Rhythm Pharmaceuticals, Inc. · NASDAQ:RYTM
Rhythm Pharmaceuticals — Investor Presentation (June 2026)
52 slides from Rhythm Pharmaceuticals's investor presentation, June 2026
Slide 1: Rhythm Pharmaceuticals Corporate Presentation June 2026
Rhythm Pharmaceuticals Corporate Presentation June 2026 ® © Rhythm® Pharmaceuticals, Inc. All rights reserved.
Slide 2: 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 3: MC4R Agonism Development Across Three Pillars
MC4R Agonism Development Across Three Pillars Next-generation MC4R agonists Genetic MC4R Pathway Diseases RM-718 Bivamelagon (weekly injection) (daily oral) Hypothalamic Obesity Global commercial foundation Prader-Willi Syndrome driven by IMCIVREE in BBS ® 3
Slide 4: IMCIVREE: First and Only Therapy Approved for Acquired HO
IMCIVREE: First and Only Therapy Approved for Acquired HO ✓ U.S. launch underway following March 19th FDA Approval ✓ European Commission Granted Marketing Authorization ❑ Country-level launches expected to begin in 2027 ® 4 NOTE: Approved for patients with HO 4 years old and older; See US FDA-approv
Slide 5: MC4R Pathway Biology is Clear
MC4R Pathway Biology is Clear Hypothalamus Upstream Downstream Downstream AgRP neuron MC4R activity Low Normal LEPR AgRP Adipose Hyperphagia tissue PCSK1 MC4R Obesity MC4R neuron α-MSH POMC α-MSH Leptin β-MSH β-MSH Blood-brain POMC Energy barrier neuron Expenditure LEPR AgRP, agouti-related peptide;
Slide 6: Patient Spotlight: Living with Acquired Hypothalamic Obesity
Patient Spotlight: Living with Acquired Hypothalamic Obesity Setmelanotide Patient Isaac "Everything with day-to-day life was harder for him. Dealing with hyperphagia on top of that…he would suffer, his quality of life was not good" “He was so overweight that everything was a struggle." - Brenda, mo
Slide 7: Expanding Pipeline in Rare Neuroendocrine Diseases
Expanding Pipeline in Rare Neuroendocrine Diseases Patient Population Pre-clinical Phase 1/2 Phase 3 Regulatory Approval Setmelanotide1 Acquired hypothalamic obesity US, EU daily sc injection Bardet-Biedl syndrome or US, EU, UK, Canada biallelic POMC, PCSK1 or LEPR deficiency Setmelanotide daily sc
Slide 8: Significant Market Opportunity for MC4R Agonists
Significant Market Opportunity for MC4R Agonists U.S. patent protection for next-generation assets bivamelagon and RM-718 extends into 2040s IMCIVREE approved in IMCIVREE approved in U.S. Prader-Willi U.S., EU,+ and EU for acquired HO syndrome 4,000 – 5,000* ~10,000 ~20,000 Bardet-Biedl syndrome est
Slide 9: Well Capitalized: Cash Sufficient to Fund Planned Operations for at least 24 Months
Well Capitalized: Cash Sufficient to Fund Planned Operations for at least 24 Months $340.6M Guidance 68.5 Million Cash, cash equivalents RYTM expects cash to Common shares and short-term be sufficient to fund outstanding as of investments as of planned operations May 1, 2026 March 31, 2026 for at le
Slide 10: Rhythm Leadership – Strong Team with Broad Biopharma Experience
Rhythm Leadership – Strong Team with Broad Biopharma Experience David Meeker, MD Hunter Smith Jennifer Lee Yann Mazabraud Joe Shulman Alastair Garfield, PhD Chair, President and Chief Financial Officer Executive Vice President, Executive Vice President, Chief Technology Officer Chief Scientific Offi
Slide 11: Anticipated Upcoming Milestones
Anticipated Upcoming Milestones Hypothalamic Obesity Prader-Willi Syndrome Mid 2026: Disclose data in the Ph1/2, Part C trial Q2 2026: Disclose six-month results from evaluating RM-718 in acquired hypothalamic exploratory Ph2 trial evaluating setmelanotide obesity in Prader-Willi syndrome H2 2026: D
