Welcome to the Jefferies Healthcare Conference. My name is Dennis Ping, biotech analyst here. I have the great pleasure of having Rhythm Pharmaceuticals here. We have the CFO, Hunter Smith. Welcome. Before I get into Q&A, I'm going to turn it over to you, Hunter, to make some opening remarks and just talk about the state of the business. I know that Prader-Willi data is going to be at ENDO next week. Maybe talk a little bit about that as much as we can, then we'll go from there. First of all, let me thank you, Dennis, and the great team at Jefferies for hosting this conference. This is one of the highlights of the conference year. To be here in the heart of Manhattan, we get a lot of great investors, packed schedule, obviously Jefferies delivers on its great relationships and gives us a lot of terrific exposure, we're very appreciative of that. It's a very exciting moment for Rhythm in many respects. We have the newly approved HO launch in the United States, where we unveiled six weeks of launch data at our Q1 call. It was at the end of April, six weeks post-approval, where we said we had greater than 150 new patient start forms written by 110 physicians, of whom 80% were new to IMCIVREE. That included about 40 conversions of clinical trial patients. We expect the balance of those patients, 30-ish patients, to convert in the next couple of months following that initial start. We are also anticipating near-term approval in Japan in the latter part of the year, and the ability to hopefully launch IMCIVREE in Japan, which we are doing ourselves, by the year-end. Thirdly, we are approved for IMCIVREE in HO in Europe, and we are working through the G-BA exemption process in Germany, which we have received previously for POMC, LEPR, and Bardet-Biedl, and we do expect to receive for HO, which hopefully enables a launch in Germany either towards the end of the year or early next. As Dennis alluded, the ENDO conference is coming up next weekend in Chicago. We have quite a bit of new data being presented there. There's a lot of anticipation about the updated data from our phase II study of IMCIVREE in Prader-Willi syndrome, which there will be a poster presentation of that data. Because we are so close to the presentation date, I'm not going to make any comments about that data or anything specific about it, and I'm going to defer questions on it until next weekend. Suffice to say that we expect to show 17 patients' worth of data out six months, and we will be focused just as we were in the earlier interim update on three significant endpoints,% change in BMI, point change in quality of life as measured by HQ-CT, which is primarily focused on hyperphagia, and then lastly,% change in body fat as measured through DEXA scan. With that, I think that covers what we can say today about PWS. Really exciting time for Rhythm on multiple fronts. We have our next generation compounds. Particularly excited about starting the phase III study for bivamelagon in hypothalamic obesity, which we hope to start before the end of the year. Separately from that, we're doing a multiple ascending dose studies in patients with HO and with Prader-Willi syndrome for our weekly injectable RM-718. Lots going on both in the clinical front, the regulatory front, and the commercial front, and lots of potential exciting opportunities for Rhythm to progress as the year continues. Perfect. As much as you may can or cannot say about Prader-Willi, maybe is it possible to remind us what you guys have said historically around the trial and the signals that you guys would be trying to achieve? Our primary objective has been to achieve a change in BMI. We believe that Prader-Willi is an MC4 pathway-mediated disease, at least in part, and that is due to the fact that the truncation tends to remove the MAGEL2 gene, which is tied to the MC4 pathway, and we have seen in both the knockout mice as well as in individuals with MAGEL2 deletion that they are responsive to IMCIVREE. We have enough translational and clinical indications that it should work in Prader-Willi. We do believe that our mechanism, which does impact hyperphagia, is what will, at least in part, potentially drive an improvement in BMI. Perfect. Thanks so much for that. Maybe we can shift over to the HO launch. You guys have disclosed more than 150 start forms in just six weeks, so it's been about a month since then, but maybe comment around some of the early feedback from physicians where IMCIVREE is being used in HO and et cetera. Sure. There's a lot of excitement in the community about IMCIVREE as a treatment for HO, and I think we increased the size of our sales force from 16 to 45. We said we were targeting a total of 5,000 patients whose claims data indicated would have at least one HO patient under their care. About half of those are in our first and second tier of targeted physicians, then within that, there is a group of 42 specialized centers where the majority of HO patients will experience treatment for their pituitary brain tumor that causes the HO in and of itself. We were pleased in the initial 150 that about half of those 42 centers had been the source of at least one of the prescriptions written. That was a positive step there. I think the 110 writers represents very substantial breadth early in launch. I think there are physicians who have represented that they're well acquainted with HO. They have a large number of HO patients in their practice, they are, as we see it, probably likely to start slowly, even though they believe in the therapy and they understand the disease, because they want to understand how the process is going with reimbursement and when the patients are coming in to have their visits, so they can work them through the medicine. That bodes well for future opportunity, especially over the next six months, as we see P&T committees start to put policies in