Rhythm Pharmaceuticals : Corporate Presentation – January 2021

Rhythm Pharmaceuticals

Targeting MC4R pathway and transforming the care of patients with rare genetic diseases of obesity

January 2021

®

© Rhythm® Pharmaceuticals, Inc. All rights reserved.

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 without limitations statements regarding the potential, safety, efficacy, and regulatory and clinical progress of setmelanotide and RM-853, anticipated timing for enrollment and release of our clinical trial results, the timing for filing of NDA, MAA or other similar filings, our goal of changing the paradigm for the treatment of rare genetic disorders of obesity, the application of genetic testing and related growth potential, expectations surrounding the potential market opportunity for our product candidates, and strategy, prospects and plans, including regarding the commercialization of setmelanotide. Statements using words such as "expect", "anticipate", "believe", "may", "will" and similar terms are also forward-looking statements. Such statements are subject to numerous risks and uncertainties, including but not limited to, our ability to enroll patients in clinical trials, the outcome of clinical trials, the impact of competition, the impact of management departures and transitions, the ability to achieve or obtain necessary regulatory approvals, risks associated with data analysis and reporting, our expenses, the impact of the COVID-19 pandemic on our business operations, including our preclinical studies, clinical trials and commercialization prospects, and general economic conditions, and other risks as may be detailed from time to time in our Annual Reports on Form 10-K and Quarterly Reports on Form 10-Q and other reports we file with the Securities and Exchange Commission. Except as required by law, we undertake no obligations to make any revisions to the forward-looking statements contained in this presentation or to update them to reflect events or circumstances occurring after the date of this presentation, whether as a result of new information, future developments or otherwise.

2

®

Working Toward Changing the Paradigm for the Treatment of Rare Genetic Diseases of Obesity

Validation	Meaningful	Growth
Opportunity	Potential
FDA approved	Positive topline	Establish proof-of-concept
for chronic weight	results in	in new indications in
management for obesity due	Bardet-Biedl	Phase 2 Basket Study
to POMC, PCSK1 or LEPR	syndrome	Update early 1Q 2021
deficiency
Drive COMMUNITY BUILDING and GENETIC SEQUENCING

3

®

Living with Early-onset, Severe Obesity and Hyperphagia

Hallmark Symptoms of Rare Genetic Diseases of Obesity

Adalissa and Solomon with their

siblings (unaffected)

"They are constantly, all day

long saying they are hungry and asking what's for the next meal and what are we eating the next day. We keep a menu planned and if we deviate from that menu it's a disaster."

"We have had to put locks on our cupboards and fridge and freezer to protect them from themselves!"

• Olivia, Mother of Adalissa and Solomon, siblings diagnosed with BBS

"It causes extreme unrelenting hunger and excessive eating. As a child…the fridge and food was controlled massively…but nobody could understand that I was desperately hungry and just wanted to stop that feeling."

- Katy, diagnosed with POMC

heterozygous deficiency obesity

Katy, at 23 years old, 450 pounds

4

®

MC4R Pathway Regulates Hunger, Caloric Intake, and Energy Expenditure, and, Consequently, Body Weight

When signaling cascade is impaired, setmelanotide restores function by replacing MSH stimulating hormone

POMC NEURON

Leptin ALMS1

BBSx

MC4R-EXPRESSING

NEURON

LEPR

SH2B1

Satiety Signals	SRC1
(e.g. Leptin)

RAI1

MC4R	 Appetite
ACTIVATION	 Weight
MSH	 Energy expenditure

POMC

PCSK1

UPSTREAM

DOWNSTREAM

Setmelanotide

5

®

Rare Genetic Diseases of Obesity Associated with the MC4R Pathway Comprise a Significant Opportunity Distinct from General Obesity

Obesity	Rhythm is
focused on rare
affects tens of
genetic disorders
millions
of obesity:

LEPR, leptin receptor, POMC, pro-opiomelanocortin; MC4R, melanocortin-4 receptor.

• Estimated prevalence of U.S. patients based on company estimates; ** Estimated prevalence of U.S. patients with addressable variants of the
  MC4R; † Prevalence estimate for Alström syndrome is worldwide.

Obesity due to POMC, PCSK1 deficiency ~100-500*

Obesity due to LEPR deficiency	~500-2,000*
Bardet-Biedl syndrome	~1,500-2,500*
Alström syndrome	~500-1,000†
HETs POMC or LEPR	>20,000 *
heterozygous deficiency obesity
SRC1 deficiency obesity	>23,000 *
SH2B1 deficiency obesity	>24,000 *
MC4R deficiency obesity	~10,000 **
Smith-Magenis syndrome	~1,500-2,500*
Pivotal Indications	Phase 2 indications

6

®

Validation

FDA Approved for obesity due to POMC, PCSK1 and LEPR

deficiency obesities and MAA under review

7

®

Now Approved in the United States

8

®

Approval of IMCIVREE Based on Phase 3 Data from Largest Studies Conducted in Obesity due to POMC, PCSK1 or LEPR Deficiency

POMC/PCSK1

0%

80%

of participants achieved ≥10% weight loss

(95% CI, 44.39% to 97.48%); P=0.0002; n=10

in Body

-5%

PRIMARY ENDPOINT

-10%

5.5 kg mean increase in

Change

Weight

-15%

weight during double-blind

%

withdrawal period*

Mean

-20%

-25%

BL

V2

V3

V4

V5

V6

V7

V8

V9

V10

V11

V12

FV

Visit

45.5%

LEPR

P<0.0002; n=11

of participants achieved ≥10%

weight loss (95% CI, 16.75% to 76.62%);

