Good morning, welcome once again to TD Cowen's 46th Annual Healthcare Conference. I'm Phil Nadeau, one of the biotech analysts here at Cowen, and it's my pleasure to moderate a fireside chat with Rhythm. We have with us today David Meeker, CEO. David, maybe I'll kick it to you to start. Can you give us a brief state of the company review, biggest strengths, biggest challenges, and what does Rhythm need to do to create shareholder value? Sure. Thanks, Phil, and I'm great to be here. Thanks for hosting. Rhythm, the way we talk about Rhythm right now is we're built around this melanocortin-4 pathway. Our currently approved molecule, setmelanotide, brand name IMCIVREE, is essentially an analog of a hormone, alpha-melanocyte-stimulating hormone, which is deficient in patients who have impaired signaling through this melanocortin-4 pathway. We think of our three pillars. One is which genetic causes of impaired signaling, and there's a bunch of genes. We have an M&A trial coming up here shortly. That's really the beginning of work. We did a phase II DAYBREAK study where we looked at as many as 30 genes to try to get a sense of, other genes that might be, impacting the pathway. We think there's multiple genes there, and that'll be part of our work going forward. The second pillar is around anatomic, hypothalamic dysfunction, most specifically acquired hypothalamic obesity. PDUFA date's upcoming here on March 20th, for that indication. That's a significantly larger, indication than Bardet-Biedl syndrome, our previous, only approved genetic indication. About 10,000 patients in the U.S., similar in Europe, larger prevalent population in Japan, actually. When we think about anatomic disruption to the hypothalamus, it includes direct injury, often surgery, for patients who have tumors in that area, but it could be inflammatory, viral infections, for example, chronic inflammatory conditions or trauma, head trauma. Those tend to be much less well-recognized, but I think they're out there, that's another opportunity to grow. Also in that category are congenital deficiencies where the hypothalamus just doesn't develop, and as a result, they also have absent signaling through this pathway. That's our middle pillar. Our third pillar is Prader-Willi. Obviously a very well-defined disease, huge unmet medical need. First drug was recently approved, there's been a lot of optimism there that now there's, you know, a route to getting some drugs approved. We're very focused on our developmental strategy for Prader-Willi. We've, from the beginning, two things have sort of anchored our thinking around being all in on melanocortin four pathway. I think if you're a rare disease company, you should be thinking globally. I think it's really hard to create maximal value if you're not thinking, if you're US-centric. I mean, these are small global communities, and being present globally is actually quite an advantage, and we have been from day one. The second is, like I said, we're all in, we have our next generation therapies. Our current is a daily subq injectable, and we have two next gens. One is a daily oral, and we just reported out phase II data in HO out through nine months. The nine-month data on our last earnings call last week, that looks really good. We have weekly injectable, and that data we'll be reporting out around mid-year. Lifecycle management coupled with a global approach, three pillars. We also, we haven't talked so much about our basic science efforts, but we don't have wet labs, but we do have a pretty strong and growing small basic science effort. You work through CROs and the like to do the experiments you wanna do. We're very interested in how you can complement or build out around this pathway. Great. Maybe turning to the launch in HO, there was some updated data presented over the weekend or released over the weekend. Can you summarize the data that you released over the weekend and the potential impact on the PDUFA? Yeah. I think to answer that question, just to go back in time. If you remember, we had our PDUFA date, originally for December. In November, we updated all of you that we'd gotten an extension, pushed our PDUFA date out to March twentieth. They had asked us a pretty routine question, we felt, or a little bit unusual question, which we answered quickly. Net net, they judged that a major amendment and pushed us out. We can hypothesize why that might have been. In that discussion or subsequent discussion, said, "Well, if we're gonna push it out, we'd really like to have all data, we'd filed on the 120 patients that they had requested or required as part of our original agreement." We had over-enrolled that trial, both with patients in the Western Hemisphere and also 12 patients which we added late in the trial as a strategy for getting into Japan, very positive interactions with Japan regulatory agencies. There were a total of 142 patients. They only had 120. They wanted the full 142 package. We worked with them in terms of when the last patient would be out and how we would get them that data. We'd given them the safety data on a regular basis going forward, so there's no surprises there. Then the last piece, which went in today, was the updated efficacy data for the full 142. We know or we had a sense that there was a little bit of angst in the community out there that, gee, if the FDA is getting a new set of data this close to PDUFA, doesn't that put the PDUFA at risk? The goal of that was to say, one, here is the data. It's exactly the same. There's nothing, virtually the same. There's nothing in terms of news in that dataset, one. Two, this was all previously