Slide 1: Forward-looking statements
This presentation contains certain statements that are forward-looking within the meaning of Section 27A of the Securities Act of 1933, as amended, and Section 21E of the Securities Exchange Act of 1934, as amended, and that involve risks and uncertainties, including statements regarding Rhythm's ex
Slide 2: Positive Topline Results from Pivotal Phase 3 Trials in POMC and LEPR Deficiency Obesities
Both studies met primary and key secondary endpoints, with statistically significant and clinically meaningful results in reductions of weight and hunger POMC: 8/10 participants met greater than 10% weight loss threshold (p<0.0001) LEPR: 5/11 participants met greater than 10% weight loss threshold (
Slide 3: Setmelanotide is a Targeted Therapy that Restores the Impaired MC4R Pathway
Upstream XXXX XXXX XXXX XXXX XXXX XXXX XXXX XXXX ALMS1 BBSx LEPR PCSK1 POMC LEPR deficiency Alström syndrome POMC deficiency Bardet-Biedl syndrome Homozygous, compound heterozygous, heterozygous, epigenetic dysfunction MC4R pathway genes Activation Downstream MC4R MC4R expressing neuron Setmelanotid
Slide 4: Summary of Efficacy Endpoints: POMC
Summary of Efficacy Endpoints: POMC Primary: Proportion of Participants Achieving at Least 10% Change in Body Weight 80.0% p<0.0001 Key Secondary: Mean Percent Change from Baseline in Body Weight -25.4% p<0.0001 Key Secondary: Mean Percent Change from Baseline in Most Hunger Rating -27.8% p=0.0005 K
Slide 5: Summary of Efficacy Endpoints: LEPR
Primary: Proportion of Participants Achieving at Least 10% Change in Body Weight 45.5% p=0.0001 Key Secondary: Mean Percent Change from Baseline in Body Weight -12.5% p<0.0001 Key Secondary: Mean Percent Change from Baseline in Most Hunger Rating -41.9% p<0.0001 Key Secondary: Proportion of Particip
Slide 6: Summary of Efficacy Endpoints: LEPR
| Summary of Efficacy Endpoints: LEPR Primary: Proportion of Participants Achieving at Least 10% Change in Body Weight Key Secondary: Mean Percent Change from Baseline in Body Weight Key Secondary: Mean Percent Change from Baseline in Most Hunger Rating Key Secondary: Proportion of Participants with
Slide 7: POMC and LEPR Phase Trials – Trial Design
POMC and LEPR Phase 3 Trials – Trial Design Adult starting dose 1.0 mg Adolescent starting dose 0.5 mg Adult therapeutic dose set Adolescent therapeutic dose set Open Label Dose Titration Open-label treatment at therapeutic dose Placebo withdrawal sequence Open-label treatment at therapeutic dose Op
Slide 8: POMC and LEPR Phase Trials — Trial Design
POMC and LEPR Phase 3 Trials — Trial Design (pen Label Dose Titration (Oper {abel Treatment and Placebo Withdrawal Variable duration = 2-12 weeks 10 weeks B weeks weeks End of Last dose study Weeko Week2 Week 12 Week 20 Week 52
Slide 9: POMC Participant Demographics
POMC Participant Demographics Age at Trial Enrollment (years) Mean (range) 18.4 (11-30) <12 years old (n) 2 Gender, M,F 5, 5 Weight (kg) Mean 118.7 Range 55.9-186.7 BMI (kg/m2) Mean 40.4 Range 26.6-53.3 Most Hunger (>12 years old) Most hunger in 24 hours 8.0 Range 7.0-9.0
Slide 10: POMC Phase Trial – Topline Results
POMC Phase 3 Trial – Topline Results Endpoint Proportion of Participants Achieving at Least 10% Change in Body Weight 80% p<0.0001 90% CI (49.31, 96.32) Mean Percent Change from Baseline in Body Weight (%)* -25.4 Range: -35.6 to -2.4 p<0.0001 90% CI (-28.80, -21.98) Mean Percent Change from Baseline
Slide 11: POMC Phase Trial – Change in Weight and Hunger Over Year
POMC Phase 3 Trial – Change in Weight and Hunger Over 1 Year BL, baseline; V, nominal visit; N, number; error bars are confidence intervals (90%) *, endpoint analyzed on evaluable population, which includes participants who achieved weight loss threshold (5kg or 5% if <100 kg) after open label perio
Slide 12: POMC Phase Trial – Substantial Weight Gain and Hunger Increase During Placebo Withdrawal
POMC Phase 3 Trial – Substantial Weight Gain and Hunger Increase During Placebo Withdrawal Change in Weight (kg) 0 -10 -30 -40 BL V2 V3 V4 V5 V6 V7 V8 V9 V10 V11 V12 Final Visit** -20 0 10 20 30 40 50 60 10 9 8 7 6 5 4 3 2 1 0 Daily Hunger Score (Most in 24 hours) During Placebo Period: Change in we
Slide 13: Taking a Closer Look at POMC
