Financial Data and Key Metrics Changes - Rhythm Pharmaceuticals reported global revenue of $51.3 million for Q3 2025, a sequential increase of 6% from $48.5 million in Q2 2025 [28] - The number of patients on reimbursed therapy increased by 10% globally during the quarter [28] - Year-over-year, net product revenues increased by $18 million, or 54%, compared to Q3 2024 [32] Business Line Data and Key Metrics Changes - InSibiri sales reached $51.3 million, driven predominantly by Bardet-Biedl Syndrome (BBS), with a 10% increase in the number of patients on reimbursed therapy [4][28] - The proportion of prescriptions for pediatric versus adult patients began to normalize, with 50% of new patients being adults, 22% adolescents, and 28% pediatrics [16] Market Data and Key Metrics Changes - In the U.S., $38.2 million or 74% of Q3 net revenue was generated, while $13.1 million or 26% came from international markets [28] - International revenue decreased by $3.4 million quarter-over-quarter, but patients on reimbursed therapy increased at a low double-digit percentage [30] Company Strategy and Development Direction - The company is preparing for the launch of InSibiri for hypothalamic obesity, pending FDA approval, with a PDUFA date set for December 20, 2025 [5][11] - Rhythm is focused on engaging with physicians and payers to establish InSibiri as a foundational treatment for acquired hypothalamic obesity [20] - The company aims to complete enrollment of the RM-718 weekly phase 2 study in HO patients during Q1 2026 and initiate a phase 3 study with Bivamelagon next year [12][13] Management's Comments on Operating Environment and Future Outlook - Management expressed confidence in the upcoming launch of InSibiri for hypothalamic obesity, highlighting strong growth in BBS and promising regulatory dialogues [5][11] - The company anticipates that the upcoming data readouts and regulatory approvals will position it for sustained long-term growth [4][5] Other Important Information - Rhythm raised approximately $189 million in net proceeds from a follow-on equity offering completed in July 2025, ending Q3 with $416.1 million in cash [28] - The company expects to have sufficient cash to fund planned operations for at least 24 months [34] Q&A Session Summary Question: Can you share your latest thinking on the trial design for your phase 3 HO study? - The HO trial will be a double-blind randomized controlled trial, with expectations for a full year of data [39] Question: Can you provide more details on the efficacy endpoints for Prader-Willi syndrome? - Success will be defined by a BMI percent change, with a target of a 5% threshold in BMI decrease in 52 weeks [45] Question: What are the drivers behind the changes to the ongoing Prader-Willi trial? - The trial was extended to allow patients to continue beyond the initial six months if they wish, and there is a possibility of adding additional sites [51] Question: How should investors think about the launch curve in hypothalamic obesity? - The company has a solid foundation based on learnings from the BBS launch, but the process of getting patients diagnosed may take time [60][62] Question: What is the anticipated gross to net in HO relative to BBS? - The gross to net mix is uncertain, but the company expects to work through reimbursement processes similar to those for BBS [66]

Clinical Trial Results - Bivamelagon achieved statistically significant BMI reductions in patients with acquired hypothalamic obesity at 14 weeks[5] - At 14 weeks, the 200mg Bivamelagon group saw a mean BMI reduction of 268%, the 400mg group saw a mean BMI reduction of 769%, and the 600mg group saw a mean BMI reduction of 931%[27] - In the placebo group, there was a mean BMI increase of 218% from baseline at 14 weeks[27] - A significant percentage of patients achieved clinically meaningful BMI reductions: 167% in the 200mg Bivamelagon group, 714% in the 400mg group, and 75% in the 600mg group achieved at least a 5% BMI reduction[33] - Bivamelagon also achieved meaningful reductions in 'most' hunger scores at Week 14[44] Safety and Tolerability - Safety and tolerability results were generally consistent with an MC4R MOA and setmelanotide trials in acquired hypothalamic obesity, with limited instances of localized hyperpigmentation[5] - The most common AEs with >=10% in all BIVA dosing (N=21) were nausea, diarrhea, vomiting, and headache[47] Market Opportunity and Future Development - Rhythm Pharmaceuticals intends to request an End-of-Phase 2 meeting with the FDA with intentions to move forward to Phase 3[5] - The company estimates the U S prevalence of acquired hypothalamic obesity to be 5,000 – 10,000 patients[13] - U S patent protection for bivamelagon and RM-718 extends into the 2040s[13]

Core Insights - Rhythm Pharmaceuticals announced positive topline results from its Phase 2 trial of bivamelagon, showing significant BMI reductions in patients with acquired hypothalamic obesity [2][3] - The company plans to engage with regulatory authorities for a Phase 3 trial design and has requested an End-of-Phase 2 meeting with the U.S. FDA [7] Group 1: Trial Results - Bivamelagon achieved BMI reductions of -9.3% in the 600mg cohort and -7.7% in the 400mg cohort at 14 weeks [1][4] - A post-hoc analysis indicated that the BMI reductions from bivamelagon were consistent with those achieved by setmelanotide in similar patient populations [3][5] - Patients reported a mean reduction of -2.8 points in hunger scores in both the 600mg and 400mg cohorts [1][3] Group 2: Safety and Tolerability - The trial demonstrated safety and tolerability consistent with MC4R agonism, with limited instances of localized hyperpigmentation observed [4][6] - The most common adverse events included mild diarrhea and nausea, with one serious adverse event reported [6] Group 3: Next Steps and Regulatory Plans - Rhythm plans to seek input from U.S. and EU regulatory authorities regarding the Phase 3 trial design for bivamelagon [7] - The company is refining the formulation of bivamelagon to potentially improve tolerability before initiating the Phase 3 trial [7] Group 4: Company Background - Rhythm Pharmaceuticals is focused on transforming the lives of patients with rare neuroendocrine diseases and has in-licensed bivamelagon from LG Chem, Ltd [2][13] - The company’s lead asset, setmelanotide, is already approved for treating certain types of obesity [13][14]