Good day. Thank you for standing by. Welcome to the Rhythm Pharmaceuticals, Inc. fourth quarter and fiscal year 2025 earnings conference call. At this time, all participants are in a listen-only mode. After the speaker's presentation, there will be a question-and-answer session. To ask a question during this session, you will need to press star one one on your telephone. You will then hear an automated message advising that your hand is raised. To withdraw your question, please press star one one again. Please be advised that today's conference is being recorded. I would now like to hand the conference over to your first speaker today, Dave Connolly. Please go ahead.

Thank you, Tanya. I'm David Connolly here at Rhythm Pharmaceuticals, Inc. For those of you participating on the conference call, our slides can be accessed and controlled by going to the Investors section of our website, ir.rhythmtx.com. This morning, we issued our press release that provides the fourth quarter of 2025 and full year of 2025 financial results and a business update. That press release is also available on our website. Our agenda is listed on slide 2. On the call today are David Meeker, our Chairman, Chief Executive Officer, and President, Jennifer Lee, Executive Vice President, Head of North America, Hunter Smith, Chief Financial Officer, and Yann Mazabraud, Executive Vice President, Head of International, is on the line joining us from Europe. On slide 3, I'll remind you that this call contains remarks concerning future expectations, plans, and prospects, which constitute forward-looking statements. Actual results may differ materially from those indicated by these forward-looking statements as a result of various important factors, including those discussed in our most recent annual or quarterly reports on file with the SEC. In addition, any forward-looking statements represent our views as of today and should not be relied upon as representing our views as of any subsequent dates. We specifically disclaim any obligation to update such statements. With that, I'll turn the call over to David Meeker, who will begin on slide 5.

Thank you, Dave. Good morning. Thank you all for joining. We pre-announced our revenue for the fourth quarter, highlighting the continued strong performance by our commercial teams. The BBS opportunity continues to grow at a steady rate, both in the United States and ex-US markets. Jennifer's North American team, which was fully hired and in place at the start of the fourth quarter, continues to take full advantage of the PDUFA extension to prepare for our expected launch. Our growing early access experience with HO in Europe reinforces our belief in this opportunity, as Yann will highlight. I'm pleased to report we had our end of phase 2 meeting with the FDA for the bivamelagon HO study. We were able to share the nine-month data, which included a minimum of six months on drug for the original placebo patients. I will share these new data that show persistent BMI reductions and consistent safety and tolerability over the next few slides. Our goal will be to present the data, including the full 52-week data, at a medical meeting mid-year. Slide 6 is to remind you of the original bivamelagon phase 2 design. Patients were randomized to either placebo or 1 of 3 dosing cohorts for a period of 14 weeks. Last July, we announced positive top-line results at 14 weeks, with patients in the 400 mg and 600 mg arms achieving a mean BMI reduction of 7.7% and 9.3%, respectively. Similar BMI reductions as achieved by setmelanotide at the same time point. At the end of 14 weeks, the study remained blinded. All patients were then redose escalated to preserve the blind from 200 milligrams to the target dose of 600 milligrams for the balance of the open label extension period. Slide 7 shows the disposition of the 28 patients. As…

Thank you, David. Starting with BBS, we had another steady quarter of growth in prescriptions as our teams continue to focus on educating healthcare providers to expedite patient diagnosis and working with payers to secure approval for reimbursement. Importantly, patients are benefiting from IMCIVREE therapy as it is the only approved therapy that targets the root cause of rare MC4R pathway diseases like BBS. We continue to be inspired by patient success stories. For example, 1 adult male patient with BBS, who is a resident of an assisted living facility, had such severe hyperphagia and preoccupation with food that he could not participate in group outings. After 6 months on IMCIVREE therapy, he not only lost 40 pounds, but his hyperphagia had quieted down meaningfully, and now he's able to socialize with others and participate in group activities. On slide 15. Our teams are continuing to prepare for the Acquired Hypothalamic Obesity launch, pending regulatory approval and our March 20th PDUFA goal date. Acquired HO is a distinct post-injury neuroendocrine disease characterized by impairment of the MC4R pathway, leading to hyperphagia and accelerated and sustained weight gain. With an estimated prevalence of 10,000 in the United States, Acquired HO represents a significant opportunity for Rhythm Pharmaceuticals, Inc. to expand the reach of IMCIVREE and the benefit it brings to patients. If approved, IMCIVREE would be the first therapy for these patients that currently have no approved treatment option. As we've discussed previously, we expanded our sales force from 16 to 42, all highly experienced launching new therapies in rare diseases. With the extra time ahead of launch, our engagement efforts have continued. Claims data helped us identify healthcare providers who we believe are caring for patients with Acquired HO. Our HCP engagement has been focused on disease awareness to help…

