Hi everybody. Good evening. Thank you all so much for joining us in the room. It's so nice to see some familiar faces and really nice to see some new faces as well. My name is Lindsey Allen. For those of you who don't know me, I head up Investor Relations and Corporate Communications for Amylyx Pharmaceuticals. Thank you all for joining us on the webcast too. During today's presentation you'll hear from leading experts about post-bariatric hypoglycemia or PBH and avexitide, a potential GLP-1 receptor antagonist with Breakthrough Therapy designation. Before we begin, I think all of you know we'll be making forward-looking statements. Please refer to this slide as well as our investor website. Here's a brief look at our agenda. We'll start out with a short video from a community member who's living with PBH, then our KOLs will talk about the unmet need, what it's like to live with PBH from their perspective, the symptom onset, and how the disease progresses. We'll talk about avexitide's mechanistic rationale as well as the data that have been generated to date that informed the ongoing LUCIDITY clinical trial. We'll close with some remarks from Josh and then open it up to Q&A. I did just want to take a minute to thank Dr. Lawler, Dr. Tan, and Dr. Craig for joining us today, not only for their participation in this event but also for their ongoing commitment to the avexitide clinical development program. Thank you. Dr. Lawler was an investigator or a co-lead investigator on the Phase 2 PREVENT clinical trial. She's an investigator on our LUCIDITY clinical trial, and she's the Associate Professor of Medicine and Endocrinology at University of Colorado at Denver School of Medicine. Dr. Tan is the principal investigator on the LUCIDITY trial. She was the co-lead on PREVENT, and she's a Clinical Associate Professor of Medicine at Stanford University School of Medicine. Dr. Colleen Craig co-led the proof of concept and the first-in-human studies of avexitide and PBH. She was the leader of the avexitide development program during the Phase 2 PREVENT clinical trial, and she's now a scientific advisor and consultant for us at Amylyx. I know a lot of you know Josh, Camille, Jim, Justin. I'm really excited to introduce you to Dr. Jamie Timmons, who's our VP of Medical Affairs. Medical Affairs here at Amylyx. My name is Margaret Olinger. I'm a single mom to three awesome kids, and I live with post-bariatric hypoglycemia, also referred to as PBH. I had Roux-en-Y gastric bypass surgery in 2006. It far surpassed my expectations. At first, I lost over 100 pounds. In less than six months. Physically, moving around was easier. All of a sudden, just having a body that works and felt normal for the first time, that was really lovely. I had a long journey to get. To a diagnosis for hypoglycemia and an. Even longer journey to get to a. Diagnosis of post-bariatric hypoglycemia. It took from August of 2018, which was when I was first diagnosed with hypoglycemia, and I met my endocrinologist in May of 2020. Most of that time I was homebound. Looking back, I knew there was something wrong. I can see a lot of episodes that I think were blood sugar related. There were a couple times that I almost passed out in public. Had no idea that blood sugar was. An issue for me. I went to the emergency room. When they got my blood work back, they pulled me back so quickly and said, your blood sugar is 37. You should not be able to walk or talk or stand up right now. There's a wide range of symptoms I experience. A lot of people don't understand. The speed of the ups and downs that I deal with is so different than what most people who deal with blood sugar issues are used to dealing with. What that looks like is I eat food and then about 45 minutes later, my blood sugar is too low, my heart rate goes crazy really fast. I feel really hot internally. A lot of times I'm very sweaty. It's this weird feeling. Usually within 20 to 30 minutes of eating, I've gone through the up and then I start to come down. There are times where it drops really, really low and my body will kind of shut off most of my eyesight and I'll feel like I might be at risk of falling. I lay myself on the ground until I'm coming back up. Most of my vision will get blurred out or grayed out and I can't communicate clearly. I can't think clearly, I can't plan effectively. I have to have a recovery amount of food, some type of sugar, and then an hour later, I may have a whole other episode to deal with. There are days where every single hour for five or six hours straight, I have at least one episode an hour. What I really would like other people to understand about this disorder is that the treatment and recovery of using glucagon to bring your blood sugar back up is also very likely to set you back into another problem very soon after, and you just can't get on top of it. Even when I do everything right with my diet and nutrition, I can eat the same thing every day of the week and have a very different response to the same thing every single time. There's nothing on the market available. That's one of the hardest things to come to terms with when you're early on in diagnosis, realizing I have to live with this forever. I don't ever get to get better. I don't ever get to be a normal person. I don't ever get to be okay. Because of living with this condition, it limits my ability to do work, to drive a car, just to function as a normal person. It really sunk in for me when my endocrinologist explained to me that I. Was just not going to have the. Stability and health to be able to drive again in the future. I'm not healthy enough to work 40 hours a week at a regular job, to make income for my family and have choices about my financial stability. In a week's time, I can go from handling things and pretty functional physically to being in the hospital. My children deserve the best mom in the whole wide world. There are times where my blood. Sugar drops too low. I keep our world small to make sure that I can take care of them effectively. I always meet their needs, but I do sometimes have to delay meeting their needs to meet mine first. I have to educate everyone that spends time with me regularly about this condition. They have to know on a basic level what's going on and when I need someone else to step in. I really just want a chance to find better options, to seek a life with more normalcy. I just want to feel more normal. Pretty powerful. That is just one example of many, many patients that are going through this. I'm Helen Lawler. My disclosures are Amylyx as well as Voginex, where I'm a PI as well as consultant. I'm going to give you some background information on post-bariatric hypoglycemia. This is hypoglycemia that usually occurs about one to three hours after eating meals. It's worse after high carbohydrate foods. There was one study that showed about 33% of patients who've had bariatric surgery have reported hypoglycemic symptoms after eating. Pretty high prevalence. Dr. Craig will be talking more about this as well. It usually develops about two to three years after bariatric surgery, but it can happen anywhere from two up. I think there was a case report here at Endo. Up to 20 years was one of the case reports that were presented after surgery. Typically two to three, but can. Happen pretty much any time. If the onset is less than six months after surgery, then we look for other etiologies because we think it takes a little bit of time for this pathophysiology to develop. What happens is because of the altered anatomy, the food rapidly enters the small intestine, causing hyperglycemia and a large GLP-1 incretin response. This causes hyperinsulinism and then subsequent hypoglycemia. We'll also go more into detail about that later. The hypoglycemia can be very severe and debilitating, as you saw in the video, where patients can no longer drive, they can't maintain employment, they get very high rates of depression and anxiety because of fear of severe hypoglycemic events. The symptoms that they experience are autonomic symptoms, such as the hot, shaky, sweaty you've probably heard about. They also get neuroglycopenic symptoms. This is when the brain is starving for glucose and the brain doesn't have enough glucose, so they get confused, blurred vision, seizures, coma, weakness, dizziness, and trouble