Okay, good morning, everybody. Welcome to day three of Guggenheim's Healthcare Innovations Conference. I'm Seamus Fernandez, one of the Senior Biopharma Analysts here at Guggenheim, and really pleased to be joined by Rhythm Pharmaceuticals CEO David Meeker here to my right, and he's the Chair, Chief Executive Officer, and President of Rhythm. David, thanks so much for joining us. Really pleased to have you here. Obviously been a truly phenomenal year for Rhythm across the board, you know, not just in the performance of the stock, but in terms of what you're bringing to patients. You know, maybe you can just start off and remind us a little bit of the sort of dynamics and benefits of, you know, targeting the MC4 access, and its benefits in not just genetic obesity, but also early acquired obesity, particularly as it relates to Hypothalamic obesity. Yeah, thanks, Seamus. Yeah, it's been a great year. I think it does speak to the biology that we're working on, and we've increasingly come to appreciate the fact that this pathway in the brain sitting in the hypothalamus, which governs our satiety. Just to remind people, you know, we eat a meal and gut hormones signal to the adipocyte, leptin's released, it goes to the brain and signals back through this arcuate nucleus inside the hypothalamus, and it, the leptin inhibits the appetite-stimulating side, and then it activates this POMC neuron where the melanocortin pathway is, which releases the hormone, alpha-MSH, melanocyte-stimulating hormone that tells us, one, we're full, and two, and people sometimes forget this, food's on board, and so you can increase your energy expenditure. If you have a defect in signaling through that pathway, then you're hungry all the time, despite perhaps having eaten, but also your body's keeping your energy expenditure low. The combination of those two is what leads to the severe obesity many of these patients suffer from. That biology is really solid. I think what we're discovering is that the number of places where signaling through this pathway can be affected is much larger than was originally thought. I mean, there were some classic genetic defects, two of which we studied in our first indications, the POMC and the leptin receptor defects, but there's many more genes, as we're learning, and that's one whole side of the equation that we're interested in pursuing more. We have our MNA trial coming up next year, which is looking at four different genes. Where the world really got excited, I think, realizing that it was not just a genetic, the driven impairment, but this anatomic disruption, which is the whole hypothalamic obesity world. Classically, as people know, that is the tumor, but these benign tend to be pediatric tumors, but benign tumors that can grow into the hypothalamus. They rise between the pituitary and the hypothalamus, and that either the tumor itself, as it enlarges, and/or the surgical resection slash radiation used to manage the tumor, injures this hypothalamus, and about half the patients with that problem end up with, you know, quote unquote hypothalamic obesity. The surprise there was just how incredibly sensitive it was. You know, where I think, you know, the excitement for the future, in addition to sort of peeling that part of the onion, is MC4 receptors, they're in other parts of the brain. We do not talk about so much. They clearly interact with the autonomic nervous system, nervous system, and the hindbrain and the brainstem. What other aspects of the disease might get better? They're not, MC4 receptors are not in the liver, but, you know, we talked about on our last earnings call that, you know, one of the investigators in Europe has seen some really interesting stuff on, you know, the degree of liver improvement. Now, weight loss itself, you know, often improves steatosis and associated liver abnormalities, but this seemed to be unrelated or not tightly correlated with weight loss per se. It's an example again of, I just think we're in a really rich space of biology, so lots more to work on and, you know, we'll see where it goes. Right. And, you know, as we, you know, maybe the first thing we can just sort of jump right into is, you know, remind us again, what happened at least with regard to the PDUFA update. And, you know, our look at the data, and we were just talking about this earlier, you know, even though there were no changes in the confidence intervals around that sensitivity analysis as presented on your website, there was a delay. I guess even though we're confused, I think we were all quite settled, and comforted by the data that you showed. So what's the meaning of that, you know, to you commercially, if anything, and any dynamics that we should be thinking about? Maybe just update folks on what happened with regard to the, you know, March, now March 20 PDUFA. Yeah, first evening, I mean, we got the letter you never want to get, or it was the worst letters you could get, but the letter we got, which said they're extending our PDUFA date by three months, and the FDA is allowed to do that. It's triggered by, based on their judgment, there's no quote unquote rule, but specifically about what constitutes a