8 of the 10 POMC participants achieved the primary endpoint threshold of 10% weight loss vs. baseline These individuals achieved between 25.8% – 35.6% weight loss Of the participants who did not meet the primary endpoint: One participant had confounding comorbidities making their response difficult
Slide 14: Taking a Closer Look at POMC
| Taking a Closer Look at POMC + 8 of the 10 POMC participants achieved the primary endpoint threshold of 10% weight loss vs. baseline * These individuals achieved between 25.8% — 35.6% weight loss * Of the participants who did not meet the primary endpoint: + One participant had confounding comorbi
Slide 15: LEPR Participant Demographics
LEPR Participant Demographics Age at Trial Enrollment (years) Mean (range) 23.4 (12-37) <12 years old (n) 0 Gender, M,F 3, 8 Weight (kg) Mean 133.3 Range 89.4-170.4 BMI (kg/m2) Mean 48.2 Range 35.8-64.6 Most Hunger (>12 years old) Most hunger in 24 hours 7.1 Range 5.0-8.0
Slide 16: LEPR Phase 3 Trial – Topline Results
*, endpoint analyzed on evaluable population, which includes participants who achieved weight loss threshold (5kg or 5% if <100 kg) after open label period 1; †, score is based on 0-10 Likert scale from question, “In the last 24 hours, how hungry did you feel when you were the most hungry?” for part
Slide 17: LEPR Phase 3 Trial – Change in Weight and Hunger Over 1 Year
Change in Weight (kg) 0 Final Visit V12 V11 V10 V9 V8 V7 V6 V5 V4 V3 V2 BL -5 -15 -10 -20 -25 LEPR Phase 3 Trial –Change in Weight and Hunger Over 1 Year* BL, baseline; V, nominal visit; N, number; error bars are confidence intervals (90%) *, endpoint analyzed on evaluable population, which includes
Slide 18: LEPR Phase 3 Trial – Substantial Weight Gain and Hunger Increase During Placebo Withdrawal
Change in Weight (kg) 0 Final Visit V12 V11 V10 V9 V8 V7 V6 V5 V4 V3 V2 BL -5 -15 -10 -20 -25 Week 0 Week 10 Week 20 Week 30 Week 50 Week 60 0 -2 -4 -6 Daily Hunger Score - (Most in 24 hours) Week 40 LEPR Phase 3 Trial – Substantial Weight Gain and Hunger Increase During Placebo Withdrawal* Change i
Slide 19: Taking a Closer Look at LEPR
5 of the 11 LEPR participants achieved the primary endpoint threshold of 10% weight loss vs. baseline These individuals achieved between 15.2% - 23.3% mean weight loss Of the participants who did not meet the primary endpoint: Three participants showed initial meaningful responses but after the plac
Slide 20: No Safety Concerns and Generally Well-tolerated in POMC and LEPR
Treatment-emergent related adverse events included injection sites reactions, hyperpigmentation and nausea/vomiting One participant withdrew due to mild hypereosinophilia No reported setmelanotide-related cardiovascular AEs No SAEs related to treatment with setmelanotide Non-setmelanotide related SA
Slide 21: Rhythm Expects Significant Progress in 2019 and 2020
Rhythm Expects Significant Progress in 2019 and 2020 Updated interim data for HET obesity Topline data from both POMC and LEPR Phase 3 studies 4Q19 Presentation and publication of full POMC and LEPR Phase 3 results 4Q19-1Q20 Initial NDA submission filings for setmelanotide in POMC and LEPR 2H19 Comp
Slide 22: Rhythm Expects Significant Progress in 2019 and 2020
| Rhythm Expects Significant Progress in 2019 and 2020 Vv Updated interim data for HET obesity v Topline data from both POMC and LEPR Phase 3 studies 4q19 Presentation and publication of full POMC and LEPR Phase 3 results 4Q19-1020 Initial NDA submission filings for setmelanotide in POMC and LEPR 2H
Slide 23: POMC and LEPR Phase Trials — Statistical Plan
Primary endpoint: Proportion of participants who received at least one dose of setmelanotide and demonstrate at least 10% weight reduction at ~1 year compared to baseline Analyzed using an exact binomial test which tests whether the percentage of participants who reach at least 10% loss in body weig
Slide 24: POMC and LEPR Phase Trials — Statistical Plan
POMC and LEPR Phase 3 Trials — Statistical Plan Primary endpoint: Proportion of participants who received at least one dose of setmelanotide and demonstrate at least 10% weight reduction at ~1 year compared to baseline + Analyzed using an exact binomial test which tests whether the percentage of par