talking with slurred speech. Oftentimes, these patients develop hypoglycemia unawareness, and those autonomic symptoms go away. They don't have those warning signs of hot, shaky, sweaty, and they just frankly get confused, can pass out, and very dangerous and debilitating. How do we treat this? The key first step that we advise all patients is dietary modification. We tell them to limit their carbohydrates to under 30 grams per meal, to limit their added sugar to under 4 grams per meal and per snack, no carbs. We tell them to avoid liquids with meals to try to slow down the transit of food going into that small intestine, mainly low glycemic index food, avoiding all the simple sugars. Unfortunately, with these dietary modifications, patients fail this very frequently. We're stuck with, unfortunately, no FDA approved medication. We often try first to get continuous glucose monitors for these patients. It's difficult to get approval because the FDA has only approved CGMs for patients with diabetes. Oftentimes these patients are paying for CGMs out of pocket, but they are helpful because they'll warn the patients when they're starting to get low. They can see the peak in their sugar and then they know they're probably going to crash and try to treat their sugar before they have a dangerous low. This is just to help them, but obviously isn't necessarily a treatment. The medication that we use off label, we give them glucagon in case they're having a severe low. Unfortunately, oftentimes this doesn't work either. Because they carb restrict so much in their diet on a daily basis, they don't have a lot of glycogen stores. Sometimes glucagon can be ineffective. We often tell them they can try cornstarch mixed with their meal to try to slow down that digestion. The case reports that have been done on that, it's very large amounts of cornstarch, it's three tablespoons three times a day and six tablespoons in the evening. I don't have a lot of patients that do this on a consistent basis. Oftentimes it's ineffective as well. After trying that, our first line off label agent that we usually try next is acarbose. It's cheap, we can usually get it even though it's off label. Unfortunately, the side effect profile is pretty bad. I'd say more than 50% of my patients can't tolerate the side effects they get: gas, bloating, belching, abdominal pain. Oftentimes they throw in the towel after the first dose because the symptoms were so bad and won't take it anymore. I do have some patients that will continue taking it and it has helped some. Others, they fail it even if they can't tolerate it. The failure rate is pretty high as well with acarbose. If the acarbose isn't doing anything, they're not tolerating it or they fail it, we look at some of these other agents here, somatostatin analogues and diazoxide. They work by decreasing the overall insulin secretion by the pancreas. I overall haven't had great success with these, so I honestly don't try them that often. I'll usually try the octreotide or somatostatin analogues prior to trying the diazoxide because the side effect profile isn't as bad. There is diarrhea, it's very expensive and the failure rate is high. Even though it's supposed to suppress insulin, they have a large insulin surge and crash on these medications. I was speaking earlier with Alex about pasireotide and I tried that before in a patient. I got compassionate use about 10, 11 years ago to use that, and it unfortunately did not work well. The patient got QT prolongation and continued to have hyperglycemia followed by hypoglycemia with baseline hyperglycemia on that. I haven't had great success. There are GLP-1 receptor agonists that we've been trying as well, which might seem counterintuitive because we know the GLP-1 levels are very high in this patient population. The problem with that is these patients that have severe PBH, they're already really thin because they're carb restricting, trying to follow the diet. The issue is oftentimes we're nervous of starting that because their nutrition is poor and they're very thin and we're worried about weight loss. In addition, it doesn't work for everyone. I've had some patients where it's made it worse, other patients where it's done nothing, and it has helped some. As I mentioned, the weight loss is very concerning. Surgical approaches for patients that fail all of these things we throw at them, our last resort is putting a G tube into their remnant pouch of their stomach and feeding them only through a G tube, nothing by mouth, to see if we can get rid of that GLP-1 surge in the subsequent hypoglycemia. If their hypoglycemia resolves with tube feeds for a couple weeks or so, then we can do a bypass reversal to try to eliminate the hypoglycemia. This is a last resort and obviously not preferred. The patients don't want their bariatric surgery reversed because they want the continued weight loss they're getting with the surgery. Here are the clinical trials, the former trials that were in development, that are no longer in development. Was this ready to use glucagon, mini use? There's a trial that we did with that, that they no longer are pursuing further trials with that. Zoma358 was an insulin receptor antibody, where the data wasn't that promising either. They stopped doing research on that. There was canagliflozin trial, the HYPOBAR trial, that they no longer are pursuing either. They stopped that trial short because it was ineffective. My fellow today presented our poster we did of a case series of canagliflozin in some of our patients. We really didn't see benefit in it either. Empagliflozin, which is an SGLT2 inhibitor, once again, mixed data on that. Some small studies showed some benefit, some didn't. The problem with SGLT2 inhibitors is that these patients are carb restricting so much that they're at risk for euglycemic DKA if you put them on an SGLT2 inhibitor. It's very dangerous for a lot of my colleagues, you know, don't want to try this in their patients, rightfully so, because of the risk of DKA in this patient population group. The current clinical trials, obviously avexitide you're going to hear a lot about tonight. Pasirotide is in trials right now, and as I mentioned, I did not join that clinical trial because I didn't personally have success when I've tried it in my patients. Mesagliflocin is also being looked at. This is a direct SGLT1 inhibitor to reduce glucose absorption, similar somewhat to acarbose but different mechanism. We have MBX, which is long-acting, once-weekly GLP-1 receptor antagonist that's just starting to do clinical trials at the moment. These are just a few examples of some of my patients that I take care of in clinic. I could give you many more, but I just selected a few. I take care of a woman in her late 30s, and she works as a healthcare specialist. She told me that she eats nothing all day long in order to maintain employment. She'll eat one meal daily in the evening when she gets home from work, and that's it, and that's how she's capable of keeping her job. She said if she doesn't do this, she wouldn't be able to work. I also take care of a woman, 40 years old, who is a city bus driver. Unfortunately, just recently I told her she could no longer do her job because it was just not safe for her or anyone on the road because she just has such debilitating hypoglycemia. She's recently been hospitalized three times now with hypoglycemic episodes. Currently unemployed, severely depressed, very anxious, wants to enter our clinical trial if we can get her into the trial. She lives far away, but we're working on it. I have two women in their 40s who were so done with the hypoglycemia and not feeling like they had any control and the fear of hypoglycemic events, that they just begged the surgeon to do a total pancreatectomy, which has definitely fallen out of favor. They had pancreatectomies, and now they have type 1 diabetes the rest of their life on insulin pumps because the hypoglycemia is so severe. I also have a man in his early 50s, and he eats a ketogenic diet but still will have hypoglycemia. He's pretty emaciated right now. We're considering giving him tube feeds in his Roux-en-Y pouch just to provide some nutrition. Unfortunately, with him, reversal is not a great option because he'd had a Nissen prior, and if he were to reverse it, he'd have