On Today's Call Rhythm Pharmaceuticals Fourth Quarter and Year End 2025 Financial Results and Business Update February 26, 2026 ® © Rhythm® Pharmaceuticals, Inc. All rights reserved. ® 2 • David Connolly, Executive Director of Investor Relations and Corporate Communications • David Meeker, MD, Chair, President and Chief Executive Officer • Jennifer Lee, Executive Vice President, Head of North America • Yann Mazabraud, Executive Vice President, Head of International • Hunter Smith, Chief Financial Officer Fo ...

-- Fourth quarter 2025 net product revenue from global sales of IMCIVREE® (setmelanotide) of $57.3 million -- -- March 20, 2026 PDUFA goal date for sNDA for setmelanotide in acquired hypothalamic obesity (HO) ---- Phase 2 open-label extension data showed bivamelagon achieved persistent BMI reductions at six and nine months; Completed positive end-of-Phase-2 meeting with FDA ---- On track to report topline data from 12-patient Japanese cohort of setmelanotide Phase 3 trial in acquired HO in March 2026 -- -- ...

Rhythm Pharmaceuticals Conference Call Summary Company Overview - **Company**: Rhythm Pharmaceuticals (NasdaqGM:RYTM) - **Focus**: Treatment of rare neuroendocrine disorders, specifically targeting the MC4R pathway - **Key Product**: IMCIVREE (setmelanotide), the first approved agonist of the MC4R pathway, with three current indications and a fourth pending approval for hypothalamic obesity (HO) on March 20, 2026 [2][3] Core Points and Arguments Product and Pipeline - IMCIVREE is approved for three indications, with a significant upcoming indication for hypothalamic obesity [2] - Recent interim phase 2 data in Prader-Willi syndrome shows promise [3] - Two additional pipeline compounds: - Bivamelagon (oral small molecule MC4R agonist) - RM-718 (weekly injectable therapy) [3] Market Dynamics - **Sales Growth**: - $57 million in sales reported last quarter, with a 9% quarter-over-quarter growth for the bulk of the previous year [9] - 10% growth in reimbursed patients and a 7% increase in BBS prescriptions in Q4 [9] - **Patient Population**: - Targeting approximately 1,000 patients in the U.S. for BBS, with a potential peak sales opportunity of $300 million [12] - For HO, estimates suggest upwards of 10,000 patients in the U.S., indicating a larger market potential compared to BBS [13] Clinical Data - HO study showed a 16.5% reduction in BMI for patients on setmelanotide, with a placebo-adjusted difference of 19.8% at 52 weeks [20] - High response rates: 80% of patients had more than a 5% BMI reduction, and 60% had more than a 10% reduction [20] Commercial Strategy - Increased sales force from 16 to 42 representatives in anticipation of the HO PDUFA date [22] - Utilization of claims data to identify potential HO patients, with 2,000 suspected or diagnosed patients identified in targeted physician practices [24] - Challenges include physician awareness and the reimbursement process, particularly for Medicare patients [30] Regulatory and Development Updates - Delay in PDUFA due to additional analysis requested by the FDA regarding BMI Z scores for patients under 18 [36] - Ongoing studies in Prader-Willi syndrome, with interim data showing positive results for patients on setmelanotide [44] Other Important Considerations - The company is navigating the complexities of physician education regarding hypothalamic obesity, which is not widely understood among endocrinologists [26] - The potential impact of Medicare reimbursement policies on the launch trajectory for HO treatment [30] - Cash runway of approximately $418 million, providing at least 24 months of operational funding [51] This summary encapsulates the key insights from the Rhythm Pharmaceuticals conference call, highlighting the company's strategic focus, market opportunities, clinical data, and regulatory challenges.

Core Viewpoint - Rhythm Pharmaceuticals reported strong preliminary unaudited net product revenues for IMCIVREE, indicating significant growth in 2025 and outlining future milestones for product development and regulatory approvals [2][3][6]. Financial Performance - Preliminary unaudited net product revenues for Q4 2025 are expected to be approximately $57 million, reflecting an 11% increase from Q3 2025 [3][6]. - Full-year 2025 net product revenues are projected to be around $194 million, a 50% increase compared to $130 million in 2024 [3][6]. - U.S. sales contributed approximately 68% of Q4 revenues and about 69% of full-year revenues for 2025 [3][6]. Upcoming Milestones - The company plans to launch IMCIVREE for acquired hypothalamic obesity in the U.S. pending FDA approval, with a PDUFA goal date set for March 20, 2026 [7]. - Top-line data from the Japanese cohort of the Phase 3 trial in acquired hypothalamic obesity is expected in Q1 2026 [6][8]. - Top-line data from the Phase 3 EMANATE trial evaluating setmelanotide in genetically caused MC4R pathway diseases is also anticipated in Q1 2026 [6][8]. Product Development - Rhythm is advancing setmelanotide for Prader-Willi syndrome, with positive preliminary data from a Phase 2 trial showing reductions in BMI and hyperphagia [9]. - The company plans to initiate a pivotal Phase 3 trial for bivamelagon in acquired hypothalamic obesity in 2026, pending feedback from regulatory agencies [10]. - Enrollment in the Phase 1 trial for RM-718 is expected to be completed in Q1 2026 [11].

