Rhythm Pharmaceuticals, Inc.

Good day and thank you for standing by. Welcome to the Rhythm Pharmaceuticals 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 the session, you will need to press star 1-1 on your telephone. You will then hear an automated message advising that your hand is raised. To withdraw your question, please press star 1-1 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 Dave Connolly here at Rhythm Pharmaceuticals. For those of you participating on the conference call, our slides can be accessed and controlled by going to the investor section of our website, ir.rhythmtx.com. This morning, we issued our press release that provides the fourth quarter 2025 and full year 2025 financial results and a business update, and that press release is also available on our website. Our agenda is listed on slide two. On the call today are David Meagher, our Chairman, Chief Executive Officer, and President, Jennifer Lee, Executive Vice President, Head of North America, Hunter Smith, Chief Financial Officer, and Jan Mazzebro, Executive Vice President, Head of International, is on the line joining us from Europe. On slide three, 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 five.

Thank you, Dave. Good morning and 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 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 Jan will highlight. I'm pleased to report we had our end of phase two meeting with the FDA for the Bivomelagon 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 six is to remind you of the original Bivomelagon Phase II design. Patients were randomized to either placebo or one of three dosing cohorts for a period of 14 weeks. Last July, we announced positive topline results at 14 weeks with patients in the 400 and 600 milligram arms, achieving a mean BMI reduction of 7.7% and 9.3%, respectively. similar BMI reductions as achieved by set melanotide at the same time point. At the end of 14 weeks, the study remained blinded and all patients within 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 seven shows the disposition of the 28 patients. As a reminder, one patient discontinued after the first visit due to rectal bleeding, judged unrelated to study drug. One 64-year-old male who had lost 14.5% at 14 weeks in the 600 milligram cohort chose not to continue into the open label for personal reasons. Since then, one patient has stopped taking the drug but remains in the trial as a retained dropout. In summary, 26 of 28 patients remain active in the trial, including the retained dropout patients, so 25 out of 28 remain on active drug. The next four slides show individual patient data at 40 weeks. Slide eight shows the placebo patients whose baseline BMI was calculated, in this slide, whose baseline BMI was calculated from their 14-week clinic visit when they converted to active drug. With the exception of the 12-year-old female, who we believe was not compliant, all patients showed a response to drug after 14 weeks, which included the up titration period. With further deepening at 26 weeks, the week 40 visit, And of note, one patient did not have her 40-week visit, but she remains in the trial. Similarly, for the original 200 milligram cohort on slide 9, all patients with the exception of the retained dropout patient who is actively gaining weight and the patient who we believe is not compliant have had a response at 28 weeks and further deepening at 40 weeks. The modest response on 200 milligrams alone at 14 weeks does suggest that this dose is probably sub-therapeutic for many patients. Slides 10 and 11 show the data for the original 400 and 600 milligram cohorts. With the exception of the two patients who are not fully compliant, one each in the original 400 and 600 milligram cohorts, all patients have had a good response to drug, with 11 of 14 patients decreasing by 10% or more. The mean BMI decrease for the 400 milligram cohort at 40 weeks, including the non-compliant patient, was 10.8%. And the mean BMI decrease for the 600 milligram cohort, including The non-compliance patient who gained 7.5% and the patient who dropped out at 14 weeks was 14.3%. Of note, the set melanotide phase 3 data at the 40-week time point in patients not on a concomitant GLP-1 from our phase 3 study was 15%. With regard to safety, the drug is better tolerated when taken with a small amount of food. The side effect profile continues to mimic what we see with set melanotide. The nausea and vomiting tends to occur early and then patients tolerize. The episodes of diarrhea tend to be a little more sporadic, are mild in severity, and no patients have discontinued because of diarrhea. In this trial, the compliance issues have been predominantly in the younger teenagers who we believe have struggled with the size of the pills. As we have indicated, we will have an easier to swallow single pill formulation going forward for each of 200, 400, and 600 million doses, and we will have a chewable tablet for younger patients. Next steps for this program will include bioequivalent studies comparing the new and old formulations, a drug-drug interaction study, and a hepatic impairment study. We expect to have the majority of this work completed in drug supply for phase three studies by the end of the year, with a goal of initiating the phase three HO study by year end 2026. I would characterize our FDA meeting as highly constructive on multiple fronts. They confirmed that BIVO was ready to move to phase three. As many of you know, we were hoping, given the prior set melanotype data and the placebo cohort data, that we could negotiate a six-month double-blind period and a smaller number of subjects given the effect of the drug. They were firm that with a new chemical entity, a full 12-month double-blind randomized control trial would be required, as well as a larger number of patients to build up the safety database. We are awaiting the final minutes from that meeting, but expect that number to be closer to the full 142 patients studied in our Cetmalanotide trial. Our plan will be to run this trial largely in countries where Cetmalanotide will not be available for acquired HO in the near future, which should facilitate enrollment. There was no discussion of set melanotide in the upcoming PDUFA date, but the FDA is communicating with us on the expected timeline, and we have received the first feedback on the label. I'm not going to make further comments today on that feedback, as it is preliminary and pending the final submission of data on all 142 patients, which will be incorporated into the label. As shown on slide 13, we have multiple upcoming milestones with BDUFA for HO, top-line data from our Japanese HO cohort, and the M&A readout all coming in March. For M&A, we are working to get the top-line data with the goal of releasing that data by the end of March. The PWS trial continues on track to get to the full six-month data by mid-year. At our December release, we indicated that one patient had discontinued his trial, Since then, we've had no further dropouts with all remaining 17 patients continuing on treatment. We have taken no further data cuts and have no further patient updates to provide on this call. The 718 weekly formulation continues to enroll in HO, and we are on track to have initial three-month data by mid-year. With that, I'll turn the call over to Jennifer.

