Rhythm Pharmaceuticals, Inc. (RYTM) Earnings Call Transcript & Summary

Good morning, everybody. Thank you for joining us today. I'm Dave Connolly, IR here at Rhythm Pharmaceuticals. Before we begin the speaking program, I'll just remind you that this event may include remarks concerning future expectations, plans and prospects, which constitute forward-looking statements. Actual results may differ materially from those indicated by these forward-looking statements as a result of various important factors, including those discussed on our most recent annual or quarterly reports on file with the SEC. In addition, any forward-looking statements represent our views as of today and should not be relied upon as representing our views as of any subsequent dates. We specifically disclaim any obligation to update such statements. Today, we have a brief program, Rhythm's Commercial Readiness for Acquired Hypothalamic Obesity, an event for investors. This morning, we'll hear from Dr. David Meeker, Rhythm's Chairman, CEO and President; and Jennifer Lee, Executive Vice President, North America. In addition, we have Dr. Ashley Shoemaker, Assistant Professor of Pediatric Endocrinology and Diabetes at Vanderbilt University Medical Center; and Dr. Lewis Blevins, Endocrinologist, Professor of Medicine and Medical Director of the California Center for Pituitary Disorders at UCSF, is joining us virtually. And then for the agenda today, we'll begin with Dr. Meeker, who will be followed by a short video featuring Carmelo, a high school freshman with acquired hypothalamic obesity and then a moderated panel discussion with Doctors Blevins and Shoemaker, during which we will take a few questions from the audience here in Boston as time allows. Then we'll hear from Jennifer Lee, followed by David Meeker and a second Q&A panel with Jennifer, David, Rhythm's CFO, Hunter Smith; and Dr. Shoemaker. Now I am pleased to welcome Dr. Meeker to the podium.

Thank you, Dave. I should make one minor correction. I think we just demoted Ashley there, Associate Professor of Medicine. So thanks for all coming. This is an incredibly exciting moment for Rhythm. We're -- we've known this has been coming for a long time. We have our PDUFA date, as you know, coming up on December 20th, which is right around the corner and getting ready for launch. There's a lot to do. And as you'll hear from Jennifer, her teams have been doing that. We feel really good about where we are. So I'm just going to provide a few very introductory high-level comments to try to set the stage for what you're going to hear today. One is, as what we all aspire to do in this industry is to address unmet medical needs and HO is a true unmet medical need. There's no approved therapies, and these patients live a really tough life, and you'll hear a lot more about that today. In a surprising way, as you remember back to when we reported this data in July of 2022, setmelanotide remarkably, and I'll go through the Phase III data briefly, but remarkably seems to be treating a very fundamental defect here. And so based on both Phase II and Phase III, we think we're going into our final regulatory lap here with strong clinical data. And it's a big opportunity. Rhythm, we've always characterized ourselves as a rare disease company and rare diseases come in many flavors, some small and large. But this is meaningful. It's still ultrarare, if you will, by the numbers. We'll talk about the 5,000 to 10,000 epidemiology we highlighted when we came out, and we'll update that a bit today. But that number of patients in this unmet need does represent a truly transformative opportunity. It's obviously hopefully transformative for the patients. But for a company like Rhythm, it will be transformative. I'm going to show this cartoon again. You'll see it as long as probably I'm at Rhythm and Rhythm exists. Because it speaks to the fundamental biology. And when you launch a drug, one of the most valuable things you can have is clear understandable biology. It's always a little tougher to launch if your drug is kind of magical. You can report it and if you get an effect and as people say, that's good enough, you don't have to know why it works. But we do know why it works, and that's helpful. And it's going to help, I think, the treating community, the patient community understand why this makes sense. And if you -- as you remember from this cartoon, the way our physiology works, we eat a meal, got hormone signal to the pancreas and the adipocyte, the adipocyte releases leptin, leptin goes to the brain and it does two things, it does many things, but we use two. One is, it interacts in this arcuate nucleus and activating the POMC neuron side of the equation with the release of alpha melanocyte stimulating hormone, which when that interacts with its receptor, MC4R, you get the signal you're full. And what's perverse about this is, that signal not only tell the body you're full, it says you have food on board and you can increase your metabolic rate. So your energy expenditure goes up. So in the absence of that signaling, then you don't get the signal you're full. And perversely, your body thinks there's no food on board. So it keeps your energy expenditure low. And so that's where you get the extreme obesity that we see in many examples of MC4R deficiency that we're studying. And this is one of those extreme examples where patients can rapidly gain weight in the absence of that signal. The other thing leptin does is, it inhibits the appetite stimulating side of the equation, the goody related peptide side, which is as you would want, you'd want to signal you are full and shut down the appetite signaling side, and that a goody-related peptide protein interferes with signaling through the MC4 receptor. Now in HO, arguably, and we don't have good biologic pathologic data to confirm this, but the injury -- HO occurs due to injury, as I'll show on a slide in a moment. And that injury is not -- it's blunt. And so, it's not like you lose the POMC neuron and preserve probably the good related peptide neuron. So in all probability, we're losing the arcuate nucleus here in those patients who develop HO. So again, very well understood. Fundamental biology, we can feel good about that. This is a journey. I joined the Board of Rhythm in 2015. Rhythm had been working at this for probably 5-plus years prior to that. I think we fit right in the paradigm of what it takes to develop a drug, 10 to 15 years. And we got our first approval in 2020. As many of you remember, for POMC and lipton receptor biallelic, incredible proof-of-concept, very small opportunity. We didn't put a sales force on the ground. Followed by European EMEA approval in 2021, and that's been, as you've heard us say many times, I mean a core part of our strategy is we're global. These are healthcare diseases don't tend to follow geographic boundaries. And so we're going to look to address the world as we best we can. We're working our way through that. But Europe, U.K. was an early important next step in that. So approved in 2021, Bardet-Biedl, the first meaningful step in building our company, because that was a legitimate commercial opportunity, 4,000 to 5,000 patients with BBS in the U.S., similar numbers in Europe. That was approved in 2022. And then in '24, we extended our indications down to children between the ages of 2 and 6. And this is critical, not because there was a huge number of patients sitting with a diagnosis, although for a genetic disease, there's no reason in a functioning healthcare system, good functioning healthcare system. You shouldn't be able to diagnose these patients earlier. And in fact, I would argue that the data that we had from that 2- to 6-year-old group was supportive of the idea, not surprisingly, that the earlier you intervene, the better you do, like many things in life, even if you can address the underlying defect if it's been entrenched for a long time, you have a lot of other comorbidities. The ability to get the desired effect may not be the same as when you get in early and you prevent the development of some of those morbidities. And so I think that observation is probably true. I think everything we've seen is consistent with that, and we look forward to trying to help patients get to an earlier diagnosis. But that's not what we're here to talk about today. We're here to talk about HO. And HO, 2022, we read out the Phase II data. As I said, a bit of a surprise in the sense that it wasn't so clear, it made total sense that injury to that area of the brain might knock out the arcuate and you might lose signaling through the melanocortin-4 pathway, but it wasn't so clear that you would preserve your ability to respond to a medication. It's a question of, do you lose the receptors as well. And we now know, of course, there's MC4 receptors in other parts of the brain, and maybe you don't hit all the hypothalamus. So there's lots of hypothetical reasons why we're seeing the result we're seeing. But what was most striking about that Phase II data, as we've said many times, is the consistency of response. And I think as a society, we're completely focused on the percent change and the mean percent change. In this setting, we did well on the mean percent change, but what was most striking was literally, if you take this drug, almost all patients have a response. Now that response may be variable, not everybody loses 30%. Some people may be 5%. But the point is, in a population that gains weight, and I think we've got good evidence that untreated, this patient population continues to gain weight. Anything as a positive change. So following that, we obviously moved quickly to start our -- the 120 ultimately enrolling 143 patients in our Phase III trial, completed enrollment within a year. I think that's -- as people say, that's a good indicator, again, of unmet need when you can enroll a trial with relative expediency. Very strong and excited about our opportunity in Japan. We think a little -- we were, I think, late getting started there. We didn't have them in the trial initially. We didn't fully appreciate the epidemiology, but I think we've caught up. And fortunately, the Japan regulatory framework is opening up in Japan, very much wants to make sure the Japanese patients can access drug, new drugs, innovative drugs at the same time as the rest of the world. And we read the trial out in the spring of this year. I'll show you a little more of that data, 19.8% placebo-adjusted BMI reduction. And in June, we read out our Phase II trial in bivamelagon, and that's a critical piece of this. I mean, setmelanotide, great. I mean, it's a subcu daily injection. It has hyperpigmentation as a side effect of the drug, but it's doing the job. And in a world that has nothing, I mean, it's an incredibly important advance. We can do better. And I think our next generations are set out to do that. The first readout is, of course, this oral bivamelagon Phase II trial. And what was reassuring about that data, again was, it was highly similar to what we saw with setmelanotide at the same time point in the Phase II and Phase III which just tells what we knew was -- we knew we had a good MC4 agonist. This was the clinical confirmation that it's going to form. We think we have the right doses, and we're getting the right exposures and the like. And in today's world, not a given what was going to happen in terms of our regulatory review, and we highlighted early on, everything seemed to be working normally. Our regulatory teams we're working with at the FDA seem to be intact. We've worked with the same division from the beginning. These are the same people who reviewed our setmelanotide from our very first indications. And despite many people having left the FDA, we didn't seem to have lost people from our review division. So that was all very reassuring, had a very positive in-person meeting. Again, I highlighted one of the first in-person meetings that had since COVID and that was positive. So we're moving through. We got the PDUFA date exactly when we predicted and we worked hard to file this and filed it as fast as we can, a huge shout out to the clinical medical teams, regulatory teams who did this. But I'd say, we got it in there, I won't call it record time, but certainly a very competitive time and setting up this PDUFA date for December 20. So Rhythm is a company in a really good place to launch this. Sometimes you're scrambling to keep up. I think, we're launching this from a position of strength. We have a solid global foundation. We did a simultaneous filing actually almost with filing in both with the FDA and the EMEA almost at the same time. IMCIVREE is available in more than 25 countries. We've got over 350 employees now in 15 different countries, and we are also available in seven additional countries through distributors. So this graphic is going more specifically to hypothalamic obesity, and Dr. Shoemaker and Dr. Blevins will help us understand this in greater detail. But our understanding and certainly within Rhythm and my understanding of this is continuing to grow as we learn more about this. Craniopharyngioma, these benign tumors have been the best recognized cause of HO. And these are, as I said, benign tumors that develop between the pituitary on the bottom and the hypothalamus. They're very close together because they signal to each other. And so, a tumor growing up in that area of the brain, you can imagine either by itself might injure one or both of these areas of the brain and/or the treatment, which you can successfully remove these benign tumors that surgery itself and with the radiation used may also result in the injury. And so, it's that injury. And again, we look forward to getting a little insight. It looks a little bit like a biologic switch. Not everybody who gets this and we've used the 50%, and we'll test that with the experts in terms of how they see it. But the literature would say, on average, maybe 50% of these patients end up with hypothalamic obesity, but 50% don't. And so you can imagine in a very simple hypothetical way, it's just a function of your damage. If you hit this area, you get it, if you don't, you don't. And as I indicated, we're entering this world with no approved treatments for this. The burden of HO, and I'll just throw this up again, the short summary of this slide, which has a lot of words on it is, this is an incredibly complicated disease. This is data from Professor Müller, out of Germany, who spent a lifetime looking at HO, and a true expert. And in his cohort, which is reasonably large, if you get the exact number, his patients had an average 3.7 hospitalizations in the 2 years, 1/4 of those included in ICU admissions. They receive on average 5.5 active prescriptions per quarter, not yearly. The average number of unique medications over 2 years, 22. 12 is the average number of general practitioner visits and 20, the number of specialist visits in the 2 years following the injury or index event. And 89% of patients receiving three or more therapies for neuroendocrine dysfunction. I'll just tell you anecdotally, when we had our meeting with the FDA, as I was telling Dr. Shoemaker, that's really precious time with the agency. And the first slide we showed them -- I showed them was -- this is their patient medication list. Two pages of medication. And the point being it's, you've got to look at safety and efficacy in the context of this incredibly complicated medical problem, and as we'll hear more, it's interesting, amazing to me, given the complexity of their medical problems, how important HO is in terms of their quality of life. This is how I think anybody can make a diagnosis of HO. Unfortunately, as you'll hear not everybody has these curves. But if you have these curves, and on the left panel, this is a pediatric patient, the left panel is the height. And as you can see, the height is continuing and the years are on the bottom on the x-axis. And you can see they go out over 16 -- 16 years here, I guess, I can't quite read it. But height grows normally. It Increases normally. Weight in the middle panel accelerates when they have the event, this idea they leap off the curve and then BMI even more dramatically, because obviously, as we grow, we would normally put on weight, but BMI corrects for that to a certain extent. This patient also -- and we had in the trial, as we've highlighted, 31 patients who had either previously used a GLP-1 or were concurrently on a GLP-1 that was allowed during the trial. I'll show you that data. There's some interesting thoughts about that. But in general, to the extent patients have a response, it tends not to be durable. That was true of these patients in the trial. And by definition, they couldn't be losing weight. This patient had been exposed previously to a GLP-1, but as you can see, no change, really significant change in their BMI. And then they went on setmelanotide and had a pretty dramatic response. So the data -- again, I'm not going to belabor this, because you've all seen it, but 16.5% in fact, in the treated arm, really importantly is this idea that the placebo group, there is no placebo effect. These patients do tend to gain weight. This placebo group data was very consistent with a study that Dr. Shoemaker and Dr. Roth had done previously with Exenatide. They had a placebo group of 20 patients was identical in terms of that. So, I think this is the fundamental problem. You just -- and which is why part of the feedback we got early on, if you could just help these patients stop losing weight, that would be a real advantage here. Back to my point, this is to highlight 80% of the patients lost 5% or more, 60% lost 10% or more. Again, it's really if you take the medicine and for those 20% that didn't lose 5% or more, we've tried to break that out for you previously. We don't have 100% understanding. But we do for many of these patients. And for many of them, there was a reason why they didn't " have that level of response and compliance " being an obvious example of that. One of the most striking things for me, and I know this was a question that has come up -- came up earlier on. I think it was helped by the French data when we put that out at TOS a year ago. But we had identical results across the different age groups. So less than 12, 12 to 18, greater than 18, they all responded similarly. And they all had a different time period out. The oldest person in the trial was 66. That patient responded. So again, it's not -- if you think about this and I want to pressure test this with Dr. Blevins and Dr. Shoemaker, a very simple level, it's hormonal therapy. And if you have a hormonal deficiency, it kind of doesn't matter if you're young or old, you're going to not function normally until you correct the hormonal deficiency. So to the extent we fit with that, this data would be consistent with that. Hunger, back to the biology. This is the satiety signal and patients, as you can see in red. And that's a very rapid as, again, you would expect physiologically, we eat a meal and we start signaling. We feel that's hungry. You give these patients virtually immediately, they may feel some change, not everybody, but they may. And on average, you can see in these trials, we do have a very rapid effect in terms of the scores and clinically very meaningful here in terms of the reduction. GLP-1. This is a GLP-1 data. It's -- again, we had 16 patients who had previously been on GLP-1, but were not on. I think it just highlights a group of patients who -- they were seeking to use whatever they can use. Not surprisingly, GLP-1s do get used in this population. That group who was not on it had a similar response 19%, placebo group gained also 5%. Those who continued on a GLP-1, 25%. And of course, this raises the question of did that group actually do better? The trial wasn't designed to say anything about GLP-1s. We didn't even stratify for GLP-1 use. So a bit remarkably, they were pretty balanced 2:1 in terms of the treated and the placebo groups. But 25% is certainly higher than 16%. And at least open the question of did they have an incremental benefit by being on that GLP-1. And I think one reasonable hypothesis is yes, they were not responding to a GLP-1. However, once their hormonal deficiency was corrected, if that's what we're doing with setmelanotide, then the possibility that they could respond to other pharmacologic interventions might be restored. And in this case, GLP-1 is what we're looking at, but arguably any other anti-obesity medication. So if you needed incremental weight loss, you could imagine that. However, leading with a GLP-1, by definition, they weren't responding, you've got to correct the underlying physiologic defect. That would be the hypothesis. Safety, again, there was nothing new, and that was very reassuring other than I think we were working, as I said, in a very complicated medical setting and patients who have a lot going on. So they had a lot of serious adverse events, many of them related to their diabetes insipidus, this vasopressin deficiency state. Very tough to manage. And again, I think Dr. Shoemaker and Dr. Blevins can speak to that. We had one serious AE which was considered related in a patient with vasopressin insufficiency. And the argument was reasonably that the nausea and vomiting decreased their fluid intake, the challenges for these patients to maintain their fluid intake. So in the setting of not being able to maintain their fluid intake, they develop hyponatremia, needed to be hospitalized, and that was a serious adverse event resolved after 2 days. And we had one death during the actual trial period. We had additional death, as you know, on the long-term extension. This one death during the trial period was in a patient with well -- had previous seizure disorder, which was not fully controlled coming into the trial. He had a couple of different seizures during the trial and then ended up with tonic seizure status and ultimately died of that. But overall, and I think, again, this was the reassuring part is the side effects we're seeing are MC4 agonist. When you expose a patient to an MC4 agonist, I think the body doesn't have so many ways that can interpret that response and nausea is one of them. And so nausea, vomiting, in certain cases. But otherwise, nothing particularly new here. Epidemiology, again, lots of questions about this. We'll continue to have it. And my view about epidemiology and rare diseases is you just learn over time. I mean, you enter a rare disease. The data is invariably poor. There's no reason necessarily aside from a few small number of people who may take an interest who try to figure this out. But often, the motivation to really understand the epidemiology and the information, which feeds that comes once you have a therapy and the like. So we're early in that. And we started out, as I said, with this 5,000 to 10,000 range, I think as we've highlighted, we had some conservative aspects of that, one of which being the period of time post injury we looked at, which was 20 years. Many of these patients live a normal, relatively normal life longer, and so you can play around with models and that gets you to higher numbers. The other thing, and Jennifer will obviously speak to the experience that we are learning in the field, but we've started to do some claims analysis and we have boots on the ground. We have people talking to physicians and their specific practices and you learn more of that. So we're now going to lock in the higher end of the range, as we said, which is I think 10,000 is a very comfortable number. I remind you back to BBS. We started out with 2,500, 3,000. And I think over time, we got more comfortable with the 4,000 to 5,000. This is the same evolution. And I think we feel really good about that 10,000 number. Nothing new here in the Japan and an estimated incidence across multiple tumor types here for the U.S. and Europe, that's individually of approximately 500 cases per year. So with that, I think we're going to play a video now of Karmelo, which will hopefully set the stage for more discussion about the disease. [Presentation]