0%

PRIMARY ENDPOINT

Bodyin

-2%

Change

-4%

weight during double-blind

Weight

-6%

5.0 kg mean increase in

%

-8%

withdrawal period*

Mean

-10%

-12%

BL

V2

V3

V4

V5

V6

V7

V8

V9

V1

V1

FV

0

2

Long-term	• Total of 15 patients maintained durable	• 11 of 15 eligible POMC	• 12 of 15 eligible LEPR
weight loss and stable hunger scores	patients enrolled **	patients enrolled **
extension study:
with treatment up to 155 weeks*

BL, baseline; PCSK1, proprotein convertase subtilisin/kexin type 1; POMC, proopiomelanocortin; FV, final visit; V, visit. † N=9 POMC participants and N=7 LEPR participants who achieved weight loss threshold (5 kg or 5% if <100 kg) after the first open-label active treatment phase. Reference: IMCIVREE Prescribing Information; * Data as of April 16, 2020; ** Data as of Nov. 16, 2020 cutoff as presented Dec. 22, 2020, corporate conference call.

9

®

IMCIVREE Reduced Hunger Over 1 Year in Phase 3 Trials

		Study 1
Worst hunger in last 24 hours*	(POMC/PCSK1)	Study 2 (LEPR)
		(N=8)	(N=11**)
Baseline	Median	7.9	7.0
	Min, Max	7, 9	5, 8
1 year	Median	5.5	4.4
	Min, Max	3, 8	2, 8
Change from baseline	Median	-2.0	-3.0
to 1 year	Min, Max	-7,-0	-5,-1

Hunger scores generally worsened during the double-blind, placebo withdrawal period among

those patients who had

experienced an improvement from baseline, and scores improved when IMCIVREE was reinitiated.

Note: This analysis includes patients aged 12 years and older who received at least 1 dose of study drug and had available data.

• Hunger score was captured in a daily diary and was averaged to calculate a weekly score for analysis. Hunger ranged from 0 to 10 on an 11-point scale where 0 = "not hungry at all" and 10 = "hungriest possible."
• One patient in Study 2 had missing hunger data at Week 52.

10

®

Strategic Imperatives for IMCIVREE's Successful Debut in U.S. Market

Ensure positive experience for patients,	Establish efficient and scalable model to meet
	caregivers and prescribing physicians	the needs of identified and future patients

Education and	Genetic testing	Access, reimbursement and	Positive experience
	patient assistance
awareness

11

®

Meaningful Opportunity

Setmelanotide achieved statistical significance and delivered clinically meaningful weight loss and hunger reduction in Phase 3 Bardet-Biedl syndrome trial

12

®

Bardet-Biedl and Alström Syndromes Phase 3 Trial Design

Double-blind	Open-label treatment
treatment period

Pivotal cohort

• 32 BBS patients
• 6 Alström syndrome patients

Setmelanotide	Setmelanotide
3 mg	3 mg
Screening and
1:1 randomization	Setmelanotide
Placebo
3 mg
14 weeks

Long-term extension

Week 0

Week 14

Week 52 Week 66

Primary Endpoint: proportion of patients (≥12 years of age) who have at least a 10% reduction in body weight.

BBS, Bardet-Biedl syndrome.

13

®

Phase 3 Clinical Trial Met Primary and All Key Secondary Endpoints

Setmelanotide achieved statistical significance and delivered clinically meaningful weight loss and hunger reduction

Phase 3 Topline Data (n=31a)

34.5%b	-6.2%	-30.8%	60.2%
p=0.0024	p<0.0001	p<0.0001	p<0.0001
≥10%	mean	mean	≥25%
weight loss	weight	hunger	reduction in
	reduction	score	worst hunger
		reduction

All primary endpoint responders were BBS patients.

As presented on Dec. 22, 2020, corporate conference call; aStudy participants older than 12 counted in full analysis set for primary and key secondary endpoints; Five participants were younger than 12, and two participants older than 12 discontinued during placebo-controlled period prior to receiving active therapy. bResponse rate was estimated based on imputation methodology discussed with FDA.

14

®

A Closer Look at Patients with Bardet-Biedl Syndrome

28 BBS		11 BBS (38.1%)
included in primary		patients achieved ≥10%
analysis set		weight loss:
• Mean actual weight loss:		• Mean actual weight loss:
-8.7 kg		-17.2 kg
• Mean percentage weight loss:		• Mean percentage weight loss:
- 7.5%		- 14.7%
• 15 of 28 were adults		• 8 of 11 were adults

53% of adult BBS patients (8/15)

achieved ≥10% weight loss

As presented on Dec. 22, 2020, corporate conference call, reflecting data cut-off of Dec 2. 2020.

An additional 5 BBS patients had 5-9% weight loss reduction at week 52

57% of BBS patients (16/28) had ≥5% weight loss reduction at week 52, including 73% of adults (11/15)

15

®

A Closer Look at Patients with Alström Syndrome

3 Evaluable patients with Alström syndrome ≥12 years old

• 1 discontinued
• 2 gained weight (mean change was
  +8.9 kg)

2 Patients < 12 years old not included in primary endpoint

• 1 patient lost approximately 8% body weight
• 1 patient discontinued

Hunger reduction reported by Alström patients observed to be between 20% and 30%.

Alström syndrome is driven by genetic variants in the ALMS1 gene, which ranks as "moderately" tied to MC4R

pathway according to ClinGen NIH Scoring System

As presented on Dec. 22, 2020, corporate conference call, reflecting data cut-off of Dec 2. 2020. * One enrolled patients withdrew while receiving placebo.