major amendment, it's simply their judgment that you've just submitted a new data set that meets that definition. We're going to need more time to do it, and they can push it out. It also allows them to, the PDUFA goal date gets pushed out. In March, if we get approved, they will have successfully met their PDUFA goal date as well. There's some mechanics around it, which, you know, they're sensitive to and want to do it. The specific question, and we, you obviously shared it, I think, you know, we were talking about, you know, sharing things and how much gets shared often in these settings. You know, at any time, the worst part is not knowing, and then, you know, if you're left on the outside, you fill in the gaps. And so we really wanted to try to help people understand as best we could, you know, what was the request and, you know, the speculation around why, you know, they, you know, major amendment, and obviously there's a lot going on in Washington at the FDA. And that division particularly has a, you know, as you can imagine, a pretty high workload with all the obesity medicines coming through. At one level, disappointed, at another level, not surprised. The specific question that was asked, you know, we turned it around quickly. The data we released is, we show it on the call and is posted on our website, shows there's no difference. That sensitivity analysis, which was a reasonable question, I won't take it through the, the question itself because it's a little bit nuanced, but it made zero difference, the results. We put that back, but it's not that they just want to see the table. They want the raw data. The major amendment part of this is driven by the fact that, you know, it took us an intense week to redo all of the analyses to get that back in. Now they're going to take that, and obviously they may not be as focused on it as we were, but that's how we got there. That's great. And, you know, there are also, as we just sort of look at the, you know, I would say, does that create an opportunity to better prepare the commercial organization for the launch of AHO? Just absolutely not necessary. Everybody's dialed in and ready to go. What could, how could there be a benefit to the launch of setmelanotide in the AHO setting, if there were any? Yeah, I think, you know, any launch benefits from more prep time. You know, you like to get your sales force on the ground, you know, ahead of launch. We were, you know, we were on, we anticipated approval in December. We were, as Jennifer Lee, our Head of North America, you know, has explained, you know, the field force is fully hired. We've got everybody in their territories and they have been for a couple of months, but obviously having three more months, absolutely. I mean, you know, work does not stop. I think particularly in a rare disease, the incremental time is hugely advantageous. I mean, you, it is not like you are launching a drug into a space that everybody knows the disease, everybody knows their patients. What we've tried to explain, I've tried to help people think about here is if you look at Rhythm, take our first, you know, meaningful, commercial opportunity in Bardet-Biedl syndrome, that's a classic ultra rare disease. There's about, you know, four to five thousand patients in the U.S. is what we estimate, but they don't have a natural home. They may see a specialist, and on average, they see five or six specialists before they get a diagnosis, but then they tend to go back to their primary care. They're not sitting in a call point that is easily addressable, and you don't, no company does, we don't, you don't build a sales force out of, you're going to knock on doors to find these. You're trying to create awareness and, you know, a part of the healthcare system where the patient can find you as easily as you find them. That's part of Biedl. The difference with HO is that although the numbers are still ultra rare, 10,000 ish, one is there's definitely a higher rate of diagnosis. You know, we can debate what that is. We're quite struck by the fact that I do think there's a significant part of this population, despite having perhaps a classic presentation, that doesn't carry the diagnosis. I think we're also appreciating that many of these patients, they get their surgery at a specialized center, but, you know, 80% plus of these patients will have some level of pituitary insufficiency. They're being managed by the community endocrinologist, and the community endocrinologist is not necessarily plugged into HO, in the same way that, you know, at a specialty center you might be. That is our world. All that is just to say that there is a lot of work that is going to create a lot of value here. Incremental time, of course, is helpful. Yes, it might help us get out of the blocks a little quicker in March than we would in December, but overall, we just try to say, look, this is going to be faster than BBS, but different than Prader-Willi. We can talk about Prader-Willi and, you know, Soleno had a very good start to their launch, but there are some very distinct differences between these two worlds in terms of why that might be. Right. Right. Yeah, maybe you can walk us