So I think, let's see if we can get Dr. Blevins on, and we'll set up some chairs here. Dr. Blevins? Can you see us?

I can see you fine.

Beautiful.

I can hear you well also.

Okay. Excellent. Well, thank you for joining us.

It's my pleasure.

So I think, what we'll -- as Dave said, we'll start out. We'll ask a bunch of questions and get a bit of a discussion going and we will open it up to all of you present in the room, I realize we can't do it for those of you online. But for those of you in the room, we're happy to take some questions here for the end of this. So maybe we can start out by Dr. Shoemaker, if you want to just introduce yourself a little bit on your background, the practice, kind of patients you see; and then, Dr. Blevins will go to you.

Sure. So I'm a pediatric endocrinologist. I'm a physician scientist, so I spend the majority of my time conducting clinical research. If you go way back, I actually started in the lab of Roger Cone, who found the MC4 receptor and when I was a fellow, I was doing preclinical work with setmelanotide. So from the beginning. And my research program focuses on anything that disrupts how the brain controls energy balance. So really trying to understand both the pathophysiology of these diseases, genetic diseases, acquired hypothalamic obesity. And then the goal was always to start finding targeted therapeutics that actually could treat these patients. So, I see a lot of patients with rare genetic disorders as well as general endocrinology and diabetes patients. And it's exciting to have seen a lot of progress over the past few decades in obesity management.

And maybe just in terms of HO specifically, how is you organized? How many patients do you see?

Yes. So for HO, we have about 50 patients that we follow and that actually includes adults as well. Mostly because clinical trials, we usually start in adults. So from the beginning, we would be enrolling older patients. So I've got a large cohort of adult patients that we see mostly as part of research studies and then the peds patients that we care for in clinic, even when there isn't a study, but about 50 total that we follow.

Okay. Great. Dr. Blevins, do you want to introduce yourself?

Yes. So Lewis Blevins, I trained at Johns Hopkins in the pituitary unit. I spent my entire career over 35 years now as a neuroendocrinologist. I was first on faculty at Emory University, and then at Vanderbilt for about 9 years, and I've been at UCSF for 18 years. And they hired me, they said not to do research, but to develop a clinical program, but I do both, focus mostly on clinical care. I see about 50 patients a week. And I have about 300 people with craniopharyngioma, probably 150 with germinoma, and another 50 to 70 with other types of hypothalamic dysfunction that can lead to obesity. Probably we see hypothalamic obesity in 40% to 60% of my patients with these different conditions. So we have a lot of people that I manage one way or another for this condition.