further complications. He's kind of stuck right now with this quality of life, desperate for something better. As I mentioned, there's big gaps in treatment and knowledge. There's a huge lack of awareness of post-bariatric hypoglycemia in the medical community. Oftentimes patients aren't educated prior to surgery that this could potentially happen to them. I think we need to do a better job educating patients of the potential of this happening as well as educating our primary care doctors about PBH. Oftentimes by the time I see someone in clinic, on average, when I see someone, they've had this going on. For about two to four years prior. To even getting to see me. During that two to four year time, usually two to four years, they were getting it chalked up to menopause, anxiety, or something else. They had all the symptoms of PBH, but unfortunately, due to lack of awareness, they were told they were anxious or they had menopausal symptoms. We really need to increase the education about this condition. There are also very inconsistent care pathways among providers where everyone kind of treats this differently. Since there's no FDA approved medication, everyone just kind of tries things differently per their expertise. We really need an FDA approved medication. As I mentioned, these off-label medications that we use are often not that helpful. Also, the side effect profile is pretty severe for these patients. This is a population that's desperate for help to ameliorate their debilitating hypoglycemia. This is a very big opportunity to change the standard of care for this serious and underserved condition. Next, I'd like to introduce Dr. Colleen Craig. Thank you. My relevant disclosures. I am a part-time contract consultant for Amylyx. I am co-inventor on certain patents and patent applications and I'm under certain agreements related to avexitide. As you heard from Dr. Lawler, PBH represents a significant unmet medical need. Historically, it has been underdiagnosed due to inconsistencies in definitions used and methodologies used to identify incident cases. In addition, there is a lack of routine screening protocols, especially outside of the specialty care setting. There is no dedicated diagnostic code for PBH. There's no ICD-10 code, which makes epidemiological tracking a challenge. In an effort to better characterize the burden, the true burden of PBH in the U.S., colleagues and I at Stanford University undertook a systematic review of the scientific literature in order to model the U.S. incidence and prevalence of PBH. We used surgical census data over the course of the past 20+ years and used established life expectancy data and disease state modeling. Our results are shown. The prevalence results are shown on the right of this slide. We found that nearly 400,000 individuals in the U.S. experienced clinically important hypoglycemia after bariatric surgery. This is really what I'm referring to as glucose concentrations less than 54 milligrams per deciliter from time to time. With symptoms of this, almost 400,000, a subset of approximately 160,000 or 166,000 in the U.S. require medical management. They're sick enough to seek medical attention from, usually, endocrinologists. We term this medically important hypoglycemia and would consider this to be really the highest unmet medical need in the addressable population. Because this is a recurrent disease, this can occur anytime a patient eats. The much higher frequency of hypoglycemia than, for example, in diabetes causes a high degree of hypoglycemia unawareness. Dr. Lawler just described this, a loss of adrenergic warning symptoms. It makes it even more difficult for patients to get diagnosed sometimes. This also means that the current evidence estimates, the prevalence estimates that I quoted, may still yet be an underestimate of the actual true disease and reinforces the need for proactive monitoring. From an etiologic standpoint, there may be several mechanisms that contribute to the underlying pathophysiology, but it is now well known and well characterized that GLP-1 really plays the most important and central role. GLP-1, as you may likely are very well aware, is an incretin, gut hormone secreted by ileal L cells, and it causes the secretion of insulin in a glucose-dependent manner normally, and that's under normal physiologic levels of GLP-1. After bariatric surgery, GLP-1 levels, postprandial GLP-1 levels, are increased. This is a good thing normally. It is also the reason for which in over 80% of patients who have diabetes and who undergo bariatric surgery, they will have immediate resolution of their diabetes prior to surgical weight loss because of this beneficial incretin effect. However, in the subset of patients who have post-bariatric hypoglycemia, GLP-1 levels are secreted in excess, up to 10 and even up to 20-fold higher than non-surgical controls. That's what you're seeing here on the right of this slide. At these supraphysiologic levels of GLP-1, we see a potentiation of the dose dependency, and we lose that linearity, that linear dose dependency of insulin secretion on glucose and GLP-1, and we see dysregulated secretion of insulin and subsequent hypoglycemia. This physiology was not always understood. In fact, the first case series called this disease state nesidioblastosis. It was thought that the disease was intrinsic to the pancreas, with pancreatic islets thought to be hyperplastic and hypertrophied. Patients were having partial pancreatectomies followed by total pancreatectomies because the partial pancreatectomy did not resolve the disease. There was a lot of controversy for many years. Was there a missing foregut factor that we were bypassing that was pro-diabetogenic and we were getting sort of the opposite of diabetes? Is there a hindgut factor that's being overstimulated? We at Stanford University had the opportunity many years ago to systematically study whether it was a missing foregut factor or a hindgut factor. Patients had a gastrostomy tube, as Dr. Helen Lawler described this, that sometimes occurs in the remnant stomach after bariatric surgery. This allowed us to test an isoglycemic meal on one day through the oral route, using the bypass route, essentially going straight from the tiny stomach into the ileum and on from there. On the other day, we provided the same meal through the gastrostomy tube using the original route of nutrient transit into the remnant stomach and the duodenum. We found that only during oral nutrient transit did GLP-1 spike, really high insulin, go through the roof, and then the patient became hypoglycemic. This was of course reversed during gastrostomy tube feeding, really pointing to the role of altered nutrient transit and the critical role of GLP-1. This was obviously important in terms of identifying that this was something extrinsic to the pancreas because essentially this means that every time a patient eats they can have this exaggerated GLP-1 hyperinsulinemia, hypoglycemia. The recurrent nature of postprandial hypoglycemia events can impair their, as you heard from Dr. Lawler, counter-regulatory responses. It can also deplete their glycogen stores, which we all have and we rely on in order to fast, for example overnight or to exercise. These patients may not only have postprandial hypoglycemia, they also often. Avexitide is a first-in-class GLP-1 receptor antagonist that targets this central pathway of PBH pathophysiology. Avexitide binds to the GLP-1 receptor on pancreatic beta islet cells to inhibit the effects of exaggerated GLP-1 and to decrease or normalize insulin secretion and thereby stabilize glucose. This mechanism of action has been shown now in many preclinical and clinical studies. Here we see in rat pancreatic islet cells potentiation of glucose-stimulated insulin secretion by GLP-1. In red we see insulin going up quite high and the reversal thereof with avexitide treatment. That is shown in the green, the lowest curve, supporting the hypothesis that GLP-1 receptor antagonism may represent a targeted therapeutic approach to treatment of PBH. This slide shows our first clinical data from our trial that we conducted at Stanford University many years ago in eight individual patients with post-bariatric hypoglycemia who underwent a standardized hypoglycemia provocation using a 75 gram glucola drink. We