through a little bit, you know, the patient numbers that you've talked about as sort of preliminarily identified, 2,000 patients that you think are reasonably identifiable, you know, but again, you would say, okay, that could be a spectacular launch if this had this sort of same behavioral aspects of PWS. Maybe you can just kind of compare and contrast that for us, in that context. Yeah. Let me start with Prader-Willi just because I think it's, it's quite understandable that part of it. So Prader-Willi, an incredibly challenging disease, you know, families who are living with Prader-Willi in the family, I mean, maybe they've participated in a bunch of trials. I mean, they've had their hopes up for, you know, such a long period of time and been disappointed on multiple occasions. Finally, a drug's approved, and the disease itself, it's, it's so challenging to live with. I mean, it just is so disruptive to everybody around the patient and not to, you know, of course, the patient themselves, you know, living in is devastating. The motivation to get on therapy is incredibly high. One. And two, I think Prader-Willi is almost completely diagnosed in the U.S. I mean, it's hard to miss it, as a genetic disease is well recognized. It gets tested for, genetically tested for and the like. I think there's a very, very high rate of diagnosis of Prader-Willi in the U.S. Third, many of those patients may be managed at centers with clinics. There's a dedicated day or, you know, afternoon when, you know, the Prader-Willi patients are seen. Their ability to access the healthcare system is high. Their motivation is extremely high. You contrast that with HO where, even if patients carry a diagnosis, there may be a different sense of urgency. I've lived with this for a long time. I've got, you know, other things going on in my life. One, two, their ability to get in to see the endocrinologist is different. There is no question, you know, our healthcare system is under strain here, but endocrine specifically, there are many obesity treaters, non-endocrinologists as well, but certainly endocrinologists. All the interest in the, you know, general obesity space and GLP-1s and the like has put, you know, pressure on access to endocrinologists. What we have heard, and I know people who have done research in this space also, is yes, I, you know, this is great. I plan to put, you know, a high percentage or whatever of my patients with HO on this, and as soon as they come in, I will do that. You know, then the question is, why do they not just call them up and bring them all in and, you know, get it going? I think the bandwidth inside our system is so low that it is just, yeah, it may not happen. Those are different dynamics. It just says, you know, we'll ramp faster than we did for BBS, but it's not at all a Prader-Willi. There are a lot of elements of the HO space that is a rare disease world. You just do the work. It'll grow over time. I think our confidence in the overall opportunity is only growing. I mean, as we've learned more about this, I think that's absolutely clear. You tend to have it for a long time as you build it, but you don't tend to inflect out of the gate. Can you talk a little bit more about the patient numbers in particular? You know, I think originally we were talking about this and it was sort of five to seven thousand patients. Now it then worked its way up to seven to eight. I think we're now going to seven to ten. You know, where are we now in that patient number and what's kind of driving your confidence up in, that sort of the scale of the number of patients? Yeah, and I think you, again, is going back to all rare diseases, you start with the literature, which tends not to be great. The advantage here is that the tumor registries are pretty good. So the, you know, craniopharyngiomas, you can do the math on, you know, how many patients in the U.S., for example, you know, had a craniopharyngioma, how many had an astrocytoma, you know, and there's, you know, several other, you know, more less common tumors that also may contribute to this. You can get a feeling for that. I think that effort coupled with claims analyses, which again are becoming increasingly sophisticated. You know, as you may know, I mean, you can with tokenization and the like, you can now in these larger claims databases actually follow patients in terms of, you know, who they're seeing and what their network is, in terms of different specialists and points of care. That exercise gave us more confidence and Jennifer took you through the filter a bit, as to how we got to, and she was using it and we used it for both to inform sort of our overall EPI, but also to try to figure out, you know, sales force sizing and the like. Most importantly, the tiering and targeting of physicians. If there's 10,000 endocrinologists, it's, you know, in the U.S. writ large, it's 2,500 is really the top tier. That's, you know, you know, of course where you start and where she's focused. That, all of that's informed the EPI. Back to, you know, the confidence that, you know, our initial purely literature-based, you know, is now being more and more informed by these claims. In