Thank you, Jennifer. I will begin on slide 19. We had a strong year in 2025, as our international organization has grown to more than 100 employees across 13 countries. With the ongoing BBS and POMC LEPR cells and the reimbursed early access programs for Acquired Hypothalamic Obesity in France and Italy, IMCIVREE is now available in more than 25 countries outside the United States, including eight countries newly added during the year. Our growth in 2025 was driven by sales in countries with established access and new countries coming online. Our team engages with key experts across Europe to advance education and the understanding of rare MC4R pathway diseases. In 2025, 64 abstracts, both originals and anchors, were accepted for posters or oral presentations at 12 international and national scientific congresses. Next slide. Here I highlight one recent publication entitled, Early Onset of Obesity Model: Impact of Early-Onset Obesity on Comorbidity Risk and Life Expectancy, which was very recently published in Obesity Facts, the European Journal of Obesity. This peer-reviewed early-onset obesity disease model, which we developed in collaboration with leading European experts, integrates data from more than 140 publications to quantify how the age of onset, the severity, and the duration of obesity negatively affect the risk of comorbidities, the health outcomes, and the life expectancy. This reinforces that early-onset obesity is a serious progressive disease and stresses the urgent need for early intervention. This finding supports recent focus on early diagnosis and treatment of obesity, driven by impairment of the MC4R pathway. We are addressing the underlying cause earlier as a potential to reduce long-term disease burden and create meaningful benefits for patients, families, and healthcare systems. Next slide 21. Now moving to acquired hypothalamic obesity. We are planning for multiple opportunities in Europe and Japan, with…

Thank you, Yann. 2025 proved to be a strong year, with solid growth in global sales of IMCIVREE and multiple value-driving milestones achieved across our portfolio of MC4R agonists. We entered 2026 well capitalized, with more promising potential catalysts ahead. I'll begin on slide 23 and walk you through our results for the fourth quarter, which was another solid quarter, as well as the full-year revenue, both of which we pre-announced in January. Revenues from sales of IMCIVREE were $57.3 million for the fourth quarter of 2025, representing a quarter-over-quarter increase of 12% and $194.8 million for the full year, an increase of approximately 50% from 2024. On a sequential quarterly basis, revenue growth was driven by an increase of approximately 10% in the number of patients on reimbursed therapy globally. In the fourth quarter of 2025, $39 million, or 68% of product revenue, was generated in the United States, and $18.3 million, or 32% of product revenue, was generated outside the United States. On slide 24 is the walk from the $51.3 million in global sales in Q3 to the $57.3 million in Q4. In the fourth quarter, the volume of vials shipped to our specialty pharmacy in the United States was approximately 1.7 million greater than the vials dispensed to patients. This compares to an excess of vials shipped over dispense of 3 million in Q3 2025. The net effect produced a negative $1.3 million inventory swing from Q3 to Q4. For the second consecutive quarter, inventory days on hand at the specialty pharmacy increased. You have approximately 20 days versus a normalized level of around 10-15 days. As was the case with year-end 2024, as is common across our industry, this type of growth in days on hand represents a potential pull forward of revenue from the…

Thank you, Hunter. Tanya, we can open it up for questions. Thank you.

Certainly. As a reminder, to ask a question, you will need to press star one one on your telephone and wait for your name to be announced. To withdraw your question, please press star one one again. Please stand by while we compile our Q&A roster. We will now open for questions. Our first question will be coming from Derek Christian Archila of Wells Fargo. Your line is open, Derek.

Good morning, and thanks for taking the questions. Congrats on all the progress here. David, just first on bivamelagon phase 3, your comments suggest that this will largely look like setmelanotide phase 3, so, in terms of sample size and duration, but are there any changes to enrollment criteria that you would, you know, think of or other features of the trial that you can comment on?