place to reimburse IMCIVREE. Lastly, I think what we're seeing is also playing out that the patients have their initial treatment for the tumor in one of these specialty centers. They may or may not stay there for the more acute period, the hypercare period following the surgery while their hormone levels are stabilized, and then ultimately they transition to either pediatric or adult endocrinology care in a more community setting, which means that they aren't required to come back to the major metro where that center might be located. That's something we anticipated, and our field force sizing and targeting is designed to cover. The 50/50 split between centers of excellence and the community centers was, when you saw that metric, were you surprised by that? Were you thinking that this would be a little bit more centers of excellence or maybe a little bit more community center? I actually think the prevalent patients are more dispersed, but the bulk of the patients will have gone to and had their tumor treated at one of the specialty centers. It's not truly a 50/50 split. What it means is that 50% of the 42 specialty centers had written one script in the first quarter or in the first six weeks, which implies that the split is actually a little more balanced towards beyond that population, given that it's 110. Our focus on those specialty centers is designed to make sure we have a high level of ability to track and potentially provide therapy to incident patients when the situation is most acute and the opportunity for a positive intervention is greatest, and the level of awareness at the institutional level is highest. We think there's the greatest opportunity there, but we recognize that so many patients will have transitioned out of those centers that we have to pursue the prevalent patients who are more dispersed, and we're well-equipped to do that. Got it. Would you say that for the HO launch and for these patient start forms, that you're seeing momentum going from April to May and June? I know it's June 4th, so it's really early, but how much confidence do you have that these prescribers are getting comfortable with writing it so that they can write another, and that as that base builds, that there's momentum going to June, July, August? Do you have confidence in that? 110 writers are what we reported as of the first six weeks, of which 80% were new to IMCIVREE. That's a very solid breadth. We were very pleased with that breadth. That still is less than three writers per rep. That's fewer HCPs than the average rep is going to see in a week. With 5,000 potential targets, at least as we communicated previously, there's a lot of work to do, and there's a lot of opportunity in front of us, and we're comfortable that we're going to be able to reach broadly within that physician base and continue to make progress. Okay. What about reimbursement? Just any kind of early feedback there? We were pleased to see that we were getting some patients already reimbursed in the first six weeks of launch. What our general communication has been is that early in launch, we expect most patients the benefits or the reimbursement process will go through medical necessity because most payers will not have a policy in place for IMCIVREE in HO. Nonetheless, we do think the opportunity exists that process will be a bit quicker than BBS for a couple of reasons. First of all, we've been on the market for about four years now, that means that the payer is not doing another safety review in most cases, because most payers will have had a BBS patient. Certainly, most large payers will have, so they have some experience, and they will have had to make a decision previously, which will have included the safety review. The second component is that the nature of the injury and the nature of the comorbidities associated with HO are somewhat more acute than BBS, which is I don't know if this is an appropriate term, but I would consider it more of a smoldering condition, which is that they have this chronic obesity, this chronic hyperphagia, this worsening kidney disease, and this deterioration of vision. All of which are severe problems, but they're not quite as acute, and therefore, we may see the urgency to diagnose lower and the urgency to treat lower. We've worked on that, obviously, and that may transmit itself to the urgency at the payer level. These patients, frequently children, frequently with brain tumors, and very severe and complicated medical histories following their surgery, which may improve the urgency to treat. Complement that with a very large trial, the largest trial ever done in HO. Very strong results in a double-blinded study, we think it bodes well for positive payer decisions over time. Okay. When you say that the launch should look better than BBS, can you be a little bit more specific there? Do you mean in terms of revenue? Do you mean in terms of absolute start forms? When I look at the initial first six weeks, it does look better, I'm just wondering, do you expect that to continue to hold as you go through the rest of the year? We do. There are several things that favor HO relative to BBS. The first is the higher baseline diagnosis rate. Still, we believe, underdiagnosed, but it's a higher diagnosis rate than BBS. The second is the fact that HO patients tend to be concentrated still in ongoing endocrinology care. BBS patients are frequently pinging around the medical system a bit and treated more frequently in primary care, even if undiagnosed. So, getting that diagnosis pattern and that care pattern over to endocrinology is a much slower process, and that's why we don't see the same degree of overlap with BBS prescribers. That combination bodes favorably for uptake in HO relative to BBS, all other things being equal. You have what we believe will be comparable payer support. We have very good payer support