agreed to, and we got them that data ahead of when we had mutually agreed upon would be our target date to get them that data. The last thing, which we highlighted was in terms of labeling, they've been right on schedule in terms of their communications with us, and the most recent one was we got their first round of the label on the day we expected to get it. We've already sent it back in. We know they've looked at sort of our you know, initial response to their label, and we'll go back and forth, I expect, a few times here before getting to a final label. We are, quote-unquote, "On track for March 20th. What about post-market commitments? Have those been communicated? Yeah. There's two points in time that the FDA, by their regulations, in the review clock, they have to engage with you. One is, I think it's 60 days before they engage around do whatever post-market commitments you might need. There are none. They gave us that information. Secondly, the label, which came on its day. So. How does Rhythm get ready for a launch such as the one you're about to face in HO? What are the priorities for the company? Yeah, it's really interesting. You know, we think of ourselves as a rare disease company. We're treating, pursuing very rare diseases, and our mechanism is hormonal replacement. We're not a general obesity company, one. As a rare disease company, generally rare diseases, ultra-rare specifically, they don't tend to concentrate in a specialty. Bardet-Biedl syndrome, they may see many specialties before, 'cause they have a multi-system disease, before they get to a diagnosis. Once the diagnosis is given, they almost often go back to their primary care provider. They tend to be very dispersed. We put, if you remember, 16 salespeople in the field for Bardet-Biedl, not with the idea we're gonna knock on every primary care door or every nephrologist door, but to work creating awareness with the goal being that as you put these pieces in place, work with a patient organization like you create a greater level of awareness so that the patient with BBS has a greater probability of getting to a diagnosis, and then they will find us as much as we find them. That's the nature of an ultra-rare disease world, needle in a haystack kind of problem. Here's HO, a prevalence of 10,000, Bardet-Biedl's 5,000 in the U.S., so 2x, but still ultra-rare by, I think, by any definition. They're concentrated in endocrinologists, and the reason they're concentrated in endocrinologists is 80% plus of these patients have one or more hormonal deficiencies. They have pituitary insufficiency at some level, which requires almost for sure that they be seen by an endocrinologist and that an endocrinologist continues to follow them at some frequency over time. Now, depending on how brittle they are, it may be, you know, quite regular, otherwise might be a check-in once a year kind of thing, but they're gonna have an endocrinologist as part of their care. As a company, what does that mean? To Phil's question, how do we think differently is Bardet-Biedl, we're not looking to knock on every door. A specialty opportunity in endocrinology, particularly one where claims data allows us to segment the endocrinologists into those who have most likely to have patients or have the most potential patients, means we wanna call on every one of those doors, knock on every one of those doors. That's the difference. It's a different mindset. It's a different resourcing equation. We had 16, as I said, salespeople for BBS. We'll have 42 people in the field here as we launch HO. Where is Rhythm in patient identification? How has your field force used the last three months to further find patients? Yeah. We had a investor day end of September, at which point we said we had greater than 2,000 patients identified, and they fell into two groups, suspected and diagnosed. There's no ICD-10 code. Those are patients who the field force at that point in time had engaged with an endocrinologist, and either they had said, "Yes, I have X number of identified HO patients," or, and/or, I hear the description of the patient. It's pretty classic, right? Do you have any patients who've had a tumor resected, being treated for pituitary insufficiency, struggling with obesity? Specifically accelerated weight gain. It's not a complicated triad there in terms of for them to think through who might have it. This other group is the suspected, and that's the group that they're gonna go back and interrogate further. That 2,000 was the mix of those two. The majority of patients were in the suspected category, as you might expect. As awareness grows, some obviously the other will grow. Since September, yeah, that number has continued to grow. We're not updating it, but, I'd say we're, you know, all of our experience to date has reinforced the potential we see in this opportunity. It's reinforced our belief in the epidemiologies that we have out there at this point. What is Rhythm's expectation for their trajectory in their early launch? How quickly will patients go on therapy? You know, basically, how will this launch compare to what we recently saw from BBS from you or, from in Prader-Willi from another company? Yeah. Let's use those two examples 'cause I think they bracket it quite well. There's elements of Bardet-Biedl syndrome in this launch. Meaning in Bardet-Biedl world, it took on average about three months from the time a patient got a script written to when they were on drug, meaning they had to go through a prior auth, often a medical exception at the level of the payer. As we've worked our way through payers, gotten policies in place, that