No. I mean, those are the principal things that we were looking to get feedback on. I think, you know, to your point, the trial will largely mimic our phase three. We continue to look at our patient reported outcome measures, some other things we can do to get better and better at, for example, understanding hyperphagia slash hunger. Some of these patient-reported outcome tools have not been validated, et cetera. That's an area which, as a company, we might modify, but we didn't get specific feedback from the FDA.

Got it. Maybe just to follow up, you know, on the guidelines potentially for HO that could be implemented or, you know, kind of evolve over time, I guess specifically for post-surgical patients, where it seems like physicians want to, you know, intervene early prior to that significant weight gain. Just any comments on how that might evolve over time and what you're hearing? Thanks.

Yeah, I mean, it's a good question. You know, we've had 6 months post surgery as a entry criteria to make sure that patients were stable on their hormones. That's very much a developmental issue because you don't know everything, and you wanna have things as, or the minimal number of things that might confound your interpretation of the results. In the real world, which is your question, and we've had this feedback from multiple thought leaders and the like, I mean, earlier is better. Why would you if you know the patient has HO, why would you make them wait 6 months to begin to intervene? You wouldn't do that for their thyroid hormone replacement, for example. I don't think there'll be that kind of guidance in the label. We'll see where, you know, guidelines, quote, unquote, "come out." Those will emerge over time, but I haven't heard that. I think the consensus would be, you know, as soon as you, the treating physician, are comfortable, yeah, you want to intervene.

Got it. Thank you.

Our next question will be coming from the line of Tazeen Ahmad of Bank of America. Tazeen, your line is open.

Okay, thanks, guys, and good morning. Can you give us an update on where you are with the PWS study? When is the next data update from that? What type of deepening response are you looking for? Are you looking for more weight loss, or are you looking for better hunger control? Or just can you give us a sense of that? Thank you.

Yeah. Thanks, Tazeen. As I said in my comments, we're still on track for mid-year, in terms of providing that update for the 17 patients who remain on drug. I think, you know, the one piece of updated data I gave you today was that 17 of 18 patients remain on treatment. I think for a challenging disease, these patients tend not to remain on drug if they don't feel like they're benefiting, so we would take that as encouraging. I don't have an additional cut of the data, so as I said, I don't have further updates there. In terms of what we're looking for, again, we've been very clear and continue to learn, this is a more challenging disease in the sense that there's a lot of other things going on. They have multiple genes affected, not just those potentially impacting the MC4R pathway that are at play in this disease and can confound results. I think our goal remains the same. We'd be looking to clear 5% on the BMI change. We'll see how we do there, and of course, we'll collect hunger. I mean, the hyperphagia scores, HQ-CT, we shared that data in December with the caveat, you know, this is an uncontrolled trial, so those kind of measures, you really need a placebo control group to know exactly how you're performing. We will have that data, and of course, we'll share it.

Our next question will be coming from the line of Unknown Analyst of Morgan Stanley. Your line is open.

Good morning. Thanks for taking the question, and congratulations on all the progress as well. Maybe just one question on IMCIVREE trends. You mentioned the potential for dampening of sales in 1Q, given some pull forward in 4Q. Maybe you can give a little bit of color on how to think about the growth. Is it just a slowing of growth, or should we think more flattish? Thanks.

Well, I'm not, I'm not gonna give you comment sort of on where external estimates are. We did see negative growth Q4 to Q1 in 2024 into 2025. The buildup of inventory this year in absolute terms is less. You know, we'll see how that shakes out, you know, but it's just that dynamic in and of itself, that inventory represents a pull forward of sales from 1 quarter into, from Q4 out of Q1 into Q4. I think the only other thing is we have the typical experience that faces us every Q1, where there are a lot of plan renewals and plan changes for individual patients. Some patients rotate on to our bridge program, and then those get resolved, and they rotate off.

Understood. Very helpful. Thank you.

Our next question comes from the line of Whitney Ijem of Canaccord Genuity. Your line is open, Whitney.

Hey, good morning, guys. I just wanted to follow up on EMANATE. You guys have talked about POMC PCSK1 and the SH2B1 substudies as being higher probability. Can you just talk to us a little bit, remind us, is that just driven by the enrollment and the powering of those substudies, or are there genetic biological considerations there as well?