16

®

Setmelanotide's Path Forward for Bardet-Biedl and Alström Syndromes

1H21 Additional Analyses Expected

Further analysis of data	Analyses on	Data from 14-week
specific to BBS and	BMI and BMI-Z	placebo-controlled
Alström syndrome	scores	period

2H21 Supplemental New Drug Application to U.S. FDA for BBS

Breakthrough	Orphan Drug
Therapy	designation
designation

Approved for chronic weight management for obesity due to POMC, PCSK1 and LEPR deficiency1

2H21 Marketing		Orphan Drug		MAA under review for
Authorization Application	EMA PRIME
	obesity due to POMC,
to EMA for BBS	designation	designation		PCSK1 and LEPR

1In adult and pediatric patients ages 6 and older, confirmed by genetic testing.

17

®

Growth Potential

Establish proof-of-concept in new indications with

Rhythm Engine & Basket Study

18

®

Genetic Testing Expected to Drive Future Growth

through Clinical Development

UNCOVERING

RARE OBESITY

Biobanks

101-Gene Panel

Identify individuals with clear genetic underlying cause of severe obesity

19

®

Phase 2 Basket Study Key to Advancing to MC4R Pathway Obesity Indication

Enrolling Multiple Cohorts with Genetic Variants

•	Seamless integration with	Cohort stratification
	sequencing efforts
•	Rapid understanding of	High impact LOF
	setmelanotide
	responsiveness
•
Efficient path to registration		Uncertain
	LOF

Likely benign

Images are for illustrative purposes only and not intended to imply or suggest actual prevalence estimates or patient identification yields.

20

®

Significant Opportunity with MC4R Pathway Diseases Now Enrolling on Phase 2 Basket Study

~2,400*		~10,000*		>20,000*		>23,000*		>24,000*
Smith-Magenis		MC4R		POMC or LEPR		SRC1		SH2B1
syndrome		deficiency		heterozygous		deficiency		deficiency
		obesity		deficiency		obesity		obesity
				obesity

Total potential patient population approximately 80,000

• Company estimates calculated based on the following assumptions: US pop 327 million; 1.7% has early onset, severe obesity (Hales et al in JAMA - April 2018: Trends in Obesity and Severe Obesity Prevalence in US Youth and Adults by Sex and Age, 2007-2008 to 2015-2016); Allele frequency based on Rhythm genetic sequencing (June 2019)

21

®

Setmelanotide Generally Well-tolerated Across Development Program

Setmelanotide has been evaluated in more than 400 patients with obesity, with individual patient treatment duration now exceeding four years

Setmelanotide has been generally well-tolerated Most AEs are mild:

• Mild injection site reactions
• Hyperpigmentation and skin lesions, mediated by the closely related MC1 receptor
• Nausea/vomiting: mild and early in treatment

Discontinuations are rare; no increase in CV parameters

• In POMC and LEPR pivotal trials, setmelanotide was not associated with significant changes to blood pressure or heart rate

Patient experience with setmelanotide*

Duration on therapy	# of patients
< 1 year	> 440
> 1 year	44
> 2 years	20
> 3 years	3
> 4 years	2

• Estimates as of April 2020, inclusive of patients likely randomized to treatment in certain double- blinded clinical studies.

22

®

Interim Data Showed Once-weekly Formulation of Setmelanotide Achieved Safety and Efficacy Results Comparable to Daily in Phase 2 Study with 85 Healthy Obese Participants

Gel-like depot with slow diffusion, designed to be more patient-friendly and convenient and less burdensome

			Weekly			Daily
	10mg	20mg	30mg	10mg/	20mg/	2mg/3mg	Placebo
	20mg	30mg
Weight Change from
Baseline at Week 12	-2.6	-3.3	-3.0	-1.1	-3.6	-2.1	0.5
(kg)*
Percent Change from
Baseline in Most	-44.6	-39.8	45.51	83.511	-50.2	-35.6	10.1
Hungry Score at
Week 12 (%)*

• As of data cutoff of April 17, 2020, weekly setmelanotide was well-tolerated, with no serious treatment-emergent AEs, similar to daily administration and consistent with prior clinical experience.

Mean trough drug concentrations

• PK: Mean trough drug concentrations for 20mg and 30mg doses of weekly formulation similar to 3mg daily dose

Next step:Discuss registration path forward with FDA

23	1. Increased percent change from baseline due to missing data values and outliers.		®
Data presented at The Obesity Society's ObesityWeek® 2020, held November 2-6, 2020. *Data presented as of a cutoff date of April 17, 2020.

Rhythm Milestones and Next Steps

POMC/

PCSK1 and

LEPR Phase

IMCIVREE

granted FDA approval for

adults and

children > 6 years with obesity due to POMC/ PCSK1

BBS and AS Phase 3 trial meets primary and key secondary endpoints

(all primary

Updated data in HET

patients expected

Initial data in SRC1 and SH2B1 deficiency obesities expected

				NEJM
		IND filed and	publication
		on Phase 2
Licensed	first patient
POMC/
dosed with
setmelanotide
PCSK1 data
setmelanotide
from Ipsen

2010 2011 2016

Initiation of

obesity due to

POMC/ PCSK1

deficiency

Phase 3 trial

Breakthrough

Therapy

Designation

received

Positive Phase 2 Data in BBS

2017

Initiation of obesity due to LEPR deficiency Phase 3 trial

Nature

Medicine

publication on Phase 2 LEPR data

2018

3 trials

meet

primary

endpoints

Enrollment complete in BBS and AS Phase 3 Trial

2019

or LEPR

deficiency*

2020

endpoint

responders

were BBS

patients)

2020

2021

24	* Indicated for chronic weight management in adult and pediatric patients 6 years of age and older with obesity due to POMC, PCSK1 or LEPR deficiency confirmed by	®
genetic testing demonstrating variants in POMC, PCSK1, or LEPR genes that are interpreted as pathogenic, likely pathogenic, or of uncertain significance.

