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2014 FPWR Research Conference Keith Gottesdiener, MD CEO, Rhythm Pharmaceuticals November 2014.

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Presentation on theme: "2014 FPWR Research Conference Keith Gottesdiener, MD CEO, Rhythm Pharmaceuticals November 2014."— Presentation transcript:

1 2014 FPWR Research Conference Keith Gottesdiener, MD CEO, Rhythm Pharmaceuticals November 2014

2 April 29, 2015 CONFIDENTIAL 2 Prader Willi Syndrome Ph2a 3Q-4Q15 Rhythm Highlights Peptide-based therapies for metabolic disorders Two Peptides in Phase 2 Development Relamorelin (Ghrelin) Pan-GI prokinetic 1st indication Diabetic Gastroparesis Positive Ph2 data Expect NDA filing by 2018 RM-493 (MC4) MC4 is key pathway controlling appetite and weight regulation For treatment of obesity caused by genetic defects in MC4 pathway Positive Phase 1b Proof of concept PWS a key target population Large Unmet NeedsNear-Term Milestones Prader Willi syndrome 1:25k US pop Diabetic Gastroparesis 2.3M US pts Obesity caused by MC4 genetic deficiency 1M US pts Diabetic Gastroparesis Ph2b 4Q15-1Q16 MC4 genetic deficiency Ph2a 4Q15-1Q16 Study Results:

3 April 29, 2015 CONFIDENTIAL 3 3 First-in-class MC4 agonist RM-493 Genetic Causes of Obesity

4 April 29, 2015 CONFIDENTIAL 4 MC4 Agonist RM-493 MC4 is key pathway that regulates energy homeostasis, food intake First-generation MC4 agonists = predominantly small molecules with safety issues (blood pressure) and limited efficacy RM-493 peptide retains specificity, functionality of naturally occurring hormone Initial Phase 1 and Phase 2 clinical trials: promising weight loss without adversely increasing blood pressure A compelling target for weight loss

5 April 29, 2015 CONFIDENTIAL 5 MC4 Agonist RM-493 Obesity due to Genetic Deficiencies in MC4 Pathway MC4 Pathway Prader Willi Syndrome: Rationale  PWS: Loss of function on part of Chr 15 (including MAGEL2 gene)  Patients null for MAGEL2 alone: PWS-like syndrome with obesity  MAGEL2 KO mice (a model of PWS): Defective POMC neurons upstream of MC4R; hyper-responsive to MC4R agonists  Appetite  Weight

6 April 29, 2015 CONFIDENTIAL 6 Phase 1B proof-of-concept trial in another MC4 Genetic Deficiency Dose ~0.01 mpk/day x 28 days Weight  = -2.62 kg Preliminary data; N=8 (6 active/2 pbo); Circum=circumference; Daily Intake=average difference in caloric intake in over 28d 4 weeks Waist Circum  = -5.1 cm Daily Intake  = -291 kcal Placebo Subtracted Differences P=0.088 P=0.188 Positive results in MC4 heterozygous patients

7 April 29, 2015 CONFIDENTIAL 7 RM-493: Efficacy Confirmed in 5 Phase 1b cohorts Placebo-Subtracted Difference in Weight 4-week WEIGHT LOSS MC4 Heterozygous Positive proof-of-concept results Wild-Type Obese N=9 per group (6 active, 3 placebo) except Cohort 6; BID=twice daily  = 2.82 kg  = 3.97 kg  = 1.58kg 0.0075 mg/kg BID SC injection 0.01 mg/kg  = 2.62 kg  = 2.37 kg 0.015 mg/kg p=0.02 p<0.001 p=0.14 p<0.001 p = 0.08 0.01 mg/ kg 2-week

8 April 29, 2015 CONFIDENTIAL 8 Three cohorts completed with interim data:  Rhythm remains blinded for most data except weight  At 3 months pbo-subtracted weight loss up to -4.67% (p<0.001)  Some challenges in PK delivery (compliance and consistency) RM-493 Ph2a General Obesity: Weight Loss (Initial Cohorts) Weight Loss with SC Formulation Percent Weight Loss: Change (LS Mean +/- SE) from Baseline Change from Baseline (Mean +/-SE) PlaceboRM-493 1.5 mg Once Daily * *** *p<0.05; ***p<0.001 vs Pbo Pbo= placebo; QD = once daily