Okay. That's great. So obviously, both of you have a ton of experience here on both with the underlying biology, but also specifically HO as a disease. So maybe we can just start with HO. And Dr. Blevin, maybe you can just talk a little bit about what's the life like for these patients today with HO? And maybe contrast a little bit with the pediatric world and the adult world and then...

Yes. So I take care of a lot of kids as well. And it's a difficult life. And I think the paper you referenced from Germany pretty much described it. These patients have multiple medical problems, not only as a consequence of their surgery in their underlying disease process, but also because of the obesity and their comorbidities of other neuroendocrine dysfunction, the diabetes that results poikilothermia, that you can see in these patients. And many of them are on multiple medications. Some of them are fully functional in spite of their conditions, some require full care by a caretaker in their homes. The interesting thing is, in spite of these multiple medical problems, sometimes the biggest concern is the weight gain and the obesity. So it is ever present. It's on the top of their list of concerns when they come to the office. Forget the fact that they might have adrenal insufficiency, which, for example, is some most common cause of death in children with craniopharyngioma. But -- so it's a serious problem, but they're more concerned about their hypothalamic obesity. It limits mobility. It affects their perception by other people in society, because of the societal sense of what's a normal body weight and things of that nature. And it also affects our family members who are concerned that they're eating all the time they want to control it, they recognize it's unhealthy behavior. So it's a real problem in this setting. And it's often one of the more concerns, because it's something that we haven't and don't now been able to do much about.

Dr. Shoemaker. Maybe building on that a little bit?

Yes. I think one of the big things about hypothalamic obesity is that there's a before and an after, so it's most similar to our patients with Prader-Willi syndrome and very different from our other genetic obesity disorders where the symptoms have been present since birth. And I find a lot more distress for the patients and families when they had it before. So they really have something to compare it to. And like the patient video, there was who they were and then both the obesity and the fatigue and sort of limited mobility oftentimes really changes what they enjoy doing just sort of how their day-to-day life goes. So it is fascinating to watch. You would think from an outside perspective that a patient that's dealing with potentially a lot of vision loss and tons of other medical problems that they'd be less worried about the weight. But the weight is often the part that never goes away and is very different from who they were before. So the patients do care about this more than you would realize before you start taking care of them.

And is the weight fundamentally -- so if you have a child who's being seen for early onset obesity may be ultimately determined to have general obesity factors. What's fundamentally different about this obesity as compared to that?

Yes. I mean, one, it's this sudden onset. So they really have this comparator or most of our patients with general obesity it's a slower process. They Maybe -- they've always kind of struggled. Some of the patients have really severe hyperphagia that was like -- was described in the video, which is quite disruptive to the whole household. And it's extraordinarily refractory. So we can do locks on refrigerators and strict diets and they still tend to really struggle to lose weight. So we just never -- it never feels like you're making any progress.

Dr. Belvins, in terms of today's management, how do you manage your patients? And what are your options there?

Yes. So before I talk about that, let me just add to it, Dr. Shoemaker said that it's also the trajectory of the gain. We've all or most of us have experienced up and down with our weight and things like that. We know we have to exercise as we get older. We're going to continue to gain weight changing by the composition, et cetera. But these patients not only start to gain weight after an incident such as surgery or what have you. But it's a tremendous amount of way. I've had patients double their body weight from 125 to 250 pounds in 2 years. Most patients will gain about 17% of their body weight in the first year after therapy. So it's definitely an abnormal weight gain. It's not just a normal weight gain hey, I weigh 250, I want to weigh 175. These patients can get to 400, 450 pounds over time. So it's clearly a distinct and unusual type of obesity. And sometimes it's compounded by genetic factors. People come in and -- I had one patient who was at 500 pounds, we got her down to 300 pounds that she came in with her mother and her sister, wondering why she couldn't lose any more weight. Her mother and her sister also weight 300 pounds. So we won't fix them 100%, but we improved her from 500 to 300. So that was different. That was a different trajectory than you would expect it based on genetic factors related that were probably heritable at that time. So that's the thing. How we treat it? Well, there are a couple things that concern me about the management of these patients. One is, I see a lot of people who've come to me, they've already had their therapy. They had a diagnosis. They had their surgery 10 years ago, they're markedly overweight. So I have to do something to try to get to them under control. The other group is the patient who's going to have surgery tomorrow, for example, who, in a year, may gain 17% of their body weight. And one of the things that I'm most concerned about is that we need to have approval to use a drug like setmelanotide. In those patients, if we say a 5% or 10% increase in their body weight and not wait until they get to a particular BMI before we could use a drug that simply is, as you mentioned, a hormone replacement. So that's what I'm hoping for in the future is that, we can sort of stay that off. What I have been able to do until now is to treat patients usually with dexedrine to increase their metabolic rate. And that's really the only pharmaceutical drug that I found to be effective. Some of the other drugs, the GLP-1 drugs do work in these patients, but you get partial responses. They may go from 450 pounds to 300 pounds, but they really need to be 175 pounds. So we need something to finish it off and help them get to really truly where they need to be, to be healthy and to have less morbidity and mortality and less arthritis in the future, for example. So I feel like I'm pretty much handicapped with not much to do other than in some of those with hyperphagia, the behavioral modifications where the family has to get very intensely involved. I have a patient right now with Prader-Willi syndrome, who the family has to lock the refrigerator, lock the cabinets, lock the kitchen, make sure that he's not hiding food in his room and things like that to keep his weight under control. So it's really behavioral therapy in dexedrine which, as you know, is an addictive amphetamine. But it increases the metabolic rate. So I really enjoy the concept of setmelanotide and related compounds, because they are hitting a receptor, replacing a deficient system. And it makes perfect physiological sense to use this drug, it sort of bypasses the hypothalamic dysfunction. So we need this compound -- related compounds you come up with to treat our patients. And I think it really offers a bright future for these patients that really have nothing that sticks, so to speak, at the present time.

Yes. Dr. Shoemaker, how do you manage your patients?

Yes. So we do a lot of environmental restrictions trying to decrease calorie intake. We use physical therapy to try to get patients moving in more active. And we use GLP-1s when we're able to get access, particularly for our patients with diabetes, because at least it's not weight gaining. And we've had some success with having that help slow that rate of weight gain, because as Dr. Blevins mentioned, the rate can be really impressive and just slowing it down is a bit of a victory. So that's kind of all we have access to right now. So we're trying to do things to mitigate not a lot of success in normalizing weight or really kind of relieving the symptoms at this point.

And can we -- for both of you, I start with you, Dr. Shoemaker. The fatigue part of this, is it asking you to hypothesize here, what you would see in somebody who just gain a lot of weight quickly? Or is there something else?

Yes. And I don't know whether some of it is such an abrupt change that they feel even more inhibited by the weight gain than maybe somebody who gained weight over a longer period of time. I don't have a great data on it. But our patients' desire to do exercise seems dramatically changed. And the best example I have, I've told people before. I had two adults that were competitive triathletes before their tumor diagnosis and both of them totally separate don't know each other. Both of them were very -- like very clearly able to articulate having no joy and exercise post their onset of hypothalamic obesity and even before they gained significant amounts of weight, just or wanted to do all the exercise and they had more discomfort and they just didn't feel like it. So they -- the kids have a harder time articulating how they feel. But the adults, it seems clear that there is some sort of increase in fatigue and drive or joy and exercise that's different than just I gained in one women's case and she'd only gain like 20 pounds, I think, at the point where they started. And you wouldn't think that would be enough to make you not willing to get on your road bike anymore if you used to do that 5 days a week. So it does appear to be more extreme than other obesity disorders.

And Dr. Blevins, how do you see the fatigue here?

Well, certainly common and it's common even when you've gone to great lengths to try to replace other pituitary hormone deficits even to the point of giving some of these patients if their disease is controlled growth hormone. And I don't know whether it's simply related to the diminished autonomic outflow or whether the brain is doing something else to limit activity. And it seems to me that there's something that we don't really fully understand about it. When you actually study the hypothalamus, it is one of the most complex parts of the brain, in my opinion, and all the different pathways and neurotransmitters and hormones and connections. It's got to be something more than what meets the eye or is on the surface that explains a fatigue, but it's universal in these patients.

Yes. Okay. Helpful. How do we make a diagnosis? So Ashley, maybe you want to go first?

So I have the advantage of most of my patients are pediatrics, and we have growth charts. So I think in the world of pediatric endocrinology, there's a lot more awareness of hypothalamic obesity, because -- and when you saw Dr. Abuzzahab's patients growth chart, you can't ignore when all of a sudden, there's a line going straight up. I have noticed in my adult patients that there's oftentimes more blamed being put on their testosterone dose or the thyroid hormone dose or their hydrocortisone dose, and that there's some confusion about why the person may be gaining weight and a lack of recognition. But if you graph it, it's quite obvious. It's hard to miss.

And Dr. Blevins. I know both of you have big referral practice as well. But is the diagnosis missed? Is this a hard diagnosis to make back to the adults. Pediatrics may be a little more straightforward, but...

I think it is missed often, because people aren't in tune with it. And heightened awareness will help. In my practice, if anybody gains 5% of the weight, I consider that to be circumspect and evidence of hypothalamic dysfunction. And I'd like to coach it in terms of that leading to the weight gain. There certainly are well defined criteria looking at BMIs to diagnose obesity and all of that in regular adult patients. But I think we need to look at it differently in these people, because if they go from 125 to 160. I mean to me, that's a 50% increase in weight. And a lot of people would see them in the mall or on the street and think, well, you're not really obese, you're just a little overweight. So I don't know that we have criteria yet to call it, but I think probably we need to have a summit to trying to figure out how to actually diagnose what the criteria are to defining this, not only for treatment, but also for medical purposes and establishing close follow-up, et cetera. We need to define it before the insurance company is get to deciding who gets drug in the future, we needed to find that for them. So it's one of my concerns as a practitioner is that, you recognize that therapies become available, insurance companies will deny those treatments. So we need to define it.

Yes. So maybe to build on that, Dr. Blevins, the idea that it's not a BMI threshold to change. So do you want to...