Let me summarize what I've said previously, you know, important to remind. The way we've handicapped this is, yes, we think that the POMC heads are the most likely to be positive, and that's based on the fact that, you know, we did have an assay going into the trial that allowed us to determine which of the variants were most likely to be pathogenic, meaning that they had true loss of function. There's a range of variants there, of course, the assay has its limitations. The bottom line is we felt that in that cohort, we were enrolling predominantly patients who would have true loss of function. That was our best, and we were able to enroll that cohort fully. The leptin receptor, we also had insight into which patients might have true loss of function. It turns out the leptin receptor head group is extremely rare, those that have this potential loss-of-function variant. That cohort was very significantly under-enrolled, and we weren't so optimistic there or not. SRC1, mostly VUS, Variant of Unknown Significance. Variants of Unknown Significance disproportionately tend to be benign. Again, we think there's a high risk that one may not be positive. The reason we remain somewhat hopeful on SH2B1 is that there's two groups there. One is those who have this deletion, 16p11.2 deletion. By definition, with a deletion, they would have loss of function. The other part, group of that, and that's enrolled, the missense mutations associated with SH2B1, you're back in this, you know, how many of those are VUS, and of the VUS, how many are benign versus pathogenic? Long story short, that's how we handicapped it. Again, we're working to, you know, get that data out by the end of the year. The other thing I've said is, you know, you're, you know, we, like I said, we've been, you know, careful and modest in terms of our, you know, projections here and what we think might happen. I think whatever we get, we're gonna learn a lot from these studies, and minimally, you know, they will form the basis for the next round of studies with our next generation studies, molecules, which we would do anyway. When we report out, we'll try to give you some insight into how we think about the future there.

Got it. That's helpful. Just one quick follow-up. Should we still be thinking about kind of the 5% weight loss as the kind of bar for success, either based on powering or just how you're thinking about it?

Yeah, I mean, 5% is the guidelines. That's why we, you know, Prader-Willi, of course, where we think, you know, it's a really tough disease. I mean, that is the minimal threshold, so that's certainly the threshold here. I think in some of our other indications, you know, you get into, you know, where the world expects more today from a weight loss drug. Yeah, technically, it's 5% plus. I think, you know, what we would look at is, A, is the study positive? Then, B, do we think it's clinically meaningful and would be a meaningful offering, to the, you know, to patients with that, you know, specific genetic defect?

Our next question will be coming from the line of Corinne Johnson of Goldman Sachs. Your line is open, Corinne.

Good morning, everyone. Maybe you mentioned this study for BIVA and that the FDA was pretty explicit that new molecules would require a year-long phase three, I guess. How are you thinking about that then, as it relates to the planned development of RM-718 in the same indication? Kind of separately, but in the same vein, how do you think about managing kind of quality control of the phase three program as you think through enrolling patients kind of ex U.S. in order to get that patient population? Okay, thanks.

Good question. First on RM-718, yes, the read-through there would, you know, highly likely to be the same. I mean, you know, to be honest, you know, we'd go back, I would look to have another conversation with them. I think part of BIVA is it's a small molecule. I think RM-718's a peptide. It's highly analogous to setmelanotide. I don't know if they would look at that any differently, but, you know, a conservative base case here is, yes, RM-718 will have to do the same thing that we're being guided to for BIVA. Quality control outside the U.S., you know, the world's small. I mean, the sophistication of running trials, outside in these other countries, I mean, there's a number of centers and, you know, one or more centers in many or most countries, which are pretty sophisticated. CROs are structured to run trials globally. I'm not at all worried about quality. I mean, you pay attention to that, and we'll be careful, of course, but I think quality control is not the issue. Our challenge as always is, you know, rare diseases, you wanna find sites that have good access to patients.

Good. Thank you.

Our next question will be coming from Philip M. Nadeau of TD Cowen. Your line is open, Phil.

Morning. Congrats on progress, and thanks for taking our questions. Two from us. First, in the bivamelagon phase 3 trial, what dose will you be exploring? It seems like you think 200 milligrams is underdosed. 600 did look a little bit more potent, but the patient numbers were small, so we're curious what dosing paradigm you will use. Second, on hypothalamic obesity, I think the last number of identified patients that you gave to us was 2,000. Sounds like, as your sales reps are out there shaking the trees and doing medical education, you're finding more and more patients. Any update to that number? Thanks.

