Rhythm Pharmaceuticals Conference Call Summary Company Overview - **Company**: Rhythm Pharmaceuticals (NasdaqGM:RYTM) - **Event**: Conference call discussing the phase 3 EMANATE trial results - **Date**: March 16, 2026 Key Points Industry and Company Context - Rhythm Pharmaceuticals focuses on developing therapies for genetic diseases related to obesity, particularly those affecting the MC4R pathway [2][16] Core Findings from the EMANATE Trial - The trial missed its primary endpoint across all four genetic cohorts, but there were positive signals in the POMC heterozygous cohort and a clear signal in the SRC1 cohort [4][15] - The SH2B1 cohort did not show expected results, with a modified intent-to-treat analysis indicating no significant effect [15] - The dropout rate was notably high, averaging between 40%-60%, which complicated the analysis [9][30] Statistical Analysis and Results - The primary endpoint was defined as the change in BMI at 52 weeks, with the trial being a double-blind, placebo-controlled design [8] - The modified intent-to-treat analysis using conservative multiple imputation showed no significant difference for the primary endpoint across cohorts [10] - A post-hoc analysis using last observation carried forward methodology indicated a statistically significant difference of 5.53% in the modified intent-to-treat population [10] - In genetically confirmed patients, a significant difference of 6.8% was observed [11] Genetic Cohorts and Patient Enrollment - The trial included cohorts based on genetic variants affecting POMC, PCSK1, LEPR, SRC1, and SH2B1, with varying levels of understanding regarding the pathogenicity of these variants [7][8] - The SRC1 cohort had a low probability of success due to all variants being classified as variants of unknown significance (VUS) [12] - The LEPR cohort was particularly challenging to recruit due to its rarity [8] Adverse Events and Dropout Reasons - Common adverse events included injection site reactions, gastrointestinal complaints, and hyperpigmentation [9] - The most common reason for discontinuation in the placebo group was patient choice, while adverse events were the primary reason for those on setmelanotide [9][35] Future Directions and Strategic Focus - Rhythm plans to focus on next-generation therapies targeting the MC4R pathway, with priorities including HO studies, Prader-Willi syndrome, and other genetic diseases [16][26] - The company aims to improve patient identification for future trials to minimize the number of patients without true loss of function variants [36][42] - There is an emphasis on learning from the current trial to enhance future study designs and patient recruitment strategies [36][49] Regulatory Considerations - Rhythm will not file for regulatory approval based on the current trial results, as the data did not support a positive outcome [20][25] - Future trials will utilize insights gained from the EMANATE trial to better define patient populations and improve the likelihood of success [25][53] Conclusion - Despite the disappointing results, Rhythm Pharmaceuticals remains optimistic about the learnings from the trial and the potential for future therapies targeting genetic obesity disorders [61]

Core Insights - Rhythm Pharmaceuticals announced topline results from its EMANATE trial, indicating that four substudies did not meet their primary endpoints [1][2] - Despite the disappointing primary results, the company noted encouraging signals from additional analyses of specific substudies, which may inform future development of next-generation MC4R agonists [2][4] Study Overview - EMANATE was a global, randomized, double-blind, placebo-controlled Phase 3 trial designed to evaluate the efficacy and safety of setmelanotide in patients with rare, genetically-driven obesities of the MC4R pathway [2][3] - The trial included four independent genetic substudies focusing on patients with obesity due to heterozygous variants of the POMC/PCSK1, LEPR, SRC1, and SH2B1 genes [2] Topline Results - The primary endpoint was the difference in mean percent change in BMI from baseline to Week 52 versus placebo [3] - Post hoc analyses showed statistically significant and clinically meaningful BMI reductions at Week 52 in the POMC/PCSK1 Hets and SRC1 substudies [3][4] - Specific results included a 5.5% least-squares mean difference in BMI for POMC/PCSK1 Hets patients and a 6.2% difference for SRC1 patients, both statistically significant [5] Safety Profile - No new safety signals were observed with setmelanotide, and the safety profile was consistent with prior studies [3] - Common treatment-emergent adverse events included skin hyperpigmentation, injection site reactions, nausea, vomiting, and headache [3][20] Future Plans - The company plans to continue analyzing the EMANATE dataset and evaluate potential clinical development paths for SRC1 and POMC with next-generation MC4R agonists [4][6] - Rhythm is also advancing a broad clinical development program for setmelanotide and investigational MC4R agonists [9]