that, claims is not, there's no ICD-10 code. There will be, but it's a presentation which says the probability that this patient has it and is, is reasonably high. Included in our patients we've identified, you know, we talked about the 2,000-ish, 2,000 plus now, of course, patients are suspected and confirmed, but the suspected, you know, that constellation of having the trigger, the injury itself, having associated pituitary insufficiency slash vasopressin insufficiency. Just remind people that the diabetes insipidus, vasopressin insufficiency part of that, that hormone's made in the hypothalamus and, you know, transports down to the pituitary where it's released. A deficiency there again tells you the probability of injury to the hypothalamus is higher. All of these things, you know, weight, you know, what is the probability that that claim set of data, that presentation, you know, is likely to carry this. And then, you know, of course, the accelerated weight gain being the key. Right. And, you know, we've talked about this in the past. I think it was maybe a little bit more of a historic controversy, but not much of a controversy anymore. The, you know, the pipeline of obesity assets that continues to advance, you know, how has your data differentiated from at least claims reports or small, physician-initiated trials of GLP-1s, versus your own, you know, 20% weight loss in the AHO setting? Yeah, I mean, it was the logical question out of the gate, A, because the timing of this was, you know, we were emerging just as GLP-1s were emerging. And of course, there are amazing drugs and one assumption was they were going to work for everything. I think it's quite clear that, you know, obesity is, you know, it's a disease, that's been pretty well defined, but it's not one disease, it's many diseases. The idea that, you know, you have very specific biology and, you know, what I just remind people, what our drug is, it's an analog of the alpha-MSH, alpha-melanocyte -stimulating hormone. At a very simple level, we're just hormonal replacement. GLP-1s are not hormonal replacement. They're an indirect way of triggering weight loss. They work in different parts of the brain and, and, and the like. All that is to say is that they work differently. Can you get weight loss in HO? Absolutely. That has been very well documented. I think what is clear both through what we hear from thought leaders who have used the drugs, and our own experience now in clinical trials is, you know, some small percentage, 20% or less, may have a response. That response tends to be modest, and by modest, meaning 10% or less, not to say there are not exceptions, but I am just saying in general, I think that has held up pretty well overall. In our clinical trials, we allowed GLP-1s into the trial. We shared that data. Dr. Roth just presented it at TOSS again, and we'll get a, hopefully the paper out because we have the, what's most informative, we have the growth charts for all 31 of the patients who either were previously on a GLP-1 and stopped or were on a GLP-1 and continued. This included probably about 50% of the patients actually having been on a semaglutide or a tirzepatide. It was not just that they were on earlier things. What you can see very clearly, but not surprising because it was a requirement, these patients had been on, maybe they lost a little bit of weight and they started to regain, but they were not losing weight on a GLP-1. Once they went on setmelanotide and you correct the underlying hormone deficiency, they had a very good response, which raises the question, trial did not prove it, that once you correct the underlying biology and make an individual more physiologically normal, then their ability to respond to other anti-obesity medicines goes up, as you might expect, including GLP-1s. Before we get to just sort of how that's differentiated from PWS, maybe we can talk about the commercial opportunity that you see overseas, in particular, and which markets you're particularly excited about. Yeah, I mean, you know, Europe is historically challenging and, you know, we believe, as you know, from the beginning, if you're a rare disease company, think global. I mean, it just, and you can, you know, very carefully, make your investments. You don't need to get ahead of it too much. It's a bit of a pay as you go. When we get success, when we get approvals and reimbursement in an area, then we ramp up our resourcing. Europe, epidemiology is similar to the U.S. Advantages of Europe in rare diseases is these diseases, they tend, patients with these diseases tend to be a little more concentrated often in different, you know, major markets. That's that. The other thing is in a rare disease, every patient, if you're just talking about value, they, you know, these are lifelong therapies. You have them for a long time. You know, you just keep working away at it. Europe for sure valuable. Then Japan, I mean, we're excited about Japan and we've made that point. The epidemiology is surprisingly high, that 5,000-8,000, you know, for a population, so per capita, I mean, it's about half the U.S. in terms of population size. It's almost the same, you know, overall, prevalent