Rhythm Executing with Transformational Progress

1 Validation with first approval for IMCIVREE for obesity due to POMC, PCSK1 or LEPR deficiency

• 4Q: FDA Approved with Priority Review Voucher
• MAA under review by the European Medicines Agency (EMA)

2 Meaningful opportunity with Bardet-Biedl and Alström syndromes in Phase 3

• 4Q: Topline data from Phase 3 trial
  1H21: Additional data analyses from Phase 3 BBS and Alström syndrome trial
  2H21: U.S. and EU regulatory submissions for BBS

3 Growth potential

Early 1Q21: Proof-of-concept data in HET patients, initial data in SRC1 and SH2B1 deficiency obesity with update on genetic sequencing and epidemiology data

2021: Clinical development update for once-weekly formulation

25

®

Appendix

26

®

Strong Leadership Team with Broad Biopharma Experience

David Meeker, MD	Hunter Smith	Yann Mazabraud	Jennifer Chien	Murray Stewart, MD	Simon Kelner
Chair, President and	Chief Financial Officer	Executive Vice President,	Executive Vice President,	Chief Medical Officer	Chief Human Resources
Chief Executive Officer		Head of International	Head of North America		Officer

	25-plus years; focus on rare	Financial leadership for	20 years leading global	More than 20 years	20-plus marketed	25-plus years global HR
	genetic disease treatments,	Otezla®; 20-plus years	leading global
	commercial strategy in	products and NDAs	leadership experience in
	including Aldurazyme®,	in finance, M&A,	commercial strategy in
	rare diseases	10-plus INDs			biopharma
	Fabrazyme® and
	capital markets	rare diseases
	Myozyme®

27

®

Setmelanotide: Investigational MC4R agonist

FDA Breakthrough Therapy

Designation

▪ POMC deficiency obesity ▪ LEPR deficiency obesity ▪ Bardet-Biedl syndrome ▪ Alström syndrome

FDA Orphan Drug Designation	Setmelanotide
▪	POMC deficiency obesity

• LEPR deficiency obesity
• Bardet-Biedlsyndrome
• Alström syndrome

EMA PRIME Designation

• For treatment of obesity and control of hunger associated with deficiency disorders of the MC4R pathway

Eight-amino-acid cyclic peptide

Daily subcutaneous injection; once-weekly formulation in development

Retains specificity, functionality of naturally occurring hormone that activates MC4R

Composition of matter patents in all major markets

Highly competitive cost of goods

28 POMC, pro-opiomelanocortin; LEPR, leptin receptor		®

Rhythm Pipeline Focused on MC4R Pathway Diseases

Setmelanotide

	Disorder	Early-stage	Phase 2	Phase 3	Regulatory	Approved
	development	Submission
	Obesity due to POMC/PCSK1 deficiency*				EU	U.S.
	Obesity due to LEPR deficiency*				EU	U.S.
Pivotal	Bardet-Biedl syndrome
Studies	Alström syndrome
	POMC/PCSK1 or LEPR heterozygous
	deficiency obesity
	SRC1 deficiency obesity
Basket
SH2B1 deficiency obesity
Study
MC4 receptor deficiency obesity
	Smith-Magenis syndrome
	Additional disorders**
	Weekly Formulation

RM-853 GOAT inhibitor

• Indicated for chronic weight management in adult and pediatric patients 6 years of age and older with obesity due to POMC, PCSK1 or LEPR deficiency confirmed by genetic testing demonstrating variants in

29	POMC, PCSK1, or LEPR genes that are interpreted as pathogenic, likely pathogenic, or of uncertain significance ; ** Rhythm is currently assessing setmelanotide in additional diseases of obesity, as part of	®
investigator-initiated protocols within the basket study. Given the recent discovery of these rare disorders of the MC4R pathway, there is currently limited or no genetic sequencing or epidemiology data that

defines prevalence. However, Rhythm believes that these are rare disorders which may be setmelanotide-responsive.

Cash Expected to be Sufficient to Fund Operations Through at Least End of 2021

SHARES OUTSTANDING

as of 10/23/2020

44,204,745 (basic share count)

CASH, CASH EQUIVALENTS AND
SHORT-TERM INVESTMENTS	$ 201.8 million

as of 09/30/2020

On Jan. 5, 2021, the Company announced that it has entered into a definitive agreement to sell its Rare Pediatric Disease Priority Review Voucher for $100 million, which is in addition to the above cash and cash equivalents on-hand.

30

®

Setmelanotide Demonstrated Statistically Significant, Clinically Meaningful Reductions in Weight and Hunger in Phase 3 Trials

POMC Phase 3 Topline Data* (n=10)

80%	-25.4%	-27.8%	31.9kg /
>10% weight	mean weight	mean hunger	70.2lbs
loss	reduction	score reduction	mean weight loss
			in 1 year
LEPR Phase 3 Topline Data* (n=11)
45.5%	-12.5%	-41.9%	16.7kg /
>10% weight	mean weight	mean hunger	36.8lbs
loss	reduction	score reduction

mean weight loss

in 1 year

Validation

• FDA approved
• Priority Review Voucher
• MAA submitted to EMA in 2Q2020
• Additional supporting data
• • 100% of POMC (4) and LEPR (4) supplemental patients achieve >10% weight loss
  • 15 patients in LTE study maintained durable weight loss and stable hunger scores with treatment up to 155 weeks**

*Data announced by Rhythm in August 2019 and presented at The Obesity Society annual meeting during ObesityWeek in November 2019. ** Data as of April 16, 2020; LTE study is ongoing; two additional LEPR patients expected to enroll pending local regulatory approval. One POMC patient did not continue in LTE study.