Yes. I think his point is correct. It's the rate of change. It's that trajectory. And it would be nice to -- we are working to define it. I think that is a goal of everybody in this world now is to kind of put better definitions on this. And I agree, it's a rate of weight change. And if you can show that you've changed over a 6-month period, that really should be enough and we would like to not have to wait. Some of the patients come in underweight to depending on where their tumor location was. So if we wait until they're obese, it could be a really large change. Yes. So agreed, the rate of weight change in a short period of time is what we're most interested in.

One of the things -- if you don't mind. One of the things I thought to address earlier that came up in the presentation is that it's not universal that we see hypothalamic obesity. So they use craniopharyngioma as our modeler as an example. And that's because these lesions sometimes are located within the pituitary. Sometimes they're in the region of the pitutary stalk and sometimes in region of hypothalamus. So those that are hypothalamic or the ones that are what we call suprasellar in the region of the pituitary stalk if the surgeon injures the hypothalamus, those are the people where you see it. So if you look at all craniopharyngiomas, for example, there's one study, I think it might have been from Japan, you'd mentioned Japan earlier, showed that only 40% of adult patients with craniopharyngioma had hypothalamic obesity. That's usually related to the location of the tumor itself. So really for the HO, we're talking about people with third ventricular tumors or suprasellar tumors where the surgeon tries to peel the tumor away, it damages the blood vessels that supply the hypothalamus. So that's why it's not universal. I just want to make sure your audience, if they had that question understood why we don't say it 100%. Some studies say it's as high as 70%, some says low as 40%. But it's not universal in the adult patients with craniopharyngioma.

So Dr. Belvins and Dr. Shoemaker, can you talk a little bit about -- it sounds what we understand is a patient who is diagnosed with a tumor gets pretty good preoperative education about the complications that may occur. It's not clear that they are educated about HO specifically. And I know what your experience was and what do you think?

So I educate my patients who have surgery in this region for craniopharyngioma or other lesions. I tell them all about the potential for this, and we'll watch their weight, and I need to hear from them. Let's say, if we have visits at 1 and 3 months after surgery, then another one at 6 months, then another one at 6 months or the year anniversary. I want to know if they're having weight gain in the interim. So my patients hear about that, but I don't think that's universal across the country, in the world. where patients are informed of this possibility. And some of that is just we need to heighten the awareness of treating physicians. I know everybody who takes care of these patients knows the hypothalamic obesity can occur, but I'm not sure that -- when I talk to my endocrine colleagues that it's always addressed, because there's not been an effective treatment. So part of the work of the educational team with Rhythm is going to be to inform people of this drug and the possibility that patients may actually require treatment and there is a treatment for this, so that you can decrease morbidity and mortality later in life.

So the other issue is patients and families don't always hear it. So even if we talk about hypothalamic obesity at the beginning, when you're also mentioning brain surgery, vision loss, and here are the five hormones you're going to have to take, including adrenaline insufficiency and vasopressin deficiency, things that are really complicated and scary. Most families don't latch on to HO and especially because right now, there isn't a treatment. So you're telling them all the things you're going to do, and that's not one. So we often find it takes -- oftentimes about 3 months before we get the families kind of to engage on the idea that, oh, this weight gain that's happening, that's a separate problem that we need to deal with. That's not going to be fixed with just getting them back to school or adjusting their thyroid hormone. So one is, it's a difficult thing for people to wrap their head around. And the other problem we're running into is increasingly, I see patients with HO and its post radiation. We do -- we see many fewer aggressive surgeries than we used to, where it was, okay, they're going to go in and do the surgery. And then immediately afterwards, you have this onset of HO. Now a lot of our patients are going straight to radiation. And so then you have some delayed effects, because radiation takes a while to actually kill the cells. And so, then the timing of the discussion is another challenge. But I think even if people are -- even if doctors are trying to tell their patients, I don't know that patients are grasping the problem immediately.

So just to pick up on your point about the change in practice here, and I love to hear from both of you. So hypothalamic sparing surgery, more radiation, do you think that's going to decrease the frequency of "HO" or is it just delay its onset?

Hopefully, it decreases it a little bit. But certainly, we're still seeing it post radiation. I haven't seen any great data to look at change in incidents. That's certainly the goal, but we're still seeing it post radiation.

Dr. Blevins, any?

Yes, I agree with what Dr. Shoemaker said there. We still see it after radiotherapy. This approach of trying to spare the hypothalamus, I think, is key if you can get some of the children, especially through puberty and maybe through fertility so that they can be fertile and finish their growth. That's tremendous. But you have to use the radiotherapy, ultimately going to lose those pituitary functions in probably 2/3 of people and you are going to see hypothalamic obesity, especially because we know that the radiotherapy probably affects the vascular supply of hypothalamus more than kills the neurons. So they're going to die one way or another, either from radiation-induced damage or radiation-induced damage of the blood vessels. So you do see it. I consider radiotherapy as a targeted therapy, just a surgery is targeted therapy and targeted therapies regardless, do increase the likelihood of HO in adult patients.

Yes. Moving to the drug. I know Dr. Blevins, you weren't part of the trials. Dr. Shoemaker, you were. So can you talk about your experience with the drug in HO, and...

It worked. To echo, I mean, what you talked about earlier, when the Phase II trial was proposed, I think most of us were pretty skeptical whether it would work. I mean, it's a really interesting scientific question, right? Like we know there's damage there. And what I expected was a heterogeneous response. Like I expected that there would be some patients that had unilateral damage, the hypothalamus or partial where they'd have some neurons remaining and that those patients were going to respond really well to setmelanotide and some of the patients with more complete destruction, maybe they wouldn't respond. And I think we all. I didn't hear anybody who thought that MC4 receptor outside of the hypothalamus was so critical. And so the thing that was most surprising about the Phase II data where it was the uniformity of response. These are a really heterogeneous group of patients. They had different underlying causes. They had different degrees of damage. They had a different number of years since it originally happened. We expected there to be more variability in their response to a therapy. So that was what was most impressive or noticeable to me in the Phase II was how many patients responded and that it really did look -- we, endocrinologists, we love hormone replacement. Usually, if someone's missing hormone and you give it back, it just works. And that's what this looked like. So that was a pleasant surprise.

And can you talk a little bit about quality of life? We've seen the numbers, but...

Yes. So I mean for some of the patients, it's been a normalization. And I will echo what Dr. Blevins said, I'm in the south. There is a high rate of underlying obesity. And so for some of our patients, their BMI is right back down to the 50th percentile or where it was before. And for other patients their BMI dropped to where it was before, which may have still been at the 95th percentile or above. So there -- it doesn't normalize other obesity drivers. But yes, I saw a real improvement in quality of life for the patients who had hyperphagia, that would be a really noticeable change if they didn't have to start -- keep thinking about food as a family, the same way they used to anecdotally improvement in energy and ability to kind of want to participate in daily activities. And then just for some of the patients, a real normalization of weight. So basically, a return to more of who they were before. Because like I said, they have a before and an after, so they really are able to tell you what they used to be like and how they feel now. So for some of these patients, it was a return to who they were at the baseline.

Dr. Blevins, having seen the data, how do you see using the drug, introducing a 2-year patients? What's the process there?

Well, I will say that I had one patient who was enrolled in a trial at another site, and it was pretty impressive to see her response as well. She had already had other forms of therapy and was able to lose some weight, but I was able to really -- I had a visit with her, and it's like, what happened to you? You look like you're at a normal weight now. And she told me that she's been in this trial with one of the investigators. I was pleased to see that type of response. So I have the N of one experience. I think, as you said and as Dr. Shoemaker confirmed, this is hormone replacement therapy, and that's what we as an neuroendocrinologists do. We play Goldilocks, if something is too high, we knock it down to normal. If it's too low, we bring it up to normal. And these patients have too low of the activity in this hormone system. We're going to bring it up to normal with this drug. So I foresee using it in a significant number of my patients. I'm not sure I'll use it in all. But I'm a firm believer in weight management in these patients. So those who certainly have hypothalamic obesity or have a gain and wait after an intervention I want to treat them. I consider it as a preventive therapy too, not only treatment, but people have established the basic preventive therapy to keep them from getting there. So they don't want to get all these other morbidities and mortalities. So I can see this being used regularly in the armamentarium of things that I do for patients with hypothalamic dysfunction.

And just maybe one obvious point. Can you do a drug holiday here?

We don't usually take away hormones. If you need them, you need them. So ideally no.

No. The answer would be no.

Patients unfortunately take their own holidays, even an important medication. So I'm sure we'll see that, that will happen, but we don't really care for that approach. So one of the other things I'll comment on is that, I have patients whose hypothalamus is, for lack of a better word, destroyed I expect them to respond to this drug, because of the location of the MC4 or neurons that are in the brain stem, in the spinal cord, in the thalamus and the cortex. So I think that -- that's the beauty of this drug. You can wipe the hypothalamus out. You're going to respond to this drug because those neurons are important in those other areas. It's probably the ones under medulla that are largely regulating autonomic outflow. And we want to see an increased metabolic rate in those people. So I think that's what makes this drug and compounds related to it even more special. Is that -- you almost bypass that signaling pathway through the hypothalamus in patients who have no hypothalamus whatsoever and get the same clinical effect. And that's just the beauty of how these neurons are distributed. It's just our anatomy or physiology are fascinating. And it's incredible that you don't need some hypothalamus to respond to this medication. You can be without and still respond.

And how -- again, for either one of both. The melanocortin-4 pathway signaling in the endocrinology world, how well understood is that? Is this a commonly discussed research? What do you think?

My colleagues only know about it, because I talk about it. But no, I would not say it's a well understood or discussed in general endocrinology. Maybe there's like one board question that throws in -- actually just that throws in POMC deficiency or something that leptin, but this is not a super well understood. However, really as practicing clinicians, usually, we're kind of driven by what we can treat. So unfortunately, you need the ability to diagnose and the ability to treat to make us in clinic interested in a pathway. So the drug kind of has to come first to get people to care about the MC4 receptor.

I couldn't agree more. Clinical endocrine training is largely based on what we can do for patients.There's some basic physiology. I mean, we all know that alpha-MSH can stimulate melanocytes and can cause hyperpigmentation in patients with Cushing's or adrenal insufficiency. And we know about POMC production that people focus on its regulation of the hypothalamic pituitary adrenal axis. And I think that this pathway is going to be sort of new stuff, so to speak, for clinical training programs, existing endocrinologists, some of whom are very out of touch with current research and all of that. And that's where the medical science liaisons for Rhythm have their work cut out for them.

I mean, if you go back, people -- we also didn't know GLP-1. If you would go back even 10 years and asked physicians about GLP-1 or GIP or some of these hormones, that was basic physiology stuff that got mentioned but wasn't part of your day-to-day practice. So it's very easy to get people to catch up, but there has to be a motivation as to why they care about some basic science.