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 Incivry therapy as it is the only approved therapy that targets the root cause of rare MC4 pathway diseases like BBS. We continue to be inspired by patient success stories. For example, One 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 six months on emcevery 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. Now on slide 15. Our teams are continuing to prepare for the Acquired Hypothalamic Obesity launch, pending regulatory approval, and our March 20th Bidufrit goal date. Acquired HO is a distinct post-injury neuroendocrine disease characterized by impairment of the MC4 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 to expand the reach of MCIVRI and the benefit it brings to patients. If approved, MCIVRI 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 drive suspected cases to formalized diagnoses of acquired HO. We already have engaged with HCPs who care for more than 2,000 patients diagnosed with or suspected to have acquired HO. Let me outline an example of the ongoing dialogue around patients suspected to have HO. Our team engaged with an endocrinologist who treats several patients with sustained hypothalamic injury. During a meeting with a field team member who outlined that injury in the hypothalamus could cause impairment of the MC4 pathway, leading to acquired hypothalamic obesity, the physician noted that one patient in particular stood out. This patient experienced severe weight gain following treatment of a brain tumor, subsequently underwent gastric bypass surgery and later initiated GLP-1 therapy with minimal benefit. Now with a clear understanding of the clinical diagnosis of acquired hepatolymic obesity and appropriate screening criteria, this physician indicated that he suspects additional patients may have acquired HO and healed bring them back for evaluation and diagnosis confirmation. Moving on to the next slide. We have also learned more about the management of AHO patients through our territory manager's disease education efforts. In addition to the ongoing engagement of our MSL or medical science liaison team, we have identified approximately 40 priority medical centers throughout the nation based on their significant concentration of AHO patients. Approximately one-third of the potential AHO patients who we have identified via claims data are managed within these centers. The majority of these have pituitary centers where hypothalamic disorders are managed by multidisciplinary teams. While there are similarities within these organizations relating to which specialty is brought in to manage the tumor and treatment, as well as the hormonal dysfunctions associated with the procedure, there is variability in terms of who manages AHO. In one center, the endocrinologist involved in the treatment of the hormonal dysfunctions would also take on the responsibility to treat the weight gain. In another center, these patients' hormonal dysfunctions would be managed by the endocrinologist, but they would be sent to the community PCP or obesity specialist to be treated for their weight gain. Understanding these differences allows us to better pinpoint who would potentially be the diagnoser of AHO versus the obesity treater and future potential prescriber of MCIVRI if approved for AHO. Our team continues their ACP engagement and identification of patients who would benefit from Incivry once approved. Now onto my last slide. Beyond ACP engagement, we also continue to engage with payers to secure access for patients as soon as possible following approval. Our education and engagement around BVS established a robust base for securing access for AHO as payers have come to recognize the differentiation of MC4 pathway diseases and the value that MC4 offers patients. For acquired hypothalamic obesity, pair coverage following approval, our expectation is for policy updates to occur within three to nine months. We are excited by the progress we have made and are ready for launch pending approval in acquired hypothalamic obesity. Now let me turn it over to Jonas.