had them drink this big carb load and then infused avexitide continuously or placebo in crossover design. The solid line on the left, that's spiking really high, that's insulin in response to their meal. This is what happens. Their insulin goes through the roof in response to the GLP-1 that their body is secreting and that causes, on the right, we see that solid line plummeting, that's their glucose dropping. At about 120 minutes, which is typically about two hours after they eat, their glucose will plummet. All of our patients had to be rescued when they got below 50, otherwise that curve would continue to have dropped more steeply and amazingly, and it really was amazing to experience this. This did not occur during avexitide infusion. On the left, we see the dotted line is the avexitide treatment. The peak postprandial insulin concentrations matched that of non-surgical controls. That's that other solid line with the open circle. The postprandial glucose nadir on the right also matched that of non-surgical controls. This was really a great effect. Perhaps even more importantly, we also evaluated patients' symptoms using a standard survey, the Edinburgh Hypoglycemia Symptoms Survey, and also showed significant improvements in patient symptomatology. Since that first IV infusion study, we've run many studies and we introduced subcutaneous injection formulation, ran a single ascending dose study followed by a multiple ascending dose study, the PREVENT Phase 2 study, and you'll hear more later about the Phase 2b study. In these four studies, Phase 1, SAD, MAD, and PREVENT studies, we conducted standardized hypoglycemia provocation. In the clinic setting, we were able to look specifically at the postprandial glucose nadir concentrations and consistently observed significant improvements in the postprandial glucose nadir. Perhaps even more importantly, in the PREVENT study, in the Phase 2b study, we were able to assess the outpatient real-world patient responses to treatment and observe significant improvements in clinically important hypoglycemia, specifically level 2 and level 3 hypoglycemia. Level 2 hypoglycemia is defined as glucose concentrations less than 54 milligrams per deciliter as measured by SMBG or finger stick. Less than 54 milligrams is clinically important because it is below this threshold, and we've shown this in this specific patient population. That's where patients start to experience neuroglycopenic signs and symptoms. Their brain is just not getting enough glucose and they'll start to be altered, and Dr. Lawler describes some of those symptoms that they experience. Level 3 hypoglycemia is defined as a severe event characterized by altered cognitive physical functioning requiring third party assistance, irrespective of whether assistance was rendered. You'll see that avexitide cut the rates of level 2 and level 3 hypoglycemia events by over 50%, which was pretty remarkable. On the basis of the severity of the disease, the high medical need, and the preliminary evidence of clinical effectiveness on clinically important endpoints, FDA granted Breakthrough Therapy designation for avexitide for reducing the risk of hypoglycemia events. Avexitide is the only drug in development to date to have been granted Breakthrough Therapy designation for treatment of PBH. These Phase 2 and Phase 2b results informed the dose and endpoints for the LUCIDITY Phase 3 trial. The Phase 3 program, and you'll be hearing more about the LUCIDITY trial from Dr. Jamie Timmons shortly. In brief, the Phase 3 program will evaluate the 90 milligrams once daily in people living with PBH, evaluating this on the FDA-agreed primary endpoint of the composite of level 2 and level 3 events. Dr. Marilyn Tan will also be describing this same endpoint as applied to the PREVENT and the Phase 2b data. These data were also just presented today at Endo. Lastly, I'd like to describe the safety and tolerability profile of avexitide to date. In general, avexitide has been very well tolerated with mild to moderate and transient AEs and no treatment-related SAEs or discontinuations. There have been no clinically meaningful increases in fasting or peak post-glucose concentrations, and there have been no appreciable increases or decreases in body weight observed. We have observed injection site reactions. This is not unexpected. They have, however, been generally mild and transient with no grade 3 events or resulting discontinuations. With that, I'd like to turn it over to Dr. Marilyn Tan. Okay, good evening everybody. I think I've met many of you here before, but my name is Marilyn Tan. I am the Principal Investigator on the Phase 3 LUCIDITY trial. First off, my disclosures are that I am receiving research funding for the LUCIDITY trial from Amylyx Pharmaceuticals and I have received consulting payments from Amylyx Pharmaceuticals and Novo Nordisk. As you heard Maggie describe earlier in her video, the clinical reality of living with post-bariatric hypoglycemia is that it is essentially like a roller coaster. With the ingestion of certain foods, the blood sugar may rapidly rise and then patients have to prepare themselves for this inevitable drop. If they have a continuous glucose monitor, it may or may not alert them. We know that CGMs can lag behind actual blood sugar by many minutes and then patients have to prepare themselves for this drop in their blood sugar. As Maggie described, sometimes you try to correct for it or correct for it inappropriately and you end up running high again and then dropping again. There is this constant unpredictable up and down nature which is not even consistent from day to day. This really leaves the patients feeling uncertain and unsure of what they can and cannot do. There has been a significant innovation gap in post-bariatric hypoglycemia. As Dr. Lawler mentioned, there are often diagnostic delays. There is no gold standard for the diagnosis. The awareness of this condition has only recently increased in the last 10 years or so. Many patients also have nonspecific symptoms and present to their healthcare providers with the symptoms and are told, we don't know what's going on. This is probably all in your head. The patients start to feel marginalized and distrusting of the medical system. They have a serious metabolic condition, but are left to manage this on their own with really limited resources. They get inconsistent care from healthcare teams. For those who are actually lucky enough to be established with an experienced healthcare provider or endocrinologist, even then, the tools are limited. We essentially ask patients to have severe dietary modifications and maybe can provide them CGMs or glucagon for rescue. Beyond that, as Dr. Lawler said, the off-label therapies are limited by lack of efficacy, lack of tolerability, and also insurance coverage issues. Importantly, they're off-label and are not treating the underlying disease. In extreme cases, surgical procedures or interventions may be used, but they're not effective and they're very invasive. The cascading events of PBH lead to social isolation and inability to work and function independently for these patients. They may have severe medical consequences, ending up in the emergency department seeking emergency care, utilizing more healthcare resources. That hypoglycemia episode in your patient is just the tip of the iceberg. It has cascading effects for them, their family members, their community, and for the greater healthcare system overall. How do we redefine success for patients living with PBH and for the healthcare providers? As a clinician with many patients with PBH, I need a treatment that is safe and effective, that fits into the real world setting. We need reduced frequency of hypoglycemia events and ideally, fewer emergency interventions trying to catch up with these low blood sugars. Ideally what we do is target the underlying physiology of the disease rather than putting a band aid on the consequences of it. What this means is to shift from managing around post-bariatric hypoglycemia to actually treating it. For the patients, they want more predictable symptom control. They want a sense of knowing what to expect so that they can have regular activities like exercise, driving, working, taking care of their children, and they need some flexibility in