Setmelanotide (RM-493) Phase 2 Treatment Trial in Patients With Rare Genetic Disorders of Obesity
Phase: PHASE2
Conditions: Genetic Obesity, Obesity, Obesity Due to Melanocortin 4 Receptor Deficiency
Sponsor: Rhythm Pharmaceuticals, Inc.



Protocol Amendment 10 
 
RM-493-014 
Rhythm Pharmaceuticals, Inc. 
2 of 87 
Confidential 
 
  
 
APPROVAL SIGNATURE PAGE 
 
Protocol Title: 
Setmelanotide (RM-493) Phase 2 Treatment Trial in Patients with 
Rare Genetic Disorders of Obesity 
Protocol Number: 
RM-493-014 
Document Version: 
Amendment 10 
Document Date: 
20 February 2020 
 
REVIEWED/APPROVED BY: 
 
 
  
,  
Rhythm Pharmaceuticals, Inc. 
 
Signature  
 
Date 
 
 
 
 

Protocol Amendment 10 
 
RM-493-014 
Rhythm Pharmaceuticals, Inc. 
3 of 87 
Confidential 
 
  
 
INVESTIGATOR STATEMENT 
 
Protocol Title: 
Setmelanotide (RM-493) Phase 2 Treatment Trial in Patients with 
Rare Genetic Disorders of Obesity 
Protocol Number: 
RM-493-014 
Document Version: 
Amendment 10 
Document Date: 
20 February 2020 
 
I understand that all documentation provided to me by Rhythm Pharmaceuticals, Inc. (Rhythm) 
or its designated representative(s) concerning this study that has not been published previously 
will be kept in the strictest confidence. This documentation includes the study protocol, 
Investigator Brochure (IB), case report forms, and other scientific data. 
This study will not commence without the prior written approval of a properly constituted 
Institutional Review Board/Ethics Committee. No changes will be made to the study protocol 
without the prior written approval of Rhythm and the Institutional Review Board/Ethics 
Committee, except where necessary to eliminate an immediate hazard to the patient. 
I have read, understood, and agree to abide by all the conditions and instructions contained in 
this protocol. 
 
Investigator Name 
 
Investigator Signature 
 
Date 
 
 
 
 
Investigational site (or name of institution) and location (printed) 

Protocol Amendment 10 
 
RM-493-014 
Rhythm Pharmaceuticals, Inc. 
5 of 87 
Confidential 
 
  
 
Number of Patients (planned):  
It is expected that approximately 150 patients will be included in this protocol across multiple 
subgroups. Since the subgroups in this study are all rare, it is expected that the size of each subgroup 
will range from 1 – 15 patients.  
Diagnosis and Main Criteria for Inclusion:  
Inclusion Criteria: 
1. Patients with the following genotypes and/or clinical diagnosis: 
a. POMC/PCSK1/LEPR heterozygous  
b. POMC/PCSK1/LEPR compound heterozygous (two different mutations in gene) or 
homozygous deficiency obesity 
c. POMC/PCSK1/LEPR composite heterozygous (two or more mutations in two or more 
genes) deficiency obesity 
d. Smith-Magenis Syndrome (SMS) 
e. SH2B1 deficiency obesity 
f. Chromosomal rearrangement of the 16p11.2 locus causing obesity 
g. CPE compound heterozygous or homozygous deficiency obesity 
h. Leptin deficiency obesity with loss of response to metreleptin. 
i. 
SRC1 deficiency obesity  
j. 
MC4R deficiency obesity 
Note: The specific genotype for all patients must be reviewed by the Sponsor prior to study 
enrollment to confirm that the patient meets Inclusion Criterion #1. In addition, enrollment of 
patients in some subgroups may be prioritized by the Sponsor in order to ensure enrollment of 
patients with (1) well described, loss of function genetic mutations, (2) a variety of genetic 
variants, or (3) genetic variants likely to respond to setmelanotide. 
2. Age 6 years and above.  
3. Obese, defined as Body Mass Index (BMI) ≥ 30 kg/m2 for patients ≥16 years of age or BMI ≥ 
95th percentile for age and gender for patients 6 up to 16 years of age. 
4. Study participant and/or parent or guardian is able to communicate well with the Investigator, 
to understand and comply with the requirements of the study, and is able to understand and 
sign the written informed consent/assent.  
5. Female participants of child-bearing potential must be confirmed non-pregnant, and agree to 
use contraception as outlined in the protocol. Female participants of non-childbearing 
potential, defined as surgically sterile (status post hysterectomy, bilateral oophorectomy, or 
bilateral tubal ligation), post-menopausal for at least 12 months (and confirmed with a 
screening Follicle Stimulating Hormone [FSH] level in the post-menopausal lab range), and 
failure to have achieved menarche, do not require contraception during the study.  

Protocol Amendment 10 
 
RM-493-014 
Rhythm Pharmaceuticals, Inc. 
6 of 87 
Confidential 
 
  
 
6. Male participants with female partners of childbearing potential must agree to a double-
barrier method if they become sexually active during the study. Male patients must not donate 
sperm during and for 90 days following their participation in the study. 
Exclusion Criteria: 
1. Recent intensive (within 2 months) diet and/or exercise regimen with or without the use of 
weight loss agents including herbal medications that has resulted in > 2% weight loss.  
2. Use of any medication that is approved to treat obesity within three months of first dose of 
study drug (e.g., orlistat, lorcaserin, phentermine-topiramate, naltrexone-bupropion).  
Note: Glucagon-like peptide-1 (GLP-1) receptor agonists may be used up to the dose 
approved for the treatment of diabetes mellitus (e.g., liraglutide up to a daily dose of 1.8 mg) 
as long as (1) is it not being prescribed for the treatment of obesity, (2) the dose has been 
stable for at least three months prior to enrollment, (3) the patient has not experienced weight 
loss during the previous three months, AND (4) the patient intends to keep the dose stable 
throughout the course of the study.  
3. Gastric bypass surgery within the previous six months or any prior gastric bypass surgery 
resulting in >10% weight loss durably maintained from the baseline pre-operative weight 
with no evidence of weight regain. Specifically, patients may be considered if surgery was 
not successful, or resulted in <10% weight loss compared to pre-operative baseline weight or 
clear evidence of weight regain after an initial response to bariatric surgery. All patients with 
a history of bariatric surgery must be discussed with and receive approval from the Sponsor 
prior to enrollment.  
4. Diagnosis of schizophrenia, bipolar disorder, personality disorder, or other psychiatric 
disorder(s) that the Investigator believes will interfere significantly with study compliance. 
Neurocognitive disorders affecting ability to consent will not be disqualifying as long as an 
appropriate guardian able to give consent has been appointed.  
5. A PHQ-9 score of ≥ 15 or any suicidal ideation of type 4 or 5 on the C-SSRS during 
Screening, any lifetime history of a suicide attempt, or any suicidal behavior in the last 
month.  
Note: Patients who are unable to complete the PHQ-9 or C-SSRS due to significant 
neurocognitive defects may be enrolled in the study, as long as in the opinion of the Primary 
Investigator there are no clinical signs or symptoms of suicidal behavior. 
6. Current, clinically significant pulmonary, cardiac, or oncologic disease considered severe 
enough to interfere with the study and/or confound the results. Any patient with a potentially 
clinically significant disease should be reviewed with the Sponsor to determine eligibility. 
7. HbA1c >9.0% at Screening  

Protocol Amendment 10 
 
RM-493-014 
Rhythm Pharmaceuticals, Inc. 
7 of 87 
Confidential 
 
  
 
8. History of significant liver disease or abnormal liver tests on Screening (i.e., > 1.5 x upper 
limit of normal [ULN] for alanine transaminase [ALT], aspartate transaminase [AST], 
alkaline phosphatase, or serum bilirubin). 
Note: Patients entering the study with SRC1 haploinsufficiency obesity must be evaluated 
during the Screening Period for hepatic fibrosis by appropriate imaging techniques (e.g., 
transient elastography or magnetic resonance elastography). Any patient with moderate or 
greater fibrosis (e.g., the equivalent of a METAVIR score ≥ 2) will be excluded from the 
study. 
Note: A patient with a diagnosis of non-alcoholic fatty liver disease (NAFLD) or non-
alcoholic steatohepatitis (NASH) may be allowed to enroll in the study, after consultation with 
the Sponsor. Other significant liver disease, such as cirrhosis, are exclusionary. 
9. Glomerular filtration rate (GFR) <30 mL/min at Screening.  
10. History or close family history (parents or siblings) of skin cancer or melanoma (not 
including non-invasive/infiltrative basal or squamous cell lesion), or patient history of ocular-
cutaneous albinism. 
11. Significant dermatologic findings relating to melanoma or pre-melanoma skin lesions 
(excluding non-invasive basal or squamous cell lesion), determined as part of a 
comprehensive skin evaluation performed by a qualified dermatologist during Screening. Any 
concerning lesions identified during the Screening Period will be biopsied and results known 
to be benign prior to enrollment. If the pre-treatment biopsy results are of concern, the patient 
may need to be excluded from the study.  
12. Patient is, in the opinion of the Study Investigator, not suitable to participate in the study. 
13. Participation in any clinical study with an investigational drug/device within 3 months prior 
to the first day of dosing. 
14. Patients previously enrolled in a clinical study involving setmelanotide or any previous 
exposure to setmelanotide.  
15. Significant hypersensitivity to any excipient in the study drug.  
16. Inability to comply with QD injection regimen. 
17. Females who are breastfeeding or nursing. 
Investigational product, dosage and mode of administration:  
Investigational product: Setmelanotide, 10 mg/mL in a sterile solution for injection 
Dosage: Once daily dosing; for patients 6 up to 16 years of age, 1.0, 2.0, or 3.0 mg, and for patients  
≥16 years of age, 2.0 or 3.0 mg 
Mode of administration: Subcutaneous (SC) injection 

Protocol Amendment 10 
 
RM-493-014 
Rhythm Pharmaceuticals, Inc. 
9 of 87 
Confidential 
 
  
 
2. 
TABLE OF CONTENTS, LIST OF TABLES, AND LIST OF 
FIGURES  
TABLE OF CONTENTS 
1. 
SYNOPSIS ...................................................................................................................4 
2. 
TABLE OF CONTENTS, LIST OF TABLES, AND LIST OF FIGURES .................9 
3. 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS .............................14 
4. 
SUMMARY ................................................................................................................18 
5. 
INTRODUCTION ......................................................................................................20 
5.1. 
Regulation of Appetite, Energy Expenditure, and Body Weight ...............................20 
5.2. 
The Central Melanocortin Pathway (Melanocortin4 Receptors Pathway) .................21 
5.3. 
The Melanocortin4 Receptors .....................................................................................22 
5.4. 
Rare Genetic Disorders of Obesity (RGDO) ..............................................................23 
6. 
STUDY OBJECTIVES AND ENDPOINTS ..............................................................24 
6.1. 
Study Objectives .........................................................................................................24 
6.2. 
Study Endpoints ..........................................................................................................24 
7. 
INVESTIGATIONAL PLAN .....................................................................................26 
7.1. 
Overall Design and Plan of the Study .........................................................................26 
7.2. 
Rationale for the Doses ...............................................................................................27 
7.3. 
Justification of the Study Design ................................................................................28 
7.4. 
Study Termination ......................................................................................................28 
7.5. 
Data Safety Monitoring Board ....................................................................................29 
8. 
STUDY POPULATION .............................................................................................30 
8.1. 
Number of Patients .....................................................................................................30 
8.2. 
Inclusion Criteria ........................................................................................................30 
8.3. 
Exclusion Criteria .......................................................................................................31 
8.4. 
Patient Identification and Registration .......................................................................32 
8.5. 
Withdrawal of Patients ...............................................................................................32 
8.6. 
Duration of Patient Participation ................................................................................33 
9. 
STUDY TREATMENTS ............................................................................................34 
9.1. 
Study Drug ..................................................................................................................34 

Protocol Amendment 10 
 
RM-493-014 
Rhythm Pharmaceuticals, Inc. 
10 of 87 
Confidential 
 
  
 
9.2. 
Study Drug Dose Levels .............................................................................................34 
9.3. 
Blinding ......................................................................................................................34 
9.4. 
Packaging and Labeling of Study Drug ......................................................................34 
9.5. 
Handling and Storage of Study Drug ..........................................................................34 
9.6. 
Assessment of Treatment Compliance and Study Drug Accountability ....................35 
9.7. 
Prior and Concomitant Treatment ..............................................................................35 
10. 
SCHEDULE OF ASSESSMENTS .............................................................................36 
11. 
PATIENT ASSESSMENTS AND REQUIREMENTS .............................................42 
11.1. 
Sponsor Review of Patient Genetics and/or Genetic Testing .....................................42 
11.2. 
Informed Consent/Assent ...........................................................................................42 
11.3. 
Inclusion/Exclusion Review .......................................................................................42 
11.4. 
Demographics, Concomitant Medications and Medical History Review ..................42 
11.5. 
Physical Examination .................................................................................................43 
11.6. 
Comprehensive Skin Exam .........................................................................................43 
11.7. 
Fitzpatrick Scale .........................................................................................................43 
11.8. 
Weight .........................................................................................................................43 
11.9. 
Waist Circumference ..................................................................................................44 
11.10. 
Height .........................................................................................................................44 
 
