Thanks, everybody. Really pleased this afternoon here at Guggenheim's sixth annual biotech conference to have Rhythm Pharmaceuticals here with us. Unfortunately, David Meeker was not able to join us. There definitely is something going around. But I'm really pleased to have Hunter Smith, Chief Financial Officer, here to my left. And I know we've got a lot to go through. So maybe, Hunter, if you can maybe just provide a brief overview of Rhythm, and you know, we'll dive right into questions. Sure. Thanks so much, Seamus, and thanks to you and the team at Guggenheim for including us in today's conference. It's a great experience. Rhythm Pharmaceuticals is a company focused on developing and commercializing treatments for rare neuroendocrine disorders, and we have been focused since our founding on the development and now approval of the first melanocortin-4 receptor agonist, setmelanotide, or known under the brand name, IMCIVREE. The melanocortin-4 pathway or agonizing that pathway has been a well-validated pharma target for, you know, 20–25 years. It's understood to have very profound roles in regulation of satiety and resting energy expenditure. There have been numerous attempts, large programs at many large pharma companies to drug the MC4R pathway, all of which had failed. We, for a variety of reasons and with a variety of ebbs and starts, fits and starts, were able to successfully drug the pathway in a safe way. And IMCIVREE's been approved for a couple of years now, and we're now in the sixth quarter of launch in Bardet-Biedl syndrome. One of the big developments the company had was the proof of concept that our melanocortin-4 receptor agonist could treat hypothalamic obesity, where we've shown now 12-month open-label data in a cohort of patients with HO. This is a very difficult condition arising from pediatric brain tumors and the surgery that results from those tumors. And we had, starting in the fourth quarter of last year and going into January, I would say a very, very eventful period for us. We showed 12-month data in pediatric patients, 2- to 5-year-old, which we believe supports registration for that, and we will be filing that soon. We unveiled that we have an internally discovered weekly formulation of a new melanocortin-4 receptor agonist, that's RM-718, which is MC1-sparing and therefore avoids hyperpigmentation. And that'll be entering the clinic this quarter. As I said, we had 12-month data in HO, which showed, you know, 25.5% mean weight loss, 3 of 11 pediatric patients achieving normal body weight, the majority of pediatric patients moving 1 or more obesity classes down. So very profound and powerful responses. And we also showed some phase II data in a group of new genetic obesities where we were pretty, pretty pleasantly surprised by the quality of the responsiveness. And then finally, in January, we announced an agreement with LG Chem Life Sciences, a global company based in Korea, to in-license LB54640, their oral small molecule MC4R agonist, which we're very excited to pick up responsibility for the phase II study in HO that they had begun to initiate prior to the transaction. So very eventful quarter, very exciting quarter, continued commercial progress, broadening of the pipeline and broadening of the potential patient population. Great. In terms of just the absolute size of the market opportunity, maybe you can scale Bardet-Biedl for us, and you know, and that opportunity, then the hypothalamic obesity patient population, just in terms of the patient size- Mm-hmm. and the numbers, and then obviously, the urgency to treat of those two, you know, how should we sort of think about the demand and the unmet need in each of those? Sure. So in Bardet-Biedl syndrome, this is a clinical syndrome, that's a ciliopathy, and it has a variety of features, in addition to the powerful hyperphagia and obesity that is early-onset in nature. We estimate that's a 4-5 thousand patient opportunity in the United States. And we've based that through a variety of ways of view that you triangulate on rare disease epidemiology, but one of the most significant is the diagnosed patient populations in France and Germany and how those patient populations map to, you know, cross-map to what a US prevalence should be based on that. So you know, we, it's 4,000–5,000 in the US. We think in the EU4 plus UK, it's a similar size, but with a much higher level, much higher diagnosis rate initially. Okay. And so there's the opportunity, both those countries. By the way, we are approved in the E.U. for IMCIVREE, we are approved in the U.K., and we are working our way through the reimbursement processes and commercializing it ourselves, as we intend to continue to do globally or with distributors in select markets. Then when we progress to HO, we believe that's a 5,000-10,000 patient opportunity in the U.S., comparable size in Europe, significant patient populations outside of Europe that may be accessible in the long term, and that also has an incidence component of about, say, 500 per year in the U.S. And that is the difference between... There are many differences between the two. I think the way one estimates the prevalence of HO is the incidence of craniopharyngioma and then a couple of the less frequent tumor types, astrocytoma and hemangioblastoma, the incidence of HO from after the surgery for removal of the tumor, which for craniopharyngioma runs around 50%.... and then estimates of the overall, the 10-year overall survival from those tumors. So, so that, that's how you get to the 5,000-10,000 plus the incidence, comparable levels, maybe slightly less