Rhythm Pharmaceuticals, Inc. · NASDAQ:RYTM
Rhythm Pharmaceuticals — Corporate Update (March 2026)
29 slides from Rhythm Pharmaceuticals's corporate update, Mar 16, 2026
Slide 1: Phase 3 EMANATE Trial Topline Results
© Rhythm® Pharmaceuticals, Inc. All rights reserved. ® Rhythm Pharmaceuticals Phase 3 EMANATE Trial Topline Results March 16, 2026 EXHIBIT 99.2
Slide 2: On Today's Call
® 2 On Today’s Call • David Connolly, Executive Director of Investor Relations and Corporate Communications • David Meeker, MD, Chair, President and Chief Executive Officer • Alastair Garfield, Chief Scientific Officer • Hunter Smith, Chief Financial Officer
Slide 3: Forward-looking statements
® 3 This presentation and the accompanying oral presentation contain forward-looking statements within the meaning of the Private Securities Litigation Reform Act of 1995. All statements contained in this presentation that do not relate to matters of historical fact should be considered forward-look
Slide 4: David Meeker, MD, Chair, President and CEO
® 4 David Meeker, MD Chair, President and CEO
Slide 5: Phase 3 EMANATE Topline Results
® 5 Phase 3 EMANATE Topline Results Encouraging signals seen in POMC Hets and SRC1 substudies to inform development of next- generation MC4R agonists • Post hoc LOCF analyses demonstrated setmelanotide achieved statistically significant BMI reduction in POMC Hets and SRC1 substudies Deepened underst
Slide 6: Topline Results from Phase 3 EMANATE Trial of Setmelanotide
® 6 PRIMARY ENDPOINT: Difference in mean percent change in BMI from baseline to 52 weeks vs. placebo analyzed with pre-specified multiple imputation analysis of mITT population1 Topline Results from Phase 3 EMANATE Trial of Setmelanotide LEPR Hets -3.6% (N=23) p-value = 0.94 SRC1 (NCOA1) -4.0% (N=73
Slide 7: MC4R Pathway Impairment May Lead to Increased Hunger and Early-onset Obesity
® 7 MC4R Pathway Impairment May Lead to Increased Hunger, Decreased Energy Expenditure and Early-onset Obesity AgRP, agouti-related peptide; LEPR, leptin receptor; MC4R, melanocortin-4 receptor; MSH, melanocyte-stimulating hormone; NPY, neuropeptide Y; PCSK1, proprotein convertase subtilisin/kexin t
Slide 8: Variant Pathogenicity Defines MC4R Pathway Dysfunction
® 8 Variant Pathogenicity Defines MC4R Pathway Dysfunction and Is Subject to Reclassification Pathogenic (P) Likely Pathogenic (LP) VUS Likely Benign Benign N um be r o f v ar ia nt s Pathway impact*ACMG Guidelines Richards et al, 2015 Suspected Pathogenic (SP) ACMG Classification entry criteria EMA
Slide 9: EMANATE Trial Comprised of Four Independent Sub-studies
® 9 Each sub-study: Patients randomized 1:1 Phase 3 EMANATE Trial Comprised of Four Independent Sub-studies Enrolled patientsGenetic sub-study N=79* POMC/ PCSK1 Hets N=23LEPR Hets N=73SRC1 (NCOA1) N=121SH2B1 Setmelanotide Placebo 52 weeks Open-label extension Primary Endpoint: Difference in mean per
Slide 10: Baseline Demographics
® 10 SH2B1 (N=121) SRC1 (NCOA1) (N=73) LEPR hets (N=23) POMC / PCSK1 hets (N=79)Baseline Demographics 27.2 (17.98)29.0 (18.16)23.0 (13.94)25.3 (17.09) Mean (SD) (Range) Age, years 29 (24.0)11 (15.1)7 (30.4)20 (25.3)<12 years old, n 28 (23.1)23 (31.5)5 (21.7)22 (27.8)>12 years and <18, n 64 (52.9)39
Slide 11: Common Adverse Events with Setmelanotide
® 11 Common Adverse Events with Setmelanotide SH2B1SRC1 (NCOA1)LEPR HetsPOMC/PCSK1 HetsAdverse Event Events with ≥30% incidence in a setmelanotide (Set) arm in any substudy are shown SET N=61 n (%) PBO N=60 n (%) SET N=36 n (%) PBO N=37 n (%) SET N=11 n (%) PBO N=12 n (%) SET N=39* n (%) PBO N=39 n
Slide 12: High Discontinuation Rate across All Cohorts
® 12 High Discontinuation Rate across All Cohorts 46.2% 27.3% 58.3% 47.5% 40.0% 50.0% 59.5% 48.3% 0% 10% 20% 30% 40% 50% 60% 70% POMC /PCSK1 Hets LEPR Hets SRC1 (NCOA1) SH2B1 Setmelanotide Placebo 18/39 16/40 3/11 6/12 21/36 22/37 29/61 29/60
Slide 13: Discontinuation Rates Driven by Multiple Factors
® 13 Discontinuations – Placebo (All Substudies) Discontinuation Rates Driven by Multiple Factors in Placebo and Active Arms 48% 21% 11% 10% 5% 5% Subject Decision Withdrawal of Consent Subject Non-Compliance / Protocol Violation(s) Adverse Event Lost to Follow-Up Physician Decision Discontinuations
Slide 14: POMC / PCSK1 Hets
® 14 POMC / PCSK1 Hets
Slide 15: POMC/PCSK1 Hets: Significant BMI Reduction in mITT Patients (LOCF)
® 15 POMC/PCSK1 Hets: Setmelanotide Achieved Statistically Significant BMI Reduction in mITT Patients Based on LOCF Analysis Post hoc analysis of mITT cohort based on last observation carried forward (LOCF) Setmelanotide (N=38) Placebo (N=40) -4.65 (1.106)0.98 (1.151)% change BMI baseline to week 52
Slide 16: POMC/PCSK1 Hets: BMI Reduction in Genetically Confirmed Patients
® 16 POMC/PCSK1 Hets: Setmelanotide Achieved Statistically Significant BMI Reduction in Genetically Confirmed Patients Based on LOCF Analysis Post hoc analysis of genetically confirmed patients based on last observation carried forward (LOCF) Setmelanotide (N=32) Placebo (N=35) -5.04 (1.171)2.20 (1.