Oh, dosing. Sorry. So the dosing will be we’ll dose escalate from 200 up to 600. 600 will be the target dose. You know, we look at the data the same way you did. I think there is a difference between 400 and 600 milligrams. I think we're still on a dose response part of the curve there. The other thing, which has been pretty encouraging, and I will say, you know, we've got, you know, a number of patients out for the full year. What happens, so I have a little insight there. I mean, what happens in HO is many of the patients continue to just gradually deepen over time. I'll remind you back to a patient from our phase 2 study, the most fairly affected oldest individual in that trial, a 24-year-old man who had a starting BMI of 52, 50+, and over a period of 4 years, he just continued to gradually decrease his BMI down to a normal BMI of 24. I think, you know, what we're seeing here is not inconsistent with that, is a gradual, you know, deepening over time. So short answer to your question is yes, the target dose will be 600. There'll be patients who maybe do fine on 400, just as there are patients who do okay on 2 milligrams as opposed to 3 with setmelanotide. I think, you know, we're incredibly encouraged here, and I think, you know, this data gives us high confidence that this pathway is central to HO, and we're correcting, as you might expect, in a hormonal replacement strategy. With regard to patients, you know, we updated in September, and, you know, we've stayed away from sort of giving you monthly or quarterly updates on those patient numbers, 'cause after a while, I'm not sure how helpful that is. You are absolutely correct, and as Jennifer highlighted in her comments, you know, the team's been doing a lot of work. You know, we're continuing to find more patients. Yes, that number's gone up. We're learning a lot about, you know, the nature of this community, you know, how many patients carry a diagnosis of HO and how many patients are, quote, unquote, "in suspected category." You know, this belief in the overall opportunity, the 10,000, is high, and it's higher than it was last September, for example, and we feel really good about the progress we're making.

That's very helpful. Thank you.

Thank you. Our next question will be coming from the line of Jonathan Wolleben of Citizens. Your line is open, John.

Hey, thanks for taking the question. Just one on Japan. Hunter, you mentioned the investment you guys will be making there. Just wondering how we should think about the opportunity in Japan and the trajectory of a potential adoption.

Yeah. Yann, you want to take that? Yann, are you... Did we lose you?

Yeah, I'm back. Okay, sorry. Yes. Potential first, as I said earlier, we estimate the prevalence between 5,000 and 8,000 patients, and it's a well-documented prevalence, we are quite sure of this number. The second point was your question about our capabilities. We are currently building out our team. We have set up an affiliate. We have a full management team in place, and we already have a field medical team in the ground. From a timeline point of view, David mentioned the data in March, following that, you can count on 12 months of regulatory and market access and pricing aspects, which means that we should have a launch in the next 12 months from now.

Thank you. Great. Thanks.

Our next question will be coming from the line of Unknown Analyst of Leerink Partners. Your line is open.

Hey, guys. Good morning. Thanks for taking the questions. Just on the HO expansion, appreciate the color on the regulatory interactions. It sounds like you're entering labeling negotiations, which is great. As we think through some of the color you're giving here around reimbursement and payer coverage and activating sites and patients, can you just elaborate a little bit on how you think about the launch cadence relative to BBS? Thanks so much.

Yeah. From the perspective of HO versus BBS, one, I think there are similarities and some differences. I think from a similarity perspective, you know, there's still a lot of opportunity, as we've outlined, just in terms of getting these patients to an actual diagnosis of Acquired Hypothalamic Obesity, versus just being seen as a patient with obesity for many causes that it may not be the root cause just in terms of what they are going through. There's still opportunity there. I think the other piece is from the perspective of a timeline of care coverage. You know, although we have a great starting point, just in terms of all the dialogue we had with BBS, in terms of the differentiation of, you know, MC4R pathway diseases, versus general obesity, it's still gonna take some time just in terms of going through the process of having specific CNT meetings, so that we get, you know, a specific policy for the expansion of the indication in place. We're similarly, in the meantime, going to be working through the process as we get the RXs in, pair by pair. There are some similarities. I think some of the differences is that in terms of HO, the precision and confidence, just in terms of the data we have to really pinpoint it down to the right physician to educate, to get these patients to a diagnosis, we feel a lot more confident about that. I think in comparison to BBS, you know, those sort of crumbs to lead us to the right physicians is stronger. I think the other aspect is, you know, we know even though, like, our teams are targeted by the data and following where the patients are, it just made sense that we are actually being led to these medical centers that have these pituitary, you know, centers and capabilities. We know where they go once they have the brain tumor, where they're treated, and they stay in that situation for a period of time so that as they start to encounter the symptoms of HO, we have the ability to really target those incident patients to get to a diagnosis that is not missed. That's a bit different than what it was like for BBS, which once again, gives us a bit more confidence just in terms of being able to identify them earlier in their journey.