in Europe. Got it. And a source of potential confusion might be how enthusiastic everybody is about the treatment of obesity in the context of the GLP-1 category. Sure. I think it's important that we compare and contrast maybe the two, you know, your approach and do GLP-1s even work- Sure. in these conditions? So obviously, the two marketed GLPs are incredibly important drugs. They are going to be societally impactful, and they're terrific. You know, we've come to believe, and we think others are coming to believe, that obesity is not just one disease, it's many diseases, and that diseases of the MC4R pathway are distinct because there is essentially a hormonal deficit. Patients do not produce or cannot, you know, effectively utilize alpha-melanocyte-stimulating hormone. Our drug is an analog for alpha-melanocyte-stimulating hormone, so we are replacing a deficit. I think that's an important thing to level set up on. Yeah. So, you know, obviously, the GLPs have—earlier generation GLPs have been tried in hypothalamic obesity. There was a blinded patient study in exenatide that showed no effect, a double-blind, randomized study in exenatide that showed no effect a number of years ago. But, you know, you know, physicians will continue to try to use these, drugs for this patient population. Dr. Abuzzahab at Minneapolis Children's, who's one of our investigators, said that she believes, you know, 10%-20% of HO patients may have some form of response, and that response is going to be on the order of 10% or so. When we think about urgency to treat, I think the example of our phase III enrollment is instructive. So we announced in December that we had closed screening at 140 patients, you know, so above our 120 target. We closed a quarter early, and as you know, one of our board members, Stuart Arbuckle, likes to say, "Clinical trial enrollment in rare disease is a great proxy for both the urgency to treat and the commercial opportunity." So, you know, these, the centers involved in our study are the, you know, among the most significant endocrinology centers in the country, and among the strongest teaching hospitals and university system or hospital systems in the country, and they know all about the GLPs. And so they're making a decision to say, "I would rather risk putting a child on placebo for 60 weeks with the potential outcome that at the end of 60 weeks, they get setmelanotide- Yeah. than trial them on Wegovy in the meantime. Got it. That's, that's a pretty powerful message. Yeah. Thank you. When we think about the genetic variants, so you mentioned the genetic variant opportunity. Can you talk a little bit more about those that are, you know, uniquely tied to the MC4R pathway? I know you've cited 53,000 potential patients. Are there genetic variations or mutations that actually scale to look more like hypothalamic obesity, so that there's a different severity? Or, you know, is that how do you, you know, sort of identify these patients and, you know, do the genetic variants behave similarly? It's a great question. We started with treatment of patients who had homozygous defects in the POMC gene, and they almost uniformly have very profound responses. So in some ways, you know, people have said that the HO is physiologically recreating POMC deficiency. Okay. That's the effect there. But POMC, most POMC patients have been described in the medical literature. They are extraordinarily rare, and you know, when we received that approval, we didn't put a sales force in the field. We just made the drug available commercially. Yeah. What we've been studying since then are patients with pathogenic or likely pathogenic or suspected pathogenic variants in the POMC, you know, single, single allele variants in the POMC gene, the LEPR gene, and then two transcriptional coactivators, SRC1, also known as NCOA1, and SH2B1. That's what we're studying in our phase 3 MNAT study, where each of those genes is being studied in a single cohort. We hope to complete enrollment in several of those cohorts this year. What we revealed in early December at our R&D day was open label data from our Daybreak study, and that's, you know, we revealed data in six different genotypes with varying degrees of responses at 16 weeks on therapy. But several of the genotypes, you know, PHIP being the most prominent, where we showed greater than 50% of the patients were seeing greater than 5% weight loss at sixteen weeks. So, there's a lot of promise there. I think the challenge that all of these face is understanding the variants and how much of an impact the variant is having on protein function. And I think we've been making some good progress there, and if we can truly separate out the more pathogenic variants from the variants that have less of an effect, we will be able to enrich for response over time. ... Got it. And in terms of the cited number of patients, is the 53,000 the narrowed patient population, or is it, you know, sort of the identified? So that's the MNAT population. That's based on the prevalence that we're encountering through our own sponsored genetic test program, URO. And then it gets larger than that, but there are, you know, there are estimates of, you know, there are—as you move from sort of POMC and LEPR, where the variants have been very well characterized, to some of these newer genotypes, the assays aren't as well developed, and so we're working, you know, with our lab partner and with other researchers to try and figure out more ways to develop strong assays to understand the function of the genes and characterize them more effectively. Got it. Okay, great. And