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-LiPAR cells and the reimbursed early access programs for acquired hypothalamic obesity in France and Italy, Immisivri is now available in more than 25 countries outside the United States. including eight countries newly added during the year. Our growth in 2021-25 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 MC4 or 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 a recent focus on early diagnosis and treatment of obesity driven by impairment of the MC4 pathways. We are addressing the underlying cause earlier as a potential to reduce long-term disease burden and create meaningful benefit for patients, families, and healthcare systems. Next slide, slide 21. Now moving to acquired hypothalamic obesity. We are planning for multiple opportunities in Europe and Japan. With a higher per capita prevalence of acquired HO than the United States and Europe, and an estimated population of 5,000 to 8,000 patients, Japan represents a meaningful long-term opportunity for our MC4 agonist franchise. We continue to make significant progress ahead of our anticipated Japanese launch. establishing a strong leadership team focused on engaging with experts and health care centers. Earlier this month, our team had a very positive in-person meeting with the Japanese PMDA, and as David said, we anticipate top-line data from the Phase III cohort of Japanese patients in March. In Europe, our EME submission for HO is under review. We anticipate a CHMP opinion in Q2 and the EU marketing authorization in the second half of 2026. The steady growth in our reimbursed early access programs for HO in France and Italy is a very positive indicator for success in Europe and helped establish foundational relationships with expert physicians and local authorities. The French regulatory authorities renewed this month the authorization for the MC3-AP1 reimbursed early access program, which clearly illustrates the benefits patients are receiving as part of this program and the high unmet need. Pending marketing authorization from the EMA in the second half of 2026, we will begin established reimbursement for acquired HO in Europe on a country-by-country basis, as we have done before for POMC-DPAR and BBS. With that, I will turn over to Hunter.