 
11.12. 
Hepatic Fibrosis ..........................................................................................................44 
11.13. 
Vital Signs ..................................................................................................................45 
11.14. 
ECG (12-lead) .............................................................................................................45 
11.14.1. 
ECG Procedures ..........................................................................................................45 
11.14.2. 
Reading ECGs ............................................................................................................46 
11.15. 
Pregnancy Test ............................................................................................................46 
 
 

Protocol Amendment 10 
 
RM-493-014 
Rhythm Pharmaceuticals, Inc. 
11 of 87 
Confidential 
 
  
 
 
 
 
 
11.18. 
Safety Laboratory Tests ..............................................................................................50 
 
 
 
11.21. 
Anti-drug Antibody Samples ......................................................................................52 
 
 
 
 
11.24. 
Injection Site Inspection .............................................................................................52 
11.25. 
Telephone Call ............................................................................................................53 
11.26. 
Study Drug Administration .........................................................................................53 
11.27. 
Dispensing/Return of Study Drug ..............................................................................53 
11.28. 
Adverse Event Assessment .........................................................................................53 
11.29. 
Concomitant Medication(s) Review ...........................................................................53 
12. 
ADVERSE EVENTS ..................................................................................................54 
12.1. 
Definitions, Documentation, and Reporting ...............................................................54 
12.2. 
Procedures for AE and SAE Reporting ......................................................................55 
12.2.1. 
Assessment of Severity ...............................................................................................55 
12.2.2. 
Adverse Events and Risks ..........................................................................................56 
12.2.3. 
Monitoring of Adverse Events and Period of Observation ........................................56 
12.2.4. 
Guidelines for Additional Monitoring and Suspension of Dosing for a Patient .........57 
13. 
DATA ANALYSIS/STATISTICAL PROCEDURES ...............................................58 
13.1. 
Sample Size Estimation ..............................................................................................58 
13.2. 
Hypotheses ..................................................................................................................58 
13.3. 
Definition of Population(s) for Analysis ....................................................................58 
13.4. 
Statistical Methods ......................................................................................................58 
13.5. 
Timing of Analyses .....................................................................................................59 
13.6. 
Statistical Analysis Plan .............................................................................................59 

Protocol Amendment 10 
 
RM-493-014 
Rhythm Pharmaceuticals, Inc. 
13 of 87 
Confidential 
 
  
 
APPENDIX I. BEDSIDE SCHWARTZ EQUATION ...............................................................85 
APPENDIX J. CONSIDERATIONS FOR REDUCING PAIN AND DISTRESS IN THE 
PEDIATRIC POPULATION .....................................................................................86 
 
LIST OF TABLES 
Table 1: 
Abbreviations and Specialist Terms ...........................................................................14 
Table 2: 
Study Drug Dose Levels by Study Week and Patient Age .........................................34 
Table 3: 
Schedule of Assessments ............................................................................................37 
 
LIST OF FIGURES 
Figure 1: 
Schematic Diagram of the Hypothalamic MC4R Pathway Indicating Some of 
the Potential Molecular Defects in the MC4R Pathway, Upstream of the 
Receptor, a Focus of Rhythm Clinical Studies ...........................................................20 
Figure 2: 
Schematic Outline of Hypothalamic Food Intake Control .........................................21 
Figure 3: 
Flow Chart for Study RM-493-014 ............................................................................27 
 

Protocol Amendment 10 
 
RM-493-014 
Rhythm Pharmaceuticals, Inc. 
14 of 87 
Confidential 
 
  
 
3. 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
The following abbreviations and specialist terms are used in this study protocol. 
Table 1: 
Abbreviations and Specialist Terms  
Abbreviation or  
Specialist Term 
Explanation 
ADA 
Anti-drug antibody 
AE 
Adverse event 
AgRP 
Agouti-Related Peptide 
ALT 
Alanine transaminase 
aPTT 
Activated partial thromboplastin time 
ARC 
Arcuate nucleus of the hypothalamus 
AS 
Alström syndrome 
AST 
Aspartate transaminase 
AUC 
Area under the curve 
BBS 
Bardet-Biedl syndrome 
BIA 
Bioelectrical impedance 
BMI 
Body mass index 
BP 
Blood pressure 
BPM 
Beats per minute 
BUN 
Blood urea nitrogen 
CCK 
Cholecystokinin 
 
 
CNS 
Central nervous system 
CO2 
Carbon dioxide 
CPE 
Carboxypeptidase E 
CPK 
Creatine phosphokinase 
CRA 
Clinical research associate 
CRF 
Case report form 
 
 
CTCAE 
Common Terminology Criteria for Adverse Events 

Protocol Amendment 10 
 
RM-493-014 
Rhythm Pharmaceuticals, Inc. 
15 of 87 
Confidential 
 
  
 
Table 1: 
Abbreviations and Specialist Terms (Continued) 
Abbreviation or  
Specialist Term 
Explanation 
CV 
Cardiovascular 
 
 
DIO 
Diet-induced obese 
EC 
Ethics Committee 
EC50 
Half-maximal effective concentration 
ECG 
Electrocardiogram 
eCRF 
Electronic case report form 
FDA 
Food and Drug Administration 
FSH 
Follicle Stimulating Hormone 
Free T4 
Free thyroxine 
GCP 
Good Clinical Practice 
GFR 
Glomerular Filtration Rate 
GGT 
Gamma-glutamyltranspeptidase  
GLP-1 
Glucagon-like peptide-1 
Hg 
Mercury 
HR 
Heart rate 
 
 
IB 
Investigator Brochure 
ICH 
International Conference for Harmonisation 
IEC 
Independent Ethics Committee 
IML 
Intermediolateral column 
INR 
International Normalized Ratio 
IRB 
Institutional Review Board 
IUD 
Intrauterine device 

Protocol Amendment 10 
 
RM-493-014 
Rhythm Pharmaceuticals, Inc. 
16 of 87 
Confidential 
 
  
 
Table 1: 
Abbreviations and Specialist Terms (Continued) 
Abbreviation or  
Specialist Term 
Explanation 
Ki 
Inhibitory constant 
LDH 
Lactate dehydrogenase 
LEPR 
Leptin receptor  
MC 
Melanocortin 
MC1R – MC5R 
Melanocortin Receptor types 1-5 
MDRD 
Modification of Diet in Renal Disease 
MedDRA 
Medical Dictionary for Regulatory Activities 
MHP 
Mental health professional 
MSH 
Melanocyte Stimulating Hormone 
NAFLD 
Non-alcoholic fatty liver disease 
NASH 
Non-alcoholic steatohepatitis 
NHLBI 
National Heart, Lung, and Blood Institute 
NOAEL 
No observed adverse effects level 
 
 
 
 
POMC 
Pro-opiomelanocortin 
PT 
Prothrombin time 
PTT 
Partial thromboplastin time 
PVH 
Paraventricular Hypothalamus 
PWS 
Prader-Willi Syndrome 
PWS-FPD 
Prader-Willi Syndrome – Food Problem Diary 
PWS-SEQ 
Prader-Willi Syndrome – Significant Event Questionnaire 
PYY 
Peptide YY 
QD 
Once daily (from the Latin: quaque die) 
QW 
Once weekly (from the Latin: quaque week) 

Protocol Amendment 10 
 
RM-493-014 
Rhythm Pharmaceuticals, Inc. 
17 of 87 
Confidential 
 
  
 
Table 1: 
Abbreviations and Specialist Terms (Continued) 
Abbreviation or  
Specialist Term 
Explanation 
RGDO 
Rare Genetic Disorders of Obesity 
SAE 
Serious adverse event 
SAP 
Statistical analysis plan 
SC 
Subcutaneous 
SMS 
Smith-Magenis Syndrome 
SOA 
Schedule of assessments 
TEAE 
Treatment-emergent adverse event 
 
 
TSH 
Thyroid Stimulating Hormone 
US 
United States 
ULN 
Upper limit of normal 
UV 
Ultraviolet 
WMA 
World Medical Association 

Protocol Amendment 10 
 
RM-493-014 
Rhythm Pharmaceuticals, Inc. 
18 of 87 
Confidential 
 
  
 
4. 
SUMMARY 
Setmelanotide (also known as RM-493) is a synthetic 8-amino acid cyclic peptide that functions as a 
potent melanocortin-4 receptor (MC4R) agonist. Three setmelanotide formulations have been used 
in nonclinical and clinical studies: setmelanotide in saline; setmelanotide in N-(Carbonyl-
methoxypolyethylene glycol 2000)-1,2-distearoyl- glycero-3-phosphoethanolamine sodium salt 
(setmelanotide/mPEG-DSPE); and setmelanotide-Once-Weekly (setmelanotide QW). Note that only 
the setmelanotide/mPEG-DSPE formulation and setmelanotide QW formulations are in use in 
clinical studies; the setmelanotide saline formulation is no longer employed. 
Setmelanotide is being evaluated for the treatment of severe early-onset genetic forms of obesity and 
associated co-morbidities, including subjects with pro-opiomelanocortin (POMC) deficiency 
obesity, leptin receptor (LEPR) deficiency obesity, Prader-Willi syndrome (PWS), Bardet-Biedl 
syndrome (BBS), Alström syndrome (AS), and other genetic forms of early-onset extreme obesity 
arising from defects demonstrated or hypothesized to impact the hypothalamic MC4R signaling 
pathway. Based on accruing genetic and clinical insights, other genetic forms of early-onset extreme 
obesity may also be evaluated in setmelanotide clinical studies. It is expected that setmelanotide 
would be indicated to treat the obesity and excess appetite or feeding behavior symptoms of these 
severe forms of genetic obesity. 
Setmelanotide binds with high affinity (inhibitory constant [Ki] = 2.1 nM) to the human MC4R and 
is efficient in activating MC4R (half-maximal effective concentration [EC50] = 0.27 nM). 
Setmelanotide was initially selected for clinical development based on its acceptable circulating 
half-life as a saline formulation administered as a continuous subcutaneous (SC) infusion (2.8 to 3.5 
hours in non-human primates) and the ability to decrease body weight gain and suppress food intake 
in normal rats. Additional studies demonstrated the efficacy of setmelanotide in suppressing food 
intake and body weight gain in diet-induced obese (DIO) mice, rats, dogs, and monkeys. Later 
studies in obese monkeys showed that setmelanotide did not increase blood pressure (BP) or heart 
rate (HR), a potential concern observed with other MC4R agonist compounds. 
Setmelanotide has also been studied in relevant genetic models of obesity, including leptin-receptor 
deficient Zucker fa/fa rats (a rodent model of genetic obesity impacting the MC4R pathway) and 
Magel2-null mice (a mouse model for PWS). Treatment of Zucker fa/fa rats with setmelanotide 
resulted in reductions in both body weight and food intake relative to placebo control. Furthermore, 
treatment of Magel2-null mice with 0.1 mg/kg setmelanotide demonstrated a statistically significant 
decrease in cumulative food intake. These data demonstrate that setmelanotide is effective in rodent 
models of PWS and genetic obesity, supporting the potential efficacy and testing in both monogenic 
and syndromic obesity. 
Significant safety margins are provided from a comprehensive set of toxicology studies, including 
repeat-dose and chronic toxicology studies in rats and monkeys, developmental and reproductive 
toxicology studies, and juvenile toxicology studies to support pediatric subject enrolment. These 
studies support the setmelanotide doses that have been used in clinical studies and that are 
anticipated in additional chronic studies in genetic obesity populations based on the no-observed-
adverse-effect level (NOAEL) of various parameters evaluated in the toxicity studies. 

Protocol Amendment 10 
 
RM-493-014 
Rhythm Pharmaceuticals, Inc. 
20 of 87 
Confidential 
 
  
 
5. 
INTRODUCTION 
Rhythm is focusing the development of setmelanotide as a treatment for patients with rare genetic 
disorders of obesity (RGDO) due to specific genetic defects that impact the functioning of the 
MC4R pathway, a highly conserved hypothalamic pathway critical for regulation of appetite, energy 
expenditure, and body weight. The MC4R pathway is the key pathway regulating weight and 
hunger. Genetic defects in the MC4R pathway cause insatiable hunger, leading to severe and early-
onset obesity 
Figure 1 depicts a schematic of the MC4R pathway and includes specific “upstream” genes in which 
an inactivating mutation results in RGDO. Specifically, we are focusing on obesity arising from lack 
of activation of MC4Rs due to defects in “upstream” genes. By activating the MC4R (downstream 
portion of the pathway), setmelanotide is hypothesized to provide compelling and persistent 
efficacy. Setmelanotide, as a potent MC4R agonist, has demonstrated proof-of-concept in obesity 
resulting from POMC and LEPR deficiencies as well as obesity associated with BBS and AS, 
genetic syndromes that lead to cellular defects in LEPR signaling. Setmelanotide also has the 
potential to restore lost activity in the MC4R pathway in other “upstream” defects in genes such as 
PCSK1 (responsible for POMC processing and thereby producing bioactive POMC peptides) and 
Magel2 (postulated to contribute to some of the features of Prader-Willi syndrome [PWS]). In this 
way, setmelanotide may serve as a form of “personalized replacement” therapy to re-establish 
appetite and energy homeostasis regulation, and ultimately restore weight control in patients with 
specific genetic defects. 
Figure 1: 
Schematic Diagram of the Hypothalamic MC4R Pathway Indicating Some of 
the Potential Molecular Defects in the MC4R Pathway, Upstream of the 
Receptor, a Focus of Rhythm Clinical Studies 
 
5.1. 
Regulation of Appetite, Energy Expenditure, and Body Weight 
In mammals, body weight regulation is a function of energy intake (in the form of caloric 
consumption) and energy expenditure (in the form of basal metabolism/physical 
exertion/thermogenesis). Persistent disturbances in this equation result in alterations in body weight 