Rhythm Pharmaceuticals Conference Call Summary Company Overview - **Company**: Rhythm Pharmaceuticals (NasdaqGM:RYTM) - **Focus**: Development of therapies targeting the melanocortin-4 (MC4) pathway, specifically for rare diseases related to obesity and hormonal deficiencies [2][5] Key Points and Arguments Current Products and Pipeline - **Approved Drug**: Setmelanotide (brand name IMCIVREE), an analog of alpha-melanocyte-stimulating hormone, targeting genetic causes of impaired signaling in the MC4 pathway [2] - **Pillars of Development**: 1. **Genetic Causes**: Focus on multiple genes affecting the MC4 pathway, with an upcoming M&A trial [3] 2. **Anatomic Hypothalamic Dysfunction**: PDUFA date for this indication is March 20, 2026, with a patient population of approximately 10,000 in the U.S. [3] 3. **Prader-Willi Syndrome**: A well-defined disease with significant unmet medical need, with ongoing developmental strategy [4][5] Market Strategy - **Global Approach**: Emphasis on a global strategy for rare diseases to maximize shareholder value [5] - **Next Generation Therapies**: Development of daily oral and weekly injectable formulations to improve patient compliance and treatment outcomes [6] Launch Strategy for Hypothalamic Obesity (HO) - **Sales Force Expansion**: Increase from 16 salespeople for Bardet-Biedl syndrome (BBS) to 42 for HO, focusing on endocrinologists due to the hormonal deficiencies in patients [17] - **Patient Identification**: Over 2,000 patients identified, with a focus on suspected and diagnosed cases [18] - **Launch Expectations**: Anticipated average time from script to therapy initiation is around three months, with potential for improvement based on prior experience with BBS [20] Risks and Challenges - **Regulatory Risks**: Concerns about the impact of new data on the PDUFA date, but confidence in established safety and supply chain [27] - **Market Awareness**: Need for increased awareness among endocrinologists regarding acquired hypothalamic obesity [21] International Strategy - **Japan Market**: Higher prevalence of HO in Japan compared to the U.S., with plans to establish a local presence and build a qualified team ahead of launch [29][32] Clinical Trials and Data - **Prader-Willi Data**: Open-label trial showing modest weight loss in patients, with plans for further studies [34] - **Phase 3 Trials**: Ongoing discussions about the design and execution of Phase 3 trials for both HO and Prader-Willi [37][39] Intellectual Property and Commercial Life - **Patent Protection**: Current composition patent for setmelanotide extends to 2032, with formulation patents extending to 2034 in the U.S. and longer in Europe [45] - **Next Generation Molecules**: Expected patent extensions through 2040+, providing a long commercial runway [46] Future Directions - **Bivamelagon Development**: Plans for a Phase 3 trial for HO, aiming for initiation by the end of the year [47] - **Exploration of Additional Indications**: Consideration of smaller indications for future development [48] Additional Insights - **Market Potential**: Strong belief in the opportunity for growth in the rare disease market, with a focus on building awareness and patient access [49] - **Investor Communication**: Emphasis on the company's future potential rather than past performance [49]