Thank you, Jan. 2025 proved to be a strong year with solid growth in global sales of MCIVRI 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 preannounced in January. Revenues from sales of MCIVRI 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 shipped 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, ending at approximately 20 days versus a normalized level of around 10 to 15 days. As was the case with urine 2024, and as is common across our industry, this type of growth in days on hand represents a potential pull forward of revenue from the quarter of actual patient demand, and can, with all other things being equal, have a dampening effect on the first quarter of the year. U.S. revenue grew by 2.1 million quarter-over-quarter due to increases in product dispensed to patients. Ex-U.S. revenues increased 5.2 million, or 40%, versus the third quarter of 2025, The sequential increase was largely due to the negative impact on the third quarter of a one-time $3.2 million charge related to the final agreement with France on the reimbursed price for MCIVRI for the treatment of BDS, POMC, and LEPR deficiencies. On slide 25 is the financial snapshot of year-over-year performance as well as the fourth quarter 2025 results compared to the fourth quarter 2024. Net product revenues in Q4 2025 increased by $15.4 million, or 37%, over Q4 2024. Gross-to-net for U.S. sales was approximately 84.6%, generally in line with the gross-to-net percentage from previous quarters. Cost of goods sold this quarter was 8.5% of product revenue, and was mostly attributable to cost of materials and our royalty payment on set melanotide due to Ipsen. COGS as a percentage of product revenue was down slightly this quarter based on an increase in finished goods inventory. We generally expect cost of goods sold to be between 10% and 12% of net product revenue with variation due to how our inventory balances change and the corresponding capitalization of labor and overhead costs, as was the case in Q4. Research and development expenses were $42 million for Q4 compared to $41.2 million in the same quarter last year. Sequentially, R&D expenses decreased by approximately $4 million compared to the third quarter of 2025. More than half of that decrease was due to the transition of our area development managers in the United States to sales reps or territory managers, moving their salaries and stock compensation to SG&A effective October the 1st. Costs in the fourth quarter from our Phase III HO trial with set melanotide and our Phase II trial with bifamelegon decreased from the third quarter. SG&A expenses were $57.5 million for Q4 2025 as compared to $38.1 million in Q4 last year. Sequentially, SG&A expenses increased by $5.1 million or approximately 10% compared to the third quarter of 2025. Increased SG&A spend from Q3 to Q4 was due to increased headcount costs and professional fees associated with the anticipated launch in acquired hypothalamic obesity, including the transfer of the field force described previously. For Q4 2025, weighted average common shares outstanding were approximately 67 million. Our GAAP EPS for the fourth quarter of 2025 was a net loss per basic and diluted share of 73 cents, which includes two cents per share from 1.3 million of accrued dividends on convertible preferred stock. Cash used in operations was approximately 25 million in the fourth quarter and 116 million for the full year. We ended 2025 with approximately $389 million in cash, cash equivalents, and short-term investments, which we expect to be sufficient to fund planned operations for at least 24 months. On slide 26, a few additional items of note. First, our GAAP operating expenses for 2025 totaled $362.3 million. That included $66.8 million in stock-based compensation. Non-GAAP operating expenses for the year were $295.5 million. This came in at the lower end of the range that we guided for at this time last year. Our common share count is 68,285,039 shares as of February 24th. This number includes 729,164 shares of common stock which were converted from preferred shares since the end of the third quarter. Recall we raised $150 million in gross cash proceeds through the issuance of convertible preferred shares in April 2024. Following this partial conversion, there are 202,395,831 potential common shares that could be converted from the remaining preferred shares. The recent conversions represented almost 25% of the initial preferred shares, hence reducing our liability of dividends payable to preferred shareholders. Lastly, on slide 27, we are offering annual guidance on non-GAAP operating expenses. For 2026, we anticipate approximately 385 million to 415 million, which includes non-GAAP R&D expenses of 197 million to 213 million and non-GAAP SG&A expenses of 188 million to 202 million. The overall increase in non-GAAP operating expenses for 2026 of approximately 104.5 million at the midpoint which is about 35% over 2025, is the result of the success of our clinical programs in 2025 and represents future investments driving long-term growth and increasing shareholder value. There are three primary drivers of the growth in anticipated 2026 spending. First, Approximately 30% of the year-over-year increase will come from increased spending on formulation development, manufacturing, and clinical supply of our next-generation MC4 agonists, Bivomelagon and RM718, as we continue to move both compounds through proof-of-concept studies and hopefully registrational studies in the coming years. Second, approximately 25% of the increase will be on U.S. commercial operations in support of the HO launch. Approximately 15% of the increase will be to build out Rhythm's operations in Japan in anticipation of a potential approval in HO. Overall, this forecasted year-over-year growth in operating expenses is the product of the last few years' clinical, regulatory, and commercial success and represents a meaningful opportunity to invest in Rhythm's long-term potential to serve patients with MC4 or pathway diseases. With that, I'll hand the call back over to David. Thank you.

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

Thank you. Certainly. As a reminder, to ask a question, you will need to press star 11 on your telephone and wait for your name to be announced. To withdraw your question, please press star 11 again. Please stand by while we compile our Q&A roster. Our first question will be coming from Derek Archila of Wells Fargo. Your line is open, Derek.