their lives. Medically, obviously they need fewer life-threatening hypoglycemia events. For some patients who have protein calorie malnutrition due to the severe dietary restrictive nature of the diet, they need to have their nutritional status restored as well. I think some of you came by the poster earlier today and were at the oral presentation. For those who were not there, I would like to review some of the exploratory data that we did, the exploratory analysis that we did for avexitide from the Phase 2 studies of PBH. For those who are not aware, the Phase 2b study was an investigator-initiated trial at Stanford University. It was a 28-day open-label crossover trial examining 90 milligrams once daily of avexitide and 45 milligrams twice daily. In the patients receiving 90 milligrams once daily, which is the dose that we are examining in the Phase 3 LUCIDITY trial, there was a statistically significant reduction in both level 2 and level 3 events by self-monitored blood glucose as well as the e-diary. Similar statistically significant reductions in level 2 and level 3 events were also seen in the multicenter PREVENT trial, which Dr. Colleen Craig had mentioned earlier. Importantly, as Dr. Craig mentioned, there were no serious adverse events. The adverse events were mostly mild to moderate without the need for medical treatment, and nobody discontinued the medication. Regarding what I presented earlier today, we sought to reanalyze the data from the Phase 2 studies looking at the FDA agreed upon primary endpoint for the Phase 3 LUCIDITY trial, which is a composite of level 2 and level 3 hypoglycemia events. You can see here that at the 90 milligram once daily dose of avexitide, which we are evaluating in the Phase 3 study, there was a 64% statistically significant relative risk reduction for hypoglycemia events. Importantly, more than half of the patients did not experience any hypoglycemia events during the treatment period. Consistent reductions in these composite events were also seen in the PREVENT trial as well. The key takeaway is that avexitide significantly reduces the composite of level 2 and level 3 events at the 90 milligram once daily dose, which we are examining in the Phase 3 study. This is not only statistically significant, but really clinically significant for a vulnerable patient population that has no FDA approved therapies and no targeted therapies for this serious metabolic condition. The 90 milligram once daily dose was well tolerated. This 64% statistically significant reduction in level 2 and level 3 hypoglycemia events, with more than half of the participants having no hypoglycemia events during the treatment period, is notable. We look forward to the rest of the study and are really grateful for not only the investigators, but also the patients and their communities and their healthcare providers for what they do in contributing to the science. Now for Dr. Jamie Timmons. Great. Thank you so much. I will start with the PK PD data and then go into the LUCIDITY clinical trial design. We've talked about GLP-1 a fair amount and just an illustrative example of really the problem that we're trying to solve in PBH. We've mentioned that after eating in healthy people who have not had surgery, we are going to see a small increase in GLP-1 that's shown in the blue line. After meals, an increase and then a decrease. In PBH, we see a much exaggerated form of that increase, as shown in the purple line. As we've mentioned, this can be 10 or 20-fold higher compared to individuals who have not had surgery. That's, of course, typically postprandial after meals. We've talked a lot about this elevated GLP-1. A big question is, can avexitide block that GLP-1 activity when the levels are so high? Shown here are in vitro studies that are looking at the potency of avexitide in blocking the GLP-1 receptor activity. What we see is that, yes, in fact avexitide is able to block and inhibit the GLP-1 receptor even at increasing and high concentrations of GLP-1, including at the concentration that aligns with our clinical dose in the LUCIDITY trial. That's in vitro data. What about clinically? I know many came by the poster yesterday that detailed some PK PD results from avexitide, specifically the 90 mg dose that's being used in LUCIDITY. Shown here is a pop PK model from people with PBH data from the Phase 2b study. The 90 mg dose is in purple. What we see is that the 90 mg dose does result in a Cmin above the IC50 for the duration of 24 hours. We saw what that dosing means clinically in the Phase 2b study in terms of the consistent reduction in both the level 2 and level 3 hypoglycemic events. Everything that we've presented so far, the preclinical data, the rationale, the mechanism, it really all brings us here to today, to the LUCIDITY trial, the Phase 3 study, the pivotal Phase 3 study and multicenter U.S. randomized double-blind clinical trial. Just to go through the design of LUCIDITY briefly, participants enrolled will have had Roux-en-Y gastric bypass surgery. There is a 21-day run-in period during which participants need to have hypoglycemic events in order to continue in the study. Importantly, the event rate we're looking for is at least three events over those 21 days, so on average at least one event per week. Participants that meet that and other eligibility criteria are randomized to receive either avexitide or placebo. That placebo-controlled period is 16 weeks long. After the placebo-controlled period, they continue into the open-label extension for another 32 weeks. LUCIDITY is a U.S.-only study. We are anticipating about 20 sites, and as we've mentioned, we're evaluating the FDA-agreed upon primary endpoint, which is the composite of level 2 and level 3 events. When we designed LUCIDITY, a goal was to be as consistent as possible with the previous successful Phase 2 studies. It's not broken, why fix it? Shown here are some of those key study design elements where we retained consistency, starting with the surgery population as mentioned, Roux-en-Y gastric bypass in LUCIDITY, and same as in PREVENT and same as in the Phase 2b study as well. These participants are having hypoglycemic events despite dietary management. They have a run-in event rate of at least one event per week, which was consistent across all three trials. They're receiving the 90 milligram once-daily dose, which is the same as the Phase 2b study. This dose is administered as two sequential injections during the double-blind treatment period and OLE Part A, and then one injection during the second half of the OLE. We've mentioned a few times now the composite level 2 and level 3 events, which were evaluated in the previous studies and which we also did the same type of analysis that was presented today. In terms of status, the trial is underway. We began dosing. Our first participant was dosed in April of this year. We do expect to complete recruitment by the end of the year and have data in the first half of 2026. As Marilyn mentioned, as Dr. Tan mentioned, we are incredibly grateful for the engagement from the sites and the participants thus far. With that, I'll hand over to Josh to close us. Thanks, Jamie. Thanks, Dr. Craig, Dr. Tan, Dr. Lawler. Really appreciate the insights today and spending the time with us. Thank you also, everyone, for being here today, both in person and virtually. Lots of familiar faces, a couple new faces, but, you know, really great to see everybody. I think, you know, watching Maggie, hearing from the physicians here with us today, it just brings home what a disease this is for people who live with it. People live these very narrowed lives. They're facing these hypoglycemic events on a very regular basis. I think that's really what inspires us and the whole Amylyx team to work as efficiently as we possibly can to bring a therapy that can hopefully help people living with this disease. As Jamie said, we're moving eagerly forward. We're actively recruiting. We expect to complete recruitment by the end of the year with data thereafter in the first half of 2026, and hopefully that leads to a therapy on the market for people living with PBH. With that, I'm going to pass it over to Dr. Camille Bedrosian for question and answer. Camille is our Chief Medical Officer. We're very fortunate to have her. She was the past Chief