when we look at programs like Daybreak, can you help us understand, are there differences between the MNAT population, you know, and sort of the Daybreak population? You mean clinical differences? Yes. I would say that it is. In MNAT, there are three groups: POMC, LEPR, and SH2, or and SRC1, which are really just genetic, genetically determined. There's no clinical presentation that distinguishes them. Okay. They have obesity, they have hyperphagia, it's early onset in nature, but there are no other clinical features that are very distinguishing. There's a group within SH2B1 called 16p11.2 truncation. It's more of a genetic truncation as other clinical features. And the same is true with one or two of the Daybreak genes, that there are some more syndromic aspects that facilitate patient identification. Okay. Great. You just acquired an oral MC4. Can you talk a little bit about what you would hope to accomplish with an oral MC4, and what that, you know, sort of brings to Rhythm, you know, as a company relative to just setmelanotide itself? Sure. So, there are two major factors. You know, the burden of a daily injectable exists. We have found it, you know, a decent amount, pretty good patient persistence despite a daily injection burden, but it nonetheless persists. And I would add to that, that one of the most significant AEs leading to discontinuation, either in the clinical setting or the commercial setting, is hyperpigmentation, tanning, however you wish to characterize it. Some patients don't mind that at all. Some patients really dislike it. Patients invariably look different when they're taking the medication. Mm-hmm. So the fact that the LG compound is MC1 -sparing and appeared not to cause hyperpigmentation in the phase one study, you know, is very compelling in addition to relieving the injection burden. We saw comparable efficacy in phase one in people with general obesity that we saw with setmelanotide. They saw that comparable efficacy that we saw with setmelanotide, so positive there. So we think it has some very exciting commercial and therapeutic potential, and we believe, and this was their belief too, that we're in the best position to bring this to patients most quickly. Yeah. We plan to bring it forward in HO phase 2, and that's really the test. The HO patients have shown to be so responsive, so uniform, not uniformly, but very consistently across that population, with the result that, you know, we'll know within HO phase 2 how, you know, how well the drug is working. Okay. You know, maybe we can talk a little bit about, you know, the persistence of patients on setmelanotide and then the importance of improving upon that formulation. Sure. So, our persistence has been quite good so far. Now, I think anybody would expect that clinical trial patients and first patients on commercial therapy, especially for a rare disease, they're motivated patients and they're motivated caregivers. And so the initial patients tend to be the most persistent, and as the number of prescribers, you know, increases, the number of patients increases, there's some heterogeneity there, and the persistence will sort of normalize over time. And so, you know, we see most dropouts occur within the first two months, nausea, vomiting being a factor, hyperpigmentation being a factor, injection burden being a factor, and then obviously, some people just are lost to follow-up. That happens with any drug, right? Yeah. So we expect our discontinuation rate to increase and to sort of normalize with, you know, consistent with many rare disease drugs. What tends to bring patients back or what tends to maintain the persistence is the hyperphagia. Mm-hmm. If patients are off drug for, on... They go on drug, and after they've been on drug for a while, we hear stories about them feeling like they forget how hungry they were before they were on the drug. Right. They go off the drug, the signal comes back very quickly. So that tends to be reinforcing of persistence, and we do have patients who have dropped and have, you know, come back on therapy. But we do expect discontinuation rates to increase and be in the range of, you know, normal rare disease discontinuation. Okay, maybe in terms of 7-1-8, maybe you can talk a little bit about 7-1-8 and, you know, sort of the next steps there. Sure. Very excited about RM-718. As mentioned, we discovered it ourselves. It is very selective for MC4R, even more so than the LG compound. It's a weekly formulation. You know, we don't own a royalty on it since we discovered it ourselves. And so the economics are very attractive. And it also has composition of matter out to 2041 as opposed to 2032 with setmelanotide. So very exciting on a number of fronts, and we, this quarter, are initiating first in human studies with RM-718. We're gonna do a typical SAD/MAD, and then we'll do a multiple ascending dose study in HO patients. Mm-hmm. That will be the third component of phase 1- Got it. where we'll be looking to see, you know, what's the right dose for the HO patients with this therapy. Got it. How confident are you? So we've seen a number of... I think I'm not going to call it follow-on compounds, but, compounds that have longer duration, where the phase 1 data and the PK/PD data that come out of that are actually very predictive of the ultimate capabilities of that drug- Mm-hmm. to replace a prior drug. Mm-hmm. How do you think about this, you know, sort of phase one data set? You know, when might we see the 718 data? So, I think we feel like we've had the right amount of experience, both in preclinical terms and in early clinical terms, to