Slide 1: Phase 3 EMANATE Trial Topline Results
Rhythm Pharmaceuticals Phase 3 EMANATE Trial Topline Results March 16, 2026 ® © Rhythm® Pharmaceuticals, Inc. All rights reserved.
Slide 2: On Today's Call
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 ® 2
Slide 3: Forward-Looking Statements
Forward-Looking Statements 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
Slide 4: David Meeker, MD
David Meeker, MD Chair, President and CEO ® 4
Slide 5: Phase 3 EMANATE Topline Results
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 understandi
Slide 6: Topline Results from Phase 3 EMANATE Trial of Setmelanotide
Topline Results from Phase 3 EMANATE Trial of Setmelanotide 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 POMC/PCSK1 LEPR Hets SRC1 (NCOA1) SH2B1 Hets -4.3% -3.6% -4.0% -1.
Slide 7: MC4R Pathway Impairment May Lead to Increased Hunger, Decreased Energy Expenditure and Early-onset Obesity
MC4R Pathway Impairment May Lead to Increased Hunger, Decreased Energy Expenditure and Early-onset Obesity Hypothalamus UPSTREAM DOWNSTREAM AgRP/NPY Neuron Food intake LEPR SH2B1 AgRP ADIPOSE Increased TISSUE MC4R- Expressing + body weight MC4R Neuron LEPTIN PCSK1 Energy POMC α-MSH expenditure BLOOD
Slide 8: Variant Pathogenicity Defines MC4R Pathway Dysfunction and Is Subject to Reclassification
Variant Pathogenicity Defines MC4R Pathway Dysfunction and Is Subject to Reclassification ACMG EMANATE Sub- Classification study entry criteria POMC/ • P/LP PCSK1 Hets • VUS-SP • P/LP Number of variants LEPR Hets VUS • VUS-SP SRC1 (NCOA1) • All VUS • P/LP SH2B1 • VUS Likely Likely Benign Pathogenic
Slide 9: Phase 3 EMANATE Trial Comprised of Four Independent Sub-studies
Phase 3 EMANATE Trial Comprised of Four Independent Sub-studies Each sub-study: Patients randomized 1:1 Genetic sub-study Enrolled patients Setmelanotide Open-label POMC/ extension N=79* PCSK1 Hets Placebo LEPR Hets N=23 52 weeks Primary Endpoint: Difference in mean percent change SRC1 (NCOA1) N=73
Slide 10: Baseline Demographics
POMC / PCSK1 hets LEPR hets SRC1 (NCOA1) SH2B1 Baseline Demographics (N=79) (N=23) (N=73) (N=121) Mean (SD) (Range) 25.3 (17.09) 23.0 (13.94) 29.0 (18.16) 27.2 (17.98) <12 years old, n 20 (25.3) 7 (30.4) 11 (15.1) 29 (24.0) Age, years >12 years and <18, n 22 (27.8) 5 (21.7) 23 (31.5) 28 (23.1) ≥18 y
Slide 11: Common Adverse Events with Setmelanotide
Common Adverse Events with Setmelanotide Adverse Event POMC/PCSK1 Hets LEPR Hets SRC1 (NCOA1) SH2B1 Events with ≥30% incidence in a PBO SET PBO SET PBO SET PBO SET setmelanotide (Set) arm in any substudy are shown N=39 N=39* N=12 N=11 N=37 N=36 N=60 N=61 n (%) n (%) n (%) n (%) n (%) n (%) n (%) n (
Slide 12: High Discontinuation Rate across All Cohorts
High Discontinuation Rate across All Cohorts 70% 21/36 22/37 60% 6/12 58.3% 59.5% 29/61 29/60 50% 18/39 50.0% 48.3% 46.2% 16/40 47.5% 40% 40.0% 30% 3/11 27.3% 20% 10% 0% POMC /PCSK1 Hets LEPR Hets SRC1 (NCOA1) SH2B1 Setmelanotide Placebo ® 12
Slide 13: Discontinuation Rates Driven by Multiple Factors in Placebo and Active Arms
Discontinuation Rates Driven by Multiple Factors in Placebo and Active Arms Discontinuations – Placebo (All Substudies) Discontinuations – Setmelanotide (All Substudies)* 1% 1% 5% Subject Decision 4% Adverse Event 5% 15% 10% Withdrawal of Consent Subject Decision 42% Subject Non-Compliance / Withdra
Slide 14: POMC / PCSK1 Hets
POMC / PCSK1 Hets ® 14
Slide 15: POMC/PCSK1 Hets: Significant BMI Reduction in mITT Patients Based on LOCF
POMC/PCSK1 Hets: Setmelanotide Achieved Statistically Significant BMI Reduction in mITT Patients Based on LOCF Analysis Placebo Setmelanotide (N=40) (N=38) % change BMI baseline to week 52: Mean (SE) 0.98 (1.151) -4.65 (1.106) ANCOVA LSM (SE) 0.75 (1.329) -4.79 (1.367) [95% CI] [-1.90, +3.39] [-7.51
Slide 16: POMC/PCSK1 Hets: Significant BMI Reduction in Genetically Confirmed Patients Based on LOCF
POMC/PCSK1 Hets: Setmelanotide Achieved Statistically Significant BMI Reduction in Genetically Confirmed Patients Based on LOCF Analysis Placebo Setmelanotide (N=35) (N=32) % change BMI baseline to week 52: Mean (SE) 2.20 (1.290) -5.04 (1.171) ANCOVA LSM (SE) 2.61 (1.628) -4.17 (1.511) [95% CI] [-0.