Slide 12: IMCIVREE Global Commercial Execution
IMCIVREE Global Commercial Execution ® 12
Slide 13: IMCIVREE available in >25 countries outside the United States
IMCIVREE available in >25 countries outside the United States Continued execution >100 employees in 13 countries Eight countries added in 2025 64 abstracts at 12 international scientific congresses ® 13
Slide 14: Steady Growth in Net Product Revenues since BBS Launch
Steady Growth in Net Product Revenues since BBS Launch FDA approved IMCIVREE for BBS in June 2022 $70 $60.1M $57.3M $60 $51.3M $48.5M Global net sales in $M $50 $41.8M $37.7M $40 $33.3M $29.1M $30 $24.2M $26.0M $22.5M $19.2M $20 $11.5M $8.8M $10 $4.3M $2.3M $- 2Q 22 3Q 22 4Q 22 1Q 23 2Q 23 3Q 23 4Q
Slide 15: U.S. Launch of IMCIVREE for Acquired HO off to a Strong Start
U.S. Launch of IMCIVREE for Acquired HO off to a Strong Start Patients Prescribers Payers ~110 Early approvals >150 Unique prescribers secured Patient Expect 3 - 9 months for start forms ~80% policies to become New IMCIVREE established prescribers Note: As of May 1, 2026 ® 15
Slide 16: Hypothalamic Obesity
Hypothalamic Obesity Acquired and Congenital ® 16
Slide 17: Hypothalamic Obesity: A Rare, Acquired Form of Obesity Following Injury to the Hypothalamic Region
Hypothalamic Obesity: A Rare, Acquired Form of Obesity Following Injury to the Hypothalamic Region Craniopharyngioma (CP) and other suprasellar brain tumors and treatment – tumor resection surgery and radiation – is most common cause MC4R pathway deficiency following injury to hypothalamic region ca
Slide 18: Severe, Life-long Burden for Patients with Acquired HO
Severe, Life-long Burden for Patients with Acquired HO Frequent visits with multiple specialists, a complex regimen of medications, and hospitalization “Treatment of patients with tumor/treatment- 3.7 average hospitalizations during the two years following index; 12 average number of general practit
Slide 19: HO: Aggressive, Rapid Weight Gain follows Therapy for CP
HO: Aggressive, Rapid Weight Gain follows Therapy for CP Patient Case Study: Setmelanotide therapy achieved rapid, significant weight loss Setmelanotide GLP1 therapy therapy Patient case of M. Jennifer Abuzzahab, MD, Pediatric Endocrinologist, at Children's Minnesota ® 19
Slide 20: Approval Supported By Statistically Significant and Highly Clinically Meaningful BMI Reduction in Phase 3
Approval Supported By Statistically Significant and Highly Clinically Meaningful BMI Reduction in Phase 3 Acquired HO Trial Primary analysis cohort (N=142) -16.4% BMI change from baseline in -18.8% +2.4% BMI change from baseline in Placebo-adjusted Setmelanotide arm difference in BMI reduction Place
Slide 21: Significant BMI Reductions Observed in Patients with Prior Use or Concomitant Use of GLP-1s
Significant BMI Reductions Observed in Patients with Prior Use or Concomitant Use of GLP-1s Prior use of GLP-1 (n=16) Concomitant GLP-1 (n=15) -24.7% -27.1% Placebo-adjusted Placebo-adjusted difference in BMI difference in BMI reduction from reduction from baseline baseline ® 21
Slide 22: Mean BMI Reduction Consistent Across Stratified Age Groups
Mean BMI Reduction Consistent Across Stratified Age Groups in Phase 3 Trial Evaluating Setmelanotide in Acquired HO < 12 Yrs 12 – < 18 Yrs ≥ 18 Yrs -19.5% -21.0% -19.2% p <0.0001 p <0.0001 p <0.0001 (n=31: 20 setmelanotide, 11 placebo) (n=40: 28 setmelanotide, 12 placebo) (n=49: 33 setmelanotide, 16
