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

2014 FPWR Research Conference

Keith Gottesdiener, MDCEO, Rhythm Pharmaceuticals

November 2014

April 18, 2023 CONFIDENTIAL2

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 Needs Near-Term Milestones

Prader Willi

syndrome

1:25k US pop

Diabetic Gastropares

is

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:


First-in-class MC4 agonist

RM-493

Genetic Causes of Obesity


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


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 obesityMAGEL2 KO mice (a model of PWS): Defective POMC neurons upstream of MC4R; hyper-responsive to MC4R agonists

Appetite

Weight


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=0.088P=0.188

Positive results in MC4 heterozygous patients


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/kg0.01 mg/kg

= 2.62 kg

-4.00

-3.50

-3.00

-2.50

-2.00

-1.50

-1.00

-0.50

0.00

= 2.37 kg

0.015 mg/kg

p=0.02

p<0.001

p=0.14

p<0.001p = 0.08

0.01 mg/ kg

2-week


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

Ch

an

ge

fro

m B

ase

line

(M

ea

n +

/-S

E)

Placebo RM-493 1.5 mg Once Daily

*

******

*p<0.05; ***p<0.001 vs PboPbo= placebo; QD = once daily


RM-493: Rhythm/NIDDK Energy Expenditure Study

Endpoint RM‐493 Placebo % change p‐value

Resting Energy Expenditure- Chamber (kcal/24hrs)

1856±369 1745±359 6.85% 0.028

Resting Energy Expenditure- Hood (kcal/24hrs)

1849±388 1770±379 4.7% 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


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


First-in-class MC4 agonist

RM-493

Study in Prader Willi Syndrome Patients


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 RandomizedWithdrawal Period

RM-493 QD (N=6)

RM-493 QD (N=6)

RM-493 QD (N=6)

• 50% of active pts in double-blind withdrawal

• Control for effects on hunger/appetite

2 WeekOpen-label

RM-493 Active Dose

Extension

1 WeekFollow-up

Period

ScreeningDay

-43 to -15

Pbo QD (N=6)

Pbo QD (N=6)

Primary Efficacy Timepoint Secondary Efficacy Timepoint

Single-blind Run-in

Day -14 to -1Pbo QD (N=6)


Inclusion/Exclusion Criteria:

Key Inclusion CriteriaAge 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 CriteriaRecent 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


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

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

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