for BBS. We expect it for BBS. That may occur a little more quickly in HO. I think the only things we still are waiting to learn more about, as you know, we're not reimbursed for Medicare today. We expect that age-eligible Medicare may be more significant in HO than it is in BBS. We're still trying to figure out how much that is. Okay, got it. It seems like in the early stages of launch, and it's only been a month or so, the mix is more towards pediatrics, right? It started off more pediatric, that's correct. Yeah, but at some point- And we expected that- Yeah because that's where the knowledge of the injury is more acute. The opportunity, the caregivers are more engaged. The handoff is not necessarily been made yet. These patients can go through multiple care handoffs over a couple of years. We expect it to be more pediatric at the outset, and then to normalize as to more representative on a slightly younger average basis, but a little bit more representative of the total population over time. Yeah. Okay. Would love to ask a little bit more around your phase II oral program, bivamelagon. Sure. Where are we with that? When are you guys going to start phase III? What are some of the gating factors there? We in-licensed this program about two years ago from our good partners at LG. Good to see them in the audience today. We subsequently ran a phase II study in HO, which was very positive. At the highest dose, we saw about 10% weight loss at six months, which was comparable to what we saw in IMCIVREE. Very pleased with the comparable efficacy. The pills themselves were quite large pills, one of the things that we wanted to do out of the gate was do some formulation development to increase the drug load in the individual pills and create a number of pills that we could have smaller pills with comparable dosing, then ultimately get to a 600 milligram pill, which is actually comparable in size to the old 200 milligram pill and is beveled. It's just easier to swallow. We're also working on finalizing, and this is one of the gating items, finalizing a chewable form, as well as a suspension form for the youngest patients. We've done all of that formulation development work. We're pleased to say that the phase II patients are now more than a year out across the board, and we are actually presenting the one-year data at ENDO next week as well, and they're doing very well, and the efficacy remains comparable to setmelanotide at comparable dosing. 28 of 30 patients who entered phase II are still on therapy as of today, so we're very positive about the persistence. We are currently working on our approach to the FDA, which we hope to have relatively soon, and our goal is to start a phase III before the end of the year. Okay. For the 12-month bivamelagon data end, how should we think about the magnitude of weight loss going from 12 to 24 to 48 weeks, just over time? In the highest dose, the poster indicates it's 16.6%, so it's not the full group, but that's comparable to what the active arm in setmelanotide was at the comparable timeframe. We're pleased with that. Okay. The shape of the curve over time, should it get deeper in terms of the. We believe that as long as patients remain above-- This is what we've seen across indications, including HO, that as long as patients remain compliant with therapy, most patients have the potential to achieve normal body weight over time. It may take longer for some, it may take less for others, but what MC4R agonism does is it restores normal physiology for a lot of these patients, and therefore it's not magic. If they overeat or if they don't exercise, they can still have challenges in that regard. We do believe that over time, patients can achieve normal body weight. We see no reason as of now that that would be different for bivamelagon than it is for IMCIVREE. Perfect. Then RM-718, that's your weekly subQ. Yep. You guys will have some phase I-B or phase I open-label Part C- Yeah data. I believe it's mid-2026 is when you guys are guiding the data? Second half. Second half. Yeah. Okay. Second half. What should investors expect out of that data set? We'll have two different components of data. The first is multiple ascending dose study in HO patients. What has been very helpful about the HO indication for Rhythm in general has been the fact that the HO signal is quick and that it's very consistent across patients. We don't think it will take us a lot of patient data to understand if we have something that is working comparably to the other two therapies. That's item one. We've done the PK work to understand the dosing equivalence, so we think we should be able to understand what our target dose is for HO just on that basis. We're trying to do something similar with a group of PWS patients, where we will be going to a higher dose, just like we've done with the daily injectable. Okay. In terms of the magnitude of efficacy when you guys do report the Part C data, should we expect weight loss on an absolute basis to look similar to bivamelagon and also setmelanotide? That we're in the same neighborhood is what we would hope for. Same neighborhood on a dose and duration-adjusted basis is what we would hope for. Is there any kind of scenario where you could eke out a little bit better efficacy, given this is a weekly subQ and the PK is a little bit more stable over a week relative to the daily peak to trough variability with setmelanotide? Is that something that you guys have seen or have considered as an outcome? It's certainly possible. I think we're still learning about the diseases and whether trough is more of a driver of response or less. We're very pleased with the efficacy we've seen to date. I think our goal is we would hope to achieve comparability. If anything comes out above that, then that would be upside. Okay. Taking a step back, you guys have essentially three products