Slide 23: TRANSCEND Results: Data from 12-patient Japanese Cohort Consistent with Full Data Set
Phase 3 TRANSCEND Results: Data from 12-patient Japanese Cohort Consistent with Full Data Set -18.8%* -13.0%* p <0.0001 p = 0.0388 (n=142: 94 setmelanotide, 48 placebo) (n=12: 8 setmelanotide, 4 placebo) 10% LLSM Percent Change from BL (SE) 5% 2.4% -0.9% 0% -5% -10% -15% -13.9% -16.4% -20% All Patie
Slide 24: Congenital HO Represents Additional Opportunity with Significant Unmet Need
Congenital HO Represents Additional Opportunity with Significant Unmet Need Congenital HO occurs due to dysfunction or damage to the hypothalamus from birth, with patients often experiencing >1,000 hyperphagia and difficulty managing their weight Patients The weight gain and appetite changes accompa
Slide 25: 34-week Substudy in Congenital Hypothalamic Obesity Added to Pivotal, Ph3 HO Study
34-week Substudy in Congenital Hypothalamic Obesity Added to Pivotal, Ph3 HO Study Independent substudy leverages existing Ph3 trial infrastructure; Enrollment completion expected in H1 2026 Dose titration Double-blind, placebo-control 39 Setmelanotide QD (n=26) patients randomized Open-label extens
Slide 26: SIGNAL Trial: 14-week, Phase 2 Open-label Trial Evaluating Bivamelagon
SIGNAL Trial: 14-week, Phase 2 Open-label Trial Evaluating Bivamelagon in Patients with Hypothalamic Obesity RDZ 1:1:1:1 200 mg 200 mg 400 mg Long-term Screening 200 mg 400 mg 600 mg Extension (LTE) Trial 200 mg 400 mg 600 mg Placebo 2 weeks 12 weeks Open-label Week 0 Week 2 Week 14 Week 15 Week 16
Slide 27: Overall Baseline Demographics
Overall Baseline Demographics N=28 38.7 kg/m2 Mean BMI Overall bivamelagon 46.4% 82.1% population Female Patients with craniopharyngioma 25.4yo 7 years Mean Age Mean time from hypothalamic (13 of 28 <18yo) injury to trial enrollment ® 27
Slide 28: Bivamelagon Achieved Statistically Significant BMI Reductions at All Doses
Bivamelagon Achieved Statistically Significant BMI Reductions at All Doses Placebo 200 mg 400 mg 600 mg +2.18% -2.68% -7.69% -9.31% Mean BMI increase Mean BMI reduction Mean BMI reduction Mean BMI reduction from baseline from baseline from baseline from baseline (n=7) (n=6) (n=7) (n=8) p-value = 0.0
Slide 29: Post-hoc Analysis: Bivamelagon Achieved BMI Reductions Consistent with Setmelanotide
Post-hoc analysis: Bivamelagon Achieved BMI Reductions Consistent with Setmelanotide Setmelanotide Bivamelagon Phase 2+3 combined* All patients Removing 2 patients with documented non-compliance 400 600 400 600 5.0 mg mg mg mg Mean percent BMI reduction, % n=59 n=64† n=8 n=7** n=7 n=6** 0.0 -5.0 -10
Slide 30: AEs consistent with MC4R Mechanism, Setmelanotide Trials in Acquired Hypothalamic Obesity
AEs consistent with MC4R Mechanism, Setmelanotide Trials in Acquired Hypothalamic Obesity BIVA 200mg BIVA 400mg BIVA 600mg Placebo n (%) (N=6) (N=7) (N=8) (N=7) Any AEs 6 (100) 7 (100) 8 (100) 6 (86) Serious AEs 0 (0) 1 (14) 0 1 (14) Treatment-Related AEs 6 (100) 7 (100) 8 (100) 3 (43) Treatment-Rel
Slide 31: Prader-Willi Syndrome
Prader-Willi Syndrome ® 31
Slide 32: Revisiting Prader-Willi Syndrome
Revisiting Prader-Willi Syndrome PWS is a complex, multi-system disorder ~20,000 Constant sense of hunger usually begins at 2yo; if not managed by stringent food restrictions and environmental controls, often Patients results in life-threatening obesity Estimated U.S. prevalence* Currently limited t
Slide 33: Exploratory Phase 2, Open-label Trial of Setmelanotide in PWS