Protocol Amendment 10 
 
RM-493-014 
Rhythm Pharmaceuticals, Inc. 
21 of 87 
Confidential 
 
  
 
(weight gain if intake > expenditure, and weight loss if intake < expenditure). In principle, 
regulation of body weight is predicated on two key steps: 1) evaluation of current energy needs 
(sensory actions) and 2) subsequent generation of physiological responses (appropriate modulation 
of food intake and expenditure) to meet those needs (Gautron, 2015; Greenfield, 2009). The 
hypothalamus serves as a key sensory region that integrates information regarding energy state as 
communicated by several circulating humoral factors. Information about short-term energy needs 
(hunger vs satiety) is communicated by circulating factors such as cholecystokinin (CCK), ghrelin, 
and peptide YY (PYY); in contrast, longer-term energy state (adiposity) is conveyed by leptin and 
insulin. Upon receiving this information, neuronal pathways within the hypothalamus adjust their 
activity and modulate food intake and/or energy expenditure to achieve the acceptable energy state. 
One of the most critical neuronal pathways within the hypothalamus responsible for body weight 
regulation is the central melanocortin pathway.  
5.2. 
The Central Melanocortin Pathway (Melanocortin4 Receptors 
Pathway) 
The melanocortin pathway represents a fundamental component of centrally regulated energy 
balance.  
Melanocortin actions are initiated in the arcuate nucleus of the hypothalamus (ARC) by two distinct 
and functionally opposing neuronal populations, POMC neurons that produce endogenous 
melanocortins (α-, β-melanocyte stimulating hormone [MSH]) and a neuronal population that 
produces agouti-related peptide (AgRP), an endogenous antagonist of melanocortins (Cone, 2005). 
Both these neuronal populations form the “upstream” part of the central melanocortin pathway 
(Figure 2). The primary role of both AgRP and POMC neurons is to evaluate energy demand by 
sensing humoral and neuronal inputs and to subsequently adjust its activity reflecting the current 
energy state. Once activated, both AgRP and POMC neurons release neurotransmitter/neuropeptides 
to engage “downstream” MC4R-expressing neurons to modulate food intake and energy expenditure 
to meet the energy demand (Krashes, 2016).  
Figure 2: 
Schematic Outline of Hypothalamic Food Intake Control 
 

Protocol Amendment 10 
 
RM-493-014 
Rhythm Pharmaceuticals, Inc. 
22 of 87 
Confidential 
 
  
 
The AgRP-producing neuronal population forms the anabolic arm of the melanocortin pathway: 
activated by caloric deficit (i.e., ghrelin) → release neuropeptide (i.e., AgRP) → inactivation 
(hyperpolarization) of downstream MC4R-expressing neurons → increase in energy intake, decrease 
in energy expenditure and weight gain (Liu, 2012; Yang, 2011; Aponte, 2011; Krashes, 2011). In 
contrast, POMC-expressing neurons form the catabolic arm: activated by caloric surplus (i.e., leptin 
[LEP]) → release of bioactive product of POMC processing (α-, β-MSH) → activation 
(depolarization) of downstream MC4R-expressing neurons → suppression of food consumption, 
increase in energy expenditure and weight loss (Atasoy, 2012; Zhan, 2013; Dodd, 2015). Consistent 
with catabolic actions of α- and β-MSH, inactivating mutations in POMC and MC4R results in 
early-onset extreme obesity defined by excessive hyperphagia and reduced energy expenditure (Yeo, 
1998; Vaisse, 1998; Krude, 1998). Given the importance of this pathway in long-term body weight 
regulation, inactivating mutations in many critical components (LEP, LEPR, POMC, PCSK1, 
MC4R) of this pathway have been shown to cause RGDO characterized by intense feelings of 
hunger and marked hyperphagia.  
5.3. 
The Melanocortin4 Receptors 
The melanocortins regulate a wide range of physiological processes such as energy balance, 
steroidogenesis, sexual function, cardiovascular (CV) function, glucose homeostasis, emotional 
behavior, and secretion of several endocrine and exocrine factors (Marks, 2001; Foster, 2003; 
Wikberg, 2008; Tao, 2010). All these diverse functions are regulated via five melanocortin 
receptors, MC1-5Rs. The MC1R is the classical MSH receptor expressed in skin and hair follicles 
that regulates pigmentation. The MC2R is the classical adrenocorticotropic hormone (ACTH) 
receptor expressed in the adrenal cortex that regulates adrenal steroidogenesis and stress response. 
The MC3Rs are predominantly in the central nervous system (CNS) and their role is not well 
defined (Giradet, 2014). The MC5R is expressed widely and involved in regulating exocrine gland 
secretions (Chen, 1997). MC4R is predominantly located in the CNS; however, MC4R expression in 
also observed in gut. MC4R regulates many different physiological endpoints such as appetite, 
energy expenditure, glucose homeostasis, and CV functions (Krashes, 2016).  
Over last 2-3 decades, a myriad of pharmacological studies in rodents and humans have suggested 
that MC4Rs are critical for regulation of appetite and overall body weight (Theile, 1998; Millington, 
2001; Semjonous, 2009). This was corroborated by genetic findings that show the absence of MC4R 
signaling causes profound obesity and hyperphagia in both rodents and humans. While 
pharmacological studies (Theile, 1998; Millington, 2001; Semjonous, 2009) in rodents have 
implicated many different brain regions mediating appetite regulating effects, conditional knock-out 
mouse models suggest that the paraventricular hypothalamus (PVH) is the major site of action for 
MC4R-mediated appetite regulation (Balthasar, 2005; Shah, 2014; Garfield, 2015). It is believed 
that MC4R-regulated energy expenditure is mediated by cholinergic preganglionic sympathetic 
neurons in the intermediolateral column (IML) of the spinal cord (Berglund, 2014). In addition to 
energy balance, MC4R activation is also associated with increase in BP and HR via the autonomic 
nervous system. Collectively, these observations suggest that an MC4R agonist should be effective 
for treating genetic forms of obesity by producing persistent and robust weight loss.  

Protocol Amendment 10 
 
RM-493-014 
Rhythm Pharmaceuticals, Inc. 
23 of 87 
Confidential 
 
  
 
5.4. 
Rare Genetic Disorders of Obesity (RGDO) 
Human obesity is recognized as being influenced by both inherited and environmental factors, with 
few single genes demonstrated to carry major phenotypic effects on their own (Stunkard, 1986; 
Wardle, 2008). Although obesity is widespread and becomes more prevalent during adolescence and 
adulthood, many of the most severe forms of obesity begin early in infancy and childhood. Recent 
research has revealed numerous genetic mechanisms and specific mutations that lead to rare 
monogenic disorders characterized by RGDO (van der Klaauw, 2015; Martos-Moreno, 2014). 
Complementary experiments in genetic rodent models and RGDO patients have led to the 
identification of a critical set of genes in the MC4R pathway (van der Klaauw, 2015). The MC4R 
hypothalamic pathway was initially validated as an important genetic underpinning for some forms 
of obesity with the discovery that single genetic defects in MC4R result in early-onset and severe 
obesity (Vaisse, 1998; Yeo, 1998). Now, an expanding set of monogenic obesity defects (in addition 
to loss of function mutations in the MC4R itself) have been identified; these obesity mutations 
involve genes in this pathway that are either upstream of MC4R – specifically, POMC deficiency 
obesity, pro-hormone convertase 1 (PCSK1) and LEPR deficiency obesity – or genes that are 
downstream of MC4R (O'Rahilly, 1995; Ramachandrappa, 2011).  
Human genetics studies have identified several diseases that are the result of genetic defects 
affecting the MC4R pathway, including: 
• POMC deficiency obesity due to mutations in the POMC gene 
• PCSK1 deficiency due to mutations in the PCSK1 gene, leading to a hormone processing 
defect that also causes POMC deficiency obesity 
• LEPR deficiency obesity due to mutations in the LEPR gene 
These MC4R pathway mutations can cause RGDO that progresses over time and can become life-
threatening in severity. 
Rhythm is developing setmelanotide for the treatment of severe early-onset genetic forms of obesity 
arising from defects demonstrated or hypothesized to occur upstream of the MC4R receptor and 
impact the hypothalamic MC4R signaling pathway. Based on accruing genetic and clinical insights, 
different genetic forms of early-onset extreme obesity may also be evaluated in setmelanotide 
clinical studies. It is expected that setmelanotide would be indicated to treat the obesity and excess 
appetite or feeding behavior symptoms of these severe forms of genetic obesity. 

Protocol Amendment 10 
 
RM-493-014 
Rhythm Pharmaceuticals, Inc. 
26 of 87 
Confidential 
 
  
 
7. 
INVESTIGATIONAL PLAN 
7.1. 
Overall Design and Plan of the Study 
This is a Phase 2, proof-of-concept study to assess initial safety and efficacy of setmelanotide within 
each identified subtype of rare genetic disorders of obesity.  
Screening Period 
Upon providing informed consent, patients will enter the Screening Period, during which they will 
be assessed for eligibility and complete all screening procedures as described in the Schedule of 
Events. Each patient’s genetic information will be reviewed by the Sponsor to confirm the patient is 
eligible for the study. During the Screening Period, each patient will be instructed to complete a 
hunger questionnaire on a daily basis and will be required to have completed at least four days of the 
questionnaire prior to first dose. 
Treatment Period 
Eligible patients will return to the clinic within 8 – 2 weeks of completing the Screening Visit for 
the Baseline Visit (Visit 2) and first dose of setmelanotide. 
Dose levels for all patients will escalate to a final dose of 3.0 mg/day during an initial dose-titration 
phase, but the starting dose will depend on patient age. Patients 6 up to 16 years old will initially be 
dosed at 1.0 mg/day for 2 weeks, beginning at the Baseline Visit on Study Day 1. Starting on Day 
15, the dose will escalate to 2.0 mg/day and remain at that level for 2 weeks, until the patient returns 
to clinic for Visit 3 on Day 29. At Visit 3, the dose will be escalated to 3.0 mg/day; the patient will 
continue dosing at 3.0 mg/day for 12 weeks.  
Patients ≥16 years old will initiate dosing at 2.0 mg/day at the Baseline Visit, and continue dosing at 
that level for 2 weeks. The dose will be escalated to 3.0 mg/day beginning on Study Day 15, and the 
patient will continue that dose for 14 weeks.  
Study site staff will call all patients at their homes after the first 2 weeks of treatment to ensure the 
escalation occurred as planned and collect any AEs. 
Patients will continue dosing at 3.0 mg/day, and return to the clinic every four weeks (Visits 3-5) to 
complete the assessments in Table 3. After 16 weeks in the study, patients will return to the clinic 
for Visit 6. At Visit 6, the patient will receive the last setmelanotide injection. Participation in the 
study will then conclude in one of the following two ways: 
• Complete Visit 6 and enroll in a separate extension study, Rhythm Study RM-493-022. If 
RM-493-022 is not yet open at the clinic site, the patient will continue daily 
setmelanotide injections and other activities per the current study, as presented in the 
SOA (Table 3). The patient will return to the clinic for Bridging Visits every 12 weeks 
for up to one year, until the extension study opens at the site. Additional clinic visits may 
be scheduled at the discretion of the PI. 

Protocol Amendment 10 
 
RM-493-014 
Rhythm Pharmaceuticals, Inc. 
27 of 87 
Confidential 
 
  
 
• Decide not to participate in the extension study and proceed to the final study visit (Visit 
7) in 4 weeks.  
Patients on study per a previous amendment should transition to dose escalation as outlined in this 
protocol:  
• Patients who are in the dose titration phase and are not currently at a dose of 3.0 mg/day 
will be assessed by the Primary Investigator and the Sponsor, to determine if an increase 
in the dose to 3.0 mg/day is appropriate.  
• Patients who have completed dose titration and are assigned to a dose of less than 
3.0 mg/day will be assessed by the PI to determine if an increase in the dose to 
3.0 mg/day is appropriate.  
• Patients who are post 16 weeks may roll into the separate extension study (RM-493-022) 
directly or via Bridging Visits, or proceed to the final study Visit 7 and finish the study.  
A flow chart summarizing Study RM-493-014 is presented in Figure 3.  
Figure 3: 
Flow Chart for Study RM-493-014 
 
 
7.2. 
Rationale for the Doses 
All patients will escalate to 3.0 mg/day after 2 – 4 weeks on treatment, depending on age. Patients 6 
up to 16 years old will start at a dose of 1.0 mg/day for 2 weeks, escalate to 2.0 mg/day for 2 weeks, 

Protocol Amendment 10 
 
RM-493-014 
Rhythm Pharmaceuticals, Inc. 
29 of 87 
Confidential 
 
  
 
Circumstances that may warrant termination include, but are not limited to: 
• Determination of unexpected, significant, or unacceptable risk to patients. 
• Failure to enter patients at an acceptable rate. This is particularly important, as the 
number of patients hoped to enroll in this study represents a substantial portion of all 
already identified patients worldwide.  
• Insufficient adherence to protocol requirements. 
• Insufficient complete and/or evaluable data. 
• Plans to modify, suspend, or discontinue the development of the study drug. 
• Termination of an individual population for a specific disorder of obesity if data from at 
least two, and possibly up to five, patients in that disorder fail to show substantial weight 
loss (e.g., no patients meet the threshold for continuation into extensions).  
In addition, it is still unclear how many patients will be required to assess the safety and efficacy of 
setmelanotide in each of these rare conditions before it is appropriate to transition to pivotal trials. 
Therefore, this study (or enrollment of any individual population within the study) may be either 
temporarily held or terminated when Rhythm determines that there are sufficient patient data in 
Phase 2 to support initiation of pivotal efficacy and safety studies.  
7.5. 
Data Safety Monitoring Board 
As this is an open-label study, all data will be available to the Sponsor on a real-time basis. Primary 
Investigators will be responsible to review and evaluate safety data from their patients in a 
continuous manner. Cumulative safety data from the study will be reviewed by the Sponsor on an 
ongoing basis for any safety signals or tolerability concerns. Additionally, this study will be 
monitored by a Data Safety Monitoring Board, which will include outside advisors and will meet on 
a periodic basis to review the cumulative safety data from the trial and will make a recommendation 
to continue or modify the study, if needed. 