Slide 17: POMC/PCSK1 Hets: Genetically Confirmed Patients Reaching Week 52
® 17 POMC/PCSK1 Hets: Setmelanotide Achieved Statistically Significant BMI Reduction in Genetically Confirmed Patients who Reached Week 52 -9.7% Week 52 placebo-adjusted difference (PBO n=21; SET n=20) p=0.0002 Placebo, N 21 21 21 20 20 21 Setmelanotide, N 20 20 20 19 20 20 NOTE: Post hoc analysis o
Slide 18: LEPR Hets
® 18 LEPR Hets
Slide 19: Highlights from the LEPR Hets Substudy
® 19 Highlights from the LEPR Hets Substudy *Patient with -7.2% BMI reduction at Week 28 subsequently discontinued treatment. Eligible LEPR Hets patients were rare and hard to recruit Eight (8) of 11 setmelanotide-assigned patients were down classified (predominantly one variant) Positive response i
Slide 20: SRC1 (NCOA1)
® 20 SRC1 (NCOA1)
Slide 21: SRC1 (NCOA1): Significant BMI Reduction in mITT Patients (LOCF)
® 21 SRC1 (NCOA1): Setmelanotide Achieved Statistically Significant BMI Reduction in mITT Patients Based on LOCF Analysis Post hoc analysis of mITT cohort based on last observation carried forward (LOCF) Setmelanotide (N=36) Placebo (N=37) -4.87 (1.192)1.44 (0.837)% change BMI baseline to week 52: M
Slide 22: SRC1 (NCOA1): Genetically Confirmed Patients Reaching Week 52
® 22 SRC1 (NCOA1): Setmelanotide Achieved Statistically Significant BMI Reduction in Genetically Confirmed Patients who Reached Week 52 -8.0% Week 52 placebo-adjusted difference (PBO N=15; SET N=14) p=0.0158 Placebo, N 15 15 15 13 15 15 Setmelanotide, N 14 14 14 12 14 14 NOTE: Post hoc analysis of g
Slide 23: SRC1 (NCOA1): Variants in Critical Protein Binding Domain
® 23 SRC1 (NCOA1): Analysis of Genetically Confirmed Patients with Variants in Critical Protein Binding Domain Demonstrate Compelling Response -12.7% Week 52 placebo-adjusted difference (PBO N=6; SET N=6) p=0.055 Placebo, N 9 9 8 7 6 6 Setmelanotide, N 10 9 8 5 6 6 NOTE: Post hoc analysis of genetic
Slide 24: SH2B1
® 24 SH2B1
Slide 25: SH2B1/16p11.2: Genetically Confirmed Completers
® 25 SH2B1/16p11.2: Analysis of Genetically Confirmed Completers Shows No Significant Difference in BMI Reduction at Week 52 -3.0% Week 52 Placebo-adjusted difference (PBO N=30; SET N=32) p=0.1772 Placebo, N 30 30 29 25 29 30 Setmelanotide, N 32 32 32 30 32 32 NOTE: Post hoc analysis of genetically
Slide 26: 16p11.2 Subgroup Analysis
® 26 16p11.2 Subgroup Analysis Shows No Significant Difference in BMI Reduction at Week 52 Placebo, N 8 8 8 7 8 8 Setmelanotide, N 13 13 13 12 13 13 -3.4% Week 52 Placebo-adjusted difference (PBO n=8; SET n=13) p=0.3006 NOTE: Post hoc analysis of genetically confirmed completers using a student’s T-
Slide 27: Encouraging Results Leading to Next Steps
® 27 Encouraging Results Leading to Next Steps Encouraged by positive analyses of POMC/PCSK1 and SRC1 substudies Continue to interrogate POMC/PCSKI, SRC1 plus DAYBREAK genes to improve LOF determination Advance next- generation MC4R agonists in genetic indications LOF, loss of function
Slide 28: MC4R Agonism Development Across Three Pillars
® 28 MC4R Agonism Development Across Three Pillars Hypothalamic Obesity • U.S. launch* • EMA authorization** • Ongoing Ph2 trial with RM-718 • Ph3 trial with bivamelagon by YE 2026 Prader-Willi Syndrome • Ongoing Ph2 trial with setmelanotide • Ph1/2 trial with RM-718 initiated Genetic MC4R Pathway D
Slide 29: Questions
Questions Rhython 29
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