So I'm asking you to look ahead, and just the data comes out, it gets published. Drug gets approved, more attention comes. Is this a specialty that you think going to move quickly to embrace something new? Or is it -- just any thoughts on how this may play? Dr. Blevins, you've been...

I think, pituitary centers of excellence are where most adult neuroendocrinologists lie and then pediatric endocrinologists who do the type of work that Dr. Shoemaker does at academic medical centers, they are going to catch on pretty quickly. And I wouldn't say that most of the complex patients are cared for in those type of centers. There are vast numbers of patients so they see people in community practices and in small towns, and they don't have the luxury of travel to a center of excellence, but I think you'll find that your rapid uptake is going to be through academic medical centers where most of these people would go for surgery to try to get the best outcomes possible.

So on that note, the world is also very focused on Prader-Willi. You mentioned it earlier. I think you both care for Prader-Willi patients. Can you just talk a little bit about: One, just the differences from a disease standpoint, because I know sometimes there's some confusion there; and secondly, a new treatment just got approved for Prader-Willi. There was a reasonably rapid uptake. I think would be the conclusion. What's different about that dynamic from this dynamic? And I highlighted wondering Prader-Willi patients having potentially their own clinics, HO patients not, maybe a better diagnosis rate, but anyway, thoughts on that.

Yes. So I direct a multidisciplinary Prader-Willi syndrome clinic. I would say a lot of differences. One, our Prader-Willi patients are usually diagnosed in infancy. So the goal is diagnosis in the first year of life. Most patients are diagnosed or the process has begun before they've left the hospital after birth. So we have a long run up with those patients of both kind of bringing them into our clinics and also discussing what's to come. Average age of hyperphagia onset and PWS is 8 to 10 years old. So you actually have a long time before they have full-blown symptoms. So that's a bit different. And they have very different medical problems. So a lot more distinctive behavioral issues. They have the similar hypothalamic dysfunctions, so some of the same hormone deficiencies, but more significant developmental delays and some very distinct behavioral phenotype. And as of now, all of my PWS patients require round-the-clock care. So I don't have any adults with PWS that live independently, and they all develop this really severe hyperphagia. And HO is a bit different. You've got the sudden onset of -- that was unexpected, and they're dealing with a lot of problems that all start at the same time. They tend to be seen in a different kind of medical setting. I mean, sometimes it's the same people, but more that they're being seen in endocrinology and potentially neurosurgery and neuro-oncology. And the hyperphagia is a bit more mixed with HO, and some of the patients are cognitively great. I mean, I have adults that have families and they work and they're not -- their whole life isn't devastated. So a bit different in how they're cared for and certainly not the same. The HO patients are very engaged with the medical community, because they have all these hormone deficiencies. So that makes it easier. There is not the same patient advocacy organization that we see with Prader-Willi syndrome. That's a very organized group of families. So it's similar, there's overlap, but they are definitely different communities.

Dr. Blevins, anything to add there?

My practice would obviously be different. Many of the patients that I see with Prader-Willi or Septo-optic dysplasia, who also have hypothalamic obesity or any of the other symptoms usually come to me in their 30s or 40s. They've long lost their pediatric endocrinologists, maybe they were handed off to a primary care physician. And ultimately, they're referred because they have some other hormone deficits and need attention, and we jump into the fact that, well, what can we do to regulate your appetite and your weight and things of that nature. So those are the ones that are usually will start with the behavioral therapies. I have a couple on dexedrine that seems to at least prevent further weight gain, but we focused large on behavioral. There are usually men living with their families still, their mother and their father participating in their lives far more than we would for most of our 30- or 40-year old men. And I think that there's probably a role for this medication in those patients as well. In fact, I first heard about setmelanotide from one of my patients with Septo-optic dysplasia a few years ago. I mean, since I want to be on this drug, let's see what happens.

So we're working on that. It makes sense that, that might work, obviously, why we're running trials. I'm going to close just and then we'll open it up to some questions. Urgency to treat here. Drug gets approved. Obviously, the data will be out there.

Yes. We get really excited to have something we can treat. I think one of the reasons that my colleagues don't really want to engage in hypothalamic obesity as doctors don't like things we can't fix. It's not very fun to take care of a medical problem that we can't address. So I think, yes, urgency is -- I don't know why I would delay. So if it's an appropriate medicine for the patient, and we're able to get access, it's something that I think we would be trying to offer as quickly as possible. And we like hormone replacement therapy. So I think it's -- the uptake should be pretty comfortable for most endocrinologists.

Dr. Blevins?

I agree.

I'll open it up to a couple of questions. Okay. I got more than a couple up already.

Appreciate it. On the -- Rhythm is going to talk about the epidemiology work they've done, but just in your experience, how prevalent is HO relative to Prader-Willi? And what's your view on the true prevalence of non-surgical HO? Do you think there's this whole group of patients out there that haven't been found? I mean, from our perspective, it's just very hard to research, but there are these really interesting case studies. So any perspective would be great.

I would say, yes, there are definitely non-surgical HO patients. My own personal practice, we've had a patient with a vasculitis with one of the most impressive onsets of HO I've ever seen and also complete loss of thirst, which is was really not fun. And we've seen dramatic brain injury patients, really anything that causes vasopressin deficiency, you definitely can see HO and post radiation. So those patients are out there. I think there are undiagnosed patients, and I think our estimates of prevalence are pretty poor. There's not an ICD -- there hasn't been an ICD-10 code for this. They're not being coded exactly. Like I said, there's not a lot of impetus to code for or describe it when you can't treat it. So a lot of our notes won't even talk about HO, because you're talking about the six other hormones you're replacing. So I do think it's under-diagnosed. In my practice, I have seen 3x as many PWS patients as HO patients. That's not a perfect descriptor, because the PWS patients come from a slightly smaller area, but I see more adults with PWS. So I think the one in 50,000 is a reasonable starting point for an HO incidence, but I think it could easily be 1 in 30 or 1 in 60, the accuracy is not great right now.

I remember a couple of months ago looking into some data, when I was just trying to educate myself about HO and this pathway. Maybe it's been 6 months ago now, reading that it was estimated that maybe 3% to 5% of people with obesity have dysfunction of one of the different components of this pathway. So if you consider them to have genetic causes of hypothalamic obese, maybe even far more common than we believe out there in society.

Yes. So just -- I mean this is part of our -- the semantics problem here, which as a company we're working and as a community, people are arguably hypothalamic obesities where these -- the regulation of hunger and energy expenditure resides. So by that definition, there's many things we are working on the different pieces. The challenge, which you're asking about, Paul, is how do we get to a true prevalence number here. I think both Dr. Blevins, Dr. Shoemaker have large populations as experts in referral populations. So we're going to be learning a lot more as we go forward. But, Jon?

Jon from Citizens. Dr. Blevins said something interesting about potentially using setmelanotide preventively after surgery to prevent weight gain. Dr. Shoemaker, wondering if you think about that use case, and I imagine that's something that will be in the initial label, but Dave, if you can maybe comment about the evolution of setmelanotide's use over time.

Yes. I don't know if we'd use it immediately after surgery. We usually like to see even with all of our hormone replacement, you want like some evidence that they have a deficiency before you start replacing. And I mean if a surgeon comes out and says, I cut out the pituitary, it's gone. Well, yes, you've got to replace that. But early, I mean, we typically can tell definitely in the first 6 months, often in the first 3 months that this is a person that's having the trajectory consistent with HO and you'd like to intervene. So I think in my -- what I would probably be leaning towards is within 6 months of diagnosis being able to have enough evidence to start. And based on what I've seen with the response, I think that the weight gain they've had in that period of time would be pretty easy to fix. But I agree, I hate the idea of waiting until someone hits a BMI of 30. If they started out with the BMI of 19 and you've got to wait until their BMI gets to 30, that seems silly. It's kind of like they're getting the age down to 2. As a pediatrician, one of the frustrations was if you're making genetic diagnosis when people are young, you don't want to wait until they're 6 or 10 or 12 to start treating, it just seems silly to say we have to keep waiting. So hopefully, we can get a definition of HO where maybe within 3 to 6 months of diagnose -- of onset that you can demonstrate a need. And obviously, similar to growth hormone, you don't have to show -- someone doesn't have to become short to need growth hormone. You don't have to wait until they're short. You just show well, they used to be at the 75th percentile and now they're at the 50th percentile and their growth rate is abnormal, and that's enough. It would be ideally, we get to the same place with this hormone replacement.

And just from a regulatory standpoint, as you probably know, the way labels often mostly work as they take your inclusion criteria and that's translated to the label. We required obesity, by definition, greater than 30 BMI. But physiologically is what you're hearing from Dr. Blevins, Dr. Shoemaker, we will have that conversation. Again, regulators, they try to do what makes sense. And so this will make sense to them, whether we can get it translated into the label, I don't know yet, but we will have that conversation for sure.

Seamus Fernandez from Guggenheim. So couple of questions. Just your experience in the clinical trial of the patient's responses, and I'm sure you had a blend of patients, but you also treated in the Phase II as well. So the nausea that you see in these patients that's reported, how does that compare to sort of GLP-1 nausea or other hormone therapies that you see. And as the patients are responding, is that something that diminishes kind of goes away over time and then they really tolerate therapy. And then the one other thing that we didn't really talk too much about is the impact of hyperpigmentation that you could see in your patient population and perhaps the future benefits that we might see from some of the newer agents that are coming.

Yes. So nausea, pretty similar, I mean, in general, I personally am pretty aggressive with treating with antiemetics, because this patient population is vulnerable to nausea and vomiting and changing their food balance or precipitating. You've got concerns of precipitating adrenal insufficiency if somebody -- or adrenal crisis if someone's having a lot of vomiting. So we were pretty liberal and I am pretty liberal with using antiemetics. And patients did well, sometimes you go slower on dose titration. Very similar to GLP-1s with some patients need a slower titration, some patients take a little longer to get up to a dose. The -- definitely gets better. So not something that people are complaining about years later. A little difficult to completely tease out as well because these patients, some of them already have nausea kind of at baseline, so some patients already had Zofran prescriptions, for example. But compared to our trials with GLP-1s in the same population, pretty similar. Hyperpigmentation definitely happens. If you're having a benefit and a large weight loss, people don't tend to care or willing to tolerate. I have some patients who love their hyperpigmentation and some patients who hate it. So I think there's certainly room for improvements there. I mean, I think that if I could offer some of my patients, an agent that had fewer off-target effects, there are definitely people who would like that. It's a hard one, because it's a very cultural, how people interpret change in skin color. So it's been interesting to watch. But I do think it's -- it would be nice to have an option that didn't have that side effect.