*** All patients in the supplemental cohorts, as well as most patients in the pivotal cohorts, were enrolled by European investigators.

31

®

POMC Phase 3 Trial - Change in Weight and Hunger Over 1 Year with Substantial Weight Gain and Hunger Increase During Placebo Withdrawal

	Change in Weight*		Change in Hunger Score*†
	0
		hours)	10
		8
			9
	-10
(kg)		in 24	7
WeightinChange	-20	(MostScoreHunger	6
			5
	-30		4
			3
	-40	Daily	2
		1
			0

BL V2 V3 V4	V5 V6	V7 V8	V9 V10 V11 V12 Final Visit	0	10	20	30	40	50	60
											Final Visit
				Open Label Period 1	Placebo		Open Label Period 2
Open Label Period 1	Placebo	Open Label Period 2

During Placebo Period:

Change in weight (kg)

Mean +5.5

Range 1.5-10.5

Change in hunger score

Mean +2.2

Range

2.0 to 9.86

These data were presented as part of the Company's topline data disclosure on Aug. 7, 2019.

	BL, baseline; V, nominal visit; N, number; error bars are confidence intervals (90%)
32	*, 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 participants at least 12 years of age

** This was the final nominal visit for all participants, except for one

LEPR Phase 3 Trial - Change in Weight and Hunger Over 1 Year with Substantial Weight Gain and Hunger Increase During Placebo Withdrawal

Change in Weight*

Change in Hunger Score *†

Change in Weight (kg)

0

-5

-10

-15

-20

-25

Daily Hunger Score - (Most in 24 hours)

0

-2

-4

-6

During Placebo Period:

Change in weight (kg)

Mean +4.9

Range 2.9-9.3

Change in hunger score

Mean +3.1

Range

4.0 to 10.0

BL	V2	V3 V4	V5 V6	V7	V8	V9 V10 V11 V12 Final Visit	Week 0 Week 10 Week 20	Week 30	Week 40 Week 50 Week 60
		Open Label Period 1		Placebo	Open Label Period 2
			Open Label Period 1	Placebo	Open Label Period 2 Final Visit

These data were presented as part of the Company's topline data disclosure on Aug. 7, 2019.

33	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 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 participants at least 12 years of age

BBS and Alström Syndrome Phase 3:

Baseline Characteristics and Demographics in Evaluable Patients

Baseline Characteristics (N=31)
Diagnosis, n (%)
BBS	28 (90)
Alström syndrome	3 (10)
Age, mean (range), years	21 (12-44)b
Overall age, mean (range) years
14 (45)
Adolescents (12-17 years old), n (%)
Male, n (%)	14 (45)
Weight, mean (range), kg / lbs	117 (62-192) /
258 (136-423)
BMI, mean (range), kg/m2	44 (24, 83)
"Most hunger" score, mean (range)a	7 (4-10)
Cognitive impairment, n (%)	15 (48)

aWeekly average at active treatment baseline for participants ≥12 years of age assessed daily using a numeric rating score from 0-10, with 0 = not hungry at all and 10 = hungriest possible. BBS, Bardet-Biedl syndrome. b14 adolescents, 11 of whom are still growing.

34

®

BBS and Alström Syndrome Phase 3:

Primary Endpoint Met: Setmelanotide Achieved Statistically Significant and Clinically Meaningful Weight Reductions at ~1 Year on Therapy

34.5%a of participants (95% CI, 17.5 to 51.6; P=0.0024) achieved the primary endpoint

threshold of ≥10% weight loss from baseline at

Week 52

Baseline	~1 year at target	Percent change
dose	from baseline

Mean (SD) body	117.0 kg	109.9 kg	-6.2%
(29.4)	(30.6)	(8.3)
weight (n=31)
		P<0.0001

1. Response rate was estimated based on imputation methodology discussed with FDA. All 11 responders were BBS patients; of the 11, 2 were initially randomized to placebo and had not reached 52 weeks of treatment at data cut.
   CI, confidence interval.

35

®

BBS and Alström Syndrome Phase 3:

Setmelanotide Achieved Statistically Significant Reduction in "Most" Hunger

Score at ~1 Year on Therapy

60.2%a of participants (95% CI, 35.3 to 85.1 P<0.0001) achieved ≥25% reduction from baseline in daily hunger score at Week 52

Baseline	~1 year at target	Percent change
dose	from baseline

"Most" hungerb	7.3	5.1	-30.8%
(n=16)	(2.0)	(2.4)	(25.1)
		P<0.0001

1. Response rate was estimated based on imputation methodology discussed with FDA.

bWeekly average of scores reported for participants ≥12 years of age assessed daily using a numeric rating score from 0-10, with 0 = not hungry at all and 10 = hungriest possible. CI, confidence interval.

36

®

BBS and Alström Syndrome Phase 3:

A Closer Look at Patients with Alström Syndrome

3 Evaluable patients with Alström syndrome ≥12 years old

• 1 discontinued
• 2 gained weight (mean change was
  +8.9 kg)

2 Patients < 12 years old not included in primary endpoint

• 1 patient lost approximately 8% body weight
• 1 patient discontinued

Hunger reduction in Alström patients observed to be between 20% and 30%.

* One of six enrolled patients withdrew while receiving placebo.