Hey, good morning, and thanks for taking the questions. Congrats on all the progress here. David, just first on divimelagons phase three, your comments suggest that this will largely look like set melanotide phase three. So in terms of sample size and duration, but are there any changes to enrollment criteria that you would 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. Are there 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. So that's an area which, as a company, we might modify, but we didn't get specific feedback from the FDA.

Got it. And then maybe just a follow-up. 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 a six-month post- surgery as an 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 want to have 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, earlier is better. Why would you If you know the patient has HO, why would you make them wait six months to begin to intervene? You wouldn't do that for their thyroid hormone replacement, for example. So 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 Ahmed. of Bank of America. Dazeen, 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? And what type of deepening response are you looking for? Are you looking for more weight loss? Are you looking for better hunger control? Or just can you give us a sense of that? Thank you.

Yeah, thanks, Justine. So, 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. But I think our goal remains the same. We'd be looking to clear 5%. on the BMI change. You know, we'll see how we do there. And of course, we'll collect hunger. I mean, the hyperphagia scores, HQCT, 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. But we will have that data, and of course, we'll share it.

And our next question. We'll be coming from the line of Mike Alls 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 incivry 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 the slowing of growth or should we think more flattish? Thanks.

Well, I'm not going to give you a 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. So, you know, we'll see how that shakes out, you know, but it's just that dynamic in and of itself that inventory represents the pull forward of sales from one 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 planned renewals and planned changes for individual patients, so some patients rotate on to our bridge program, and then those get resolved and they rotate off. Understood.

Very helpful. Thank you.

And our next question comes from the line of Whitney Agyem of CGF. 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 sub-studies 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 sub-studies, or are there genetic, biological considerations there as well?

Yeah, let me summarize what I've said previously, but, you know, important to remind. So, The way we've handicapped this is, yes, we think that the POMC HETs are the most likely to be positive, and that's based on the fact that 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, and the assay has its limitations, but the bottom line is we felt that in that cohort, we were enrolling predominantly patients who would have true loss of function. So 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, but it turns out the leptin receptor head group is extremely rare, those that have this potential loss of function variant. So that cohort was very significantly under-enrolled, and so we weren't so optimistic there or not. SRC1 mostly boosts variant of unknown significance. Variants of unknown significance disproportionately tend to be benign. And so, again, we think there's a high risk that one may not be positive. And the reason we remain somewhat hopeful on SHDB1 is that There's two groups there. One is those who have this deletion, 16P11 deletion, so by definition, with a deletion, they would have loss of function. The other part group of that that's enrolled, the sense mutations associated with SH2B1, then you're back in this, you know, how many of those are VOOCs, and of the VOOCs, how many are benign versus pathogenic. Long story short, that's how we handicapped it. Again, we're working to get that data out by the end of the year. The other thing I've said is, like I said, we've been careful and modest in terms of our projections here and what we think might happen. I think whatever we get, we're going to learn a lot from these studies. And minimally, they will form the basis for the next round of studies with our next generation studies molecules. 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. And 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, pray to Willie, of course, where we think, you know, it's a really tough disease. I mean, that is the minimal threshold, and so that's certainly the threshold here. I think in some of our other indications, you know, you get into... You know, the world expects more today from a weight loss drug, but technically it's 5% plus. I think, you know, what we would look at is A, is the study positive? And then B, do we think it's clinically meaningful and would be a meaningful offering to patients with that specific genetic defect?

Very helpful. Thanks very much.

And 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 718 in the same indication? And 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-US in order to get that patient population? Okay, thanks.

Yeah, it's a good question. So first on 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 VIVA is it's a small molecule. I think 718 is a peptide. It's highly analogous to set melanotide. I don't know if they would look at that any differently, but, you know, a conservative base case here is, yes, 718 will have to do the same thing that we're being guided to for VIVA. 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 one or more centers in many or most countries, which are pretty sophisticated. CROs are structured to run trials globally. So I'm not at all worried about quality. I mean, you pay attention to that. We'll be careful, of course, but I think quality control is not the issue. Our challenge, as always, is in rare diseases, you want to find sites that have good access to patients.

