Amylyx Pharmaceuticals, Inc. Common Stock Morgan Stanley 24th Annual Global Healthcare Conference

Hey, everybody. We're going to get started if you could find your seats. Thank you. Perfect. Welcome, everybody. I'm Cailin McGurk. I'm a member of the investment banking team at Morgan Stanley. It is my pleasure, my absolute pleasure, to welcome Josh Cohen and Justin Klee, co-founders of Amylyx, to the stage today. Just a very brief disclaimer before we get started. You've been to many of these before. Please visit the Morgan Stanley Research Disclosure website, www.morganstanley.com/researchdisclosures, for important information about this and other presentations. Without further ado, fantastic to have you at our conference. It's been a highly eventful and highly successful summer at Amylyx with the amazing data you had on avexitide in PBH over August. Let's start there, because obviously, it's the burning question. Let's talk a little bit about the data.

Firstly, in terms of the headline results, what you saw, what you were expecting, and then obviously, a lot of follow-up questions on this topic.

Sure. Yeah. At first, I'd say we had high expectations given all of the prior trials of avexitide, but I'd say this exceeded our expectations. The data, just to kind of highlight our pre-specified primary outcome, which was the rate of level 2 and level 3 hypoglycemia in people living with PBH. These are events that are extremely debilitating. Any one of these events is considered a medical emergency. We saw a 55% reduction with the active versus placebo, with a P value of 0.000003. We hit all of our secondary outcomes also with high statistical significance, similar effect sizes as well. I'll note what's nice about the secondaries, too. Those include looking at level 2 individually by finger stick or by CGM, both of which were met, as well as looking at level 3 hypoglycemia, which is a clinical event.

That's when basically people have become so hypoglycemic that they're incapacitated, basically warranting rescue from another person. Safety profile was also consistent with prior studies with a very favorable safety profile. So overall, we were thrilled, and I think maybe most so, we've gotten to know a number of physicians that treat PBH, patients living with PBH over the last years. For many people with PBH, this is a completely disabling condition. There was a survey recently where 90% of people with PBH interviewed described themselves as having a disability due to the condition. So it's just been incredibly gratifying, incredibly exciting. It's really our mission as a company to be able to deliver therapies to diseases that have either nothing or completely inadequate options, and that's certainly the case in PBH.

Coming off this, we're planning to submit our NDA by the end of the year and then already prepping to launch in 2027, if approved.

Maybe just a follow-up question. This was a 78-patient study with a crossover design. You saw very impressive statistical significance on the primary endpoint. What does that tell you about the targets, the underlying biology in an era where everyone is trying to agonize GLP-1 and you're antagonizing? How should we sort of see the result relative to the underlying biology in the disease?

Well, I think that I'd start with the prior work that had been done in post-bariatric hypoglycemia. Post-bariatric hypoglycemia, PBH, doesn't occur in most people. It happens to about, we estimate about 8% of people who get bariatric surgery in the years following. It takes years to manifest. What appears to occur is that nutrient transit has been increased because a significant portion of the GI tract has been resected. In some individuals, this causes a very significant increase in their body's own production of GLP-1. This is a condition that is driven by this excessive exaggerated GLP-1 response. People have 10 times, 15 times, sometimes 20 times normal levels of GLP-1 in response often to nutrients, but it can be for other triggers as well. GLP-1 is a very strong potentiator of the insulin response.

What occurs in people with PBH is that their GLP-1 has this inappropriate production and secretion, which causes this exaggerated insulin response, which causes, of course, blood sugar to drop significantly. In these cases, this sort of drop in low blood sugar is by definition a medical emergency because, of course, our bodies, particularly our brains, need glucose to function to do all of our sort of daily activities to fuel all the cells in our bodies. When your blood sugar gets to this very significant low, essentially the brain starts shutting down its functioning. That's why we see these essentially neurological complications. People get severe dizziness, confusion, even loss of consciousness, seizures.

This biology had been known for a long time, actually going back to the 80s, some really elegant work showing that in response to various gastric surgeries, people could develop this very debilitating chronic condition. There was a group, particularly at Stanford University, who reasoned that, well, then if we have an antagonist of the GLP-1 receptor, then we would block that GLP-1 response, and maybe that would then block the downstream hyperinsulinemic hypoglycemia. That is what they saw in five consistent studies. The LUCIDITY trial, which we just read out, was the longest, largest duration study that had been run to date. That was really testing the question of, in a real-world setting, when people are at home following their dietary guidance and the sorts of things to control their PBH, if you inhibit this GLP-1 response, can you prevent these hypoglycemic events from occurring?

That's indeed what we saw with the clinical data. I think this is really exciting because, to your point, not only are the results very promising for PBH, but we really feel like we're getting at the heart of what's causing this very debilitating condition. I think that's why we've seen such strong results of avexitide now consistently through six studies.

Yeah. Very minor correction, too, also. Parallel group study. Parallel group study.

Yes, correct. Maybe we should just think about patients have this condition chronically. How should we be thinking about the durability of the benefit beyond 16 weeks and sort of any thoughts on that?

Yeah. One, with avexitide, we start seeing a benefit at a single dose. In our prior studies, there were studies where people basically took a single dose of avexitide, had a meal test, and you could see a significant difference from placebo with just the single dose. As we've looked out further, that benefit seems to be persistent. We do not see any difference over the 16 weeks, and we would not really expect to. This pathway does not really have any feedback loop that would sort of prevent that. So we would expect kind of a persistent effect. PBH itself is also a chronic disease. Once you have PBH, you have it for life. Once you've had the surgery, the surgery does not go away. You have it for life. So we do expect that to continue deriving the benefit, that this would be a kind of chronic treatment, chronic therapy.

And just one last question around the other observations. Obviously, in this population that have been through bariatric surgery, the concern around weight regain with GLP-1 antagonism. You did, Justin, talk about the GLP-1 levels being supraphysiological, but just comment on what you saw in this study.