37

®

BBS and Alström Syndrome Phase 3:

A Closer Look at Patients with Bardet-Biedl Syndrome

28 patients with BBS ≥12 years old in primary analysis

• 13 adolescent patients < 18

11 BBS

patients achieved primary endpoint of ≥10% weight loss:

• Mean actual weight loss:

-17.2 kg

• Mean percentage weight loss:
  - 14.7%
• 8 of 11 were adults

5 BBS

patients (3 adults, 2 adolescents)

had 5-9% weight loss reduction at week 52

38

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BBS and Alström Syndrome Phase 3:

Setmelanotide Was Generally Well Tolerated in Individuals With BBS or Alström Syndrome

Parameter	n (%)
Any treatment-emergent adverse	38 (100)
event (TEAE)
Serious TEAEsa	2 (5.3)
Serious treatment-related TEAEs	1 (2.6)
TEAEs leading to discontinuation	5 (13.2)
TEAEs leading to death	0 (0.0)

• Treatment-emergentadverse events (TEAEs) included mild injection site reactions and nausea with infrequent vomiting
• There was one serious TEAE considered related to treatment: anaphylactic reaction during placebo treatment
• Five participants had TEAEs leading to discontinuation
• There were no setmelanotide-related cardiovascular TEAEs

a3 serious AEs occurred in 2 participants, including blindness, suicidal ideation, and anaphylactic reaction; 1 serious AE was considered treatment-related (anaphylactic reaction). AE, adverse event; BBS, Bardet-Biedl syndrome.

39

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Phase 2 Data in BBS Illustrate Sustained Weight Loss and Hunger Reduction

% Change in Body Weight From Baselinea

0

-5-5.48#

-10							-11.26ⱡ
-15
				-16.33§

-20

-25

Baseline 3 months 6 months 12 months

n=10 n=8 n=8 n=7

	0
b	-10
Score
-20
Hunger	-30
-40
in Most	-50	-50.93
-60		-63.96
Change
-70			-70.16
-80
%	-90
	-100
	Baseline	3 months	6 months	12 months
	n=6	n=6	n=5	n=5

Per protocol:statistical analysis was performed via a 1-sample t test at a 1-sided 0.05 significance level. Haws RM, et al. Diabetes Obes Metab 2020. a Error bars are 90% CI. #P=0.02; ⱡP<0.001, §P<0.0001.; b Three participants were unable to complete the self-reported hunger questionnaires at all timepoints because of cognitive impairment and autism with mild cognitive impairment . For these participants, hunger was evaluated by caregivers using the FPD and SEQ. Error bars are 90% CI. P<0.05.

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Strong Phase 2 Data in BBS Showed Substantial Weight Loss and Hunger Control, Supporting Advancement into Phase 3

Published in Diabetes Obesity and Metabolism 2020*

	Weight Change from	BMI change	Hunger Score
Duration	from baseline	Change from
Baseline
		Baseline**

3 months	-5.5%	−5.5%	-50.9%
90% CI, −9.3% to −1.6%
(n=8)	P=0.01	P=0.01
P=0.02
6 months	-11.3%	−11.1%	-64%
90% CI, −15.5% to −7.0%
(n=8)	P<0.001	P=0.001
P<0.001
12 months	-16.3%	−16.2%	-70.2%
90% CI, −19.9% to −12.8%	P<0.001
(n=7)	P<0.0001
P<0.0001

*Pt*. Hawsh s cognitiveRM, etimpairment,al. DiabetessoObesFood ProblemMetab 2020;Diary (FPD)Per protocol:sc re maintainedstatisticalby canalysisregiver; was**Pt.performeddid not haveviab selinea 1-samplehungrtmtestasureat .aThe1-sidedfirst score0.05wassignificancea 7, whichlevel;was notTenrecordpatientsd untilenrolledaft r thein thispatientstudyhad. Oner ceivedpatientreatment(pediatric. patientCurrentwithscoreBBS1is a 6variant.; † Patientand type5 1 (pediatricdiabetes)patientexperiencedwith BBS153.variant3% reductionand typein hunger1 diabetes)andexperiencedreduction in53hemoglobin.3% reductionA1cin(10hunger.1% toand7.6%)reductionbefore withdrawingin hemoglobin. PatientA1c (10subsequently.1% to 7.6%) beforeenteredwithdrawinglong-termextension. Patient subsequentlystudy. Two patientsent red(onel g-nonterm-geneticallyxtension study;confirmed)Two patientswithdrew(oneduenonto -lackgeneticallyofweight loss. confirmed)** 3 participantswithdrew dueweretounablelack of weightto completeloss. the self-reportedhunger questionnaire because of cognitive impairment (n=2) and autism with mild cognitive impairment (n=1). For these participants, hunger was evaluated by caregivers.

41

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Phase 2 Data in Alström Syndrome*

Age at	Baseline		% Weight	% Hunger
enroll	Treatment,	Change	Score Change
Weight
ment/	weeks	from	from
(kg)
Sex		Baseline	Baseline†
12/M	78.6	95	-20%	-25%
15/F	70.7	84	1%	-38%
16/F	91.6	68	-6%	0%

• Patient 1 has reached healthy body weight
• Patient 3 maintaining weight and reduced hunger - HbA1c decreased by 3% from 11% to 8%
• All 3 continuing patients plan to enter long-term extension trial

*As previously disclosed, patient 2 (data not shown) discontinued at ~14 weeks; Updated data announced by Rhythm in September 2019.