Corrinne Johnson from Goldman Sachs. Maybe if you could just talk about what portion of patients that you are currently treating for HO would be candidates for this drug if it came to market? And if there's patients that aren't candidates, kind of what are the features that would lead you to not use setmelanotide in those?

You want to -- Dr. Blevin, do you want to go first on that?

That's a very good question. I mean, just off the top of my head, I would say probably 80% might be candidates and the 20% here or not would be those who probably don't have a care provider or a self ability to inject. Because again, we see people who've been absolutely devastated by their hypothalamic disease and hypersomnolence and poor cognition and requiring complete care. And I know that -- and it's a multicultural population. Many of these patients all speak English. And they literally don't communicate with you. I think that those are the patients who sometimes need the treatment the most, but it's hard to find a care provider who's going to be willing to inject every day, in some of the underserved populations that we have in California. So not everybody is a candidate for therapy, because of their societal, social economic status. And cultural situation and an educational status. And I think those would probably be the ones who I would encourage treatment, but we sometimes can't even get those people on growth hormone injections just because of the things that I've mentioned. So there are barriers to carry out there, and we're not going to find it's going to be universal. But I would say 80% -- just off the top of my head 80% of our patients with HO would certainly be interested and would seemingly be candidates. So I would try to get 100% on treatment, if I could, but I've practiced long enough to know that there are obstructions to care.

Yes. There are not a lot of -- I mean assuming similar labeling, there's not a lot of contraindications. It's the main one being if there's a family history of melanoma which we don't run into a lot. So the majority of patients would be eligible and then it will come down to their interest and payer coverage. But I would expect that we would be offering it to most of our patients pretty quickly. I mean, that's what we do with Bardet-Biedl syndrome is basically just offered it to the patients as they came back into clinic.

Kris Jenner, Rock Springs Capital. In the presentation so far, there's been several references made to PWS. And Dr. Shoemaker, I know you have been kind of recently consulted on safety concerns related to PWS safety concerns, which either were part of the trial or are kind of associated comorbidities. Now in the case of HO, they're medically complex patients. You've mentioned several other hormone imbalances, several other medicines. I guess, what I'm thinking about is let's fast forward new medicine, significant unmet medical need, physicians may or may not be totally familiar with this. So we fast forward, and what should we be thinking about in terms of, let's use PWS as a learning example of things that we may see of safety concerns that are totally not related to the drug, but are related to the complexity of the medical patient in which the drug is being given?

Yes. I mean, the data was presented earlier about the percentage of patients. 23% had ICU admissions and a number of hospitalizations per year. And honestly, this is a worst population than PWS for mortality. In my experience, I have more patients with HO who have died than I do PWS, and it's a slightly smaller population. So we do expect that, unfortunately, these patients will have mortality. They do tend to get hospitalized. And the big things are those the vasopressin deficiency, so diabetes insipidus, that fluid balance and adrenal insufficiency are the two most reason, common reasons I see patients presenting to the hospital. So that's going to have to be expected. And I do think we will have to be thoughtful about how to manage nausea vomiting in these patients because it can be hard. And not all of them have the ability to monitor sodium checks at home. So it can be -- require more visits and whatnot. So they are a complex group. There will be continued issues with these patients. And yes, we can't panic if when patient goes to the hospital, because that's already happening.

So I think on that, we'll close, and thank Dr. Blevins for joining remotely. For taking time out of your day and of course, Dr. Shoemaker, thanks for being here. So with that, we have a -- go right to Jennifer. 10-minute break. Okay. So we'll take a 10-minute break. Dr. Blevins, thanks again. I look forward to connecting. And we'll be back in 10 minutes. [Break]

Thank you so much for coming today to hear our story. We are so excited about the potential upcoming launch for setmelanotide and acquired hypothalamic obesity. The unmet need, as you have heard for a therapy that addresses obesity and hyperphagia associated with acquired hypothalamic obesity is clear. We have already done a lot of work. To prepare, and we look forward to the potential opportunity, if approved, to make setmelanotide available to patients and their families. I'm going to be covering three different topic areas today. First, I would like to reflect upon what we have already built at Rhythm to transform the lives of patients living with MC4 pathway diseases through our BBS efforts and how it sets the stage for our success in acquired HO. Second, the progress we have made towards understanding the opportunity, the unmet need and future potential for setmelanotide in patients living with acquired hypothalamic obesity. And lastly, our strategic priorities and progress as we look ahead towards a regulatory decision in December of this year. As we prepare for this important next stage of growth for Rhythm, I reflect upon what made us successful in BBS and what we can leverage from that success. Let me walk through some of the areas that lay a strong foundation and jumping point for our next launch. While ahead of launch in BBS, our teams are already in the field identifying HCPs and BBS patients who could benefit from a targeted therapy to address their specific needs. This enabled us before Day 1 to have identified physicians who are treating nearly 350 potential BBS patients. As we learn more, we have updated our prevalence estimate for BBS to 4,000 to 5,000 in the United States. Since IMCIVREE's first approval in 2020, we have continued to hone our data-driven methods to identify patients with BBS. Leveraging all available data sources, including both claims data as well as genetic testing sources. We also further leveraged the input and learnings of our field teams to refine our customer base and priority targets. Through educating and engaging with the community, our teams have made a difference in the lives of many patients. Rather than falling through the cracks, as often happens with patients with rare diseases, patients with BBS are now recognized and diagnosed earlier and able to receive optimized care. Over the years, we focus our education and engagement efforts on differentiating MC4R pathway diseases, including BBS. From general obesity, we have activated a broad base of BBS diagnosers and IMCIVREE prescribers. These physicians, including endocrinologists and obesity treaters may also come across patients who may benefit from setmelanotide upon future approvals like hypothalamic obesity. Through their positive product experience, they are now motivated to look for additional BBS patients who may benefit from IMCIVREE. Nearly half of our new BBS patients have come from prior IMCIVREE writers, which is a testament to the positive product experience we are creating for both prescribers and patients as well as their appreciation of IMCIVREE as a therapy that targets the root cause of their obesity. In addition, we have continued to build on the clinical value proposition of IMCIVREE through the generation of new data. We have made significant contributions to the understanding of the MC4R pathway as we have published more than 100 posters, presentations and publications, including ENCORE's on BBS over the years. We continue to expand our customer-facing teams. Early in our BBS launch, we are able to appreciate the importance of optimizing both the patient and prescriber experience. We have learned a lot from our BBS launch and adapted the way our teams on board both the HCP and patient providing a seamless experience from prescription through the reimbursement process, to initiating and maintaining on IMCIVREE long term. Over the last 5 years, we have also educated payers on IMCIVREE's unique value proposition for approved patient population with MC4 pathway diseases. As we have shared in the past, we have seen breadth and coverage with IMCIVREE-specific policies in place or access to IMCIVREE even without a policy in place. With our Rhythm, InTune teams supporting patients and securing access and initiating and staying on therapy, we are now seeing BBS patients who have reached and surpassed 3 years on continuous therapy. We continue to advance setmelanotide, a potential first and only life-changing medicine into other MC4R diseases with a considerable disease burden and high unmet need. As we look towards our next potential approval in acquired hypothalamic obesity, we are excited to build on the considerable experience and success of our teams. Now let's transition to what we have learned in market research. Our focus here is on what we have learned about acquired hypothalamic obesity. Specifically diagnosis and management of this rare disease and the potential for securing access to setmelanotide for these patients. Our MSL team has been engaging with treaters of hypothalamic obesity for a year now, uncovering insights and establishing relationships with key opinion leaders. Over time, additional teams have also shifted towards education efforts of our customers to support patient diagnosis and identification, ongoing access to setmelanotide upon approval and community building among patients and caregivers. Here are some of the things that we have learned through the insights that we have gathered from our customers. The presentation of acquired hypothalamic obesity defers from general obesity in many notable ways, including a rapid onset of weight gain and hyperphagia following a distinct injury. Unlike monogenic and syndromic obesity, these patients, therefore, have a clear before and after. And many patients describe this sudden change as night and day. However, this is a heterogeneous disease on a spectrum. And depending on the cause of injury, the age and weight of the patients at baseline and other underlying health conditions, no two patients will present in exactly the same way. Diagnosis is further complicated by the current management approach to acquired hypothalamic obesity which currently does not differ from the treatment of general obesity because no targeted therapy exists to treat this condition today. Given this lack of distinction in the management of these patients, there is currently no strong incentive to get to a differential diagnosis between acquired hypothalamic obesity and general obesity. As we have engaged with providers, we are seeing many lightful moments through our education and discussions. Healthcare providers are able to draw a connection between weight gain and a prior hypothalamic injury. They note the presence of hyperphagia in many patients as well as the onset of fatigue. These providers readily appreciate the role that the MC4 pathway has in mediating this distinctive disease process. They understand how this deficiency can contribute towards decreased energy expenditure and onset of hyperphagia. And they appreciate that multiple causes of entry, including tumors in their treatment which is currently more readily understood as well as traumatic brain injury can all lead to acquired hypothalamic obesity. Armed with this information, healthcare providers tell us that they are now planning to go back and evaluate their patients, who they suspect may have acquired hypothalamic obesity. These patients may subsequently also be confirmed with a diagnosis through further evaluation of their physician and their future visit. While our market research tells us endocrinologists agree that acquired hypothalamic obesity is underdiagnosed in the United States. We believe this current diagnostic challenge is highly addressable through our current education efforts to both healthcare providers and patients. And we have already seen success here. As we have heard during our repeat visits to treaters, they have identified additional patients that they would like to follow up with for evaluation of acquired hypothalamic obesity. Similar to other rare diseases, and as we saw with BBS, the urgency for an accurate diagnosis will be further heightened upon approval of setmelanotide as a new and first treatment option specifically tailored to address the underlying cause of obesity for these patients. Now on to management of HO. In the early days following a hypothalamic injury, patient care is highly complex. In many cases, patients have already experienced the shock of getting a tumor diagnosis. And they are soon engrossed in a complex cascade of interventions to stabilize many hormonal insufficiencies, several which can be life-threatening. During this period, some patients may experience transient changes to their weight as a side effect of corticosteroids or other therapies. However, as these levels stabilize, the hallmarks of acquired hypothalamic obesity become readily apparent. Based off our market research among all the sequela that may follow a brain injury, endocrinologists report acquired hypothalamic obesity as their second highest concern behind pituitary insufficiencies and as concerning to them as the onset of diabetes insipidus. With that said, physicians outlined the challenges presented by weight management and hyperphagia itself and consistently outlined the difficulty effectively managing their patient's weight gain. They also expressed that a new and effective treatment option for these patients will further help to motivate the urgency to accurately diagnose and treat these patients. With the challenges that were outlined, with available treatment options, we have received very positive feedback regarding setmelanotide's clinical profile as a treatment option for hypothalamic obesity in blinded market research. Overall, the vast majority of endocrinologists surveyed consider setmelanotide's degree of weight reduction, both compelling and clinically meaningful. And all surveyed endos report that they would prescribe setmelanotide for acquired HO patients. Together, these data points give us great confidence in the benefit risk profile of setmelanotide and acquired HO. We believe the question is not whether providers will adopt setmelanotide, but when they will adopt setmelanotide. Regarding the timing of treatment initiation, approximately 60% of endocrinologists state they would initiate setmelanotide at the time of a patient's HO diagnosis. While others would wait until all the patient's hormonal deficiencies have been stabilized prior to initiating. When asked what differentiates setmelanotide as a potential treatment option, the majority of endocrinologists state that is setmelanotide's ability to target the root cause of acquired HO as a key reason to prescribe. And the positive perception of setmelanotide's clinical profile is not limited to its impact on weight alone. Here is verbatim what we heard from a pediatric endocrinologist. I love seeing that there is improvement in a patient-centered outcome, that being the change in hunger. For me, it's not all weight centric all the time. I think we get really focused on that. This quote aligns with a similar relative importance in market research, a reduction of BMI or body weight versus reduction of hunger or hyperphagia and physicians' reasons to consider setmelanotide for their acquired HO patients. Now regarding market access, we are really operating here from a position of strength, when it comes to setmelanotide. Payers have already understood the differentiation between MC4 pathway diseases and general obesity in the context of all the education we did around BBS, which has led to the breadth of policies already in place across nearly all commercial and Medicaid covered lives. This lays an incredibly strong foundation to start from for our potential launch in acquired HO. For months now, we have engaged with payers with pre-approval information exchanges regarding both the acquired HO disease date and more recently, our pivotal data. Nearly all payers report that approval and acquired HO will trigger a coverage policy update, but this will not happen on day 1 of approval. About half the payers we have engaged suggest a policy update will occur between 3 to 6 months post approval, and the other half expect a policy update within the year. With criteria required prior authorization in alignment to the labeled indication. Based off this feedback, we feel confident when it comes to market access for setmelanotide and acquired HO. I now want to shift gears and begin to outline where we are focusing our efforts as we look towards the December approval. We are focused on differentiating MC4 on pathway diseases, including AHO and associated burden of obesity and hyperphagia from general obesity. Expediting patient diagnosis and following approval establishing IMCIVREE as a foundational treatment for acquired HO, working with payers to secure access and supporting patients long term on treatment. In order to do so, we are putting the right team in place to be able to execute against these priorities. To facilitate considerations around team sizing, I want to outline some of the claims analysis we undertook to identify our key targets for launch. We used robust U.S. claims data to narrow down to a group of potential suspected acquired HO patients by outlining a number of key criteria. First, was claims data evidence of a pituitary tumor craniopharyngioma or other certain neoplasms in the brain, along with evidence of a surgical or radiological intervention. Next, we required that patients exhibit some degree of hypothalamic dysfunction such as pituitary insufficiency, diabetes insipidus, or hypothyroidism. Patients then needed to have evidence or coding of obesity. And finally, as a starting point for a field targeting, we further narrowed down to patients who had an in-person visit to an endocrinologist within the last 18 months. With suspected HO patients now identified in the claims data, we could turn towards identifying our priority HCP targets for launch. Our clinical experience in acquired ACO in addition to market research insights tell us that endocrinologists and pediatric endocrinologists are the key treaters of these patients. The treatment of these patients' hormonal insufficiencies will be chronic and patients will generally visit an endocrinology office once or a few times a year. Of all the endocrinologists and pediatric endocrinologists practicing in the U.S. our claims analysis with the recency factor included indicate about 5,000 may manage one or more potential acquired HO patient. As with many rare disease, many physicians only manage a single patient with some degree of concentration among the top treaters as you can see with Dr. Shoemaker and Dr. Blevins. Likewise, a smaller set of about 2,400 endocrinologists and pediatric endocrinologists may manage a larger percentage of potential HO patients. These treaters comprise our top-tier SAP targets upon launch. This data-driven approach was driven entirely by the tumor population. But we have learned from additional research that these targets outlined here show a high degree of overlap with those potentially treating patients with HO acquired from other sources such as TBI. It has been 1 year since we began our education efforts with acquired HO with our initial focus on the potential high-volume treaters. In that time, the healthcare providers, we have profile to date indicate approximately 2,000 of their patients may have acquired HO, whether diagnosed or suspected. We see this subsegment as our highest priority upon launch, as these physicians continue to further evaluate their patients over the course of their next visits to confirm a diagnosis. I now want to discuss the growth of our teams. During the preparation of launch of IMCIVREE and BBS, we grew our teams and since have grown incrementally to support our execution to achieve our corporate objectives. To prepare for our upcoming launch in acquired HO, we have been actively hiring and training a highly experienced team. We now have in place a larger team to unlock this exciting opportunity to make setmelanotide available to benefit patients with HO. We are increasing our sales force going from 16 to a total footprint of 43. We have expanded our patient service team to accommodate the future needs of both patients and healthcare providers. and we have also grown our internal teams to support the launch in this larger opportunity. We have an extremely seasoned team with considerable rare disease as well as launch experience, across all parts of the organization. Our disease state education programming around acquired hypothalamic obesity is also underway. differentobesity.com, an unbranded site serves as an umbrella site for both physicians and for patients with a focus on MC4 diseases with hypothalamic obesity included. In addition, a series of webinars and events for HCPs and patients paired with physicians, including Dr. Shoemaker, are well underway. All designed to raise awareness of HO, provide patients and physicians with resources to support diagnosis. I want to wrap up now by returning to some of the themes I set up at the beginning. We have a good fortune to build on the success of our prior BBS launch. We have really taken time and care to understand the needs of these patients and their providers and setmelanotide is extremely well positioned to transform the lives of patients living with acquired HO. And finally, we're ready to go. We have built a team we need, we have a strategy in place, and we have been executing to prepare for the upcoming launch and we look forward to a positive outcome December 20. Thank you very much for your time.

