Rhythm Pharmaceuticals, Inc. · NASDAQ:RYTM

Rhythm Pharmaceuticals — Investor Presentation (April 2026)

50 slides from Rhythm Pharmaceuticals's investor presentation, April 2026

1. Slide 1: Rhythm Pharmaceuticals Corporate Presentation April 2026

   Rhythm Pharmaceuticals Corporate Presentation April 2026 ® © Rhythm® Pharmaceuticals, Inc. All rights reserved.

2. 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

3. Slide 3: Well Positioned to Deliver Long-term, Sustained Growth

   Well Positioned to Deliver Long-term, Sustained Growth Global commercial infrastructure to drive growth with IMCIVREE® (setmelanotide) available >25 countries for BBS, POMC, LEPR deficiencies Acquired hypothalamic obesity (HO): IMCIVREE FDA approval in March 2026 with near-term growth opportunities

4. 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 IMCIVREE is a melanocortin 4 (MC4) receptor agonist indicated to reduce excess body weight and maintain reduction long term in adults and pediatric patients aged: • 4 years and older with

5. 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;

6. 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

7. 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 Setmelanotide* Acquired hypothalamic obesity US daily sc injection Bardet-Biedl syndrome or US, EU, UK, Canada biallelic POMC, PCSK1 or LEPR deficiency Setmelanotide daily sc inje

8. 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,+ for acquired HO syndrome 4,000 – 5,000* ~10,000 ~20,000 Bardet-Biedl syndrome estimated

9. 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 $388.9M Guidance 68.3 Million Cash, cash equivalents RYTM expects cash to Weighted average and short-term be sufficient to fund common shares investments as of planned operations outstanding as of December 31, 2025 f

10. 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

11. Slide 11: Multiple Anticipated Milestones

    Multiple Anticipated Milestones Complete enrollment in Part C of Ph1/2 trial evaluating weekly RM-718 in Q1 2026 acquired hypothalamic obesity European Commission decision on Marketing Authorization Application for Q2 2026 IMCIVREE in acquired hypothalamic obesity1 Disclose six-month results from ex

12. Slide 12: IMCIVREE Global Commercial Execution

    IMCIVREE Global Commercial Execution ® 12

13. 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

14. 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 $60 $57.3M $51.3M $48.5M $50 Global net sales in $M $41.8M $40 $37.7M $33.3M $30 $29.1M $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 23 1Q 24 2Q

15. Slide 15: Hypothalamic Obesity

    Hypothalamic Obesity Acquired and Congenital ® 15

16. Slide 16: 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

17. Slide 17: 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

18. Slide 18: 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 ® 18

19. Slide 19: Approval Supported By Statistically Significant and Highly Clinically Meaningful BMI Reduction in Phase 3 Acquired HO Trial

    Approval Supported By Statistically Significant and Highly Clinically Meaningful BMI Reduction in Phase 3 Acquired HO Trial Primary analysis cohort (N=142) -15.8% BMI change from baseline in -18.4% +2.6% BMI change from baseline in Placebo-adjusted Setmelanotide arm difference in BMI reduction Place

20. Slide 20: 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 ® 20

21. Slide 21: 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

22. Slide 22: 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

23. Slide 23: 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

24. Slide 24: 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

25. Slide 25: 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 ® 25

26. Slide 26: 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

27. Slide 27: 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

28. Slide 28: 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

29. Slide 29: Prader-Willi Syndrome

    Prader-Willi Syndrome ® 29

30. Slide 30: 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

31. Slide 31: 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

32. Slide 32: 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

33. Slide 33: 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

34. Slide 34: 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 (

35. Slide 35: Positive Body Composition Changes from Baseline to Month

    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) ® 35

36. Slide 36: Appendix

    Appendix Rhythm

37. Slide 37: 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

38. Slide 38: 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

39. Slide 39: 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

40. Slide 40: 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

41. Slide 41: 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

42. Slide 42: 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

43. Slide 43: 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

44. Slide 44: 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

45. Slide 45: 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

46. Slide 46: 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

47. Slide 47: 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=

48. Slide 48: 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

49. Slide 49: 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

50. Slide 50: Thank you

    hank you Rhythm

Rhythm Pharmaceuticals — Investor Presentation (April 2026) on 6ix