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.