Thank you, Jennifer. So as you heard, I think we're in a really good place. And we are incredibly excited about what's in front of us. And we'll start off by what we're building on, and we're building on our 2020 experience, initial commercial experience with POMC and LEPR, followed by Bardet-Biedl 2- to 6-year-old and set us up for now HO. And just looking ahead, again, I think our approach at Rhythm has been to creating comprehensively about the areas that we're in. Okay. For those who didn't hear what I said, you didn't miss much. We're in a good place. We are in a good place. But I will repeat, our general approach has been to think comprehensively about the areas that we're going into, whether it's the different indications surrounding the melanocortin-4 pathway or whether it's geographic and we're committed to the MC4 space. And that gets to setmelanotide. We think is an amazing drug. We can do better. And so the focus on the next-generation molecules is extremely important. We talked in June about the results of the Phase II study, that as a small molecule, I think as I expressed to a number of you or -- you never know what you don't know about a new chemical entity. And so although we knew it was a good MC4 agonist until we actually got into patients, we didn't know for sure that we had it. And I think that data of 28 patients has been -- was highly confirmatory. The one piece that we highlighted there that also will be part of our ongoing challenge to improve bivamelagon, the small molecule is to make a better pill. In that trial, patients had to take the three multivitamin -- large multivitamins on an empty stomach, not the best presentation for the patients. We've already learned that they can split the pill, and that makes it a little better. But, our Joe Shulman and our CMC team is hard at work in terms of making a more acceptable presentation here. So we now have the full 600 milligrams in a single pill that pills a little more -- it's a contoured and slightly smaller, and we'll have obviously a smaller 400, 200-milligram options as well, and we'll get to a chewable tablet. So we're looking forward to our Phase III trial starting again in 2026. And the 718 proof-of-concept study that's underway that is coming on the heels of the single administration, multi administration, normal volunteer study. We're now in HO patients. And again, as you know, the value an incredible advantage of being able to study an indication like HO is because it does seem to be so sensitive to MC4R agonism. It should give us a very clear understanding of how 718 is working. And so we look forward to updating you on those. Both of these have little, we believe potentially no hyperpigmentation. We'll see with 718. I think what we've seen with bivamelagon was some truly minimal and will be very significant improvement for those who are concerned about pigmentation as a side effect. And again, as I said, we look forward to updating you on that. And from a patent term extension, both of those take us to 2040 plus. So the summary before we go to Q&A for the group in the room here, clear unmet medical need, I think, as you've heard, without an existing effective treatment for acquired hypothalamic obesity. Hopefully, you've understood from Jennifer, a lot of work has been done already. We're going to be accelerating that work as we go into the close of the year, and she gets her full team on the ground in place ready to go. But good progress and feel really good about our ability to execute going forward. And as we said, yes, this is a transformative opportunity for Rhythm. So I look forward to that. With that, I see, Derek has his hand up already. Give us 1 second. We'll just get our chairs set up here.

Derek Archila from Wells Fargo. Just two questions from us. I guess, first of the 2,000 patients diagnosed or suspected with HO, I guess what percent of these may be in kind of high-volume centers or academic medical centers that, I guess, when we were talking in the prior conversation, might be the first to adopt IMCIVREE? And then a question for David. I know you've discussed in the past about getting IMCIVREE's hyperphagia benefit on the label, potentially with the HO approval. I guess how do you think that could change the commercial launch trajectory, but also in the future for indications like Prader-Willi. What does it mean for IMCIVREE's label?

So in terms of the targeting of the test right now, the MSLs were out there, clearly interfacing with the KOLs initially and to begin with. But the priority targets really for the teams moving forward has been this 2,400 physicians. Within this space, we prioritize them because from that claims perspective, they potentially have a larger volume of patients under their care. So we are, of course, prioritizing that initially just in terms of getting through that list as we work through the broader list moving forward.