Protocol Amendment 10 
 
RM-493-014 
Rhythm Pharmaceuticals, Inc. 
30 of 87 
Confidential 
 
  
 
8. 
STUDY POPULATION 
8.1. 
Number of Patients 
It is expected that approximately 150 patients will be included in this protocol across multiple 
subgroups. Since the subgroups in this study are all rare, it is expected that the size of each subgroup 
will range from 1 – 15 patients. 
8.2. 
Inclusion Criteria 
1. Patients with the following genotypes and/or clinical assessment: 
a. POMC/PCSK1/LEPR heterozygous  
b. POMC/PCSK1/LEPR compound heterozygous (two different mutations in gene) or 
homozygous deficiency obesity 
c. POMC/PCSK1/LEPR composite heterozygous (two or more mutations in two or more 
genes) deficiency obesity 
d. Smith-Magenis Syndrome (SMS) 
e. SH2B1 deficiency obesity 
f. Chromosomal rearrangement of the 16p11.2 locus causing obesity 
g. CPE compound heterozygous or homozygous deficiency obesity 
h. Leptin deficiency obesity with loss of response to metreleptin 
i. SRC1 deficiency obesity  
j. MC4R deficiency obesity 
Note: The specific genotype for all patients must be reviewed by the Sponsor prior to study 
enrollment to confirm that the patient meets Inclusion Criterion #1. In addition, enrollment 
of patients in some subgroups may be prioritized by the Sponsor in order to ensure 
enrollment of patients with (1) well described, loss-of-function genetic mutations, (2) a 
variety of genetic variants, or (3) genetic variants likely to respond to setmelanotide. 
2. Age 6 years and above.  
3. Obese, defined as Body Mass Index (BMI) ≥ 30 kg/m2 for patients ≥16 years of age or BMI 
≥ 95th percentile for age and gender for patients 6 up to 16 years of age. 
4. Study participant and/or parent or guardian is able to communicate well with the 
Investigator, to understand and comply with the requirements of the study, and is able to 
understand and sign the written informed consent/assent.  
5. Female participants of child-bearing potential must be confirmed non-pregnant, and agree to 
use contraception as outlined in the protocol. Female participants of non-childbearing 
potential, defined as surgically sterile (status post hysterectomy, bilateral oophorectomy, or 
bilateral tubal ligation), post-menopausal for at least 12 months (and confirmed with a 
screening Follicle-Stimulating Hormone [FSH] level in the post-menopausal lab range), and 
failure to have achieved menarche, do not require contraception during the study.  

Protocol Amendment 10 
 
RM-493-014 
Rhythm Pharmaceuticals, Inc. 
31 of 87 
Confidential 
 
  
 
6. Male participants with female partners of childbearing potential must agree to a double-
barrier method if they become sexually active during the study. Male patients must not 
donate sperm during and for 90 days following their participation in the study. 
8.3. 
Exclusion Criteria 
1. Recent intensive (within 2 months) diet and/or exercise regimen with or without the use of 
weight loss agents including herbal medications that has resulted in > 2% weight loss.  
2. Use of any medication that is approved to treat obesity within three months of first dose of 
study drug (e.g., orlistat, lorcaserin, phentermine-topiramate, naltrexone-bupropion). Note: 
Glucagon-like peptide-1 (GLP-1) receptor agonists may be used up to the dose approved for 
the treatment of diabetes mellitus (e.g., liraglutide up to a daily dose of 1.8 mg) as long as (1) 
is it not being prescribed for the treatment of obesity, (2) the dose has been stable for at least 
three months prior to enrollment, (3) the patient has not experienced weight loss during the 
previous three months, AND (4) the patient intends to keep the dose stable throughout the 
course of the study.  
3. Gastric bypass surgery within the previous six months or any prior gastric bypass surgery 
resulting in >10% weight loss durably maintained from the baseline pre-operative weight 
with no evidence of weight regain. Specifically, patients may be considered if surgery was 
not successful, or resulted in <10% weight loss compared to pre-operative baseline weight or 
clear evidence of weight regain after an initial response to bariatric surgery. All patients with 
a history of bariatric surgery must be discussed with and receive approval from the Sponsor 
prior to enrollment.  
4. Diagnosis of schizophrenia, bipolar disorder, personality disorder or other psychiatric 
disorder(s) that the Investigator believes will interfere significantly with study compliance. 
Neurocognitive disorders affecting ability to consent will not be disqualifying as long as an 
appropriate guardian able to give consent has been appointed.  
5. A PHQ-9 score of ≥ 15 or any suicidal ideation of type 4 or 5 on the C-SSRS during 
Screening, any lifetime history of a suicide attempt, or any suicidal behavior in the last 
month. Note: Patients who are unable to complete the PHQ-9 or C-SSRS due to significant 
neurocognitive defects may be allowed to enroll in the study, as long as in the opinion of the 
Primary Investigator there are no clinical signs or symptoms of suicidal behavior. 
6. Current, clinically significant pulmonary, cardiac, or oncologic disease considered severe 
enough to interfere with the study and/or confound the results. Any patient with a potentially 
clinically significant disease should be reviewed with the Sponsor to determine eligibility. 
7. HbA1c >9.0% at Screening  
8. History of significant liver disease or abnormal liver tests on Screening (i.e. > 1.5 x upper 
limit of normal [ULN] for alanine transaminase [ALT], aspartate transaminase [AST], 
alkaline phosphatase, or serum bilirubin). Note: Patients entering the study with SRC1 
haploinsufficiency obesity must be evaluated during the Screening Period for hepatic fibrosis 

Protocol Amendment 10 
 
RM-493-014 
Rhythm Pharmaceuticals, Inc. 
32 of 87 
Confidential 
 
  
 
by appropriate imaging techniques (e.g., transient elastography or magnetic resonance 
elastography). Any patient with moderate or greater fibrosis (e.g., the equivalent of a 
METAVIR score ≥ 2) will be excluded from the study. Note: A patient with a diagnosis of 
non-alcoholic fatty liver disease (NAFLD) or non-alcoholic steatohepatitis (NASH) may be 
allowed to enroll in the study, after consultation with the Sponsor. Other significant liver 
disease, such as cirrhosis, are exclusionary. 
9. Glomerular filtration rate (GFR) <30 mL/min at Screening.  
10. History or close family history (parents or siblings) of skin cancer or melanoma (not 
including non-invasive/infiltrative basal or squamous cell lesion), or patient history of 
ocular-cutaneous albinism.  
11. Significant dermatologic findings relating to melanoma or pre-melanoma skin lesions 
(excluding non-invasive basal or squamous cell lesion), determined as part of a 
comprehensive skin evaluation performed by a qualified dermatologist during Screening. 
Any concerning lesions identified during the Screening Period will be biopsied and results 
known to be benign prior to enrollment. If the pre-treatment biopsy results are of concern, 
the patient may need to be excluded from the study.  
12. Patient is, in the opinion of the Study Investigator, not suitable to participate in the study. 
13. Participation in any clinical study with an investigational drug/device within 3 months prior 
to the first day of dosing. 
14. Patients previously enrolled in a clinical study involving setmelanotide or any previous 
exposure to setmelanotide.  
15. Significant hypersensitivity to any excipient in the study drug.  
16. Inability to comply with QD injection regimen. 
17. Females who are breastfeeding or nursing.  
8.4. 
Patient Identification and Registration 
All patients screened for the study will be assigned a unique screening number which will be a 
combination of study number (014), 3-digit site number, and a sequential 3-digit number; this 
screening number will be used to identify patients throughout their participation in the study. 
Screening numbers will be assigned sequentially starting at 001 (i.e., the first patient screened at site 
10 would be assigned screening number 014-010-001). Once a patient number has been assigned, it 
cannot be reused. 
8.5. 
Withdrawal of Patients 
Patients will be informed that they have the right to withdraw from the study at any time for any 
reason, without prejudice to their medical care. The Investigator also has the right to withdraw 
patients from the study, after discussion with the Sponsor, for any of the following reasons: 

Protocol Amendment 10 
 
RM-493-014 
Rhythm Pharmaceuticals, Inc. 
33 of 87 
Confidential 
 
  
 
• AEs, which justify treatment or study withdrawal. For specific predefined events, 
additional monitoring and guidance for the Investigator is provided in Appendix D and 
Appendix E. 
• Non-adherence to study drug regimen or protocol requirements. 
• Non-compliance with instructions or failure to return for follow-up. 
8.6. 
Duration of Patient Participation 
After completing the screening assessments within 8 – 2 weeks, all patients will participate in the 
study for a minimum of 16 additional weeks. After 16 weeks, the duration of patient participation 
will be as follows: 
• +0 weeks for patients immediately enrolling into a separate extension study (Rhythm 
Protocol RM-493-022). Total duration: 16 weeks. 
+TBD weeks for patients completing Bridging Visits until the extension study is initiated 
at the site. The purpose of the Bridging Visits is to ensure continuous treatment for 
patients if initiation of the extension study is delayed at the site. The Bridging Visits can 
occur at a frequency of up to every 12 weeks (for a maximum of 1 year) and/or at the 
discretion of the Primary Investigator. Total duration: uncertain, but > 16 weeks, 
maximum of 16 months. 
• +4 weeks for patients not entering the extension study and proceeding to the final study 
visit. Total duration: 20 weeks. 
 

Protocol Amendment 10 
 
RM-493-014 
Rhythm Pharmaceuticals, Inc. 
34 of 87 
Confidential 
 
  
 
9. 
STUDY TREATMENTS 
9.1. 
Study Drug 
The setmelanotide injection solution is a clear to slightly opalescent and colorless to slightly colored 
solution, practically free of visible particles, prepared as a sterile solution for once-a-day 
administration by SC injection.  
The drug product is formulated at a concentration of 10 mg/mL, and 1 mL of setmelanotide is filled 
in a 2 mL glass vial which is then packaged in a cardboard carton. 
9.2. 
Study Drug Dose Levels  
The dose levels are outlined in Table 2. The dose escalation at Study Day 15 (start of Week 3) will 
occur at the patient’s home. The site will call the patient to confirm that the escalation has occurred 
and to record any AEs. 
Table 2: 
Study Drug Dose Levels by Study Week and Patient Age 
Study Week 
For Patients 6 up to 16 Years Old 
(mg/day) 
For Patients ≥ 16 Years Old  
(mg/day) 
1 and 2 
1.0 
2.0 
3 and 4 
2.0 
3.0 
5 to 16 
3.0 
Dose levels may deviate from this plan after consultation with the Sponsor, if necessary due to an 
AE, or other safety or tolerability concern. No dose greater than 3.0 mg per day will be administered 
during this study. Additionally, patients who are currently enrolled in this study at the time of this 
protocol amendment, and who are not currently at a dose of 3.0 mg per day, will be assessed by the 
Primary Investigator and the Sponsor to determine if an increase in the dose to 3.0 mg per day is 
appropriate. 
9.3. 
Blinding 
This study will be open-label, so there is no blinding.  
9.4. 
Packaging and Labeling of Study Drug 
All study drug will be labelled as per the local regulations and provided in a cardboard box that 
contains a single vial.  
9.5. 
Handling and Storage of Study Drug 
All study drug must be kept in a secure, limited-access storage area at a temperature between 2°C 
and 8°C. Setmelanotide is stable at room temperature for a short period that will allow patients to 
transport study drug home; ice packs and cooler bags will be provided to patients to transport the 

Protocol Amendment 10 
 
RM-493-014 
Rhythm Pharmaceuticals, Inc. 
35 of 87 
Confidential 
 
  
 
drug to their home. Once home, the un-opened study drug must be stored in the patient’s 
refrigerator. Opened study drug may be stored at room temperature for up to 30 days.  
9.6. 
Assessment of Treatment Compliance and Study Drug Accountability  
Accountability for the study drug at the study site is the responsibility of the Investigator. The 
Investigator will ensure that the study drug is used only in accordance with this protocol. Where 
allowed, the Investigator may choose to assign drug accountability responsibilities to a pharmacist 
or other appropriate individual. Drug accountability records indicating the delivery date to the site, 
inventory at the site, use by each patient, return of all used study drug to the study center, and return 
to Rhythm (or disposal of the drug, if approved by Rhythm) will be maintained by the clinical site. 
Reasons for departure from the expected dispensing regimen must also be recorded. The Sponsor or 
its designee will review drug accountability at the site during monitoring visits. 
Compliance to dosing will be monitored throughout the study by having the patient complete a daily 
dosing log that records daily dosing information, including the time of dosing, location of the 
injection, and the amount of drug dosed. If a patient is non-compliant with the dosing schedule, the 
Sponsor may implement steps to ensure compliance, e.g., sending a nurse to the patient’s home for 
retraining or having a nurse administer the study drug. 
9.7. 
Prior and Concomitant Treatment 
Prohibited Medication and Substances  
Unless concomitant medications are likely to present a strong potential safety concern, the general 
goal of this protocol is to allow as many patients with these ultra-rare conditions to participate in the 
study as possible. 
Medications that are approved to treat obesity (e.g., orlistat, lorcaserin, phentermine-topiramate, 
naltrexone-bupropion) are not allowed within three months of first dose of study drug (e.g., 
enrollment) and are prohibited during the course of the study. 
GLP-1 receptor agonists may be used up to the dose approved for the treatment of diabetes mellitus 
(e.g., liraglutide up to a daily dose of 1.8 mg) as long as (1) it is not being prescribed for the 
treatment of obesity, (2) the dose has been stable for at least three months prior to enrollment, (3) the 
patient has not experienced weight loss during the previous three months, AND (4) the patient 
intends to keep the dose stable throughout the course of the study. 
Other medications that may cause weight loss (e.g., stimulants) are allowed as long as the patient (1) 
has used a stable dose for at least three months prior to enrollment, (2) has not lost weight during the 
previous three months, and (3) intends to keep the dose of the medication stable through the course 
of the study. 
All concomitant medications should be kept at a stable dose throughout the course of the study, 
unless a dose change is necessary to treat an AE. 