Thank you.

And our next question will be coming from Phil Nadu of TD Cohen. Your line is open, Phil.

Good morning. Congrats on progress, and thanks for taking our questions. Two from us. So first, in the melatonin phase three 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'll use. And then 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. So any update to that number? Thanks.

Yeah. Sorry, so for the... Sorry, what was the question? Oh, dosing, sorry. So the dosing will be... 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. And 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. And I'll remind you back to a patient from our phase two study, the most fairly effective oldest individual in that trial, a 24-year-old man who had a starting BMI of 52, 50 plus. And over a period of four years, he just continued to gradually decrease his BMI down to a normal BMI of 24. And I think, you know, what we're seeing here is not inconsistent with that as a gradual, you know, deepening over time. And so the short answer to your question is yes. Well, 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 two milligrams as opposed to three, but with set melanotide. But 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 it as you might expect in a hormonal replacement strategy. With regard to patients, you know, we highlighted, we updated in September, and, you know, we've stayed away from sort of giving you monthly or quarterly updates on those patient numbers, because after a while, I'm not sure how helpful that is, but 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. So, 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 the suspected category. So, 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 John Wallaban 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. I'm just wondering how we should think about the opportunity of Japan and the trajectory of a potential adoption.

Yeah. Jan, you want to take that? Yann, did we lose you?

I'm back. Okay, sorry. Yes, so potential first. So as I said earlier, we estimate the prevalence between 5,000 and 8,000 patients, and it's a well-documented prevalence, so we are quite sure of this number. The second point was your question about our capabilities. So 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. And from a timeline point of view, David mentioned the data in March. And 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. And our next question will be coming from the line of Thomas Smith of Lee Ring Partners. Your line is open, Thomas.

Hey, guys. Good morning. Thanks for taking the questions. Just on the AHO expansion, appreciate the color and 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, so 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 type Islamic obesity versus just being seen as a patient with obesity for many causes that may not be the root cause, just in terms of what they are going through. So there's still opportunity there. I think the other piece is from the perspective of a timeline of care coverage. Although we have a great starting point just in terms of all the dialogue we had with BBS in terms of the differentiation of MC4 pathway diseases versus general obesity, it's still going to take some time just in terms of going through the process of having specific TNT meetings so that we get you know, a specific policy for the expansion of the indication in place. And we're similarly in the meantime going to be working through the process as we get the Rx's in pair by pair. So 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 we know, even though 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 centers and capabilities. So we know where they go once they have the brain tumor and 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 AHO, we have the ability to really target those incident patients to get to a diagnosis that is not missed. So 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.

And 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. I'm here for Seamus Fernandez. Just two from us. First, with sub 1.8, I saw some narrowed timelines for Part D. Curious if there's any potential strategies to accelerate timelines there. Potentially, like I say, it's 2.3, just given some of the feedback and data sets around DIVA and SETML. And then 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 end, Claire, on that last part of the question, other indications that we're thinking about, other approaches?

Is that what you were asking? Other indications or approaches for, it's mostly obesity-related treatment. Thanks. Yeah.

Okay, so for 718, is there a strategy to accelerate? I mean, we take, I think, a pretty aggressive view in general. I mean, the regulators don't always agree with our approach, and so we end up sometimes in more conservative or conventional approaches. I think 7-1A, as I said earlier, is likely to be highly similar to Bivomelagon. We'll go with this initial experience and this open-label study and move right to a Phase III. 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, set melanotide will be approved and out there, so patients will have an option. So, 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 the different areas that we're interested so one is genetics you know emanate being the first you know attempt beyond our initial approvals in palm c and lep are we have the daybreak study so 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 and every one of those genetic indications but we'll come back to you with an updated plan there and with regard to you know other approaches to obesity i mean Yes, we're open to that. We have 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.

And our next question will be coming from the line of Joseph Stringer of Needham & Company. Your line is open, Joseph.