9 April 29, 2015 CONFIDENTIAL 9 RM-493: Rhythm/NIDDK Energy Expenditure Study Endpoint RM ‐ 493 Placebo% change p ‐ value Resting Energy Expenditure- Chamber (kcal/24hrs) 1856±3691745±3596.85%0.028 Resting Energy Expenditure- Hood (kcal/24hrs) 1849±3881770±3794.7%0.059 Primary and Key Secondary Endpoints  MC4 agonism works thru both  appetite and ↑energy expenditure  This increase in EE would itself result in ~7 kg weight loss over 1 year  But critical impact may be to blunt metabolic response to weight loss First clinical proof: MC4 agonism increases energy expenditure Preliminary Data

10 April 29, 2015 CONFIDENTIAL 10 RM-493 Was Generally Well-Tolerated  Approximately 190 subjects and patients exposed to drug  Single doses up to 10 mg  Three months up to 2 mg/day  Discontinuations due to Adverse Events (AEs) were uncommon  Most AEs were due to mechanism-based effects  Little, if any change in heart rate or blood pressure  Small increase in male erections/female arousal  Some nausea and/or vomiting, mild and short-lived  Skin tanning (see next slide)  Other, non-mechanism based AEs: evenly distributed among active and placebo treatment groups  Some injection site reactions seen in both groups  One drug-related Serious Adverse Event (SAE)  Unusual chest pain w/o cardiac or respiratory cause  No concerns for labs, ECGs, physical exam

11 April 29, 2015 CONFIDENTIAL 11 First-in-class MC4 agonist RM-493 Study in Prader Willi Syndrome Patients

12 April 29, 2015 CONFIDENTIAL 12 4-Week Double Blind Randomized Treatment Period RM-493 Phase 2 Prader Willi Syndrome Study Study Diagram Randomization Pbo=placebo; Sx=symptom; Rx=treatment; QD=once daily; 10-week double blind, pbo controlled parallel group study with a randomized pbo-controlled withdrawal phase and open label active treatment extension Pbo-controlled Baseline for post-Rx analyses RM-493 0.5mg once daily (N=12) Pbo once daily (N=12) RM-493 1.5mg once daily (N=12) Weight endpoint Hunger/Satiety endpoints 2-Week Randomized Withdrawal Period RM-493 QD (N=6) 50% of active pts in double-blind withdrawal Control for effects on hunger/appetite 2 Week Open- label RM-493 Active Dose Extension 1 Week Follow-up Period Screening Day -43 to -15 Pbo QD (N=6) Primary Efficacy TimepointSecondary Efficacy Timepoint Single-blind Run-in Day -14 to -1 Pbo QD (N=6)

13 April 29, 2015 CONFIDENTIAL 13 Inclusion/Exclusion Criteria: Key Inclusion Criteria  Age 16+ years  BMI>30 kg/m 2 (under discussion)  If present, well-controlled diabetes, hypertension  Stable body weight at home ~2 months (i.e., self/guardian reported loss/gain ±5%) Key Exclusion Criteria  Recent use of weight loss drugs; investigational agents  Significant suicidal indications  Significant concomitant illnesses (e.g., severe cardiac, liver, renal disease)  Significant abnormalities in laboratories and/or ECGs  History or close family history of melanoma

14 April 29, 2015 CONFIDENTIAL 14 Study Objectives and Logistics  Primary, to assess:  Safety and Tolerability in PWS patients  The effect of RM-493 on weight loss  The effect of RM-493 on hyperphagia  Secondary, to assess:  The effect of RM-493 on body composition (DEXA)  Changes in quality of life and other food-related behaviors  The pharmacokinetics of RM-493 in PWS patients  The effects of RM-493 during a double-blind, randomized withdrawal period  Logistics:  Patients in a “home setting”  Two sites: U of Florida (J. Miller) and Vanderbilt (E. Roof)  Approximately 5 clinic visits  RM-493 administered once daily by subcutaneous injection  Everyone will receive placebo and RM-493 at some point in the study


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