right now. Right? A daily injectable, an oral, and then a weekly subQ. How are you going to approach figuring out which product to move into which indications? Sure. It's a good position to be in, and I think we do expect the MC4 agonism to have different effects in the different diseases. Part of what we want to understand is if HO is the most responsive, and we see more limited differences there, do we see greater differences in a BBS or a PWS based on the different pharmacology? I think that's question one. I think question two is making sure we understand what the patient preference may be. Our working hypothesis has been that a weekly injectable in Prader-Willi syndrome might be a better thing to go with than an oral. I'm confident that we can think about both options there. Is that easier given the behavioral complexity of those patients? Is that easier to engender consistent administration and compliance, aside from the question of relative efficacy? BBS may be a little in between. Okay. When you're thinking about, I guess, for BBS, the approved product is the daily injectable. If there is a better product out there that's more convenient and lower hyperpigmentation. I know you guys have never given peak sales for BBS, right? Do you think that having a better product profile would materially move that market higher over time? Do you think that's not even a major consideration for these patients? The most significant driver of discontinuation is hyperpigmentation. We track the reasons for discontinuation for every patient to the best of our ability. That is always number one. What we don't know is how many people avoid therapy for the fact that there is hyperpigmentation and how many people avoid therapy for the fact that there's an injection. We don't know what we don't know in terms of that uptake, but we know it's not positive. An oral form does have the potential to improve upon those factors. All other things being equal, we certainly believe that an MC1-sparing oral therapy, with good tolerability will engender better persistence than a daily injectable. What's been the discontinuation rate in the real world for BBS? In the real world, it's been about 30% globally at a year, with that rate being higher in the U.S. and then lower in some of the specific European countries where the diagnostic criteria are very tight and the care environment, particularly in Germany and France, is very supportive. Okay. What about at two years or three years? Do you have that data? We do. We haven't talked about it a ton, but it's the one-year time point that tends to be when we've seen the most drop-offs. The persistence is a little better out longer. Do you know what proportion of that is due to hyperpigmentation? If they get beyond one year, the hyperpigmentation tends not to be a reason for discontinuation. Yeah, I'm just wondering because if you have these products, that do not have any hyperpigmentation, very low rates of hyperpigmentation, then the base of your BBS patients, like you said, persistence is longer, is better. Yep. Instead of thinking about BBS as a $500 million type peak sales product, it could be $750 or $1 billion as that base is able to grow over time. Right? That's how I'm thinking about it. I see. Okay. Especially if you have better IP with your second-generation products, that is meaningful, right? Absolutely. Yeah. Maybe going back to HO. Back in 2025, you guys have talked about a 2,000 diagnosed or suspected number in the U.S. Right? Since then, you've said that that number continues to grow. You guys are not committing to providing an updated number. As you think about that, there's still a big gap between that and what you guys have talked about in terms of prevalence around 3,000. Right. What needs to be done to narrow or bridge that gap? And could you guys run some, I don't know, phase IV studies or things to build diagnosis, build awareness? Just to clarify around that number, that 2,000 patient number that we gave in September of last year was based upon actual face-to-face interactions between a Rhythm representative or MSL and an HCP representing that they had diagnosed or suspected patients in their practice, and that we had validated those patients. through claims data. That's a hard number, whereas EPI numbers tend to be calculated or derived, right? We feel that number engenders very high confidence. What builds that number, first and foremost, is reach, and our reach has continued with the 45 reps in the field, the MSLs out there, the other communications we're doing, the work of the Raymond A. Wood Foundation and others. That engenders greater reach, greater penetration of the identified patient population within the diagnosed pool in the U.S. Then the last factor is the general disease education and awareness of IMCIVREE promotion that we do, where there's a lot of activity at something like ENDO, which is very well attended by the endocrinology community. The availability of a therapy tends to build awareness and have people look for the diagnoses, with future willingness to prescribe in a way they might not have done or thought about before that opportunity existed. Okay. Last question. When you guys gave that 2,000 number, you also kind of commented that Because before you guys have said, "Oh, HO in the U.S. is between 5,000-10,000," but then at the same event, you guys specifically said it's towards the higher end, around 10,000. Is it fair to say that you have good confidence that even though you guys have identified 2,000 last year, that you have good visibility to getting to that 10,000? Yes. That's fair to say. You think 10,000 could actually be a conservative number given your comments around HO being underdiagnosed? We're very confident in 10,000 as a number, and I'll just leave it there. Okay. All right. Well, perfect. Thank you so much for the time, Hunter