number. We're making great progress. I mean, the team, Yann highlighted on our call, we've got that team very well, we're getting, we're moving on that team and we've got good people, which in, you know, international markets particularly, it's not surprising, it's not numbers, it's people. It's all about, you know, having the right people on the ground. I think, I think we're in good shape in Japan. Yeah, you've had experience building, We've done that before. It's like that before. Yeah. Great. You know, maybe we just jump into Prader-Willi quickly. We do not have a ton of time left, but, you know, as we think about Prader-Willi, maybe you can just sort of, I think you already did a great compare and contrast of the patient, but maybe a little bit of your expectations of the opportunity that you see to at least explore setmelanotide in this setting, and also just timing of when we will hopefully have some incremental answers around that. Yeah, I, so I explained on the call and I got some feedback from my earnings call that, you know, people were trying to judge, maybe I sounded more conservative or not. My whole goal in communicating around this, before we were able to release the data, because I actually haven't seen the full data set here, is just to reinforce what we said in the beginning. I think it was, that was a very fair starting point. I put the probability of success at 50-50, which is the biology, I think is compelling. There's no question the MC4R pathway is impaired in this disease and is contributing. If that's it, and we talked about the MAGEL2 gene specifically, we studied that in Daybreak. If you have for sure loss of function, I think your chance you're going to respond is extremely high. The biology is compelling. I think the drug should work on the biology. The confounder, the other 50%, is the disease is just tough. And many, you know, genes, you know, 20, 30 genes are, you know, part of a Prader-Willi background. The behaviors are incredibly difficult. I highlight the obsessive-compulsive part of this as an example. Like I'll say, if you're hardwired to have a snack at 10:00 A.M., even if you've corrected it, you no longer feel hungry, but it's 10:00 A.M., I want my snack. That's a, you know, and the families, because of the behaviors, which can be violent and the like, they give them food. It's just a really tough clinical, you know, development. We've seen this with all the drugs. I don't know if every drug has failed, didn't work. I just think it's an incredibly tough, tough disease. That's where we got to a 50-50. What we've committed to from a timing is, before Christmas break. We will meet that. We'll get some data out. All right, great. We are all looking forward to it. And, and, I think you guys have talked a little bit about patient numbers between 10 and 20. So, you know, we will just sort of leave it there. In terms of the next generation assets, you know, you guys showed really good data on Bivamelagon, but 718, maybe we can just talk about that briefly in our last sort of 45 seconds. I think we have talked about the level of selectivity between Bivamelagon and 718. Can you just remind us that? And also one oral, the other weekly. So, how does that play out in terms of how you guys think about development? 718 is really mirrored very much off of setmelanotide, you know, so it's a seven amino acid versus an eight amino acid. It's, it's more potent, if you will, than Bivamelagon, for what it's worth. Its specificities, you know, maybe more, a little more specific actually also. I think 718, you know, to the extent we've hardly seen any hyperpigmentation with Bivamelagon, we should see even less with 718. I think the biggest question is just making sure that we've got the dosing right and the weekly pharmacokinetics. Our goal is to make both available, what the patient chooses. Great. And then the timing of this. Oh, we'll complete, our goal is to complete enrollment of this open label first part in the first quarter, follow patients for 12-14 weeks, and then we'll read that out. By mid-year. Great. Given that, I guess, how consistent the Bivamelagon data were with your data for setmelanotide, apart from the hyperpigmentation, it seems like a reasonable view is that set does a really good job of hitting the target and getting the job done. Just where it's really kind of missing on the hyperpigmentation. It is. I mean, that's an important point. I don't think there's room to be quote unquote a better MC4R agonist necessarily. I do think setmelanotide is probably getting us as much horsepower. I mean, we've had some questions about dosing and that's a whole nother conversation. I, you know, clearly a three milligrams in a five year old and a three milligrams in a six year old with a 50 BMI, maybe not quite the same in terms of, you know, engagement, but overall it's been amazingly consistent that those range we've been has serviced the whole population. Super. David, thank you so much. Been a great year so far. Looking forward to, well, hopefully a Christmas present. And then, beyond that, you know, a really exciting 2026 ahead for Rhythm and your team. Thanks, Seamus. Thanks so much.