really develop a feeling for how well the drug is performing in the phase 1 setting. I think we're most excited, as I said, about the MAD/HO cohort. But, you know, we feel reasonably confident that this drug's gonna work, and it's gonna work well, and ultimately, it's certainly a superior product to setmelanotide, and we'll see how it compares in time to LB54640. Is the hope with RM-718, because of the incremental selectivity, that you'll eliminate, or are you confident that it has the opportunity to eliminate the The daily? MC1? Yeah. Or not just the daily, but also MC1. MC1, yes, yes. We're... You know, the selectivity is very high. Yeah. Okay. So it should be. It sounds like it has the opportunity to behave like the oral, but be a weekly- That's correct. -therapy. That's correct. So it sounds like you have both sides of the claimed GLP-1 market, here, that you can- From a delivery point of view, that's correct. Right. Yeah. So in terms of the scaling the market opportunity, as you go from, you know, let's call it, you know, 20,000 potential patients in the United States, and then, you know, also you're already scaling overseas. As you move into the MNAT patient population, how should we think about the commercial infrastructure that's necessary to support that? Yeah, it's a very good question. So what's exciting for us is that all of the things we're working on today are leveraging the infrastructure that we've built today. So we have the genetic testing infrastructure in place to enroll the MNAT studies, the Daybreak studies, and that infrastructure will continue to exist and continue to help drive diagnosis. We have the patient education managers who, a subset of whom drive reimbursement, a subset of whom really help with administration of therapy, management of AEs, continuity, things like that. Typical rare disease type of company capability that is really crucial for success. You have your traditional territory managers, and you know, obviously, if you get to a point where breadth and depth require recutting of the territories, you do that. That's the kind of thing that we'll contemplate as we get close to HO and ultimately, if we're successful beyond that. I think, you know, all of these indications. The difference between HO and all of these other indications is that HO is very highly diagnosed today. Mm-hmm. Patients have tended to be normal young kids who, you know, then have an onset of a pituitary brain tumor. Their lives are completely disrupted by the brain tumor and the disease that they have after the surgery affects their hypothalamus. And so, you know, they're in high contact with the medical system because of their need for hormone replacement therapy. Most of our KOLs who we were talking to about BBS would say they would have a significant multiple of their BBS patients in HO patients. So there's a difference there in terms of there's not the same need to drive diagnosis as there is in the genetic indications. Right. Okay, got it. And then just, you know, financing, and sort of the cash needs of the company. Sure. Can you just remind us, you know, what kind of runway you have at this point? And also, if there is, you know, if you talk about the sort of path to profitability. Sure. So, at September 30th, we reported $299 million in cash, and we said at that time that that got us into 2026. Just as a reminder, the HO phase 3 readout, we expect to be in the first half of 2025. For the LG compound, there was about $80 million in cash consideration, plus some incremental clinical spending, and we said that that moved the cash-out timeline from into 2026 to the second half of 2025. So, you know, that's, that's the impact there. Pretty straightforward calculation. What we've also said is that, our R&D activities in 2024 are fairly consistent with the level they were at in 2023. We're running two large phase 3 studies. They'll kind of be at full strength in 2024, and to some extent, starting to wind down in 2025. So R&D, you know, may be in, at or near a near-term peak. The U.S. organization, until we are ready to prep for the HO launch, is, you know, the size it needs to be for the time being, and our growth in OpEx will be in the international, or, you know- Right. And, you know, as we are successful in individual countries. So, for example, prior to the achievement of reimbursement in Spain, we had two employees. We had a general manager, and we had an MSL, and we wouldn't hire anybody else, but now we'll start to staff up to prepare for the launch there. And that's true in other countries. We launched in Germany with eight people. So it's very, you know, it's sort of risk-aligned and efficient way to increase spending. So the reason I give that backdrop is, historically, we've had kind of step-ups in OpEx year-over-year, and now we're starting to go to a more normalized growth rate in OpEx. Got it. And we did give guidance for 2023 OpEx of $220 million in cash OpEx, and we expect to give guidance additionally for 2024, as you know, along the lines of what I've just described. So to get back to your question, I think the path to profitability depends on people's sales forecasts. And, you know, but certainly, the amount that we're solving for in terms of total financing is becoming easier and easier to estimate. Right. Great. Well, unfortunately, we actually do have to wrap up. I think we could have gone for another 10 or 15 minutes, but, Hunter, thank you so much. Really a kind of brilliant and quick rundown of Rhythm. Okay. I'm sure you have plenty more to say, but, thanks so much for joining us. Thanks to everyone for attending.