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:

April 18, 2023 CONFIDENTIAL33

First-in-class MC4 agonist

RM-493

Genetic Causes of Obesity

April 18, 2023 CONFIDENTIAL4

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

April 18, 2023 CONFIDENTIAL5

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

April 18, 2023 CONFIDENTIAL6

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

April 18, 2023 CONFIDENTIAL7

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

April 18, 2023 CONFIDENTIAL8

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

April 18, 2023 CONFIDENTIAL9

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

April 18, 2023 CONFIDENTIAL10

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

April 18, 2023 CONFIDENTIAL1111

First-in-class MC4 agonist

RM-493

Study in Prader Willi Syndrome Patients

April 18, 2023 CONFIDENTIAL12

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)

April 18, 2023 CONFIDENTIAL13

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

April 18, 2023 CONFIDENTIAL14

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