Next question.

Our next question will be coming from Seamus Fernandez of Guggenheim Securities. Your line is open, Seamus.

Hi, guys. Thanks for the question. This is Evan Wang on for Seamus Fernandez. Just two from us. First, with RM-718, I saw some narrow timelines for Part D. Curious if there's any potential strategies to accelerate timelines there, potentially, like a phase 2, 3, just given some of the feedback and data that's around biva and setmel? Second, curious if you're exploring or planning to explore other areas of MC4R development, maybe in or other kind of avenues to treat obesity. Thanks.

Just to clarify on that last part of the question, other indications that we're thinking about, other approaches? Is that what you’re—

Other indications or approaches for, it's mostly, I guess, obesity-related treatment. Thanks.

Okay, for RM-718, is there a strategy to accelerate? I mean, we take, I think, a pretty aggressive view in general. I mean, regulators don't always agree with our approach, we end up sometimes in more conservative or conventional approaches. I think RM-718, as I said earlier, is likely to be highly similar to bivamelagon. We'll go with this initial experience and this open label study, and move right to a Phase 3. I don't know if there's an opportunity to accelerate things further there. The other thing is the pressure on the next gen in HO is we want to get it out as soon as possible. It's a little different. From an initial indication opportunity where those patients have no other treatment, and, you know, setmelanotide will be approved and out there, patients will have an option. Again, we'll move as quickly as we can, but it's not quite the same criticality as it might be if there was no treatment available at all. With regard to other indications, I mean, we've talked about, you know, the different kinds of, or the different areas that we're interested. One is genetics, you know, EMANATE being the first, you know, attempt beyond our initial approvals in POMC and LEPR. We have the DAYBREAK study, we will be coming back to specific genes. We will do that development work, as we've said, with next-generation molecules, probably not both molecules in every one of those genetic indications, but we'll come back to you with an updated plan there. With regard to, you know, other approaches to obesity, I mean, yes, we're open to that. We have, you know, early programs where we're thinking about different ways we might complement MC4R. That's all early. We're not at a point where we're prepared to talk about that yet, but we are fully committed to optimizing therapy for these patients with MC4R and deficiencies, and that would include potentially additional approaches.

Our next question will be coming from the line of Unknown Analyst of Needham & Company. Your line is open, Joseph.

Good morning, this is Eddie on for Joey. I appreciate you taking our questions. Just a follow-up on MC4R, and the M and A sub-studies, can you remind us again, if you intend to submit these as a combined sNDA, for a broader MC4R pathway, or, just talk about how the regulatory path, might necessitate sort of, mutation-specific approvals, and then how this might change, for these next gen therapies as you kind of move through the trials, in later years? A follow-up. I'm sorry if I misheard. Did you say that in the biva OLE, that you saw moderately better results, patients not on GLP-1? If I heard that right, can you describe why that might be the case? Thank you.

Yeah, let me take that last piece first. You know, when we're trying to create an apples to apples comparison, we took the patients in our RM-493-040 Phase 3 setmelanotide trial. If you remember, there was, in the treated group, about 15 patients who were on a GLP-1. That group did have a better result. If you remember, they got in the trial by not having responded to a GLP-1. Once they got setmelanotide, they had a very good response, and if you were just to look at that cohort, you know, their actual % decrease was greater than the group that did not get a GLP-1. Trial was not designed to, you know, prove that that might be a better outcome, but what we've concluded biologically is, yes, once you correct the underlying defect in setmelanotide, restore the hormonal deficiency, then your ability to respond to another anti-obesity medicine might be restored. We gain weight for a different reason if you're a patient who's got incremental weight because they love ice cream and they eat ice cream all the time, you know, then, you know, a GLP-1 in that setting, once you've corrected the hormonal deficiency might make sense. That was an apples and apples change there, and that was the goal there. Your question about EMANATE, in terms of regulatory filing strategy, no, these will be filed individually. Even if all four were positive, you know, we would file four separate sNDAs. They would be, like I said, one at a time evaluations. In the future, I mean, is there an opportunity for a mechanistic kind of approval that wouldn't require a full phase 3 for every genetic indication? I think that's possible. I would say we're definitely not, or the regulators are definitely not there today. That's not an unreasonable question for the future.