timeframe has shortened for the Bardet-Biedl world. We'll start over now with HO in the payer world. We'll start over with the advantage of they know the drug. They may have had a policy in place for Bardet-Biedl. They just don't have a part of policy in place for HO. Our guidance, if you will, would be think three months sort of as an average time. I think that's where we will start, but I expect it to pretty rapidly, hopefully improve over time because we have a little bit of an advantage, being known with the Bardet-Biedl world. other factor is two other factors, how quickly patients... One is awareness. Awareness acquired HO is very well understood by the experts. It is not widely known. There's no endocrinologist that doesn't know what hypothyroidism is. There are many endocrinologists who don't know what acquired hypothalamic obesity is. The advantage we have here in terms of educating people is that we will have our phase III data out in publication, hopefully in the not-too-distant future, ideally not too far from when we get our drug approved on our PDUFA in a well-respected journal. Not that much happens in endocrinology in the sense that it's highly likely every endocrinologist will read that paper. It will be a great accelerator in terms of what you see. To build on that point, when these patients have these tumors, which are a common precipitant for developing this condition, when they're being educated pre-surgery about what might happen, they get told about all of the endocrine, the pituitary insufficiency, that you may be hypothyroid, you may have an adrenal insufficiency and need corticosteroids. You may have diabetes insipidus and need vasopressin. I mean, they're educated on that. Why are they educated on that? A, they happen in a high% of patients. B, they can be treated. That pre-op visit is, "Look, these things may happen, but don't worry, you can do something." As a rule, they have not been told about this as a complication because you can imagine, "Oh, and by the way, about half of you may have uncontrolled hunger, accelerated weight gain, and nothing you can do about it." Whereas now with a drug, our expectation is you can add that to, there's another hormonal deficiency, here's what's gonna happen, and it can be managed. That will help us. It will not be in place when we start. The last thing, which is back to the major difference with Prader-Willi. Prader-Willi, 100% of the patients are essentially diagnosed early infancy. 2, often treated in clinics, so they have reasonably good access to the healthcare system, the ability to get a script. 3, they're living in family situations, certainly the ones who are at home, where I mean, there's a level of desperation in that community for something that would help. When the drug comes out, you know, great push to get their child on, you've got an initial bolus. Our world is gonna be more that, yes, they may have it. The endocrinologist, "Yes, I'm gonna write the script, and I'll do that as soon as I see them at their next visit six months from now." Depending on how easy they can get access to the endocrinologist when their next visit is, that will also dictate the rate at which these initial things come on. We've been pretty, you know. Don't judge us over the first three quarters. What we're gonna give you, we'll give you the start forms. We'll give you a sense of the payer landscape. Obviously, we're incredibly optimistic about how this is gonna play, but we're very realistic about sort of out of the gate. Faster than BBS, be modulated by these other factors. Give us, you know, nine to 12 months, and this thing will work, and you'll have a very strong sense of what we think is a significant opportunity. What are the key risks to the launch? If we're here a year from now and people are disappointed, why would that be? You know, one thing I love about healthcare, I'm a physician by training, things that work get used. You know, we're not in a me-too marketing battle. We're not in, you know, I mean, our, you know, things that would devastate a launch, whereas where we just tripped up on our ability to get drug to patients. I don't think that's gonna happen. We have a well-established supply chain. This is an approved drug. It's a supplemental NDA. It's already out there. We've got an established safety, you know, profile. It's not like you've got a brand-new drug where suddenly out of the gates you could have, you know, some bad thing happen in the real world, and we think all of those things are very unlikely. You know, a self-inflicted wound, but I think it's really low probability, and we're gonna try to avoid that. Always good. You mentioned the Japanese patients in the data over the weekend. What is Rhythm's strategy in Japan, and can you give us some sense of the size of that market? I'll start with that. I mean, the market, a little bit of a surprise to us, and, you know, this was on us. I think we were a little late in doing this assessment. We'd done an initial assessment on the genetic side. That wasn't so interesting. Bardet-Biedl, for example, in the Japanese population. When we went back a little bit late on HO, it turns out that the prevalence in Japan on a population basis is higher than the U.S. There's 5,000 to 8,000 patients and about half the size of the population in the U.S. The patients are there. That's based on claims data, some literature. Very similarly organized to the U.S., some centers of excellence kind of thing, well-established, KOL network that we're working closely with, and then some level of dispersion, which we'll have to address. We did as many companies do. We evaluated