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BBS and Alström Syndrome Pivotal Trial Statistical Approach

Primary endpoint	Three key secondary endpoints (after ~52 weeks of treatment)
Proportion of patients (≥12	Proportion of patients (≥12	Body weight percent	Daily hunger score percent
years old) who achieve	years old ) who achieve a	change from baseline in	change from baseline in
≥10% reduction in body	≥25% improvement in daily	patients ≥ 12 years old	patients ≥ 12 years old
weight after ~52 weeks of	hunger score
treatment
• Primary: Based on an exact binomial test, at a 1-sided 0.05 significance	• Based on a one-samplet-test with assumed mean percent change from
level; A 2-sided 90% CI will be calculated using the exact Clopper-	baseline of zero, at a 1-sided 0.05 significance level.
Pearson method. The statistical criterion corresponds to the 2-sided	• As in the POMC/LEPR pivotal trials, these percent change analyses to be
90% CI for setmelanotide of the response rate excluding 10% (i.e., lower	conducted on pivotal patients who achieve at least 5 kg (or 5% if <100
bound of the CI >0.10)		kg) weight loss after 14 weeks of active setmelanotide treatment

• Historical control response rate of 10% responders is used as a comparator for primary endpoint and responder key secondary endpoint, in the Full Analysis Set
• All prespecified primary and key secondary analyses are performed on the pooled BBS and Alström syndrome pivotal patient population
• Power Statement: A sample size of 7 patients provides ~95% power at 1-sided alpha of 0.05 and ~91% power at 1-sided alpha of 0.025, to yield a statistically significant difference, assuming the Phase 2 Basket Study 66% response for weight loss
• Although these data suggest that powering the study for the primary endpoint will require a minimal number of patients (N<10), the size of the trial is also a function of the rarity of BBS and Alström syndrome and a desire to better understand the effect of setmelanotide in these patient populations. Hence, at least 20 BBS and at least 6 Alström syndrome patients were planned to be enrolled in the study (N=38 were actually enrolled in the pivotal cohort)
• Rhythm proposed Statistical Analysis Plan; not all elements reviewed by FDA

43

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Sequencing Yield for Genetically-identified Indications Points to Significant Opportunity

Individuals with		Yield for genetically-
	identified indications**:
severe obesity
sequenced
*	POMC or	High-impact	MC4R	SH2B1	SRC1
13,567	LEPR	HETs	n = 269;	n = 245;	n = 335;
	n = 29;	n = 97;
	2.0%	1.8%	2.5%
	0.2%	0.7%

Syndromic indications, which are diagnosed based on clinical presentation, not included here

* As of June 30, 2019; sequencing efforts are ongoing.

**Basket yield includes 683 individuals with other variants; some patients have more than one variant.

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Stratifying Patients Based on Loss of Function (LOF) Variant - HET Example

U.S. prevalence approximately 1 million for

individuals with heterozygous POMC or LEPR variants, and >20,000 high-impact LOF patients in U.S.*

graph not drawn to scale

• Patients present with severe, early-onset obesity and hyperphagia
• Basket Study cohorts stratified by impact of variant on pathway function
• High-impactLOF variants expected to be most responsive to setmelanotide
• Other cohorts will clarify potential setmelanotide treatable populations
• Data update expected in 2020

* Calculated based on the following assumptions: US pop 327 million; 1.7% has early onset, severe obesity; High impact HET allele frequency based on Rhythm genetic sequencing (Feb 2019)

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Phase 2 Data in HET Patients Based on LOF Variant

All high-impact LOF patients appear setmelanotide-responsive; other subgroups have more variable responses

	Total treatment	Baseline Weight	Weight Loss	Weight loss	Change in Hunger	Hunger score
	duration2 (weeks)	(kg/(lbs))	(kg/(lbs))	Score (10 pt scale)	reduction
High-Impact	37	204 (451)	18.4 (40.5)	9.0%	-9	90.0%
29	129 (284)	22.3 (49.0)	17.3%	-5	71.4%
LOF Group
4	187 (412)	7.1 (15.6)	3.8%	-4	40.0%
	74	150 (330)	12.1 (26.6)	8.0%	-7	78.0%
	66	147 (323)	7.5 (16.5)	5.1%	-1	20.0%
Other
20	118 (259)	15.0 (33.0)	12.8%	-6	75.0%
Subgroups
16	106 (232)	7.2 (15.8)	6.9%	-7	70.0%
	7	150 (330)	4.6 (10.1)	3.0%	NA	NA

High-Impact LOF Group:

• All patients ongoing; fourth patient, still very early in dose titration, showing promising weight loss and hunger score decreases.

Other Subgroups:

• Five patients ongoing1
• Four patients discontinued treatment:
• • One patient due to lack of efficacy at 14 weeks3. Three patients with ≤ 4 weeks of total therapy, so efficacy not able to be assessed: two patients due to AE (hyperpigmentation, muscle cramps)3 and one patient withdrawn by site for patient non-compliance.

1Two of these patients were reported in June 2018. 2 Total treatment duration including any titration period, which can last 6-12 weeks. 3These three patients were reported in June 2018. AE = adverse event

46	These data were presented in March 2019.		®

Rhythm's Approach Enables Deep Understanding of Rare Genetic Diseases of Obesity and Optimizes Registration/Commercial Strategy

Rhythm's Sequencing Database

U.S. Prevalence Estimate

Conservative projection of individuals whose obesity is likely due to genetic variants in the MC4R pathway

Phase 2 Basket Study

Facilitates understanding of phenotype-genotype relationship and setmelanotide responsiveness

Translational research informs classification of genetic variants

and interpretation of clinical data

Optimized strategy for clinical development,

registration and commercialization

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Translating Rhythm Sequencing Data to U.S. Prevalence Estimates

Most stringent criteria for variant classification to establish baseline estimates of US prevalence

Rhythm database: Obese individuals with a variant

	1	Functional and computational filters
		Rare variant
Variant			High-impactloss-of-function	3
classification		2	variant
	OR	computational
filters		(literature or internal
	algorithms	*
	experimental data)