Protocol Amendment 10 
 
RM-493-014 
Rhythm Pharmaceuticals, Inc. 
36 of 87 
Confidential 
 
  
 
10. 
SCHEDULE OF ASSESSMENTS 
The Schedule of Assessments (SOA) is presented in Table 3.  

Protocol Amendment 10 
 
RM-493-014 
Rhythm Pharmaceuticals, Inc. 
37 of 87 
Confidential 
 
  
 
Table 3: 
Schedule of Assessments 
Study Period/Procedure 
Screening 
Study Treatment 
EOS 
Visit 
Bridging Visit(s) 31 
+ up to 12 weeks 
from V6  
(up to one year 
from V6) 
Treatment 
Discontinuation  
Visit 
Clinic Visit Number 
V1 
V2 
- 
V3 29 
V4 
V5 
V6 30 
V7 
Start of Week X 
-8 to -2 
0 
2 
4 
8 
12 
16 
20 
Study Day (± 3 days) 
-56 to -14 
1 
15 
29 
57 
85 
113 
141 
Sponsor review of patient 
genetics/Genetic Testing 1 
X 
 
 
 
 
 
 
 
 
 
Informed consent/Assent 33 
X 
 
 
 
 
 
 
 
 
 
Inclusion/Exclusion review 
X 
X 
 
 
 
 
 
 
 
 
Medical history review 
X 
 
 
 
 
 
 
 
 
 
Physical examination 2 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
Comprehensive skin exam 3 
X 
 
 
 
 
 
X 
 
 
X 
Fitzpatrick classification scale  
X 
 
 
 
 
 
X 
X 
 
X 
Hepatic imaging 35 
X 
 
 
 
 
 
 
 
 
 
Weight 4 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
Waist circumference 5 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
Height 6 
X 
 
 
X 
X 
X 
X 
X 
X 
X 
Vitals 8 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
ECG (12-lead) 9 
X 
X36 
 
X 
 
 
X 
 
X 
X 
Pregnancy test 10 
X 
X 32 
 
X 
X32 
X32 
X32 
 
X32 
X32 
Daily hunger questionnaires 11 
X 
Daily 32 
 
X32 
Global hunger assessment 12 
 
X32 
 
X32 
X32 
X32 
X32 
X 
X32 
X32 

Protocol Amendment 10 
 
RM-493-014 
Rhythm Pharmaceuticals, Inc. 
39 of 87 
Confidential 
 
  
 
Table 3: 
Schedule of Assessments (Continued) 
Study Period/Procedure 
Screening 
Study Treatment 
EOS 
Visit 
Bridging Visit(s) 31 
+ up to 12 weeks 
from V6  
(up to one year 
from V6) 
Treatment 
Discontinuation  
Visit 
Clinic Visit Number 
V1 
V2 
- 
V3 29 
V4 
V5 
V6 30 
V7 
Start of Week X 
-8 to -2 
0 
2 
4 
8 
12 
16 
20 
Study Day (± 3 days) 
56 to 14 
1 
15 
29 
57 
85 
113 
141 
Concomitant medications review  
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
V, Study Visit Number; EOS, End of Study; 
. 
1. Prior to conducting any screening assessments, Sponsor will review and approve the specific genotype to ensure it meets the criteria for the 
patient populations included in the study (Section 11.1).  
2. A complete physical examination will be conducted at Screening and at the EOS V7. At other timepoints, an abbreviated examination will be 
performed. The abbreviated examination should focus on heart, lungs, skin, neurologic exam, and any areas of previous abnormal findings, 
noting any changes from baseline. In addition, 
 for assessment of pubertal development will be conducted for those patients who 
have yet to reach 
 Whenever possible, the same trained health care professional will conduct the exam and 
 
(Section 11.5).  
3. A comprehensive skin evaluation will be performed by a dermatologist. The skin exam should include a full body skin exam (head-to-toe skin 
examination) from a trained and licensed dermatologist. Any concerning lesions identified during the Screening Period will be biopsied and 
results known to be benign prior to first dose of setmelanotide. If the pre-treatment biopsy results are of concern, the patient will be excluded 
from the study. Additionally, any lesion or change in an existing lesion during the course of the study must be evaluated by the dermatologist 
and biopsied, if clinically indicated in the opinion of the dermatologist. Any biopsies must be evaluated by a trained dermatopathologist, and 
biopsy reports must be part of the study information for each patient (Section 11.6). 
4. Weight (kg) is to be measured at the clinic using the same scale throughout the study, after patients have emptied their bladders and bowels and 
after fasting for at least 8 hours. Patients are to wear light clothing or underwear and no shoes, and will be weighed at approximately the same 
time of day. Weight measurements are to be done in triplicate (Section 11.8).  
5. Waist circumference (cm) will be single measures (Section 11.9). 
6. For patients ≥18 years of age, height needs to be measured at the screening visit only. Height (cm) will be measured, without shoes, socks, or 
hats, using a wall-mounted stadiometer. All measurements will be done in triplicate at each timepoint and recorded to the nearest 10th of a 
decimal place (Section 11.10).  
8. All BP and HR measurements are to be obtained in the sitting position following at least 5 minutes of rest. All measurements will be taken in 
triplicate, approximately 2 minutes apart. When possible, BP should be taken in the non-dominant arm throughout the study, using the same 

Protocol Amendment 10 
 
RM-493-014 
Rhythm Pharmaceuticals, Inc. 
41 of 87 
Confidential 
 
  
 
23. Blood samples will be collected prior to dose administration in the 
.  
24. Injection site evaluations and scoring (by the clinical staff) will include identification and measurement of areas of erythema, edema, and 
induration, as well as the presence of localized pain, tenderness, and itching. Additional evaluation data can be collected at any visit in which 
there are injection site reactions, even if not a timepoint for formal assessment (Appendix A).  
25. Site should call the patient to confirm the proper dose escalation has occurred, and to collect AEs. 
26. Patients/caretakers will draw up and self-administer/administer the drug once daily in the morning beginning the morning of Day 1 and for the 
duration of dosing. On days with clinic visits, the patients/caretakers will administer the drug in the clinic in the presence of the clinical staff to 
assure proper technique.  
27. Patients/caretakers will return all (the number recorded) used vials to the clinic when they visit, and both clinic-administered study drug as well 
as outpatient study drug administration will be recorded in a study diary. 
28. Adverse events will be recorded from the time a patient provides informed consent. AEs reported after dosing on Day 1 will be considered 
treatment-emergent AEs.  
29. Patients who are <16 years of age will receive first daily dose of 3.0 mg at V3, at clinic site.  
30. Study endpoints are analyzed at V6. After completing V6, patient enters a separate extension study (Protocol RM-493-022), does not enter the 
extension study and returns for the final study Visit 7 in 4 weeks, or completes Bridging Visits for up to one year or until the extension study is 
initiated. 
31. Bridging Visits only needed if separate extension study RM-493-022 is not initiated at site at the time of V6.  
32. Collected prior to study drug administration. 
33. Although the study procedures and assessments required per protocol are classified as “No or Minimal Risk” (with the exception of 
which 
may be classified as “Minor Increase over Minimal Risk”) according to the 2008 Guidance Document “Ethical Considerations for Clinical Trials 
on Medicinal Products Conducted with the Pediatric Population,” considerations for reducing pain in distress in participants younger than 18 
years of age are included in Appendix J. 
35. Only applicable to SCR1 patients. 
36. During visit 2 ECG will be collected prior to dosing and ~8 hours post-dose.

Protocol Amendment 10 
 
RM-493-014 
Rhythm Pharmaceuticals, Inc. 
42 of 87 
Confidential 
 
  
 
11. 
PATIENT ASSESSMENTS AND REQUIREMENTS 
Order of Assessments  
When scheduled at the same time point, the order of procedures should be as follows: obtain vital 
signs, perform 12-lead ECG, and perform blood draws (at the specified time point, if applicable). 
Adjustments may be made depending upon specific circumstances and in consultation with the 
Sponsor. 
11.1. 
Sponsor Review of Patient Genetics and/or Genetic Testing  
The genetic background of each patient must be reviewed by the Sponsor prior to study enrollment 
to confirm that the patient meets inclusion criteria. For patients that have not had a previous genetic 
sample taken, a blood sample will be obtained at Screening for genetic confirmation of a genetic 
disorder of obesity.  
In addition, enrollment of patients in some subgroups may be prioritized by the Sponsor in order to 
ensure enrollment of patients with (1) well described, high-impact genetic mutations, (2) a variety of 
genetic variants, or (3) genetic variants likely to respond to setmelanotide. 
11.2. 
Informed Consent/Assent  
A complete description of the study is to be presented to each potential patient, and signed and dated 
informed consent and/or assent is to be obtained before any study-specific procedures are 
performed.  
11.3. 
Inclusion/Exclusion Review  
Inclusion and exclusion criteria are to be reviewed per the SOA (Table 3) to ensure the patient is 
eligible for the study.  
For Exclusion Criterion 9, GFR at Screening will be determined using the Modification of Diet in 
Renal Disease (MDRD) Equation in patients ≥18 years of age (Appendix H), and the Bedside 
Schwartz Equation in patients <18 years of age (Appendix I). 
11.4. 
Demographics, Concomitant Medications and Medical History Review  
Medical history and demographic data including the patient’s gender, race, date of birth, and 
concomitant medication use will be obtained for all patients during the Screening Period 
(Appendix C). 
The medical history should be updated on Day 1 prior to first dose of study drug, to assess continued 
study eligibility and adherence to final inclusion/exclusion criteria. This medical history update 
includes a review for changes from Screening as well as a review of the patient’s recent medication 
use to assess whether any changes have occurred since the previous visit. 

Protocol Amendment 10 
 
RM-493-014 
Rhythm Pharmaceuticals, Inc. 
43 of 87 
Confidential 
 
  
 
11.5. 
Physical Examination  
A complete physical examination will include review of peripheral lymph nodes, head, eyes 
(including conjunctiva), ears, nose, mouth and oropharynx, neck, heart, lungs, abdomen, 
musculoskeletal including back, extremities, and neurologic assessments.  
Changes from baseline in any physical examination findings identified by the Investigator as 
clinically significant must be recorded as an AE on the appropriate electronic Case Report Form 
(eCRF). 
Patients will also be assessed at baseline according to
; any patients who have not 
reached
 will be assessed according to the SOA (Table 3). 
11.6. 
Comprehensive Skin Exam  
The Investigator will identify a trained and licensed dermatologist to serve as a consultant for the 
Investigative Site. 
The dermatologist will perform comprehensive skin examinations, which should include a full body 
skin exam (head-to-toe skin examination). Each patient will receive this comprehensive, head-to-toe 
dermatology examination as part of Screening and prior to the end of the study. Any worrisome 
lesion should be biopsied prior to study start, and all biopsies must be evaluated by a trained 
dermatopathologist.  
Additionally, any lesion or change in an existing lesion during the course of the study must be 
evaluated by the dermatologist and biopsied, if clinically indicated in the opinion of the 
dermatologist. All biopsies must be evaluated by a trained dermatopathologist.  
In the event a patient experiences changes to skin or skin lesions that are unresolved (or have not 
significantly improved or are close to resolution) at the end of study, the patient may be asked to 
return for additional follow up assessments to document progress towards resolution. 
Biopsy reports must be part of the study information for each patient. 
Protection from Sun 
It is also important that patients do not participate in any activities that will intentionally cause their 
skin to tan (e.g., visit ultraviolet [UV] tanning salons, use spray tanners or self-tanning lotions, etc.). 
11.7. 
Fitzpatrick Scale  
Each patient is to be categorized for skin type according to the Fitzpatrick scale (Fitzpatrick 1975), 
depicted in Appendix B. 
11.8. 
Weight 
Weight (kg) will be recorded as shown in the SOA (Table 3). All measurements will be done in 
triplicate at each timepoint. Whenever possible, the same scale should be used throughout the study, 
including the Screening Visit, and should be calibrated on a regular basis. Weight should be 

Protocol Amendment 10 
 
RM-493-014 
Rhythm Pharmaceuticals, Inc. 
45 of 87 
Confidential 
 
  
 
determined by the Primary Investigator to have moderate or greater liver fibrosis (e.g., the 
equivalent of a METAVIR score ≥ 2).  
11.13. 
Vital Signs  
Vital signs will be obtained in the sitting position following at least 5 minutes of rest at the time 
points indicated in the SOA (Table 3). 
Blood Pressure and Heart Rate 
Blood pressure (BP; mmHg) and heart rate (HR; beats per minute [bpm]) evaluations will be 
performed using the same methodology throughout the study (manual or automated). For a detailed 
description of the standardized BP measurement to be utilized in this study, see Appendix F.  
Special attention should be paid to ensure the appropriate cuff size in this patient population. 
Repeat measures and more frequent monitoring can be implemented for significant increases in BP 
or HR.  
To allow for a trough blood pressure reading, the patient should be instructed not to take the study 
medication on study days when vital signs are to be measured in the clinic. 
Body Temperature and Respiration Rate 
Body temperature (°C) and respiration rate (breaths/minute) will be obtained in the sitting position 
following at least 5 minutes of rest. 
11.14. 
ECG (12-lead) 
Single 12-lead ECGs will be performed following a period of at least 10 minutes of rest in the 
supine position. ECGs will be collected according to the SOA (Table 3). During Visit 2 ECG will be 
collected prior to dosing and ~8 hours post-dose.  
11.14.1. 
ECG Procedures 
All ECGs should be performed according to the SOA (Table 3) with the following guidelines: 
• ECG technicians should be thoroughly trained in the administration of a 12-Lead ECG, 
the institution’s specific protocols and procedures for ECG tests, and the requirements of 
the study protocol.  
• The same make and model of ECG machine with the same style of leads should be used 
for all patients. Such equipment should be recently serviced and calibrated. Machine 
calibration records and performance data should be maintained on file.  
• Patients should be in a supine position and have rested for 10 minutes. 