Good morning. This is Eddie on for Joey. I appreciate you taking our questions. Just to follow up on MC4R, the M&A sub-studies, can you remind us again if you intend to submit these as a combined SNDA for a broader MC4 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. And then a follow-up. I'm sorry if I misheard. Did you say that in the BIVA HO-OLE that you saw moderately better results of patients not on GLP-1? If I heard that right, can you describe how that might be the case? Thank you.

Yeah, let me take that last piece first. So when we're trying to create an apples-to-apples comparison, we took the patients in our 040 Phase III 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, their actual percent decrease was greater than the group that did not get a GLP-1. trial is not designed to prove that that might be a better outcome, but what we've concluded biologically is, yes, once you correct the underlying defect in setmelanotide and restore the hormonal deficiency, then your ability to respond to another anti-obesity medicine might be restored, and we gain weight for a different reason, and so if you're a patient who's got incremental weight because they love ice cream and they eat ice cream all the time, then a GLP-1 in that setting, once you've corrected the hormone deficiency, might make sense. So anyway, that was an apples and apples change there, and that was the goal there. Your question about M&A in terms of regulatory filing strategy, no. These will be filed individually. Even if all four were positive, 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 three for every genetic indication? I think that's possible. I would say we're definitely not, or the regulators are definitely not there today. But that's not an unreasonable question for the future.

And our next question will be coming from Paul Matisse of Stiefel. Your line is open, Paul.

Hi, this is Matthew on for Paul. Thanks so much for taking your question. I guess I had one on acquired HO. So for the FDA review, we appreciate the pivotal phase three 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 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. And 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, and yes, they are prepared to deal with the fact that, yes, 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.

And our next question will be coming from Samantha Seaman-Cow of Citi. Your line is open, Samantha.

Hi, good morning. Thanks very much for taking the question. Just maybe one clarification on the phase three. You mentioned that you were going to primarily enroll outside in countries where St. Melanotide is not available. How does that work necessarily for enrollment in the U.S.? ? And then just on Prader-Willi, can you just talk about your latest thinking on a potential phase three trial? Would you plan to take both set melanotide and 718 forward, or is it more likely that you choose one of these drugs to advance? Thanks very much.

Yeah. Okay. So with regard to the phase three for HO, yes, we will run it predominantly outside. I wouldn't exclude having a 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 II study. So I'm not, again, I'm not so worried about our ability to execute the trial not using the U.S., but, you know, you never say never, so I defer final decisions on that. So for Prader-Willi, set melanotide versus 718, I think, you know, this is something, as we've highlighted before, the advantage of going forward with set melanotide is, you know, we've got data in set melanotide already, maybe a supplemental NDA, and so we could, in a sense, roll into that phase three. The advantage of going with 718, for example, is that it's a next-gen, we're going to do a next-gen study sooner or later, and that's the end game. And if the 718 program is at a point where the gap between when we might start with 718 and when we could start with 718 is not so great, then I think we would take that time delay, if you will, and just go right to 718 and avoid having to run two studies there.

But that decision is yet to be made. We'll see how all of this plays forward.

And our last question will be coming from the line of Lisa Walter 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, I'll briefly repeat what I said before on the dose selection. I do think 200 is probably on the border in terms of being therapeutic for most patients. I think 400 to 600 is more likely in range, and 600 does seem to have a continued dose response, and so 600 for sure will be our targeted dose, just the way 3 mg was our targeted dose in the HO-set melanotide trial. You know, with regard to dosing down, you know, what's interesting here is the biology, pathophysiology, it's a hormonal deficiency. So, 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. So, I think our expectation is most patients will stay at their target dose. That's been true with set melanotide as we go forward. So, it's not... get your weight loss and then you can kind of go to a low dose to maintain. That's not the pathophysiology here.

And I'm sure I know some of the questions.

I'd now like to turn the call back to David Meeker for closing remarks. Great, thank you.

So thanks all for tuning in. Again, we remain really excited about the progress here at Rhythm. Lots of exciting things coming up. 2025 was a big year. I'm 2026 is going to be equally big. So look forward to the next update. Thanks all.

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