2014 FPWR Research Conference
Keith Gottesdiener, MD
CEO, Rhythm Pharmaceuticals
November 2014
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
Large Unmet Needs
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
Near-Term Milestones
Study Results:
Diabetic
Gastroparesis
2.3M US pts
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Obesity caused
by MC4 genetic
deficiency
Prader Willi
syndrome
1M US pts
1:25k US pop
CONFIDENTIAL
Diabetic Gastroparesis Ph2b 4Q15-1Q16
MC4 genetic deficiency Ph2a 4Q15-1Q16
Prader Willi Syndrome Ph2a 3Q-4Q15
RM-493
First-in-class MC4 agonist
Genetic Causes of Obesity
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CONFIDENTIAL
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MC4 Agonist RM-493
A compelling target for weight loss
MC4 is key pathway that regulates energy
homeostasis, food intake
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•
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
CONFIDENTIAL
MC4 Agonist RM-493
Obesity due to Genetic Deficiencies in 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
MC4 Pathway
 Appetite
 Weight
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CONFIDENTIAL
Phase 1B proof-of-concept trial in another MC4 Genetic Deficiency
Positive results in MC4 heterozygous patients
Placebo Subtracted Differences
Weight
 = -2.62 kg
P=0.088
Waist Circum
 = -5.1 cm
Daily Intake
 = -291 kcal
P=0.188
4 weeks
Dose ~0.01 mpk/day x 28 days
Preliminary data; N=8 (6 active/2 pbo); Circum=circumference; Daily Intake=average difference in caloric intake in over 28d
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RM-493: Efficacy Confirmed in 5 Phase 1b cohorts
Positive proof-of-concept results
Placebo-Subtracted Difference in Weight
MC4
Heterozygous
WEIGHT
LOSS
 = 2.62 kg
Wild-Type Obese
 = 3.97 kg
 = 2.37 kg
 = 1.58kg
 = 2.82 kg
0.00
-0.50
-1.00
-1.50
p=0.14
-2.00
-2.50
p = 0.08
p=0.02
-3.00
p<0.001
-3.50
-4.00
p<0.001
0.01 mg/ kg
0.01 mg/kg
4-week
N=9 per group (6 active, 3 placebo) except Cohort 6; BID=twice daily
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CONFIDENTIAL
0.015 mg/kg
0.01 mg/kg
0.0075 mg/kg
BID SC injection
2-week
RM-493 Ph2a General Obesity: Weight Loss (Initial Cohorts)
Weight Loss with SC Formulation
Percent Weight Loss: Change (LS Mean +/- SE) from Baseline
Three cohorts completed
with interim data:
0
Rhythm remains blinded for
most data except weight
Change from Baseline (Mean +/-SE)
-0.5
-1
At 3 months pbo-subtracted
weight loss up to -4.67%
(p<0.001)
-1.5
-2
*
-2.5
Some challenges in PK
delivery (compliance and
consistency)
-3
***
-3.5
***
-4
-4.5
-5
1
8
Placebo
*p<0.05; ***p<0.001 vs Pbo
Pbo= placebo; QD = once daily
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CONFIDENTIAL
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22
26
RM-493 1.5 mg Once Daily
RM-493: Rhythm/NIDDK Energy Expenditure Study
First clinical proof: MC4 agonism increases energy expenditure
Primary and Key Secondary Endpoints
Endpoint
RM‐493
Placebo
% change
p‐value
Resting Energy ExpenditureChamber (kcal/24hrs)
1856±369
1745±359
6.85%
0.028
Resting Energy ExpenditureHood (kcal/24hrs)
1849±388
1770±379
4.7%
0.059
 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
Preliminary Data
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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
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CONFIDENTIAL
RM-493
First-in-class MC4 agonist
Study in Prader Willi Syndrome Patients
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CONFIDENTIAL
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RM-493 Phase 2 Prader Willi Syndrome Study
Study Diagram
10-week double blind, pbo controlled parallel group study with a randomized
pbo-controlled withdrawal phase and open label active treatment extension
Randomization
Primary Efficacy Timepoint
4-Week Double Blind
Randomized Treatment Period
Secondary Efficacy Timepoint
2-Week Randomized
Withdrawal Period
RM-493 QD (N=6)
RM-493 0.5mg once daily (N=12)
Screening
Day
-43 to -15
Pbo QD (N=6)
Single-blind
Run-in
Day -14 to -1
RM-493 QD (N=6)
Pbo once daily (N=12)
Pbo QD (N=6)
RM-493 QD (N=6)
RM-493 1.5mg once daily (N=12)
Pbo QD (N=6)
• Pbo-controlled
• Baseline for
post-Rx
analyses
• Weight endpoint
• Hunger/Satiety endpoints
• 50% of active pts in
double-blind
withdrawal
• Control for effects
on hunger/appetite
Pbo=placebo; Sx=symptom; Rx=treatment; QD=once daily;
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CONFIDENTIAL
2 Week
Openlabel
RM-493
Active
Dose
Extension
1 Week
Follow-up
Period
Inclusion/Exclusion Criteria:
Key Inclusion Criteria
 Age 16+ years
 BMI>30 kg/m2 (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
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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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CONFIDENTIAL