Protocol Amendment 10 
 
RM-493-014 
Rhythm Pharmaceuticals, Inc. 
46 of 87 
Confidential 
 
  
 
11.14.2. 
Reading ECGs 
• Site Monitoring: Sites should read ECGs for study monitoring and eCRFs per their usual 
procedures. 
• Central Reading: The Sponsor may elect, if needed for regulatory reasons, to collect 
ECGs for Central Reading. If so, the intention will be that a single Central Reader will 
read all ECGs. Therefore, all ECGs must be available and stored for this purpose. When 
sent for Central Reading, the ECGs must be prepared to be read in a blinded fashion. 
Central Readers of ECGs should be blinded to time, treatment, and patient identifier.  
11.15. 
Pregnancy Test  
Contraception  
Females must not be pregnant and must have a negative serum pregnancy test result at the Screening 
Visit and negative urine pregnancy test on Day 1, with results known prior to initiating dosing; 
pregnancy testing will be monitored during the study. 
For females able to bear children, including pre-pubertal females if relevant, a highly reliable form 
of contraception must be used/practiced throughout the study and for 90 days following the study. 
Highly reliable acceptable forms of contraception include hormonal (i.e., oral, implantable, or 
injectable) AND single-barrier method (i.e., condom), or an Intrauterine Device (IUD) AND single-
barrier method (i.e., condom) or vasectomized partner. True abstinence is acceptable only if it is the 
preferred and usual lifestyle of the patient. 
Females of non-childbearing potential, defined as surgically sterile (status post hysterectomy, 
bilateral oophorectomy, or bilateral tubal ligation), post-menopausal for at least 12 months, or 
delayed pubertal development and failure to have achieved menarche, do not require contraception 
during the study. Younger female patients who are not sexually mature will be assessed for Tanner 
Staging and advised accordingly. Females who begin the study having failed to reach Tanner Stage 
5 or achieve menarche, but do so during the study, will be counseled on pregnancy and 
contraception, and will immediately be treated as a female of child-bearing potential for the 
remainder of the study, with the required pregnancy tests at all visits. 
It is not known if this treatment will affect spermatogenesis. Therefore, males with female partners 
of childbearing potential must agree to use contraception: (A) use a double barrier method [i.e., 
condom AND diaphragm with spermicide during intercourse]), (B) had a vasectomy, or (C) abstain 
from sexual intercourse. True abstinence is acceptable only if it is the preferred and usual lifestyle of 
the patient. Male patients must not donate sperm for 90 days following participation in the study. 
 
  
  
  

Protocol Amendment 10 
 
RM-493-014 
Rhythm Pharmaceuticals, Inc. 
53 of 87 
Confidential 
 
  
 
11.25. 
Telephone Call  
The site will call a patient’s home on Day 15 to assess AEs and ensure the patient escalated to the 
appropriate dose depending on age, as outlined in the SOA (Table 3).  
11.26. 
Study Drug Administration 
Study drug will be administered daily as outlined in the SOA (Table 3).  
11.27. 
Dispensing/Return of Study Drug 
Study drug will be dispensed as outlined in the SOA (Table 3) and Section 9.5. Any unused drug 
will be returned to the clinic site and the Sponsor as described in Section 9.6.  
11.28. 
Adverse Event Assessment  
Each patient must be carefully monitored for the development of any AEs throughout the study from 
Screening through the Final Study Visit. This information should be obtained in the form of non-
leading questions (e.g., “How are you feeling?”), and from signs and symptoms detected during each 
examination, from laboratory evaluation, observations of study personnel, and spontaneous reports 
from patients. 
All AEs, including injection site reactions and potential systemic reactions, will be graded using the 
National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) grading 
system.  
Complete details on AE monitoring are provided in Section 12. 
11.29. 
Concomitant Medication(s) Review  
A review of concomitant medications will be conducted during the Screening Period and at every 
study visit. Any medications taken by study patients will be recorded in source documents and on 
the appropriate eCRF. 

Protocol Amendment 10 
 
RM-493-014 
Rhythm Pharmaceuticals, Inc. 
54 of 87 
Confidential 
 
  
 
12. 
ADVERSE EVENTS 
Monitoring of AEs will be conducted throughout the study. AEs will be recorded in the CRFs from 
Screening through the Final Study Visit. AEs that occur after the start of study drug administration 
will be considered TEAEs. SAEs will be recorded through the Final Study Visit (EOS Visit 7, or 
Treatment Discontinuation). All AEs should be monitored until they are resolved or are clearly 
determined to be due to a patient’s stable or chronic condition or intercurrent illness(es). 
12.1. 
Definitions, Documentation, and Reporting 
An adverse event (AE) is any untoward medical occurrence associated with the use of a drug in 
humans, whether or not considered drug-related. An AE (also referred to as an adverse experience) 
can be any unfavorable and unintended sign (e.g., an abnormal laboratory finding), symptom, or 
disease temporally associated with the use of a drug, without any judgment about causality. An AE 
can arise from any use of the drug (e.g., off-label use, use in combination with another drug) and 
from any route of administration, formulation, or dose, including an overdose. 
An AE is considered serious (SAE) if, in the view of either the Investigator or Sponsor, it results in 
any of the following outcomes: 
• Death. 
• Life-threatening. Life-threatening means that the patient was at immediate risk of death 
from the reaction as it occurred, i.e., it does not include a reaction which hypothetically 
might have caused death had it occurred in a more severe form. 
• In-patient hospitalization or prolongation of existing hospitalization. Hospitalization 
admissions and/or surgical operations scheduled to occur during the study period, but 
planned prior to study entry, are not considered AEs if the illness or disease existed 
before the patient was enrolled in the study, provided that it did not deteriorate in an 
unexpected manner during the study (e.g., surgery performed earlier than planned). 
• A persistent or significant incapacity or substantial disruption of the ability to conduct 
normal life functions. 
• Congenital anomaly/birth defect. 
• Important medical event. An important medical event is an event that may not result in 
death, be life-threatening, or require hospitalization but may be considered an SAE when, 
based upon appropriate medical judgment, it may jeopardize the patient or patient and 
may require medical or surgical intervention to prevent one of the outcomes listed in the 
definitions for SAEs. Examples of such medical events include allergic bronchospasm 
requiring intensive treatment in an emergency room or at home, blood dyscrasias or 
convulsions that do not result in in-patient hospitalization, or the development of drug 
dependency or drug abuse. 

Protocol Amendment 10 
 
RM-493-014 
Rhythm Pharmaceuticals, Inc. 
55 of 87 
Confidential 
 
  
 
12.2. 
Procedures for AE and SAE Reporting 
Each patient must be carefully monitored for the development of any AEs. This information should 
be obtained in the form of non-leading questions (e.g., “How are you feeling?”) and from signs and 
symptoms detected during each examination, observations of study personnel, and spontaneous 
reports from patients. 
All AEs (serious and non-serious) spontaneously reported by the patient and/or in response to an 
open question from study personnel or revealed by observation, physical examination, or other 
diagnostic procedures will be recorded on the appropriate CRF. Any clinically relevant deterioration 
in laboratory assessments or other clinical findings is considered an AE and must be recorded on the 
appropriate CRF. When possible, signs and symptoms indicating a common underlying pathology 
should be noted as one comprehensive event. 
All SAEs that occur during the study must be reported by the Investigator within 24 hours from the 
point in time when the Investigator becomes aware of the SAE. All SAEs must be reported whether 
or not considered causally related to the study drug. SAE forms will be completed and the 
information collected will include patient number, a narrative description of the event, and an 
assessment by the Investigator as to the severity of the event and relatedness to study drug. Follow-
up information on the SAE may be requested by the Sponsor or its designee. 
 
All SAE correspondence should be addressed to 
 
 Email: RhythmSafety.SM@ppdi.com  
 
If there are serious, unexpected adverse drug reactions associated with the use of the study drug, 
Rhythm or designee will notify the appropriate regulatory agency(ies), Ethics Committees (EC), and 
all participating Investigators on an expedited basis. It is the responsibility of the Investigator to 
promptly notify the Institutional Review Board (IRB)/Independent Ethics Committee (IEC) of all 
unexpected serious adverse drug reactions involving risk to human patients. An unexpected event is 
one that is not reported in the IB (see IB Section 6.1.3, Reference Safety Information). 
For both serious and non-serious AEs, the Investigator must determine both the intensity of the 
event and the relationship of the event to study drug administration. Only those injection site 
reactions considered clinically significant by the Investigator will be recorded as AEs. 
12.2.1. 
Assessment of Severity 
Intensity of all AEs including clinically significant treatment-emergent laboratory abnormalities, 
injection site reactions, and potential systemic reactions will be graded per the CTCAE 
Version 4.03. The CTCAE grade refers to the severity of the AE and ranges from Grade 1 (mild 
AE), Grade 2 (moderate AE), Grade 3 (severe AE), and Grade 4 (life-threatening or disabling AE) 
to Grade 5 (death related to AE). 
AEs not listed by the CTCAE will be graded as follows: 

Protocol Amendment 10 
 
RM-493-014 
Rhythm Pharmaceuticals, Inc. 
56 of 87 
Confidential 
 
  
 
• Mild: discomfort noticed but no disruption of normal daily activity. 
• Moderate: discomfort sufficient to reduce or affect daily activity. 
• Severe: inability to work or perform normal daily activity. 
• Life threatening: represents an immediate threat to life. 
Relationship to study drug administration will be determined by the Investigator according to the 
following criteria: 
• None: No relationship between the event and the administration of study drug. The event 
is related to other etiologies, such as concomitant medications or patient’s clinical state. 
• Unlikely: The current state of knowledge indicates that a relationship to study drug is 
unlikely, the temporal relationship is such that study drug would not have had any 
reasonable association with the observed event, or another reasonable explanation for the 
event (e.g., a pre-existing clinical condition or other concomitant treatment) is more 
likely. 
• Possible: A reaction that follows a plausible temporal sequence from administration of 
the study drug and follows a known response pattern to the suspected study drug. The 
reaction might have been produced by the patient’s clinical state or other modes of 
therapy administered to the patient. 
• Probable: A reaction that follows a plausible temporal sequence from administration of 
the study drug and follows a known response pattern to the suspected study drug. The 
reaction cannot be reasonably explained by the known characteristics of the patient’s 
clinical state or other modes of therapy administered to the patient. 
For the purpose of safety analyses, all AEs that are classified as possible or probable will be 
considered treatment-related events. 
12.2.2. 
Adverse Events and Risks 
Overall, setmelanotide has been generally well-tolerated in previous studies. Drug-Related TEAEs 
(for which the AE was assessed as possibly or probably related to study drug by the Investigator) 
were reported. Because very few studies have been done using setmelanotide, there may be other 
unknown side effects. The Primary Investigators (or a covering clinician) will be available at all 
times to study participants in the event of a clinical emergency; both this availability and how to 
reach the Investigators in an emergency will be clearly communicated orally and in writing to study 
participants. All study interventions will be provided free of cost.  
Please refer to the current IB for a comprehensive summary of the AEs reported to date.  
12.2.3. 
Monitoring of Adverse Events and Period of Observation 
AEs will be recorded on the CRFs starting from Screening up to and including the Final Study Visit. 
SAEs and deaths will be recorded on the CRFs starting from the time the informed consent form is 

Protocol Amendment 10 
 
RM-493-014 
Rhythm Pharmaceuticals, Inc. 
57 of 87 
Confidential 
 
  
 
signed and continuing through the Final Study Visit. All AEs should be monitored until they are 
resolved or are clearly determined to be due to a patient’s stable or chronic condition or intercurrent 
illness(es). 
Any SAE that occurs at any time after completion of the study, and which the Investigator considers 
to be related to study drug, must be reported to Rhythm or its designee. 
12.2.4. 
Guidelines for Additional Monitoring and Suspension of Dosing for a Patient 
Patients will be monitored carefully during the treatment period during on-site clinic visits and 
periodic telephone calls made to the patients by the study staff. In the event a patient is withdrawn 
from treatment due to an AE, the patient should be encouraged to complete the final study/early 
termination visit in order to monitor the event to resolution and obtain additional protocol-defined 
safety assessments. 
Depression or Suicidality 
A patient should be referred to an MHP if he/she has: 
• A PHQ-9 score ≥ 10. 
• Any suicidal behavior. 
• Any suicidal ideation of type 4 or 5 on the C-SSRS. 
A referral to an MHP should also be made if, in the opinion of the Investigator, it is necessary for 
the safety of the patient. If a patient’s psychiatric disorder can be adequately treated with psycho- 
and/or pharmacotherapy, then the patient, at the discretion of the MHP, should be continued in the 
trial. 
Any elevation in PHQ-9 or C-SSRS score should be evaluated to determine whether it meets the 
criteria for reporting as an AE. 