the options. Do you partner? Japan, you know, it is tougher, and you have a level of commitment there. What we and I and just in my experience previously, and the person who's running international, who I've worked with for 20 years, opening up a country is all about is always the people, and if you can get the right person in place, you can do that. We've tapped into our network, and I think we have, you know, really, you know, highly qualified people there building up that organization. We're well on our way. By midyear, we'll have 40-ish people on the ground in Japan, which should be, you know, on the order of a year-ish plus or minus ahead of launch. We're all in. We're going direct, and I think we're in a good position to do that well. Turning to a second pillar that you mentioned, Prader-Willi, for those less familiar, could you briefly summarize the data that were released in December? Yeah. We, the Prader-Willi strategy, you know, we decided to do an open label trial. I'm not a big believer in small placebo-controlled trials and heterogeneous, noisy populations. I don't think the placebo group helps you that much, to be honest. What we did is decided to work with Dr. Miller at the University of Florida, who's one of, if not the leading expert in Prader-Willi in the U.S. She draws patients from all over the U.S. The advantage is that she really knows her patients and anybody who was able to listen into that December call, she was on that call taking care of patients in real time. The advantage of knowing her patients is she can give you color that you can't always get from the, you know, looking at a number of a BMI. Anyway. That's why we designed it the way we did. 18 patients, we gave you eight patients in December, eight who had been out three months, I think five who made it to six months, one patient discontinued. The data we saw, what we released was, six out of the eight had some degree of weight loss. Now, it was fairly modest. It was less than 5%. 1 of the patients was more than 5% at that point at three months, but it was directionally correct. Historically, no drug has really given people weight loss. We referenced back on that call to the dazloretinib data, which I think is the best data that's out there, and, you know, their data was, you know, that 4%-5%. It was exactly in the same range as I think the kinda thing that we're seeing here now with setmelanotide. You know, these pieces are pretty reassuring. The number, the change in BMI that we saw, patients had a reduction in their HQ-CT, but the trial wasn't designed to look at that. It doesn't have a blind. Because it doesn't have a placebo, you can't use our HQ-CT numbers and compare them to Soleno's, for example. That wouldn't be fair. Directionally, they moved. I think, again, BMI decrease, HQ-CT numbers decreasing, Dr. Miller's sense that, you know, these patients are doing well. 17 out of 17 patients. One patient discontinued very early, we told you that on the December call. Since then, 17 out of 17 have stayed on therapy. You know, in a difficult disease, you don't do that, I think, unless, you know, you're perceiving some benefit. We'll, we'll release that mid-year, and, hopefully, that sets us up to get our phase III plans in place. Can you talk about the phase III path? Would you move IMCIVREE forward, and what would be the next trial? The fastest route forward would, of course, be to take setmelanotide, do a supplemental NDA. You've got an established drug. We will do at Rhythm, part of the strategy building Rhythm is, of course, moving everything to next generations. The next generation molecules have patent extensions through 2040+. They're better drugs. They don't have hyperpigmentation. They have a better tolerability profile. If we went ahead with setmelanotide, we would sooner or later do a Prader-Willi study with one of the or both next gens anyway. The decision we'll make is, let's say we decided to do an RM-718 study, that was the option, our weekly injectable. How far behind is that weekly injectable with as compared to going directly with setmelanotide? If it's not that long, don't ask me what not that long is. If it's not that long, why wouldn't you just go right to RM-718? I think you can hear in my answer here, that's a bias. I'd like to do that. We'll see sort of how all the timing plays on all this stuff. Our understanding is the RM-718 data in hypothalamic obesity will be available mid-year. Prader-Willi will be somewhat later. Do you need to see Prader-Willi data from RM-718 to move that into a Prader-Willi phase III, or do you think HO data is good enough that you can do a comparison molecule to molecule and accelerate the Prader-Willi development even ahead of the initial data? Yeah. I think HO data is good enough in a sense. The beauty of HO is a gift. I mean, it's a good opportunity just from a business standpoint, of course. The gift in terms of development is that disease is so sensitive to MC4R agonism that if it doesn't work there, we're done, right? You could run a small trial, as we did with our oral small molecule, and we saw very good results. We're doing the same thing here in RM-718. It won't take that many patients to give us a sense. You know, if you're O for five, for example, I'm worried. Right? That's how we're thinking about this HO model, you know, as being. Yes, I think HO will tell us that we have a good MC4R agonist. The data, the trial we're running with setmelanotide and Dr. Miller will tell us that MC4R agonists work in this disease. Yes, we could just go right to RM-718. Now, that said, we'll see how we do on the Prader-Willi enrollment. When