, we like to get drug to people sooner. Initially, we're enrolling people who are -- who have completed Lucidity or who are in some of the past ebexatide trials. Those patients have -- many of them have reached out to Amylyx. They're very eager to get back on therapy. So that's kind of the initial cohort. And then we do envision kind of expanding beyond that as we get kind of up to the $250 million. But I think as expanded accesses go, I think it's actually a fairly large one, there's only so large you want to go prior to launch as well.

Okay. So exercises daily subcut -- can you talk about I don't know any observations with past trials that have been done, how you think patients are going to adhere to a daily injection.

Yes. I think we -- well, when we look at the past trials to start, adherence was very good. In the Phase II and Phase IIb, we didn't have dropouts. Treatment compliance was very strong. And I think it starts from how severe this disease is. Patients are really looking for treatment. In the 2 and 2B, there were structured interviews of a number of the patients. And you could hear in the interviews, they described feeling a difference as well. When you get severe hypoglycemia, you feel terrible. And patients know that. And so when you have a treatment that potentially is reducing the rate of that or helping that you hope patients can feel that as well. So this is also not a particularly needle phobic population just to manage their disease. They're doing regular fingersticks for blood glucose. So when we've done market research and asked about what do you think about a daily subcu, particularly with the super thin needle and all of that, patients really don't describe that much anxiety or fear about that. So we don't think that's going to have a significant impact in this market.

Okay. So I'm going to preface by saying I'm not asking you what you're going to price the drug at because I know you won't answer that question. But -- do you at least know in your mind where you'll price it if you produce a static benefit? Or do you think that based on the strength of the data that, that could have an impact on pricing power here?

Yes. So we do a lot of research as we kind of approach the pricing -- and included in that research, we bring our data in front of sometimes retired payers, sometimes different KOLs, patients, et cetera, to try to get kind of a multi-stakeholder view and to learn as much as we can. So yes, a little early on the price. What I will say has been encouraging for us is looking at other launches in the rare endocrine space. Some with healthy price points as well. We've seen generally good coverage. I think there's general recognition among payers and really among the medical community more broadly, that hypoglycemia is a severe and very -- can be a very bad thing, can even lead to death. And so I think there's an appreciation, I think, that if you have a drug that impacts that's really bringing value.

What do you think 1 of these patients cost the system, right, in terms of the attacks how many hospitalizations or ER visits are we talking about that could be money saved. I'm just trying to think through the pharmacoeconomic arguments.

Yes, I'd say stay tuned. We'll probably have more of that data as time goes on. Certainly, our kind of HEOR team is is working hard on kind of getting more exact numbers. But I do believe these are high health care utilizers. Even as we've gone through our claims data, you see a much higher than normal hospitalization rate in these patients. You see a lot of complications. You see a lot of drug use to treat various comorbidities in this population. So I do think that this is a pharmacoeconomically expensive population as well.

Okay. On the competitive front, some data from Recordati, I believe, recently, your thoughts on that.

Yes. So we probably don't comment too much on competitors, but I'll say, unfortunately, a trial from Recordati did not see differences on level 2 or level 3 hypoglycemia. This is with pasireotide, which is an approved drug, has an approved label. So I think overall, I think we see ourselves as very well positioned. Breakthrough status, Phase III. I think there's nothing else out there that has a profile like obexatide.

Yes. Okay. And you framed cash runway into 2028, right? So that's getting you through early launch. So it is fair to say you won't be resource constrained in 2027 go-to-market. Yes. So we tried to put ourselves in a very strong financial position. We raised last September. So as you said, cash into 2028. We also did not include revenue in our cash modeling just to be conservative. So when you add revenue in cash might even go longer than that as well. So yes, I think we'll -- in Q3, when we have our data, we'll be in a very strong financial position.

Yes. Okay. And what does the time line look like for your follow-on once weekly, I don't want to call it 1 week they have exetite, but it's effectively the same API just in different delivery technology -- so it is molecule. We did work with Gubra who are excellent to develop basically as optimize the long-acting GLP-1 antagonist as we possibly could. So basically, Uber sort of secret sauce is, they can screen quite a large number of peptides very quickly. So they screened all manner of different variance peptides to try to find ones with a long-acting profile but also good potency, manufacturability, lack of immunogenicity, good in vitro and in vivo data -- so we designed it to be at least once weekly, if not better. We'll know the profile more accurately once we're in clinic. We don't want to promise the exact PK curve in humans. And until we have a PK curve in humans. But right now, we're going through IND-enabling studies. We'll expect to submit an IND in 2027. And I do believe this disease sort of lends itself through rapid development as well. We haven't outlined the exact clinical studies we might do. But I think the main questions to answer will be optimal dose and then confirming that we're having the effect that we want in a larger group.

Okay. Maybe just a few on the earlier stage pipeline, the Phase II Wolfe syndrome program. What in the Phase 2 is sort of the the bar for advancing into Phase III from your perspective? What are you focusing in on here?

Yes. So -- we've presented a week 48 data from the Phase II. We'll be presenting week 96 data. This is for AMx35 in Wolfram syndrome. Wolfram syndrome is a monogenic disease of a protein called Wolf Amin coded for the gene WFS 1. It's an autosomal recessive disease. So it's basically a complete loss of function of this Wolfram gene -- and it's considered a prototypical disease of err-stress, which AMX35is thought to address. In our trial thus far after 48 weeks, we've generally seen stabilization or improvement across the outcomes we've measured. So we've been quite excited. Wolfram syndrome is a disease where people pass away on average in the early 30s. It starts by looking like juvenile diabetes, but it becomes clear. It's not just juvenile diabetes, when people start getting vision loss, hearing loss, eventually kind of walking difficulties, speech and swallowing the breathing difficulties. These are what eventually lead to death for people with Wolfram. So our trial is really focused on the diabetic outcomes as well as the visual outcomes because those move a little quicker as well as kind of a global outcome of global impression of change, both from the patient and the clinician. All of those moved in the direction of stabilization or improvement in a disease where you'd expect them to progress. That was for the 1-year data, that 48-week data. We'll be excited to have the 96-week data. I think we see that data as good to kind of progress to the next study. What we're still working on with FDA is what exactly does a Phase III look like in Wolfram syndrome. It is a disease that has multiple systems involved to the exact primary endpoint and the exact design takes a little time to kind of work through.

Yes. And does this asset developed through Amylyx makes sense to keep in-house? Is this a partnership candidate?

Yes, I'd say we always consider our options, but we don't see that this will be an overwhelmingly -- we would -- it's quite a rare disease, about 3,000 people. We estimate to have Will firm in the U.S. We don't estimate we're running an unduly large or long trial here. So we don't think that this will be much of a financial stream, if you want to put it that way.

Yes. I guess it's -- do you see strategically some rare orphan focused companies there's a core competency in patient finding commercially in the organization? And does it fit from that perspective with an asset like obexatide and your ALS pipeline that you have as well?

Yes. I mean I think it does. I mean, Wolfram has components of both an underground disease and components of a neurodegenerative disease, generally treated by pediatric endocrinologists who are often in a similar center as adult endocrinologists and otherwise. So I do think there's an overlap in competency. We look at similar outcomes as well on the kind of glycemic side for Wolfram. But overall, first and foremost, our focus is on Avexatid. I think we see if we're successful at Lucidity and hopefully, a very strong launch that enables us to do more things. But from a kind of capital and human resources perspective, our main focus is make sure we keep our eyes on the prize with of exit and try to get it as best as we possibly can.

All right. Great. Well, we're out of time. So thank you for joining us at the conference.

Thank you so much. Really appreciate you having us.

All right. Have a good one.