Medical Officer of Ariad, Ultragenyx, and Alexion. With that, over to Camille. Wonderful. Thanks, Josh. I appreciate your kind introduction. Hello, everyone. It is great to see all of you here, and I know there are many joining us virtually as well. I am so pleased to have this opportunity to facilitate the Q and A session this evening with a very distinguished panel of experts in the field. At the risk of being a little bit redundant, let's please thank them again for really wonderful presentations with great perspectives and insights. Thank you so much. Also, I thank all of you. Being here in the room as well. As via our webcast. For those on the webcast, I am joined this evening for our Q and A with Drs. Lawler, Tan, Craig, and Timmons. Before I begin, we do have a couple procedural requests. Please, for those in the room, if you could, please raise your hand. There is Katie with a microphone. She'll come around to provide you with the microphone so everyone can hear your questions. For those on the webcast, please enter your questions in the Q and A panel and Lindsey will retrieve those questions and provide them to me. Please also let us know your name and your firm. While we're gathering all these questions, I'll start actually with a question that we receive quite frequently by investors or from investors, actually, and that is, what is a clinically meaningful reduction in hypoglycemic events in PBH? Dr. Lawler, would you like to please kick us off with a response to that question? When I talk with my patients, this hypoglycemia is so severe and debilitating that really any reduction in hypoglycemia. Is beneficial to them. With these folks, one hypoglycemic event could be life threatening for them. They're very pleased with a very minimal reduction in hypoglycemia because it's so bad for them. Dr. Tan, you might have. I have the same experience as Dr. Lawler. One hypoglycemia episode does not sound like a lot, but one single event could lead to a catastrophic accident. For these patients, any reduction is meaningful. The data that was not presented and captured in these studies is really also the sense of independence and confidence that the patients get back. That's really clinically important for the patients, regardless of what statistics we're looking at. Dr. Craig, please. I guess all that I would add first, I would agree. Severe hypoglycemia is debilitating acutely, but it's also debilitating over time. Right. When it's recurrent, it really, as Dr. Tan is describing, it affects the patient's independence, but it also affects their security. There's a ton of anxiety and fear of hypoglycemia for these patients. That also, I would say, could be impacted, not worrying about having more catastrophic events. Great. Thank you very much. Very insightful. Hopefully that also provides additional insight into what individuals with PBH experience. I see a hand go up. Great. Please. Hi, this is Kevin Strang from Goldman Sachs on for Corinne Johnson. Just a question for the panel on your level of confidence that you've adequately optimized dosing for the Phase 3 and also done sufficient testing for regulators across a range of doses. Great. Dr. Craig, would you care to kick off that question, please? Can you hear me? Okay, we started quite low in the single ascending dose study many years ago. We didn't know what dose would be an efficacious dose. We knew by continuous IV infusion, but we started low and moved upwards from there. We found after the single ascending dose study that pointed us toward a 30 milligram dose, providing pretty gosh darn good protection against provoked hypoglycemia. That was the basis for evaluating the 30 milligram dose in the PREVENT study twice daily. That was evaluated in a multiple ascending dose study. In the Phase 2 PREVENT study, 30 mg twice daily and 60 mg once daily. Additional analysis, PK PD analysis and modeling pointed us to going up a little bit higher to the 90 milligram total daily dose, either as a 45 milligram twice daily or 90 milligram once daily. We went into that trial already having shown very good coverage in the PREVENT Phase 2 with a lower dose. The 90 did even better, provided even better protection, and in particular, for the late evening meals. Really, this is a postprandial disease. It's daytime meals going into the late evening hours. Ninety milligrams did a very good job at that. The other thing I'll say is that there's sufficient tox coverage to go even higher, though I think that we're at what I would consider to be really the optimal dose. Great. You next. Hi, this is Troy Langford from TD Cowan. Given the continual uptake of GLP-1 agonists for weight loss, what gives you all confidence that the number of bariatric surgeries performed each year won't decrease over time? Dr. Craig, you might start, and then our panel, the rest of the panel. Yeah, so we've looked to see what's happening with the surgical trends, and we've also spoken to many bariatric surgeons. First, the numbers remain. Right. Bariatric surgery numbers continue. Dr. Tan can talk a little bit about that. I think there was an endocrine grand rounds recently at Stanford University to really talk about that specific question that you're asking. I'll hand it over to Dr. Tan to talk about that. We know that the bariatric surgeons are actually using the agonist to support weight loss prior to surgery. In fact, you'll hear this from bariatric surgeons, but the numbers could increase the number of potential candidates going into bariatric surgery because they really do need to lose quite. A bit of weight. I'll hand it over to Dr. Tan. Thank you. As Dr. Craig said, our Chief of Bariatric Surgery gave an endocrine grand rounds last year titled "Bariatric Surgery: Is it a Dying Field?" I think this is a question among many because we hear about these weight loss benefits, but there are multiple shortfalls of the GLP-1 agonists. First, many patients are not tolerant of them or they can't get them covered for an entire lifetime. Even if you do, in the best clinical setting, in non-diabetes patients, see for example a 22% weight loss over the course of a year, patients have to stay on it for a lifetime. Also, you don't get the same degree of diabetes resolution, for example. We know that, for example, with Roux-en-Y gastric bypass, prior studies have cited 80% resolution, for example, for type 2 diabetes. Really, we're seeing that the disease state, especially for patients with diabetes, doesn't necessarily change as dramatically with GLP-1 agonists. Importantly, again, the coverage remains an issue. Actually, I was talking to our Chief of Bariatric Surgery from our local county hospital who said that they lost their bariatric surgeon a couple years ago and decided not to rehire. However, they are planning to hire somebody again because it's just not effective to use the GLP-1 agonist alone. Importantly, with the recent funding cuts, they are concerned that the coverage for the GLP-1 agonist for the Medicare and Medicaid patients will be even more restricted. Dr. Lawler, did you want to make. A comment as well, please? Yes, I think my colleague Neda Rasooli actually participated in the ADA. They had a debate between a bariatric surgeon and endocrinologist about this as well. I heard. As you mentioned, I don't think bariatric surgery is going away. We definitely have some patients that I'm shocked. I mean, they don't lose any weight on GLP-1 agonists. We don't really understand why it works well for some people and not others. You always have that patient group. Also, some of these patients with their BMI above 40, 45, not commonly do I see them get down to that BMI that they could potentially achieve with bariatric surgery. As she mentioned, these GLP-1 agonists need to be used long term. People reach a nadir weight and then if they stop them, you regain the weight. That's been shown in studies. I always explain to patients that they have to be on this for the rest of their life and the coverage is very difficult for obesity alone. Very rarely is it on their insurance plans where bariatric surgery is on their insurance plans. It's very, very rare that I have patients on these meds. Like she was saying, with the insurance cuts just for obesity I'm able to get it approved well for diabetes, but it's difficult for obesity