Protocol Amendment 10 
 
RM-493-014 
Rhythm Pharmaceuticals, Inc. 
58 of 87 
Confidential 
 
  
 
13. 
DATA ANALYSIS/STATISTICAL PROCEDURES 
This section describes the plans for analysis. Details of the statistical plan will be provided in a 
complete SAP. Any additional analyses and specific conventions for analysis will be described in 
the SAP and Clinical Study Report. 
13.1. 
Sample Size Estimation 
The objective of this study is to demonstrate statistically significant and clinically meaningful 
weight loss in patients with various rare genetic forms of obesity after ~3 months of treatment. The 
primary endpoint is defined as the proportion of patients in each subgroup of RGDO who achieve at 
least 5% body weight reduction from baseline, at ~3 months treatment with setmelanotide. It is 
estimated that at least 5 patients with each rare genetic disorder of obesity will be recruited.  
Given the rarity of this disorder, estimated power for expected weight change efficacy will not be 
provided, but efficacy will be only summarized.  
13.2. 
Hypotheses 
Setmelanotide leads to a clinically relevant reduction of percent body weight after ~3 months of 
treatment in each population of patients with rare genetic disorders of obesity (each population 
analyzed separately). No formal statistical hypothesis will be tested, given the exploratory nature of 
the study.  
13.3. 
Definition of Population(s) for Analysis 
This protocol includes a variety of very rare genetic obesity populations who are included in this 
protocol as a matter of administrative convenience (as each population is so rare, and this protocol 
anticipates very small numbers of patients in each population). Hence each population will be 
analyzed separately as ≥2 patients are enrolled and complete the ~3-month treatment period.  
13.4. 
Statistical Methods 
Statistical methods, populations, and approaches to missing data will be outlined in the SAP.  
The primary endpoint is defined as the proportion of patients in each subgroup of RGDO who 
achieve at least 5% body weight reduction from baseline, at ~3 months of treatment with 
setmelanotide. Summary of the primary endpoints and the associated Clopper-Pearson confidence 
interval will be provided.  
The comparison of post-treatment values versus baseline will be carried out via 1-sided statistical 
test at an alpha=0.05. No adjustment for multiplicity is needed for the single primary endpoint; 
weight change after 1 year of treatment in subjects who continue in the study past 3 months will also 
be analyzed without adjustment for multiplicity. In addition, no adjustment for multiplicity will be 
included for the many rare genetic obesity populations in this study as these different populations 
are included in this study only for administrative convenience. All the p-values and/or confidence 
intervals should be considered exploratory. 

Protocol Amendment 10 
 
RM-493-014 
Rhythm Pharmaceuticals, Inc. 
59 of 87 
Confidential 
 
  
 
For the primary endpoint, and all other endpoints, the last value obtained prior to the first dose of 
active treatment will be considered the baseline value for statistical analyses.  
As this patient population is extremely rare, efforts will be made to keep all patients in the study, 
and all data collected, even if outside of visit windows, will be included in all analyses of endpoints.  
AEs will be coded by using the most current version of Medical Dictionary for Regulatory Activities 
(MedDRA) and summarized by system organ class, preferred term, and treatment group for the 
number and percent of AEs reported, the number of patients reporting each AE, and the number of 
patients with any AE.  
A by-patient AE data listing including onset and resolution dates, verbatim term, preferred term, 
treatment, severity, relationship to treatment, action taken, and outcome will be provided.  
Safety data including laboratory evaluations and vital signs assessments will be summarized by time 
of collection and by treatment group. In addition, change from baseline to any post-dose values will 
be summarized for vital signs and clinical laboratory results. Frequency of patients with abnormal 
safety laboratory results will be tabulated by treatment. 
Plasma concentrations of setmelanotide will be summarized. Plasma concentrations may be 
compared to pharmacodynamic endpoints. 
13.5. 
Timing of Analyses 
It is planned that an analysis may be completed once ~2-3 patients in each genetic obesity 
population have completed ~3 months of treatment with setmelanotide, data have been cleaned and 
finalized, and the database is locked for assessments. Additional supplemental analyses will be 
conducted for patients who enter into long-term extensions.  
13.6. 
Statistical Analysis Plan 
The full SAP for this study will provide more detailed statistical procedures prior to any planned 
analysis. 

Protocol Amendment 10 
 
RM-493-014 
Rhythm Pharmaceuticals, Inc. 
60 of 87 
Confidential 
 
  
 
14. 
ADMINISTRATIVE REQUIREMENTS 
14.1. 
Good Clinical Practice 
The study will be conducted in accordance with the International Council on Harmonisation (ICH) 
for Good Clinical Practice (GCP) and the appropriate regulatory requirement(s). The Investigator 
will be thoroughly familiar with the appropriate use of the study drug as described in the protocol 
and IB. Essential clinical documents will be maintained to demonstrate the validity of the study and 
the integrity of the data collected. Master files should be established at the beginning of the study, 
maintained for the duration of the study, and retained according to the appropriate regulations. 
14.2. 
Ethical Considerations 
The study will be conducted in accordance with ethical principles founded in the Declaration of 
Helsinki. The IRB/IEC will review all appropriate study documentation in order to safeguard the 
rights, safety, and well-being of the patients. The study will only be conducted at sites where 
IRB/IEC approval has been obtained. The protocol, IB, informed consent, advertisements (if 
applicable), written information given to the patients (including diary cards), safety updates, annual 
progress reports, and any revisions to these documents will be provided to the IRB/IEC by the 
Investigator. 
14.3. 
Patient Information and Informed Consent 
After the study has been fully explained, written informed consent will be obtained from either the 
patient or his/her guardian or legal representative prior to study participation. The method of 
obtaining and documenting the informed consent and the contents of the consent will comply with 
ICH-GCP and all applicable regulatory requirements. 
14.4. 
Patient Confidentiality 
In order to maintain patient privacy, all source documents/CRFs, study drug accountability records, 
study reports, and communications will identify the patient by initials and the assigned patient 
number. The Investigator will grant monitor(s) and auditor(s) from Rhythm or its designee and 
regulatory authority(ies) access to the patient’s original medical records for verification of data 
gathered on the source documents/CRFs and to audit the data collection process. The patient’s 
confidentiality will be maintained and will not be made publicly available to the extent permitted by 
the applicable laws and regulations. 
14.5. 
Protocol Compliance 
The Investigator will conduct the study in compliance with the protocol provided by Rhythm, and 
given approval/favorable opinion by the IRB/IEC and the appropriate regulatory authority(ies). 
Modifications to the protocol should not be made without agreement of both the Investigator and 
Rhythm. Changes to the protocol will require written IRB/IEC approval/favorable opinion prior to 
implementation, except when the modification is needed to eliminate an immediate hazard(s) to 

Protocol Amendment 10 
 
RM-493-014 
Rhythm Pharmaceuticals, Inc. 
61 of 87 
Confidential 
 
  
 
patients. The IRB/IEC may provide, if applicable regulatory authority(ies) permit, expedited review 
and approval/favorable opinion for minor change(s) in ongoing studies that have the approval 
/favorable opinion of the IRB/IEC. Rhythm or its designee will submit all protocol modifications to 
the regulatory authority(ies) in accordance with the governing regulations.  
When immediate deviation from the protocol is required to eliminate an immediate hazard(s) to 
patients, the Investigator will contact Rhythm, if circumstances permit, to discuss the planned course 
of action. Any departures from the protocol must be fully documented in the source 
documents/CRF. 
14.6. 
Data Management 
14.6.1. 
Data Handling 
Data will be recorded at the site on source documents and reviewed by the Clinical Research 
Associate (CRA) during monitoring visits. The CRA will verify data recorded in the eCRF system 
with source documents. All corrections or changes made to any study data must be appropriately 
tracked in an audit trail in the eCRF system. Electronic CRFs will be considered complete when all 
missing, incorrect, and/or inconsistent data have been accounted for. 
14.6.2. 
Computer Systems 
Data will be processed using a validated computer system conforming to regulatory requirements. 
14.6.3. 
Data Entry 
Data must be recorded using the eCRF system while the study is in progress. All study site 
personnel must log into the system using their secure user names and passwords in order to enter, 
review, or correct study data. These procedures must comply with Title 21 of the Code of Federal 
Regulations (21 CFR Part 11). All passwords will be strictly confidential. 
14.6.4. 
Medical Information Coding 
For medical information the following thesauri will be used: 
• MedDRA for AEs 
• WHO Drug for concomitant medications 
14.6.5. 
Data Validation 
Validation checks programmed within the eCRF system, as well as supplemental validation 
performed via review of the downloaded data, will be applied to the data in order to ensure accurate, 
consistent, and reliable data. Data identified as erroneous, or data that are missing, will be referred to 
the investigative site for resolution through data queries. 
Electronic CRFs must be reviewed and electronically signed by an Investigator who signed the 
protocol. 

Protocol Amendment 10 
 
RM-493-014 
Rhythm Pharmaceuticals, Inc. 
62 of 87 
Confidential 
 
  
 
14.7. 
Direct Access to Source Data 
Monitoring and auditing procedures developed or reviewed and approved by Rhythm will be 
followed, in order to comply with GCP guidelines. 
The study will be monitored by Rhythm or its designee. Monitoring will be done by personal visits 
from a representative of the Sponsor (site monitor) and will include on-site review of the source 
documents/CRFs for completeness and clarity, cross-checking with source documents, and 
clarification of administrative matters will be performed. The review of medical records will be 
performed in a manner to ensure that patient confidentiality is maintained. 
The site monitor will ensure that the investigation is conducted according to protocol design and 
regulatory requirements by frequent communications (letter, telephone, and fax). 
All unused study drug and other study materials are to be returned to Rhythm after the clinical phase 
of the study has been completed (see Section 9.6). 
Regulatory authorities, the IRB/IEC, and/or Rhythm’s clinical quality assurance group or designee 
may request access to all source documents, CRFs, and other study documentation for on-site audit 
or inspection. Direct access to these documents must be guaranteed by the Investigator, who must 
provide support at all times for these activities. 
14.8. 
Source Document/Case Report Form Completion 
Source documents/CRFs will be completed for each study patient. It is the Investigator’s 
responsibility to ensure the accuracy, completeness, and timeliness of the data reported in the 
patient’s source document/CRF. The source document/CRF should indicate the patient’s 
participation in the study and should document the dates and details of study procedures, AEs, and 
patient status. 
The Investigator, or designated representative, should complete the source document/CRF as soon as 
possible after information is collected, preferably on the same day that a study patient is seen for an 
examination, treatment, or any other study procedure. Any outstanding entries must be completed 
immediately after the final examination. An explanation should be given for all missing data. 
The Investigator must sign and date the Investigator’s Statement at the end of the source 
document/CRF to endorse the recorded data.  
Rhythm will retain the originals of all CRFs. The Investigator will retain all completed source 
documents/CRFs. 
14.9. 
Record Retention 
The Investigator will maintain all study records according to ICH-GCP and applicable regulatory 
requirement(s). Records will be retained for at least two years after the last marketing application 
approval, or two years after formal discontinuation of the clinical development of the investigational 
product, or according to applicable regulatory requirement(s). If the Investigator withdraws from the 

Protocol Amendment 10 
 
RM-493-014 
Rhythm Pharmaceuticals, Inc. 
63 of 87 
Confidential 
 
  
 
responsibility of keeping the study records, custody must be transferred to a person willing to accept 
the responsibility. Rhythm must be notified in writing if a custodial change occurs. 
14.10. 
Liability Insurance 
Rhythm has subscribed to an insurance policy covering, in its terms and provisions, its legal liability 
for injuries caused to participating persons and arising out of this research performed strictly in 
accordance with the scientific protocol as well as with applicable law and professional standards. 
14.11. 
Publication of Study Findings and Use of Information 
All information regarding setmelanotide supplied by Rhythm to the Investigator is privileged and 
confidential information. The Investigator agrees to use this information to accomplish the study and 
will not use it for other purposes without consent from Rhythm. It is understood that there is an 
obligation to provide Rhythm with complete data obtained during the study. The information 
obtained from the clinical study will be used towards the development of setmelanotide and may be 
disclosed to regulatory authority(ies), other Investigators, corporate partners, or consultants as 
required. 
It is the intention of Rhythm and the academic Investigators to publish the results of this study in a 
peer-reviewed journal upon completion. For this purpose, a publication committee of the key 
Investigators will likely be identified and initiated during the course of this trial.  