Prevalence estimate: Obese individuals

with a likely causative rare variant

*PolyPhen: Adzhubei IA, et al. Nat Methods 7(4):248-249 (2010); SIFT: Vaser R, et al. Nat Protocol 4:1073-1081 (2009); Mutation Taster: Schwarz J.M., et al. Nat. Methods 11(4):361-362 (2014)

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New MC4R Pathway Indications Based on Supported Scientific Rationale

UPSTREAM

DOWNSTREAM

POMC NEURON

MC4R-EXPRESSING

Leptin

NEURON

LEPR	RAI1
	SH2B1	MC4R
Satiety Signals	SRC1	ACTIVATION
(Leptin)		MSH

POMC

PCSK1

• Appetite
• Weight

• Energy expenditure

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SRC1 is a Transcriptional Coactivator that Drives POMC Expression

Pathway Relevance: Drives POMC Expression

POMC NEURON

Leptin

• Transcriptional coactivator activated downstream of LEPR
• Found in POMC neurons

Autosomal Dominant

• Obesity arises due to heterozygous gene variants

LEPR

	+		MC4R	Clinical Presentation
		• Early onset obesity and hyperphagia
Satiety Signals	SRC1			• Hyperleptinemia
(Leptin)		MSH

POMC

PCSK1

Citations

• Yang et al 2019, Nat Comm. 10, Article 1718

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SH2B1 is an Adapter Protein that Regulates LEPR Activity

Pathway Relevance: Regulates LEPR activity

POMC NEURON

Leptin

• Adapter protein
• Found in POMC neurons

Autosomal Dominant

LEPR

+

SH2B1

Satiety Signals

(Leptin)

• Obesity arises due to heterozygous gene variants or chromosomal deletions

	MC4R	Clinical Presentation
MSH		• Early onset obesity and hyperphagia

• Hyperinsulinemia

POMC

PCSK1

Citations

• Doche et al 2011, JCI, 122; 4732

• Ockukova et al 2010, Nature, 463; 666

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MC4R: Receptor for POMC Ligand MSH

MC4R-EXPRESSING

NEURON

MC4R

ACTIVATION

• Appetite
• Weight

• Energy expenditure

Pathway Relevance: Receptor for POMC ligands

• Required for satiety effects of α/β-MSH

Autosomal Dominant

• Obesity arises due to heterozygous gene variants

Clinical Presentation

• Early onset obesity and hyperphagia

Setmelanotide

• Pharmacological target for setmelanotide
• Rhythm conducted small, 4-week PhIb study in MC4R deficiency obesity
• Rhythm biochemical studies indicate that setmelanotide can address specific MC4R variants
• Current indication is focused on addressable MC4R variant carriers

Citations

• Farooqi et al 2003, NEJM, 348; 1085
• Collett et al 2017, Molecular Metabolism, 6; 1321

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Smith-Magenis Syndrome: RAI1 Affects POMC Expression

POMC NEURON

Leptin

Pathway Relevance: Decreased

Pathway Function Upstream of MC4R

• Causal gene is RAI1
• Transcription factor for a number of pathway genes

LEPR		Autosomal Dominant
RAI1	• Gene variants and chromosomal
	MC4R	deletions

Satiety Signals

(Leptin)

POMC

PCSK1

MSH

Clinical Presentation

• Adolescent obesity and hyperphagia
• Sleep disturbance, cognitive impairment, craniofacial anomalies, low energy expenditure

Citations

• Edelman et al 2007, Clin Genet; 71: 540-

• Burns et al 2010, Hum. Mol. Gen; 19; 4026

RAI1

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Obesity due to POMC/PCSK1 and LEPR Deficiency Characterized by Early-onset Obesity, Insatiable Hunger

Obesity due to

POMC/PCSK1

Deficiency

Results from loss-of-

function homozygous or biallelic variants in the

POMC or PCSK1 gene

U.S. prevalence estimated to be

100 to 500 patients

Hyperphagia

Early-onset, severe obesity

Light, pale skin

Hypoglycemia

Hypocortisolism and ACTH

deficiency

Hyperphagia

Developmental delays

Early-onset, severe obesity

Frequent infections

Hyperinsulinemia

Obesity due to LEPR Deficiency

Results from loss-of-

function homozygous or biallelic variants in the

LEPR gene

U.S. prevalence

estimated to be 500

to 2,000 patients

54

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Bardet-Biedl and Alström Syndromes Associated with Severe Obesity and Hunger

Bardet-Biedl

syndrome1

Rare ciliopathy disorder resulting from genetic variants within BBS family of genes

U.S. prevalence estimated

to be

1,500 to 2,500

patients

Hyperphagia	Hyperphagia
Progressive vision	Progressively worsening
impairment/loss	vision and hearing
	Cardiomyopathy
Early-onset,	Early-onset,
severe obesity	severe obesity
Polydactyly (extra
finger or toe)
Renal disease	Type 2 diabetes
	Endocrine abnormalities

Alström syndrome2,3

Rare ciliopathy disorder associated with ALMS1 mutation

Worldwideprevalence estimatedto be

500 to1,000

patients

References: 1. Forsythe E, Beales PL. Bardet-Biedl Syndrome. 2003 Jul 14 [Updated 2015 Apr 23]. In: Adam MP et al, eds. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-

2018. https://www.ncbi.nlm.nih.gov/books/NBK1363/. 2. Marshall JD et al. Curr Genomics. 2011;12(3):225-235.3. Marshall JD et al. Alström Syndrome. 2003 Feb 7 [Updated 2012 May 31]. In: Adam MP et

al, eds. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2018. https://www.ncbi.nlm.nih.gov/books/NBK1267/.

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