still. Thank you very much. That's great. Very, very helpful perspectives for sure. I believe there's another question in the room. Yeah, hi, this is Basma Anpur Martin from Lee Ring. We have a follow-up question on the dose of the nine and also a follow-up on the new PK data showing that avexitide concentration is above the IC50 and that's maintained over 24 hours. Are you collecting any data in the ongoing Phase 3 LUCIDITY, just to confirm there's no breakthrough hypoglycemic events after dinner or late dinner? Also, another follow-up on the prevalence in the surgeries. Why have you focused on the Roux-en-Y patients? From what we've seen from the trends on the Roux-en-Y, we noticed that they actually go down. Is our estimate of 20-25% for Roux-en-Y out of the total bariatric surgery, is that a rough estimate or would you have another comment? Oh, thank you. Sorry about that. Great. Thank you. No, those are great. Two, three, maybe five questions, which is wonderful. We'll start with Jamie, please, to address the dosing and the PK. Yeah. Okay. I might need you to remind me of the other ones, too. In terms of the first question around whether or not we're evaluating if people have events after dinner and overnight, the answer is yes. Participants are trained in the study to capture their events anytime they occur. They are wearing a CGM monitor. They are not able to see the data in the CGM. It's blinded to them. The CGM will alert them if they are going low at any time of day. We are capturing events throughout the entire 24 hours. I did forget the rest of the questions, and I thought I was going to. It's okay, I believe. Does that address your question? PK and the dose. On the Roux-en-Y and the percentage of Roux-en-Y. Maybe you can start, Colleen, as well, with the great prevalence data she just shared here at Endo this evening? Absolutely. The decision to go solely with Roux-en-Y in the Phase 2 LUCIDITY trial was really, as I mentioned, to stay as consistent as possible with the population that had previously been studied with avexitide. The Phase 2 study was only Roux-en-Y. The Phase 2b study did mostly have Roux-en-Y patients, but there were other surgical subtypes. We talked about this a lot when we were designing the Phase 3 trial. The decision really was, let's stick with the previous trials, the previous successful trials. We do not believe that there is any pathophysiological difference between Roux-en-Y and sleeve gastrectomy in terms of what's causing PBH. It was more a decision to stay consistent with the previous trials. I'll pass to the colleagues here to discuss Roux-en-Y. It's, you know, currently is it increasing or decreasing? I think you were asking about surgical sensitivity, right? Numbers of procedures by surgical subtype. Historically, going way back into the 1980s and until fairly recently, Roux-en-Y was really the surgery of choice. We saw a very steep increase in the use of Roux-en-Y gastric bypass over time. Not surprising. It is the most effective both in terms of magnitude of weight loss and resolution of diabetes, and also durability of effect. Right. More recently we had seen an increase in the use of vertical sleeve gastrectomy. It's an easier procedure technically, and so that had come into favor. With increases, continued increase in use of Roux-en-Y, but even higher steep increases in vertical sleeve gastrectomy, most recently we've seen a little bit of a softening of that as the continued long-term data looking at vertical sleeve as compared to Roux-en-Y come out in terms of that efficacy. Right. The magnitude and durability of effect. You know, there really is nothing like Roux-en-Y. That said, we see PBH as Dr. Timmons just described, with both surgical subtypes. Right. We see approximately 30% of patients who have Roux-en-Y gastric bypass and 10% after vertical sleeve having clinically important hypoglycemia. I would cut that down into 12% of Roux-en-Y and 4% of vertical sleeve having what I term medically important PBH, really seeking medical attention. As these numbers continue to rise, and I'll remind you, this is a chronic, unfortunately chronic disease state. There's already this critical mass of patients that continues to grow from here. We're seeing it growing in both. I'm not sure if I utterly confused you with all of these numbers, but that's my attempt at trying to describe where things were and where things are. We also see it after other upper GI surgeries. Right. Total gastrectomy, esophagectomy. I'd like to just add that I am primarily a clinician. I take care of patients in the clinic. Even though there has been this shift towards more vertical sleeve gastrectomies, and though there is a time lag between the surgery and the diagnosis, we've only seen increasing numbers of referrals in the clinical setting. We are getting referrals for both surgical subtypes and, as Dr. Craig said, for other surgeries as well. Even with a shift towards more VSGs, it's still a higher number of PBH cases that we're getting referrals for. Doctor? Yeah. I was just wondering what the percentage breakdown is between Roux-en-Y in. In terms of prevalence, current U.S. prevalence? I mean of procedures. Like if there are 100 procedures, what%? I think there have been 1.3 million. Okay, don't quote me on this. It's about 3 million altogether, ever. I believe it's 1.3 for vertical sleeve and 1.6 for Roux-en-Y. I might have those reversed, but I think that's the history and approximately. All right, great. Any other comments? Dr. Lawler, did you want to add? Please. I just know at our institution they're still doing Roux-en-Y mainly for patients with diabetes because the resolution of diabetes is often better with Roux-en-Y. I think we could look. up the exact prevalence and get that for you too. Great, thank you. I'm going to take a pause here because we have a couple questions from our webcast. Thank you very much for sending them in. We're going to start with Jeru Fang and Jeff Meacham from Citi. Can you elaborate on the long term effects of avexitide on GLP-1 and tactical? Is there any evidence to suggest the development of resistance or tolerance over time? I'll ask Dr. Craig to address again effects of avexitide on antagonism, any evidence to develop resistance or tolerance. I'll start with the second part first. We see no evidence, and we've looked for evidence of tachyphylaxis or reduction in efficacy in clinical studies or in the preclinical studies. Right. We see preclinical studies up to six months of dosing, continued pharmacodynamic effects. We also evaluated patients in the Phase 2 PREVENT study and the Phase 2b study by treatment period to look at any changes in efficacy over time. We didn't see any differences. We also have not observed, although there have been some, and this is expected, low titers of antidrug antibodies. We see no differences with the development of antidrug antibody either in the clinical studies or in the preclinical studies. Could you comment on the nonclinical tox, the long-term toxicology, and what has or hasn't been seen? Right. There as well, we have not seen any evidence of changes in tachyphylaxis. I think your other question was. About chronic use, long-term effects of GLP-1 receptor antagonism. Right. From the efficacy standpoint, I think I just sort of commented on that. Perhaps you're also thinking about antagonizing. Right. The GLP-1 receptor. I realize there may be a tendency to think that we're running the receptor in reverse, which we're not. This disease state is exaggerated secretion of GLP-1, and the idea is to kind of modulate, I think, the thermostat to calibrate that thermostat to normal. Things like hyperglycemia were not seeing. Right. That's not an issue in this disease state with antagonism nor cardiovascular effects that you see with the agonists. Here we are preventing severe hypoglycemia, which is well known to cause the potential for arrhythmia. We hope that there's a reduction as well, not only efficacy, but nice reduction in the risk of cardiovascular events. Thank you, that was very helpful. Now this next question is for Jamie. It's from Ananda Ghosh, from HC Wainwright. What advantage does composite of level 2 and level 3 events give to individual events? Sure. I might also ask my panel too once I'm done what they think. The composite