we put out the RM-718 data midyear-ish, on HO, if we have enough, you know, to say something about Prader-Willi, we might share that as well. But yes, that's how it's all gonna come together. We're not gonna wait for specifically to have a full RM-718 Prader-Willi cohort. Moving to the M&A trial, a phase III study that will read out by the end of this month. Can you, for those less familiar, remind us of the design? Yeah. These are four different genes, identical protocols, but each individually powered, so they would read out independently. They all finished at the same time. We're reading them all out at the same time. We've handicapped them very specifically in the sense that they don't have all the same probability of success. The most likely to be positive is the POMC Het group. The reason that is most likely to be positive is that we had an assay where we were able to run all of the variants for that POMC gene through and only enroll patients who are pathogenic, likely pathogenic, or suspected pathogenic, meaning in theory, they had true loss of function at those variants. They weren't benign. We're pretty confident that MC4R agonist works in POMC Hets if you have true loss of function. The question for that trial actually is the suspected pathogenic group because we don't have the same level of conviction that we got pure loss of function there. The leptin receptor Hets, we also had the same assay, that group's very rare. We did not fully enroll, in fact, less than 50% of the patients we needed. We just declared victory. We stopped. I think we're underpowered. I think very unlikely that one's positive. SRC1, that gene, very little work had been done on that gene. All the variants we enrolled were these variants of unknown significance. Variants of unknown significance, in general, are disproportionately benign. It's likely that we have a disproportionate number of patients who have wild type, Or not wild type, but benign variants and no loss of function. I think that one's a low probability of being successful. The last one, SH2B1 16p11. The 16p11 core, that's a deletion in that region. By definition, you'd have loss of function, depending how many patients we have in that group, that should be okay. The SH2B1 part of that cohort, missense mutations is VUS. Back in that group, we're dealing with the same issue where that part of it will be disproportionately maybe benign. What I'm telling you is, when we've designed this, you know, we probably would have designed it differently now than we did then. Whatever happens, I gave you a sort of a sense of how we hierarchy these things. Whatever we get, this will be an important stepping stone in building out our genetic pillar because we'll go back to these genes if they're not positive with the learnings we've had here, assuming we have a good reason to think, you know, the hypothesis is still supported. Any DAYBREAK genes or, you know, other genes that we're pursuing, we will only be pursuing genes going forward where we'll pursue them with one or both of our next gen molecules, and we will only do it in settings where we have pretty good conviction that we know how to identify loss of function. We'll go from there. Can you discuss the commercial life of the franchise? How do the IP that you have on IMCIVREE dovetail with the nature of the orphan disorder market, plus your next gen candidates to determine how long you could have a commercial life? Sure. The our current composition of matter for our setmelanotide is 2032. I think what's a little underappreciated is our formulation patents, and these are U.S., go out to 2034. It's all two years longer in Europe. When you get a drug approved, the FDA puts out a guidance document for what a generic might need to do to get approval, and that guidance document takes you through our formulation. We think we'll probably have pretty good coverage out through 2034 in the U.S. on setmelanotide. The next gen molecules, depending on our timing of our approval, will be 2040+ including patent term extension. That's gives us a long runway. Our strategy is, you know, A, 'cause they're better drugs, and I think we're gonna be a meaningful contribution here, for these next gens. To get them in place as quickly as possible, and we will get one or both next gens approved for all of our current indications. The POMC, leptin receptor biallelic, BBS, and then of course HO. To focus on bivamelagon, what is the plan there? What are the next steps? We got good feedback from the FDA. They saw the data we showed to all of you. Again, I think they're convinced that the molecule's working and has a good level of efficacy. Safety's acceptable up to this point. We got the guidance for our HO phase III, which is a 12-month, double-blind, randomized controlled trial, which was our base case. We took a shot at something shorter unsuccessfully. We're waiting on the final number, but we think the size of that trial will be very similar to the 140 patients we ran in our current setmelanotide trial. Not surprising we got that feedback. That'll be the next thing. Goal is to get that up by the end of the year. Then in parallel, we'll look at another indication, smaller indication, that we might be able to pursue, but more to come on that. Great. With that, we are just about out of time. Anything I did not ask you that I should have? Anything that's important for investors to know as they assess Rhythm? I think what you've heard is we're pretty excited about not where we've been, but where I think this can go. I think there's a ton of opportunity here. Great. Well, thank you for coming by the conference.