And think about -- in terms of the label, so you have two questions there. As we've said, and we will continue to try. We've tried to get hyperphagia in the indication statement. We have the data -- clinical data in the label, so we can promote on it. But getting it an indication statement it's important, particularly from a Medicare approval standpoint because we need Medicare to the extent that they are going to help us, needs to understand that we are not an anti-obesity medication, because they are precluded by statute from covering anti-obese medications. So the addition of a hyperphagia to the indication statement would help with that. Doesn't guarantee we would get it, but that would be a step. So that's obviously a goal. As I said, we've tried each time. I think my confidence goes up. I'm hopeful. I've been hopeful each time, but I'm more hopeful this time, but we'll see. There's just fundamental things, not all of these patients have hyperphagia. So it's not like that's our primary indication -- primary endpoint. It's a secondary endpoint. We've hit it every time. The biology supports it. So there's a good rationale for it. And I also think that the regulators FDA specifically is sympathetic to the fact that how that label gets written may limit access. And they're not trying to limit access. They want to make sure that patients who need the drug can get the drug. Your question about Prader-Willi and today is not about Prader-Willi, obviously. That's a very different hyperphagia question. So I think your implied question was, if you got hyperphagia in the label here, would you get it for Prader-Willi? I think that's just a different disease and a different discussion, and that hyperphagia approval happened in a different division. So I'll just leave that as a big unknown, no obvious read-through there.

This is Faisal Khurshid from Leerink Partners. I have two questions, one kind of more near term and longer term for both Dr. Shoemaker and Jennifer, thank you so much. Can you talk to us about securing access and reimbursement for IMCIVREE and like how that's been like currently in the real world? And then for Jennifer, like how does that change with the update or hopeful update to the label in December?

Just one person. But in general, we've had pretty good access to rare disease drugs. I think a statement earlier about that first 3 to 6 months is often difficult, just as payers have to get it added. But in general, for all of the rare diseases that we do in our practice, so rare bone diseases, rare obesity disorders, we usually have pretty good luck. So when people ask me, for instance, Bardet-Biedl syndrome. I have not successfully gotten any of those patients access to GLP-1s, but have gotten them access to setmelanotide. So the specificity is helpful for us arguing why we need to use these drugs. I think we have an easier job arguing for a rare disease with a very specific indication in some of the more broad indications.

As it relates to the expansion of label. To be honest, the BBS indication was probably the most difficult rare disease I've ever worked in, just in terms of securing access simply because of that whole stigma associated with obesity. I think the real focus of our teams just in terms of differentiating the patient population as to the why they had the obesity made a true impact across the board and also articulating that was different in terms of what they were actually going through with the hyperphagia as well as the weight gain. And it's been years, and that's what actually established the current access situation we're in right now, which is very, very positive. And I feel very positive just based off the pie presentations. We're open in terms of the prevalence estimates, the pricing and also with the market research insights, both of those are leading us to feel very confident in terms of an expansion, in terms of access as we move forward with that timing factor in terms of -- it takes time to get another policy in place, but we will work towards that. And in the meantime, as we do get scripts, we will work with the payers in terms of gaining reimbursement even before the policy is in place.

Got it. That's helpful. And then, just one quick one for Dr. Shoemaker. So like you saw at the end of the presentation, David spoke of the next-gen programs like the daily oral and the weekly injectable. As you think about your patient population, what do you expect them to have a major preference, like assuming everything else is equal, like one way or another from a daily oral to a weekly injectable?

The weekly injectable versus daily oral, I don't know what people are going to choose. From a physician standpoint, I want something to be once a day or less, because that's where we get compliance. Once you go to more than once a day, compliance really drops off. And then I don't care if they do oral or once weekly, it's whatever they prefer. So I mean, I think most people prefer an oral or a once weekly to a once-daily injection. And it's then it comes down to oftentimes just whatever we can get access to. It's rare that we can offer our patients all choices.

This is Ellen Horste from TD Cowen here for Phil Nadeau. Rhythm previously reported a 20% to 30% discontinuation rate during the BBS launch. I'm wondering, are you seeing more of what you would call universal clinical benefit in the HO patients? And is there any reason that the discontinuation rate might be higher or lower in this population?

Yes. I mean I can tell you, it's been really interesting working with the BBS patients. They don't have the before and after. So my most eager to receive treatment for obesity and hyperphagia patients or my PWS and my HO patients because they pretty universally are upset by the change. And with some of the genetic obesity patients that had symptoms from a really young age, some of them are less upset by it or less disturbed by it. So there's a higher motivation amongst our HO patients than our -- than my BBS patients in general. Yes, they're just -- they're different.

This is Corinne Johnson again from Goldman Sachs. I have a feeling, David is going to hate this question. So I apologize in advance. But it's important. How should we think about the launch curve next year, particularly given this is double the patient population for BBS triple to quadruple the number of identified patients at the outset. Help us think about kind of that early uptake.

Sure. So let me make a comment and then Jennifer can fill in, she's much closer to this. So we feel good about the numbers. And as you said, I mean, the math, you don't have to -- this is a bigger opportunity than BBS materially. It's concentrated in a call point, the endocrinologist. All of that is hugely enabling in terms of helping patients get access to this drug. That said, I think what you've heard today and part of the reason we and the earlier panel touched on this. To the extent you're comparing Prader-Willi and HO, there's dynamics about the Prader-Willi world, violence as a behavior, for example, incredibly motivated families who are desperate for anything, a long history of trials in Prader-Willi with no positive results. So the demand there and many places with clinics focused on Prader-Willi, whereas the HO world, we may be coming in more in the mainstream of the HO endocrinology's world, which is, yes, I'm fully going to treat my patients and I'll do that when I see them in 3 to 6 months kind of thing. So I think this is the world. So don't hear any lack of conviction around the potential on this. Keep your expectations for the start, moderated by that because we'll have to deal with some of the very basic things you do in a rare disease as you try to get started for there. So, that's it. Jennifer, do you want to add anything?

Yes. Thanks, Corinne. Somebody had to ask the question. So I think that there are so many things about this indication to your point as a starting point. It's a larger prevalent opportunity. I feel very good in terms of the ability to use the existing information to get to the right physician to actually educate I think in comparison to something like BVS, where if you recall, about 40% of the prescribers were endocrinologists, but the others were pediatricians and primary care. So those patients were or dispersed to other physician types, whereas I think because of all of the ongoing management needs of an HO patient, they're more likely to be onboarding in terms of seeing an endocrinologist. So that makes different factors, very different as well as the magnitude of response that we saw in terms of our clinical studies. So very excited in terms of the launch. And as David outlined, though, what I articulated is it's similar to rare disease and that not all these patients are diagnosed, and you would suspect that they would be, but they're not. But we do feel very confident in terms of the discussions we've been having in those aha moments where the physicians are realizing that there is a differential diagnosis needed, especially if we get approval for setmelanotide, they need to get to that differential diagnosis, and it's notable just in terms of the different trajectory of weight gain to get those patients to that diagnosis. So -- but it's going to take time because those patients also need to come in, do the practice, right? The busy practice, it's going to take some time for them to go through that evaluation and then ultimately, upon approval, have that discussion about the product.

Ashley Shoemaker, anything you want to add to that?

I will highlight, I have a much closer therapeutic relationship with my HO patients than I did BBS. So BBS patients were kind of floating out there and a lot of them didn't have a distinct home, it was sort of, oh, if they had kidney problems, they were seeing a nephrologist regularly and maybe they occasionally saw an endocrinologist and the ophthalmologists aren't interested in treating weight. So they were kind of we didn't have as close of a relationship, which I do think also may have influenced the interest in starting a new medication, the HO patients much closer to. We see them very regularly, and they don't really disappear because we're managing so many hormone issues. So that will help. There's a better therapeutic relationship there.

David, you mentioned Medicare, and I was wondering, is that a relevant population here, 65 and older? And I have a couple of follow-up questions.

So we don't have the age distribution of the HO patients. I wish we had a claims to be associated with that diagnosis. Similar to BBS, we are working towards that, but we're not going to have one in place upon launch. But the -- and you can also contribute, of course, like the incidents in terms of the tumors are bimodal. And as discussed, their life expectancy may not be impacted, so they may have a normal distribution from that perspective and potentially skew to be a bit older than the BBS population in terms of what we saw. I will caveat that by also outlining and Dr. Shoemaker, you made a reference to this as well. What we heard is that it is easier to see that difference in weight trajectory in a younger patient population as well as the behaviors versus an older population. So similar to BBS, we may see a skew towards younger patients for that reason, but I imagine will resolve over time just in terms of that distribution.

Yes, they definitely are older patients with this disorder. So craniopharyngiomas have a bimodal with a second peak onset. The first is 5 to 15 years old, and then the second is in kind of the 50, 60s. So we do have patients with a new diagnosis later in life and some of those patients will live for many years afterwards. I don't do a lot of Medicare.

And just a clarifying question. The 2,400 targets -- sorry, was that prescribing physicians? Or were those centers of excellence?

So the 2,400 physicians are associated with the patients that met the criteria that was outlined in the slide in terms of brain tumors, some management, surgical radiation, dysfunction from a hypothalamic perspective with obesity. And the 2,400 HCPs are associated with more higher volume potential physicians that have more patients.

So how many centers of excellence then would you summarize?

So you could have more than one physician at a center.

At a center. Yes. So those physicians can be within the same center.

Right. But I'm asking how many centers.

I don't have that answer right now.

Okay. Maybe it's fair to -- correct me, and both of you can correct me. To the extent you're in a center, as you know, even within endocrinology, people take an interest in X, I do diabetes, I don't do X. I do obesity, I don't know why. And so and somebody like Dr. Shoemaker does this. So is that a fair statement? So it's likely to be more likely to be one who holds these patients as opposed to 6 patients in a...

And -- So, I would say with this, this type of disorder is going to be more spread throughout all the -- particularly academic centers and then any high-volume private hospital is probably going to have people as well as opposed to something like Prader-Willi syndrome, that is more -- even more multidisciplinary and oftentimes a few people sort of do it and then my patients come from states away to come see us. The HO patients usually are going to have somebody local that they're seeing. So there's most -- I would say pretty much every academic centers probably has a pot of patients and then a lot of large other hospitals, community hospitals.

And then last question, just at some steady state, what do you think the mix of insurance will be commercial, Medicaid, Medicare, et cetera?

Yes. I mean, I think where we are -- it's just too early, Kris. I think, we're going up our BBS experience, where we -- the Medicare population in that world was skewed by the disability fact. If your blind became eligible for Medicare, it wasn't an age-related piece. So for this group, we're clearly going to have more eligible because of age based on this bimodal and lifespan. But we just don't have the insight beyond that. So it will be higher than BBS probably, but how much more? Not sure. So with that, I think we hit all the questions. So with that, again, we'll thank everybody in the room and those of you listening in. As I said before, we're excited about where we are and look forward to updating you on our next opportunity. Thanks all.