Rhythm Pharmaceuticals, Inc.

Good day and welcome to Rhythm Pharmaceutical's fourth quarter and fiscal year 2024 earnings conference call. At this time, all participants are in listen-only mode. After the speaker's presentation, there'll be a question and answer session. Instructions will be given at that time. As a reminder, this call may be recorded. I would like to turn the call over to David Connolly, IR and Corporate Communications. Please go ahead.

Thank you, Michelle. 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 a full quarter of 2024 and full year 2024 financial results and a business update, and that press release is 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 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 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, everybody. Thank you for joining. So we pre-announced strong fourth quarter earnings in advance of the JPM conference. We are entering 2025 well capitalized, having recently raised $75 million in gross proceeds from our ATM program, which extends our cash run right into 2027 through multiple inflection points. And we have completed enrollment in our phase two daily oral Bivomalagon study. We feel incredibly positive about how the opportunity in genetically driven impairments to the MC4R pathway signaling is evolving. As we have highlighted many times, ultra-rare disease opportunities like BBS, where there is a significant unmet medical need, a high percentage of undiagnosed patients, and where the availability of a precision therapy can accelerate the number of patients getting to a diagnosis, these opportunities will continue to grow at a steady pace for a decade or longer. The U.S. opportunity is taking shape, and we will continue to expand internationally. We could build a business around the BBS opportunity alone. We are excited about the progress we are making with our next-generation compounds, Bivomelagon, a once-daily oral pill, and the weekly sub-Q injection, RM718. Now, our goal with the next-generation opportunity is not just to extend patent life, but to actually make a better drug. Both products have robust activity in preclinical models and have no cardiovascular activity in the appropriate models. Both are MC1R-sparing, so no hyperpigmentation, and significantly more convenient. Whether there is an opportunity to improve on efficacy remains to be seen. The Bivomelagon Phase II study is fully enrolled this quarter and will read out in the third quarter, and the 718 program is beginning to enroll this quarter. Slide 7 is the now familiar design slide for a Phase III trial of set melanotide and acquired HO, and we continue to receive the majority of our questions here. What is the timing of the readout? What is the expected percent change in BMI? We have guided to the trial reading out in the first half, and we can now be more specific that it will be a second quarter readout. Our updates remain consistent with what we have said. Our dropout rate remains below 10%, which I think is an incredibly strong metric. Patients are rolling over into the open label extension. They do remain blinded to their original assignment. And only one patient has not rolled over because that patient wanted to start a family. With regard to the percent change in BMI, it is a blinded phase three clinical trial. We have, however, reminded people that the current fervor around percent change comes out of the many trials being run in a general obesity space with some version of a GLP-1. These trials have similar designs, so comparisons can be made across trials, although this is always imperfect. When we look at set melanotide in HO, it is an apples and oranges comparison. The biology is fundamentally different. We are replacing a deficit in the hormone alpha-melanocyte-stimulating hormone. The GLP-1 approach is to provide pharmacologic doses on top of intact physiology. Our trial enrolls 4-year-old patients and 60-year-old patients, and we measure the same endpoint, the percent change in BMI at 52 weeks. In our Phase II trial, the youngest patient, age 6, lost approximately 35% of their BMI at 16 weeks, whereas the oldest patient, 24 years old, lost 14%. Now, the 24-year-old patient actually lost more weight, but on a percent basis, it was a smaller change. So these are variables which will impact the final number. That said, all of our data to date, the Phase II study, which was predominantly pediatric patients, and the French pre-approval early access data, which was all adults, suggest we will do well on the primary. The secondaries will break out the pediatric and adult patients, so the full story can be clearly understood. The Japanese cohort of 12 patients, for which we recently completed enrollment, will read out independently from the pivotal cohort, so there is no impact on timing of top-line data and subsequent regulatory filings in the United States and Europe. We expect the Japanese cohort will read out in the first half of 6. If successful, these data will enable us to seek marketing authorization in Japan, where there is a higher prevalence of certain brain tumors and hypothalamic obesity than in the U.S. or Europe. A reminder on slide 8 that the opportunity in the HO is significant, and we continue to learn more. We affirm our original estimates, which we believe were appropriately conservative. The populations reflected on the slides with 5,000 to 10,000 patients in the U.S. and a similar range in Europe and 5,000 to 8,000 patients in Japan represent a pool of patients who may be largely diagnosed and concentrated in the endocrinology specialty call point. There's an additional pool of patients with injury to the hypothalamus where the diagnosis is not so clear, and they are likely to remain undiagnosed. We look forward to expanding our understanding of this patient population. Now, the path to building the future of rhythm is clear. We have opportunities to further explore genetically driven impairments in the MC4R pathway. The M&A trial is enrolled and will read out in the first half of 2026. There are genes coming out of the Daybreak trial, which with a little more work can also be targeted. Prader-Willi syndrome is a challenging disease, but there's a sound biologic rationale as to why an MC4R agonist can work in that disease. This quarter, we have initiated, as you know, a new 26-week open-label Phase II trial to evaluate set melanotid and Prader-Willi syndrome. We plan to enroll up to 20 patients, 6 to 65 years old, in the signal-finding study. and patients will be dose escalated to five milligrams a day, which is significantly higher than the dose we used in the first attempt at Prader-Willi, and they'll be dose escalated to that five milligrams as tolerated. So we are conducting this trial at a single US site under an investigator with deep experience in Prader-Willi syndrome, and we look forward to updating you on that progress. The other pillar which is emerging as an incredibly exciting opportunity is that related to injury to the hypothalamus or failure of the hypothalamus to develop. We have focused on tumors and their associated treatment, which may lead to injury, but there are clearly many more ways the hypothalamus may be injured, leaving the patient with acquired HO. We look forward to learning more about set melanocytes activity in patients with developmental abnormalities related to congenital syndromes involving this area of the brain, and we are on track to enroll the first patients with congenital HO in an independent 39-patient, 34-week sub-study in the first quarter of 2025. Finally, we anticipate doing much, if not all, of the supplemental indication expansion work with one or both for our next generation compounds with patent lines which extend past 2040. We have completed enrollment in the Phase II Bivomaligon trial and acquired HO this quarter, and we anticipate the data readout to be in the second half of 2025. Also, we will begin enrolling patients with acquired HO in Part C of the Phase I trial of RM718 this quarter, and are aiming for a data readout before the end of the year. So in summary, 2024 was a year of execution, and 2025 is a year of readouts, which could prove to be transformative for Rhythm, in addition to some critical trial initiations. I will now turn the call over to Jennifer.