Financial Performance & Guidance - Rhythm Pharmaceuticals reported Q3 2025 product revenue of $51.3 million, compared to $33.3 million in Q3 2024[51] - The company experienced a 10% quarter-over-quarter growth in patients on reimbursed therapy globally[49] - Q3 2025 operating expenses totaled $98.5 million, including $18.8 million in stock-based compensation expense[52] - Rhythm anticipates non-GAAP operating expenses for 2025 to be between $295 million and $315 million, including R&D expenses of $150 million to $165 million and SG&A expenses of $145 million to $150 million[52] - As of September 30, 2025, Rhythm Pharmaceuticals held $416.1 million in cash, cash equivalents, and short-term investments[51] IMCIVREE & Pipeline Updates - Steady growth in global IMCIVREE sales in Q3 2025 was primarily driven by Bardet-Biedl syndrome (BBS)[10] - The FDA accepted the sNDA for setmelanotide in acquired hypothalamic obesity (HO) for Priority Review, with a PDUFA goal date of December 20, 2025[10] - A German investigator-led study showed that over 80% of BBS patients on setmelanotide exhibited either resolution of MASLD or stabilization at grade S1 after six months of therapy[12] - The same study showed 100% of patients (N=26) with both BBS and metabolic dysfunction-associated steatotic liver disease (MASLD) showed improvement[12] Strategic Initiatives & Market Access - Rhythm Pharmaceuticals estimates the U S prevalence of acquired hypothalamic obesity to be approximately 10,000 patients[15] - IMCIVREE is available in >25 countries outside the United States[36] - Rhythm estimates the European prevalence of acquired hypothalamic obesity to be approximately 10,000 patients[40] - Rhythm estimates the prevalence of acquired hypothalamic obesity in Japan to be approximately 5,000 to 8,000[43]

Core Insights - Rhythm Pharmaceuticals reported continued momentum in the third quarter of 2025, highlighted by FDA acceptance of the supplemental new drug application (sNDA) for acquired hypothalamic obesity and steady growth from Bardet-Biedl syndrome (BBS) commercial efforts [2][5] Financial Performance - Revenue from global sales of IMCIVREE (setmelanotide) was $51.3 million for Q3 2025, a 6% increase from Q2 2025, primarily driven by growth in patients and sales for BBS treatment [3][9] - U.S. revenue accounted for $38.2 million (74% of product revenue), marking a 19% sequential increase, while international revenue was $13.1 million (26% of product revenue), reflecting a 21% decrease [3][9] - The company recorded a one-time charge of $3.2 million in Q3 2025 due to a final reimbursed price agreement for IMCIVREE in France [3][9] - R&D expenses were $46.0 million in Q3 2025, up from $37.9 million in Q3 2024, mainly due to increased headcount and stock-based compensation [10] - SG&A expenses rose to $52.4 million in Q3 2025 from $35.4 million in Q3 2024, driven by higher costs associated with expanding operations and marketing [11] - The net loss attributable to common stockholders was $54.3 million for Q3 2025, compared to a net loss of $45.0 million in Q3 2024 [12] Clinical Developments - Rhythm expects to report preliminary results from the Phase 2 trial of setmelanotide in Prader-Willi syndrome in Q4 2025 [5][13] - A recent observational study indicated that setmelanotide treatment improved measures of metabolic dysfunction-associated steatotic liver disease (MASLD) and kidney function in BBS patients [6][7] Upcoming Milestones - The FDA's PDUFA goal date for the sNDA for setmelanotide in acquired hypothalamic obesity is set for December 20, 2025 [5][7] - The company anticipates completing enrollment in the Phase 1 trial evaluating RM-718 in Q1 2026 and announcing topline data from various ongoing trials in early 2026 [13] Cash Position - As of September 30, 2025, the company had approximately $416.1 million in cash, cash equivalents, and short-term investments, compared to $320.6 million at the end of 2024 [8][20]

Clinical Trial Results & Regulatory - Setmelanotide achieved a 19.8% placebo-adjusted difference in BMI reduction from baseline in the Phase 3 acquired hypothalamic obesity (HO) trial (P<0.0001)[33] - In the setmelanotide arm of the Phase 3 trial, patients experienced a -16.5% change in BMI from baseline[32] - A statistically significant reduction in Most Hunger Score was observed with setmelanotide vs placebo in participants aged ≥12 years (P=0.0086)[40] - Setmelanotide was generally well-tolerated in the Phase 3 trial, with most common adverse events including skin hyperpigmentation (55.6%), nausea (50.6%), and headache (38.3%)[45] Market Opportunity & Commercial Strategy - The estimated U S prevalence of acquired HO is approximately 10,000 individuals[48] - The estimated prevalence in Europe is also around 10,000 individuals[48] - The estimated prevalence in Japan is between 5,000 and 8,000 individuals[48] - Rhythm anticipates strong commercial and Medicaid coverage for setmelanotide in HO, similar to or better than coverage for Bardet-Biedl syndrome (BBS)[82] Company Readiness - Rhythm has established a solid global foundation with IMCIVREE available in >25 countries and >350 employees in 15 different countries[23] - The company has an experienced rare disease team in place to support ongoing growth in BBS[72]