Financial Data and Key Metrics Changes - Revenue from sales of IMCIVREE was $57.3 million for Q4 2025, representing a quarter-over-quarter increase of 12% and $194.8 million for the full year, an increase of approximately 50% from 2024 [30][31] - Gross to net for U.S. sales was approximately 84.6%, generally in line with previous quarters [33] - GAAP EPS for Q4 2025 was a net loss per basic and diluted share of $0.73, including $0.02 per share from accrued dividends on convertible preferred stock [36] Business Line Data and Key Metrics Changes - In Q4 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 [31] - The volume of vials shipped to specialty pharmacy in the U.S. was approximately 1.7 million greater than the vials dispensed to patients, resulting in a negative $1.3 million inventory swing from Q3 to Q4 [31][32] - The company expanded its sales force from 16 to 42 to prepare for the Acquired Hypothalamic Obesity launch [19] Market Data and Key Metrics Changes - The company reported a steady growth in prescriptions for BBS as teams focused on educating healthcare providers and securing reimbursement approvals [18] - The estimated prevalence of Acquired Hypothalamic Obesity in the U.S. is 10,000, representing a significant opportunity for the company [19] Company Strategy and Development Direction - The company plans to initiate the Phase 3 HO study by year-end 2026, following a constructive FDA meeting confirming readiness to move forward [13] - The company is preparing for multiple opportunities in Europe and Japan, with a higher per capita prevalence of acquired HO than the U.S. [27] - The company aims to establish reimbursement for acquired HO in Europe on a country-by-country basis, similar to previous efforts for POMC/LEPR and BBS [28] Management's Comments on Operating Environment and Future Outlook - Management expressed confidence in the growth of the BBS opportunity and the expected launch of Acquired Hypothalamic Obesity therapy [6][19] - The management highlighted the importance of early intervention for patients with hypothalamic obesity, suggesting that guidelines may evolve to allow earlier treatment [46] - The company anticipates a potential pull forward of revenue from Q4 into Q1 due to inventory dynamics [55] Other Important Information - The company ended 2025 with approximately $389 million in cash equivalents and short-term investments, expected to fund operations for at least 24 months [36] - Non-GAAP operating expenses for 2026 are anticipated to be approximately $385 million-$415 million, reflecting a year-over-year increase driven by clinical program success [39][40] Q&A Session Summary Question: Update on bivamelagon Phase 3 trial - Management confirmed that the trial will largely mimic the Phase 3 design of setmelanotide, with no specific changes to enrollment criteria [43] Question: Guidelines for hypothalamic obesity treatment - Management indicated that while current guidelines suggest a six-month wait post-surgery, feedback suggests earlier intervention may be beneficial [46] Question: Update on PWS study - Management stated that they are on track for a mid-year update and are looking for a minimum of 5% BMI change as a goal [50][52] Question: IMCIVREE sales trends - Management noted potential dampening of sales in Q1 due to inventory pull forward from Q4 [54] Question: EMANATE study substudies - Management explained that POMC heads are expected to be the most likely to be positive based on prior assays and patient enrollment [59] Question: Dosing for bivamelagon Phase 3 trial - Management confirmed that dosing will escalate from 200 mg to a target of 600 mg [72] Question: Opportunity in Japan - Management estimated the prevalence of acquired HO in Japan to be between 5,000 and 8,000 patients, with plans for a launch within 12 months [82]

Financial Data and Key Metrics Changes - Revenue from sales of IMCIVREE was $57.3 million for Q4 2025, representing a quarter-over-quarter increase of 12% and $194.8 million for the full year, an increase of approximately 50% from 2024 [30][31] - Gross to net for US sales was approximately 84.6%, generally in line with previous quarters [33] - GAAP EPS for Q4 2025 was a net loss per basic and diluted share of $0.73, including $0.02 per share from accrued dividends on convertible preferred stock [36] Business Line Data and Key Metrics Changes - In Q4 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 [31] - The volume of vials shipped to specialty pharmacy in the US was approximately 1.7 million greater than the vials dispensed to patients, resulting in a negative $1.3 million inventory swing from Q3 to Q4 [32] - Research and development expenses were $42 million for Q4, compared to $41.2 million in the same quarter last year [34] Market Data and Key Metrics Changes - The company identified approximately 40 priority medical centers in the US based on significant concentrations of Acquired Hypothalamic Obesity (AHO) patients [21] - The estimated prevalence of Acquired HO in the US is around 10,000 patients, representing a significant opportunity for the company [19] Company Strategy and Development Direction - The company is preparing for the launch of Acquired Hypothalamic Obesity pending regulatory approval, with a PDUFA goal date of March 20 [19] - The company plans to run the Phase 3 trial for bivamelagon largely in countries where setmelanotide will not be available for acquired HO in the near future [14] - The company anticipates launching in Japan within the next 12 months, with a strong leadership team already in place [80] Management's Comments on Operating Environment and Future Outlook - Management expressed confidence in the growth of the BBS opportunity, highlighting the steady rate of growth in both US and ex-US markets [6] - The management team noted that the FDA meeting regarding bivamelagon was highly constructive, confirming readiness to move to Phase 3 [13] - Management acknowledged the challenges in the PWS study but remains optimistic about the potential for positive outcomes [51] Other Important Information - The company ended 2025 with approximately $389 million in cash equivalents and short-term investments, expected to fund planned operations for at least 24 months [36] - The company anticipates non-GAAP operating expenses for 2026 to be approximately $385 million-$415 million, reflecting a year-over-year increase driven by clinical program success [39] Q&A Session Summary Question: Update on bivamelagon phase 3 trial - Management confirmed that the trial will largely mimic the phase 3 of setmelanotide, with no specific changes to enrollment criteria [43] Question: Guidelines for HO treatment - Management indicated that while current guidelines suggest a 6-month wait post-surgery, feedback suggests earlier intervention may be beneficial [46] Question: Update on PWS study - Management stated that they are on track for a mid-year update and are looking for a minimum of 5% BMI change as a goal [51] Question: Trends in IMCIVREE sales - Management noted potential dampening of sales in Q1 due to inventory dynamics but did not provide specific growth estimates [55] Question: Dosing in bivamelagon phase 3 trial - Management confirmed that dosing will escalate from 200 mg to 600 mg, with 600 mg as the target dose [74] Question: Opportunity in Japan - Management estimated the prevalence of AHO in Japan to be between 5,000 and 8,000 patients, with plans for a launch within 12 months [80]