Exploratory Phase 2, Open-label Trial of Setmelanotide in PWS 18 patients with PWS and obesity aged 6 to 65 years old enrolled Daily dose of setmelanotide Treatment period (52 weeks) escalated up to 5 mg/day as tolerated for 52 weeks Primary endpoints: safety and tolerability Key secondaries: assess
Slide 34: Baseline Demographics
Baseline Demographics Parameter Statistic Overall (N=18) N=18 Patients enrolled Mean (SD) (range) 17.1 (5.6) (6 – 23) <12 years old, n (%) 3 (16.7) Age, years >12 years and <18, n (%) 4 (22.2) n=8 ≥18 years old, n (%) 11 (61.1) patients reached Month 31 Sex, n (%) Female / Male 8/10 (44.4/55.6) Whit
Slide 35: Setmelanotide Achieved BMI Reductions from Baseline in Patients with PWS After 3 and 6 Months
Setmelanotide Achieved BMI Reductions from Baseline in Patients with PWS After 3 and 6 Months of Treatment Pt 8 Pt 7 * Pt 3 * Pt 2 Pt 6 * Pt 5 Pt 4 Pt 1 * Age/Sex/BMI 6 12/F/32.6 23/M/37.4 23/F/42.2 18/F/44.6 23/M/45.4 14/M/38.8 21/M/41.5 20/F/67.0 V V 4.2 4 % Change from Baseline in BMI 2 2.4 2 0.5
Slide 36: HQ-CT Scores Showed Meaningful Hyperphagia Reductions from Baseline
HQ-CT1 Scores Showed Meaningful Hyperphagia Reductions from Baseline Observed in 6 of 7 Evaluable Patients at Month 3 30 25 24 22 20 20 18 HQ-CT Score 15 14 11 10 10 10 7 6 5 4 4 1 0 0 0 0 Pt 8 Pt 7 Pt 3 Pt 2 Pt 6 Pt 5 Pt 4 Pt 1 Baseline Month 3 1. The Hyperphagia Questionnaire for Clinical Trials (
Slide 37: Positive Body Composition Changes from Baseline to Month 6
Positive Body Composition Changes from Baseline to Month 6 Pt 3 Pt 2 Pt 6 Pt 5 4 3.2 2 % Change from Baseline 0 -0.1 -0.2 -2 -1 -4 -6 -6.3 -8 -7.2 -7.9 -10 -10.1 -12 Fat Mass Lean Mass Note: There are no DEXA data for Patient 1 (exceeded table’s weight limits) ® 37
Slide 38: Appendix
Appendix Rhythm
Slide 39: German Investigator-led Observational Study Showed Setmelanotide associated with Improvement in MASLD, Kidney Function in BBS
German Investigator-led Observational Study Showed Setmelanotide associated with Improvement in Measures of MASLD, Kidney Function in Patients with BBS 26 patients with BBS completed six months on setmelanotide therapy. 100% >80% of patients (N=26) with of patients exhibited both BBS and metabolic e
Slide 40: Positive Real-world Setmelanotide Data Reported from French Early-access Program
Positive Real-world Setmelanotide Data Reported from French Early- access Program in Adult Patients with Acquired Hypothalamic Obesity -5.6% -12.8% -21.3% N=8* Mean BMI reduction Mean BMI reduction Mean BMI reduction patients ◼ Month 1 ◼ Month 3 ◼ Month 6 19.3 years #1 #2 #3 #4 #5 #6 #7 #8 Mean age
Slide 41: Real-world Case Reports from French Early-access Program Suggest Setmelanotide may be Effective for Congenital HO
Real-world Case Reports from French Early-access Program Suggest Setmelanotide may be Effective Treatment for Congenital HO Case reports presented at 62nd annual meeting of the European Society for Paediatric Endocrinology (EPSE) Adapted from ‘3-Month real-world setmelanotide hunger and weight outco
Slide 42: Rapid and Statistically Significant Hunger Reduction in Patients with HO Aged ≥12 Years
Rapid and Statistically Significant Hunger Reduction in Patients with HO Aged ≥12 Years Reduction in Most Hunger Score* Over Time 0.0 52-Week Most Hunger Score* Mean change in maximal daily hunger score (95% CI) ◼ Setmelanotide ◼ Placebo Reduction Change in maximal daily hunger n= 57 24 0.0 -0.5 sco
Slide 43: Significant Reductions in BMI Observed in both Adults and Children in Phase 3 Trial