Financial Performance & Outlook - Rhythm Pharmaceuticals reported $48.5 million in net product revenue from global sales in Q2 2025, a 29% sequential growth[60] - The company's cash, cash equivalents, and short-term investments totaled $291 million as of June 30, 2025[59,62] - Rhythm anticipates non-GAAP operating expenses for 2025 to be between $285 million and $315 million, including SG&A expenses of $135 million to $145 million and R&D expenses of $150 million to $170 million[63] - A public offering of common stock closed July 11, 2025, resulting in net proceeds of $189.2 million[59] Clinical & Regulatory Updates - Rhythm is on track to complete U S and EU regulatory submissions for setmelanotide in acquired hypothalamic obesity (HO) in Q3 2025[10,33] - Phase 3 trial data showed a -16.5% BMI change from baseline in the setmelanotide arm (n=81) compared to a +3.3% BMI change in the placebo arm (n=39), resulting in a placebo-adjusted difference in BMI reduction of -19.8% (P<0.0001)[21,22,23,24] - Bivamelagon achieved statistically significant BMI reductions at all doses in a 14-week, Phase 2 trial, with reductions of -2.68% (200mg), -7.69% (400mg), and -9.31% (600mg) compared to a +2.18% increase in the placebo group[25] Commercial Performance & Strategy - The company saw a 38% increase in cumulative prescribers from Q2 2024 to Q2 2025 and a 9% increase from Q1 2025 to Q2 2025 for IMCIVREE prescriptions in patients with Bardet-Biedl syndrome (BBS)[40] - IMCIVREE prescriptions for patients aged 2-12 years accounted for 40% of Q2 2025 prescriptions[43]

Core Insights - Rhythm Pharmaceuticals reported a net product revenue of $48.5 million from global sales of IMCIVREE® (setmelanotide) for Q2 2025, marking a 29% increase sequentially from Q1 2025, primarily driven by sales for Bardet-Biedl syndrome (BBS) [6][9] - The company presented strong Phase 2 and Phase 3 data demonstrating the efficacy of bivamelagon and setmelanotide for treating acquired hypothalamic obesity [2] - Rhythm strengthened its balance sheet with a public offering that raised approximately $189.2 million in net proceeds [5] Financial Performance - Revenue from global sales of IMCIVREE was $48.5 million for Q2 2025, compared to $29.1 million for Q2 2024 [9] - R&D expenses increased to $42.3 million in Q2 2025 from $30.2 million in Q2 2024, attributed to higher drug formulation and clinical trial costs [10] - SG&A expenses rose to $45.9 million in Q2 2025 from $36.4 million in Q2 2024, driven by increased headcount and marketing costs [11] - The net loss attributable to common stockholders was $48.0 million for Q2 2025, compared to a net loss of $33.6 million for Q2 2024 [14] Clinical Development Highlights - U.S. and EU regulatory submissions for setmelanotide in acquired hypothalamic obesity are on track for completion in Q3 2025 [5] - The Phase 2 trial of bivamelagon met its primary endpoint with significant BMI reductions [5] - Data from the Phase 3 TRANSCEND trial showed a 19.8% placebo-adjusted difference in BMI reduction [5] Upcoming Milestones - Rhythm plans to host an event on September 24, 2025, to discuss its global launch strategy for setmelanotide [7] - The company anticipates completing enrollment in the Phase 1 trial for RM-718 in Q1 2026 and announcing topline data from various ongoing trials in early 2026 [12] Cash Position - As of June 30, 2025, the company had cash, cash equivalents, and short-term investments of approximately $291.0 million, not including the $189.2 million raised from the public offering [8][21]

Business Highlights - Rhythm Pharmaceuticals is on track to complete U S and EU regulatory submissions for setmelanotide in acquired hypothalamic obesity (HO) in Q3 2025[9] - The company experienced solid patient demand growth for IMCIVREE (setmelanotide) in Q1 2025[9] - Data readout for the Phase 2 trial of oral bivamelagon in acquired HO is expected in Q3 2025[9] - Rhythm Pharmaceuticals expects its current cash runway to extend into 2027[9] Clinical Trial Results (Setmelanotide in Acquired HO) - The Phase 3 trial showed a statistically significant BMI reduction of 16 5% in the setmelanotide arm compared to baseline[13] - The placebo-adjusted difference in BMI reduction from baseline was 19 8% (P<0 0001)[14] - Significant BMI reductions were observed in both adults (16 3%) and children (16 8%) treated with setmelanotide[18] - A vast majority of patients with acquired HO completed the Phase 3 trial and transitioned to an extension study[27] Financial Performance (Q1 2025) - Net product revenue was $37 7 million, compared to $26 0 million for the three months ended March 31, 2024[63] - Cash, cash equivalents, and short-term investments totaled $314 5 million as of March 31, 2025[63] - The company anticipates non-GAAP operating expenses between $285 million and $315 million for 2025[66]