really allows us to capture two distinct aspects of the disease. Level 2 is a number. Level 2 is are you less than 54 or not. Level 3 is what is the impact of that low. That's not a number, it's really what symptoms were participants having and did they need assistance even if assistance wasn't rendered. As we heard from Maggie, kind of understanding that impact of the event on the participant. The composite allows us to capture both the less than 54, the number, and also that impact on the actual participant and their mental status and the impact of the event. Right, right. It also is the more power too. More power. It's also the endpoint that the ADA has designated and recommended in their guidelines for looking at hypoglycemia for anti diabetic drugs. Yeah, we may have said a few times that it's also the FDA agreed upon primary. Exactly right, yes. Great. Back to the folks in the room. I believe we have a few questions lined up here. Thank you. This is Zach Dunn on for Seamus Fernandez from Guggenheim Securities. For the panel, broadly it sounds like there's increased referrals. Can you kind of elaborate on where these referrals are coming from? It sounds like there's a strong or growing awareness at centers of excellence. How do we kind of spread this message into community centers and raise broader awareness so all these patients can receive such a therapy? Thank you. Dr. Lawler, would you like to begin, and then Dr. Tan, please? Sure. I'm often getting my referrals from actually other endocrinologists, and I think we need to change that. Right. I want the awareness of primary care doctors to be increased about this condition. Mary Elizabeth Patti is from Joslin. She and I just wrote an article and published it in a family medicine big journal to raise awareness to the family medicine docs so they know what this is like. I wrote an article a couple years ago in Cleveland Clinic Journal and that is so much a lot of interest internists read. I think we need to just raise awareness to primary care so they're aware of this condition because I think that's where the awareness is lacking right now. I definitely get referrals from my surgeons as well since we collaborate together and they know what I do at my institution. I think the surgeons are starting to have increased awareness of this. I've noticed a lot of publications in their journals as well. The issue is, as I mentioned, sometimes this is hitting people two, three, 20 years later. They're not even seeing their bariatric surgeon anymore. We really need the primary care doctors to have increased awareness about this. I think it is, I mean as she mentioned, the referrals are increasing so there's starting to be an uptick in awareness. I think we're going to have continued increased referrals in our clinic. Great. Dr. Tan, please. Yeah. At Stanford we are seeing a similar pattern where many are seen by other endocrinologists and have already tried every other off-label therapy, occasionally primary care and then certain surgical centers. Not just bariatric surgeons, but particularly for example at MD Anderson where they do a lot of gastrectomies for non-weight loss indications. We've had patients from there and I will add that we are getting more self-referrals as well. As patients are realizing the diagnosis and advocating for themselves, they are talking about the physicians and the trials in this large Facebook group and other support groups. That's really where we're also seeing an increased number of referrals. Very interesting. Thank you. Thanks. Hi, Jason from Fradel Life Sciences. I had a question on epidemiology. The numbers that you guys presented today, that's like a modeled number. How does that compare with the number of active patients in the healthcare system in your estimate? Dr. Craig? That's a tough question to answer. One of the challenges, and hopefully this will change, is that there is no ICD-10 code. Right. We are reliant on the scientific literature, surgical census data, and established life expectancy data. Once there is a dedicated ICD-10 code, I think that we can do a better job with the epidemiological tracking. Great. Hi, my name is Rohan Dalal. I am from Acute Capital. Thank you again for sharing all this information today. My question is, what portion of the about 400,000 estimated PBH cases do you see? Truly addressable under the initial label in the next decade? I would point to the 166,000 in the U.S. that are. I would actually set that as the lower number. Right. At least 166,000 in the U.S. that are seeking medical attention, that are sick enough to come in and seek medical attention. There may well be others that are not, that are sort of still falling under the radar. With greater, you know, awareness, there may be a higher rate of diagnosis, including with an ICD10 code. Right. That's where we are today, based on the flow of Archer. Great. Thank you very much. Excellent. Any other questions in the room for the moment? How about online? Lindsey? Okay. A few minutes. Only a few. Ah. Okay. Excellent. Thanks. Ed Kim from Bally asked me, is the hypoglycemia events for level 2 captured by CGM or does it require a stick? How did the FDA get comfortable with CGM if it is? I don't know the answer to that. The other question I have is, can you talk more about why the PBH is two to three years out from surgery and you kind of don't put in the definition if it's more concurrent with the surgery. Thank you. Yeah. Two questions. First, Jamie, please, could you address the question about CGM or SMBG finger stick? Certainly. The level 2 that's part of the primary endpoint is SMBG finger stick. We are capturing, as I mentioned, we are capturing CGM data for secondary and exploratory endpoints. I am really bad at remembering these questions. Yeah. The second question has to do with why are we calling the hypoglycemic events PBH when it's three years out, but what about the events that occur earlier post surgery? Right. Great question. In terms of the trial, participants need to be a year or more outside of surgery. I'll pass to the rest of the panel to discuss the pathophysiology in terms of why it takes some time to develop. If it's. We say six months. Right. If they're having hypoglycemia prior to the six-month mark after surgery or preceding the surgery, we look into other mechanisms like insulinoma or other factors that might be going on. It's just because we think it takes some time for all this pathophysiology to develop after the change in their anatomy. Add that while we can't predict who will develop the disease, we do tend to see it more in patients with greater weight loss at the six month mark. I will say that that's historically what we've seen with Roux-en-Y gastric bypass and VSG. Certainly with other surgeries we may see something different, but it hasn't been well studied in patients with gastrectomies or Nissens. Great, thank you. I saw a hand go up. Hi, Alex Muns from Driehaus. Would you remind me what the balance is that you see between men and women and what you think explained that. Go ahead. Dr. Tan, you seem ready to. You may. If you look at the detailed data, you may notice that it's very few men that have been in our studies. We did have men in the Phase 2b study, but we know that more women tend to get these surgeries, though we don't know exactly why. You're absolutely right. I asked Dr. Craig earlier today in her prevalence study if there was any sense of the breakdown between men and women, and we just don't really know. We look forward to hopefully enrolling more men. So far, not that it was powered for such, but there didn't seem to be any gender predilection for a treatment response. Did you want to comment, Dr. Craig? Yes. I'll just add that if you look at who's having bariatric surgery historically, it's very predominantly women. I think that's reflective of what we're seeing in this population. There are other upper GI surgeries, total gastrectomy, esophagectomy, and some fundoplication that has a different breakdown of sex. Thank you for asking that question. Thank you everyone, for all your wonderful. Questions, both here in the room as well. As on the webcast right now, I believe we can conclude this wonderful event. Very much a lot of learnings, a lot of insights, and appreciate everyone's attention. Thank you so much.