Our next question will be coming from the line of Paul Andrew Matteis of Stifel. Your line is open, Paul.

Hi, this is Matthew on for Paul. Thanks so much for taking our question. I guess I had one on acquired HO. For the FDA review, we appreciate the pivotal phase 3 was already large, but will you be able to supplement your data package with the Japanese cohort? Does the timing work out such that you'll be able to include this before the PDUFA? Thank you so much.

Yeah, Matthew, it's a good clarification. The answer is yes, and that's partly... I mean, when the FDA gave us their extension back in November, they were very aware of the exact timing of the last patient in visits. So they had done the calculation, recognizing that there was a very short period of time between when we would have data from that last patient, a Japanese patient, and being able to get the data in on the full 142 patients, which is what they wanted. So we're on that path, and we will get that data in. Yes, they are prepared to deal with the fact that, yes, it's now we're down to a relatively short period of time between that final data submission and the label or potential approval on March 20th.

Thank you. That's super helpful.

Our next question will be coming from the line of Unknown Analyst of Citi. Your line is open, Samantha.

Hi, good morning. Thanks very much for taking the question. Just maybe one clarification on the phase 3. You mentioned that you were going to primarily enroll outside in countries where setmelanotide is not available. How does that work necessarily for enrollment in the U.S.? Just on Prader-Willi, can you just talk about your latest thinking on a potential phase 3 trial? Would you plan to take both setmelanotide and semaglutide forward, or is it more likely that you choose one of these drugs to advance? Thanks very much.

Yeah. Okay, with regard to the phase 3 for HO, yes, we will run it predominantly outside. I wouldn't exclude having a U.S. site, but, you know, setmelanotide will be approved. Patients here have an option, so, the U.S., for multiple reasons, becomes a little more complicated. We do not need to have a site in the U.S., I mean, we already have U.S. data coming out of our phase 2 study. I'm not, again, I'm not so worried about our ability to execute the trial. I'm not using the U.S., but, you know, you never say never, so I would defer final decisions on that. For Prader-Willi, setmelanotide versus RM-718, I think, you know, this is something, as we've highlighted before, the advantage of going forward with setmelanotide is, you know, we've got data on setmelanotide already. It'd be a supplemental NDA, and so we could, in a sense, roll into that phase three. The advantage of going with RM-718, for example, is that, it's a next gen. We're gonna do a next gen study sooner or later, and that's the end game. If the RM-718 program is at a point where the gap between when we might start with setmelanotide and when we could start with RM-718 is not so great, I think, you know, we would, you know, take that time delay, if you will, and just go right to RM-718 and avoid having to run two studies there. That decision is yet to be made. We'll see how all this plays forward.

Our last question will be coming from the line of Unknown Analyst of RBC. Your line is open, Lisa.

Oh, great. Thanks so much for taking our question, and congrats on the progress. I just have one on biva. Wondering if you can expand on your dose selection comments, and I realize this might be a bit early, as the phase three is not yet even started, but long term, is it possible patients could dose down with a maintenance dose if they happen to reach a normal BMI in the real world? Any color here would be helpful. Thanks so much.

Yeah, yeah, I'll briefly repeat what I said before in the dose selection. I do think 200 is probably on the border in terms of being therapeutic for most patients. I think 400-600 is more likely in range, 600 does seem to have, you know, a continued dose response, 600 for sure will be our targeted dose, just the way 3 milligrams was our targeted dose in the HO setmelanotide trial. You know, with regard to dosing down, you know, what's interesting here is the biology, pathophysiology, it's a hormonal deficiency. You know, in theory, you take whatever amount you need to restore your hormonal deficiency, but it's not a biologic setting where dosing down makes sense. I think our expectation is most patients will stay at their target dose. That's been true with setmelanotide as we go forward. It's not, you know, you get your weight loss, and then you can kind of go to a low dose to maintain. That's not the pathophysiology.

I'm showing no further questions. I'd now like to turn the call back to David Meeker for closing remarks.

Great, thank you. Thanks all for tuning in. Again, we remain really excited about the progress here at Rhythm Pharmaceuticals, Inc. Lots of exciting things coming up. 2025 was a big year. 2026 is gonna be equally big. Look forward to our next update. Thanks, all.

This concludes today's program. Thank you for participating. You may now disconnect.