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 ...

Core Insights - Rhythm Pharmaceuticals reported a net product revenue of $57.3 million from global sales of IMCIVREE for Q4 2025, marking a 12% increase from Q3 2025, driven by sales for Bardet-Biedl syndrome (BBS) and an increase in reimbursed therapy patients globally [1][6][8] - The company is focused on long-term growth and is well-capitalized to achieve important commercial and clinical milestones, including the potential launch of IMCIVREE for acquired hypothalamic obesity (HO) pending FDA approval [2][5] Recent Business Highlights - IMCIVREE revenue for Q4 2025 was $57.3 million, with $39.0 million (68%) generated in the U.S. and $18.3 million (32%) from international sales, the latter showing a 40% sequential increase [6][8] - The company entered into Product Listing Agreements in Canada for public reimbursement of IMCIVREE for weight management in eligible patients with BBS and obesity [6] - Rhythm completed a positive end-of-Phase-2 meeting with the FDA regarding bivamelagon in acquired HO, showing promising BMI reduction data [6][12] Clinical Development Highlights - The company is on track to report topline data from a 12-patient Japanese cohort of the setmelanotide Phase 3 trial in acquired HO in March 2026 [5][12] - Anticipated milestones include the initiation of a pivotal Phase 3 trial for bivamelagon in acquired HO by year-end 2026 [5][12] Financial Performance - For the full year 2025, net product revenues were $194.8 million, compared to $130.1 million in 2024 [8] - R&D expenses for Q4 2025 were $42.0 million, a slight increase from $41.2 million in Q4 2024, while full-year R&D expenses decreased to $167.3 million from $238.0 million in 2024 [9] - SG&A expenses rose to $57.5 million for Q4 2025, up from $38.1 million in Q4 2024, primarily due to increased headcount and marketing costs [10] Cash Position - As of December 31, 2025, the company had cash, cash equivalents, and short-term investments of approximately $388.9 million, an increase from $320.6 million as of December 31, 2024 [7][15]

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 Insights - Rhythm Pharmaceuticals has experienced significant growth, outperforming major companies like Google and Nvidia over the past year, with a consensus price target indicating a potential upside of around 40% [1][2] - The company operates in the biotech sector with a market capitalization of $6.8 billion, focusing on therapies for rare genetic obesity disorders rather than high-profile conditions [4] Company Overview - Rhythm Pharmaceuticals' only approved drug is Imcivree, a first-in-class melanocortin-4 receptor (MC4R) agonist, which treats obesity due to specific genetic deficiencies and Bardet-Biedl syndrome, generating sales of approximately $194 million in 2025, reflecting a year-over-year increase of about 50% [5] - The company is advancing its pipeline with plans to move its oral MC4R agonist bivamelagon into Phase 3 clinical testing in 2026, alongside another candidate, RM-718, currently in Phase 1 testing [6] Competitive Landscape - Competition for Rhythm Pharmaceuticals is limited, with Palatin Technologies being the only notable rival developing MC4R agonists, but it is significantly behind in clinical testing [7] Upcoming Catalysts - Wall Street's optimism is bolstered by multiple upcoming catalysts, particularly the anticipated FDA approval of Imcivree for treating acquired hypothalamic obesity, with a PDUFA date set for March 20, 2026 [8] - Acquired hypothalamic obesity affects an estimated 10,000 patients in the U.S., with additional patient populations in Europe and Japan, representing a market opportunity that is at least 3.7 times larger than the current approved indications for Imcivree [9]

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].