Slide 17: POMC/PCSK1 Hets: Significant BMI Reduction in Genetically Confirmed Patients who Reached Week 52
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 NOTE: Post hoc analysis of genetically confirmed completers using
Slide 18: LEPR Hets
LEPR Hets ® 18
Slide 19: Highlights from the LEPR Hets Substudy
Highlights from the LEPR Hets Substudy Eligible LEPR Hets patients Eight (8) of 11 Positive response in 3 were rare and hard to setmelanotide-assigned setmelanotide-assigned recruit patients were patients who had a down classified pathogenic variant (predominantly one achieved BMI variant) reduction
Slide 20: SRC1 (NCOA1)
SRC1 (NCOA1) ® 20
Slide 21: SRC1 (NCOA1): Significant BMI Reduction in mITT Patients Based on LOCF
SRC1 (NCOA1): Setmelanotide Achieved Statistically Significant BMI Reduction in mITT Patients Based on LOCF Analysis Placebo Setmelanotide (N=37) (N=36) % change BMI baseline to week 52: Mean (SE) 1.44 (0.837) -4.87 (1.192) ANCOVA LSM (SE) 1.73 (1.115) -4.51 (1.68) [95% CI] [-0.50, +3.95] [-6.84, -2
Slide 22: SRC1 (NCOA1): Significant BMI Reduction in Genetically Confirmed Patients who Reached Week 52
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 NOTE: Post hoc analysis of genetically Placebo, N 15 15 15 13 15 15 confirmed completers using a
Slide 23: SRC1 (NCOA1): Patients with Variants in Critical Protein Binding Domain
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 NOTE: Post hoc analysis of genetically Placebo, N 9 9 8 7 6 6 confirmed completers using a s
Slide 24: SH2B1
SH2B1 ® 24
Slide 25: SH2B1/16p11.2: Genetically Confirmed Completers Show No Significant Difference at Week 52
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 NOTE: Post hoc analysis of genetically Placebo, N 30 30 29 25 29 30 confirmed completers using a student’s S
Slide 26: 16p11.2 Subgroup Analysis Shows No Significant Difference in BMI Reduction at Week 52
16p11.2 Subgroup Analysis Shows No Significant Difference in BMI Reduction at Week 52 -3.4% Week 52 Placebo-adjusted difference (PBO n=8; SET n=13) p=0.3006 NOTE: Post hoc analysis of genetically Placebo, N 8 8 8 7 8 8 confirmed completers using a student’s Setmelanotide, N 13 13 13 12 13 13 T-test.
Slide 27: Encouraging Results Leading to Next Steps
Encouraging Results Leading to Next Steps Encouraged by Continue to Advance next- positive analyses of interrogate generation MC4R POMC/PCSK1 and POMC/PCSKI, SRC1 agonists in genetic SRC1 substudies plus DAYBREAK genes indications to improve LOF determination LOF, loss of function ® 27
Slide 28: MC4R Agonism Development Across Three Pillars
MC4R Agonism Development Across Three Pillars Genetic MC4R Hypothalamic Obesity Prader-Willi Syndrome Pathway Diseases • U.S. launch* • Ongoing Ph2 trial with • Promising signals in • EMA authorization** setmelanotide POMC Hets and SRC1 • Ph1/2 trial with RM-718 • Ongoing Ph2 trial with • Additional
Slide 29: Questions
Questions Rhythm