Significant Reductions in BMI Observed in both Adults and Children in Phase 3 Trial Evaluating Setmelanotide in Acquired HO ≥18 Years Old (n=49) <18 Years Old (n=71) +2.4% +3.9% % Change from Baseline % Change from Baseline 10 20 0 10 0 -10 -10 -20 -20 -30 -40 -16.8% -19.2% Placebo-adjusted -30 -40
Slide 44: Rapid and Significant BMI Percent Reduction Starting at Week 4
Rapid and Significant BMI Percent A Higher Proportion Achieved Percent Reduction Starting at Week 4 BMI Reductions for All BMI Thresholds ◼ Setmelanotide ◼ Placebo ◼ Setmelanotide ◼ Placebo 100 10 n=81 n=39 Percent of participants achieving BMI percent 2.6 2.8 90 1.9 2.0 2.0 Mean BMI percent change
Slide 45: Patients Achieved 25.5% Mean BMI Reduction at One Year in Long-term Extension Trial
Hypothalamic Obesity: Patients Achieved 25.5% Mean BMI Reduction at One Year of Setmelanotide Therapy in Long-term Ext. Trial Patient who discontinued Patients on treatment at Month 12 Patient lost to follow-up (n=1) treatment because of an AE (n=1) (n=12) 0 5 Reinitiated 5 Dose Off treatment Dose O
Slide 46: Body Composition Data Show Greater Decreases in Total Fat Mass vs. Lean Muscle Mass
Body Composition Data Show Greater Decreases in Total Fat Mass vs. Lean Muscle Mass Patient number 1 2 3 4 5 6 7 8 9 10 11 12 Age at baseline 6 9 9 10 11 12 13 14 15 15 16 24 Percent change in BMI from baseline to -35.8 -20.5 -39.1 -23.9 -7 -8.7 -21.6 -29.2 -14.6 -36.6 -42.4 -27.1 Month 12 40 17.5 1
Slide 47: All Patients Achieved a Decrease in Obesity Severity at One Year
All Patients Achieved a Decrease in Obesity Severity at One Year Three of 11 pediatric patients achieved normal weight at one year based on NIH, WHO weight classifications Adults WHO Classification BMI, kg/m2 Pediatric patients (n=11)* BMI percentile6 (n=1) (NIH5) 190 ≥50 50 166 157 158 Obesity clas
Slide 48: Consistent Response to Setmelanotide Therapy Observed across Majority of Patients in Phase 3 Trial
Consistent Response to Setmelanotide Therapy Observed across Majority of Patients in Phase 3 Trial in Acquired HO 90% Setmelanotide 80% 80% Placebo Proportion of patients 70% 63% 60% 51% 50% 43% 40% 30% 20% 10% 10% 5% 3% 0% 0% 5% 10% 15% 20% P<0.0001 P<0.0001 P<0.0001 P<0.0001 Observed Reduction in
Slide 49: Individual Percentage Change in BMI from Baseline to Week 14
Individual Percentage Change in BMI from Baseline to Week 14 10 6.5 5.2 5 Percentage Change in BMI,% 2.1 1.5 1.8 1.0 1.3 0.4 0 -0.1 * -1.7 -1.4 -3.2 -3.0 -3.5 -5 -4.2 -4.2 -6.9 -8.0 -7.8 -10 -9.3 -8.9 -9.0 -9.0 -9.6 -13.7 * -15 -14.8 -14.5 -16.4 -20 Placebo BIVA 200mg BIVA 400mg BIVA 600mg (n=7) (n=
Slide 50: Patients Achieved BMI Reductions of at least 5%, 10% at Week 14
Patients Achieved BMI Reductions of at least 5%, 10% at Week 14 100 Percentage of patients achieving BMI% 90 2 80 71.4% 1 75.0% 70 reduction cut point, % 60 50 40 37.5% 30 20 16.7% 14.3% 10 0.0% 0.0% 0.0% 0 Placebo 200mg BIVA 400mg BIVA 600mg BIVA (N=7) (N=6) (N=7) (N=8) Achieved a >=5% Reduction Ac
Slide 51: Bivamelagon Achieved Meaningful Reductions in 'Most' Hunger Scores at Week 14
Bivamelagon Achieved Meaningful Reductions in ‘Most’ Hunger Scores at Week 14 Bivamelagon QD Placebo QD (n=7) Change in most hunger score 200mg (n=6) 400mg (n=6*) 600mg (n=8) 0.0 -1.0 -0.8 -2.0 -2.1 -3.0 -2.8 -2.8 Weekly average of daily scores on a 10-point scale with 10 being ‘most’ hungry. *One p
Slide 52: Thank you
hank you Rhythm
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