Protocol Amendment 10 
 
RM-493-014 
Rhythm Pharmaceuticals, Inc. 
64 of 87 
Confidential 
 
  
 
15. 
REFERENCES 
Aponte Y, Atasoy D, Sternson SM. AGRP neurons are sufficient to orchestrate feeding behavior 
rapidly and without training. Nat Neurosci. 2011 Mar;14(3):351-5. doi: 10.1038/nn.2739. Epub 
2010 Jan 5. 
Atasoy D, Betley JN, Su HH, Sternson SM. Deconstruction of a neural circuit for hunger. Nature. 
2012 Aug 9;488(7410):172-7. doi: 10.1038/nature11270. 
Balthasar N, Dalgaard LT, Lee CE, Yu J, Funahashi H, Williams T, Ferreira M, Tang V, McGovern 
RA, Kenny CD, Christiansen LM, Edelstein E, Choi B, Boss O, Aschkenasi C, Zhang CY, 
Mountjoy K, Kishi T, Elmquist JK, Lowell BB. Divergence of melanocortin pathways in the control 
of food intake and energy expenditure. Cell. 2005 Nov 4;123(3):493-505. 
Berglund ED, Liu T, Kong X, Sohn JW, Vong L, Deng Z, Lee CE, Lee S, Williams KW, Olson DP, 
Scherer PE, Lowell BB, Elmquist JK. Melanocortin 4 receptors in autonomic neurons regulate 
thermogenesis and glycemia. Nat Neurosci. 2014 Jul;17(7):911-3. doi: 10.1038/nn.3737. Epub 2014 
Jun 8. 
Chen W, Kelly MA, Opitz-Araya X, Thomas RE, Low MJ, Cone RD. Exocrine gland dysfunction in 
MC5-R-deficient mice: evidence for coordinated regulation of exocrine gland function by 
melanocortin peptides. Cell. 1997 Dec 12;91(6):789-98. 
Cone RD. Anatomy and regulation of the central melanocortin system. Nat Neurosci. 
2005;8(5):571-578. 
Dodd GT, Decherf S, Loh K, Simonds SE, Wiede F, Balland E, Merry TL, Münzberg H, Zhang ZY, 
Kahn BB, Neel BG, Bence KK, Andrews ZB, Cowley MA, Tiganis T. Leptin and insulin act on 
POMC neurons to promote the browning of white fat. Cell. 2015 Jan 15;160(1-2):88-104. doi: 
10.1016/j.cell.2014.12.022. 
Fitzpatrick TB: Soleil et peau. J Med Esthet. 1975;2:33034. 
Foster AC, Joppa M, Markison S, et al. Body weight regulation by selective MC4 receptor agonists 
and antagonists. Ann N Y Acad Sci. 2003;994:103-110. 
Garfield AS, Li C, Madara JC, Shah BP, Webber E, Steger JS, Campbell JN, Gavrilova O, Lee CE, 
Olson DP, Elmquist JK, Tannous BA, Krashes MJ, Lowell BB. A neural basis for melanocortin-4 
receptor-regulated appetite. Nat Neurosci. 2015 Jun;18(6):863-71. doi: 10.1038/nn.4011. Epub 2015 
Apr 27. 
Gautron L, Elmquist JK, Williams KW. Neural control of energy balance: translating circuits to 
therapies. Cell 2015;161(1):133-145. 
Girardet C, Butler AA. Neural melanocortin receptors in obesity and related metabolic disorders. 
Biochim Biophys Acta. 2014; 1842:482–494. 
Greenfield JR, Miller JW, Keogh JM, Henning E, Satterwhite JH, Cameron GS, Astruc B, Mayer 
JP, Brage S, See TC, Lomas DJ, O'Rahilly S, Farooqi IS. Modulation of blood pressure by central 
melanocortinergic pathway. N Engl J Med. 2009;360:44-52. 

Protocol Amendment 10 
 
RM-493-014 
Rhythm Pharmaceuticals, Inc. 
65 of 87 
Confidential 
 
  
 
Jackson RS, Creemers JW, Farooqi IS, et al. Small-intestinal dysfunction accompanies the complex 
endocrinopathy of human proprotein convertase 1 deficiency. J Clin Invest. 2003;112(10):1550-
1560. 
Jackson RS, Creemers JW, Ohagi S, et al. Obesity and impaired prohormone processing associated 
with mutations in the human prohormone convertase 1 gene. Nat Genet. 1997;16(3):303-306. 
Kievet P, Halem H, Marks DL, et al. Chronic treatment with a melanocortin-4 receptor agonist 
causes weight loss, reduces insulin resistance, and improves cardiovascular function in diet-induced 
obese rhesus macaques. Diabetes. 2013;62:490-497. 
Krashes MJ, Koda S, Ye C, Rogan SC, Adams AC, Cusher DS, Maratos-Flier E, Roth BL, Lowell 
BB. Rapid, reversible activation of AgRP neurons drives feeding behavior in mice. J Clin Invest. 
2011 Apr;121(4):1424-8. doi: 10.1172/JCI46229. 
Krashes MJ, Lowell BB, Garfield AS. Melanocortin-4 receptor-regulated energy homeostasis. Nat 
Neurosci. 2016 Feb;19(2):206-19. doi: 10.1038/nn.4202. 
Liu T, Kong D, Shah BP, Ye C, Koda S, Saunders A, Ding JB, Yang Z, Sabatini BL, Lowell BB. 
Fasting activation of AgRP neurons requires NMDA receptors and involves spinogenesis and 
increased excitatory tone. Neuron. 2012 Feb 9;73(3):511-22. doi: 10.1016/j.neuron.2011.11.027. 
Marks DL, Cone RD. Central melanocortins and the regulation of weight during acute and chronic 
disease. Recent Prog Horm Res. 2001;56:359-375. 
Martos-Moreno GÁ, Barrios V, Muñoz-Calvo MT, Pozo J, Chowen JA, Argente J. Principles and 
pitfalls in the differential diagnosis and management of childhood obesities. Adv Nutr. 2014 May 
14;5(3):299S-305S. doi: 10.3945/an.113.004853. Print 2014 May. 
Millington GW, Tung YC, Hewson AK, O'Rahilly S, Dickson SL. Differential effects of alpha-, 
beta- and gamma(2)-melanocyte-stimulating hormones on hypothalamic neuronal activation and 
feeding in the fasted rat. Neuroscience. 2001;108(3):437-45. 
NHLBI. The Practical Guide Identification, Evaluation, and Treatment of Overweight and Obese in 
Adults. NIH Publication No. 00-4084, October 2000. 
O'Rahilly S, Gray H, Humphreys PJ, Krook A, Polonsky KS, White A, Gibson S, Taylor K, Carr C. 
Brief report: impaired processing of prohormones associated with abnormalities of glucose 
homeostasis and adrenal function. N Engl J Med. 1995 Nov 23;333(21):1386-90. 
Ramachandrappa S, Farooqi IS. Genetic approaches to understanding human obesity. J Clin Invest. 
2011;121(6):2080-2086. 
Semjonous NM, Smith KL, Parkinson JR, Gunner DJ, Liu YL, Murphy KG, Ghatei MA, Bloom SR, 
Small CJ. Coordinated changes in energy intake and expenditure following hypothalamic 
administration of neuropeptides involved in energy balance. Int J Obes (Lond). 2009 Jul;33(7):775-
85. doi: 10.1038/ijo.2009.96. Epub 2009 Jun 2. 
Shah M, Vella A. Effects of GLP-1 on appetite and weight. Rev Endocr Metab Disord. 2014 
Sep;15(3):181-7. doi: 10.1007/s11154-014-9289-5. 

Protocol Amendment 10 
 
RM-493-014 
Rhythm Pharmaceuticals, Inc. 
66 of 87 
Confidential 
 
  
 
Singal R, Ginder GD. DNA methylation. Blood. 1999;93(12): p. 4059-70. 
Stunkard AJ, Foch TT, Hrubec Z. A twin study of human obesity. JAMA. 1986 Jul 4;256(1):51-4. 
Tao YX. The melanocortin-4 receptor: physiology, pharmacology, and pathophysiology. Endocr 
Rev. 2010 Aug;31(4):506-43. doi: 10.1210/er.2009-0037. Epub 2010 Feb 26. 
Thiele TE, van Dijk G, Yagaloff KA, Fisher SL, Schwartz M, Burn P, Seeley RJ. Central infusion of 
melanocortin agonist MTII in rats: assessment of c-Fos expression and taste aversion. Am J Physiol. 
1998 Jan;274(1):R248-54. doi: 10.1152/ajpregu.1998.274.1.R248. 
Vaisse C, Clement K, Guy-Grand B, Froguel P. A frameshift mutation in human MC4R is 
associated with a dominant form of obesity. Nat Genet. 1998 Oct;20(2):113-4. 
van der Klaauw AA, Farooqi IS. The hunger genes: pathways to obesity. Cell. 2015;161(1):119-132. 
Wardle J, Carnell S, Haworth CM, Farooqi IS, O'Rahilly S, Plomin R. Obesity associated genetic 
variation in FTO is associated with diminished satiety. J Clin Endocrinol Metab. 2008 
Sep;93(9):3640-3. doi: 10.1210/jc.2008-0472. Epub 2008 Jun 26. 
Weinhold, B. Epigenetics: the science of change. Environ Health Perspect. 2006;114(3):A160-7. 
Wikberg JE, Mutulis F. Targeting melanocortin receptors: an approach to treat weight disorders and 
sexual dysfunction. Nat Rev Drug Discov. 2008;7(4):307-323. 
Yang Y. Structure, function and regulation of the melanocortin receptors. Eur J Pharmacol. 2011 Jun 
11;660(1):125-30. doi: 10.1016/j.ejphar.2010.12.020. Epub 2011 Jan 3. 
Yeo GS, Farooqi IS, Aminian S, Halsall DJ, Stanhope RG, O'Rahilly S. A frameshift mutation in 
MC4R associated with dominantly inherited human obesity. Nat Genet. 1998 Oct;20(2):111-2. 
Zhan C, Zhou J, Feng Q, Zhang JE, Lin S, Bao J, Wu P, Luo M. Acute and long-term suppression of 
feeding behavior by POMC neurons in the brainstem and hypothalamus, respectively. J Neurosci. 
2013 Feb 20;33(8):3624-32. doi: 10.1523/JNEUROSCI.2742-12.2013. 

Protocol Amendment 10 
 
RM-493-014 
Rhythm Pharmaceuticals, Inc. 
67 of 87 
Confidential 
 
  
 
16. 
APPENDICES 

Protocol Amendment 10 
 
RM-493-014 
Rhythm Pharmaceuticals, Inc. 
68 of 87 
Confidential 
 
  
 
APPENDIX A. INJECTION SITE EVALUATIONS 
Injection sites will be assessed using a form similar to that presented below at the time points 
outlined in the SOA (Table 3), and in the setting of any injection site reaction adverse experience. 
Local Skin Tolerability Assessment 
Reaction 
NONE 
Mild 
Moderate 
Severe 
Measurement 
(if applicable) 
Erythemaa 
 
 
 
 
 
Edemaa 
 
 
 
 
 
Indurationa 
 
 
 
 
 
Itching 
 
 
 
 
 
Pain or Tendernessa 
 
 
 
 
 
Other: 
 
 
 
 
 
a If present, region will be measured, length and width as appropriate. 
Initials: _________________ 

Protocol Amendment 10 
 
RM-493-014 
Rhythm Pharmaceuticals, Inc. 
69 of 87 
Confidential 
 
  
 
APPENDIX B. FITZPATRICK CLASSIFICATION SCALE 
Fitzpatrick Classification Scale 
Skin Type 
Skin Color 
Characteristics 
I 
White; very fair; red or blond hair; blue eyes; 
freckles 
Always burns, never tans 
II 
White; fair; red or blond hair; blue, hazel, or 
green eyes 
Usually burns, tans with difficulty 
III 
Cream white; fair with any eye or hair color; 
very common 
Sometimes mild burn, gradually tans 
IV 
Brown; typical Mediterranean Caucasian skin 
Rarely burns, tans with ease 
V 
Dark Brown; mid-eastern skin types 
Very rarely burns, tans very easily 
VI 
Black 
Never burns, tans very easily 
(Fitzpatrick, 1975) 

Protocol Amendment 10 
 
RM-493-014 
Rhythm Pharmaceuticals, Inc. 
74 of 87 
Confidential 
 
  
 
APPENDIX F. STANDARDIZATION OF BLOOD PRESSURE 
MEASUREMENT 
For BP measurements, the patient will remain in the sitting position for at least 5 minutes before 
any BP readings are recorded. Systolic and diastolic blood pressures will be determined by 
averaging three (3) consecutive measurements obtained 2 minutes apart. None of the 3 consecutive 
readings can be >5 mm Hg from the calculated average of the 3 readings. If this occurs, obtain 
additional readings, 2 minutes apart, until 3 consecutive stable measurements are obtained. Record 
only the 3 stable readings, in addition to the mean, the initial time of the measurement and the arm 
used for the measurement in the case report forms (as outlined below). 
The following instructions will be followed for both manual and automatic blood pressure 
measurements (with steps specific to manual identified by “[MANUAL]”). 
Please pay special attention to selecting the appropriate cuff size for this patient population, as noted 
below. 
The accuracy and reliability of blood pressure readings will increase by following these standardized 
steps: 
1. Situate the individual in a quiet environment with the arm resting at heart level. 
2. [MANUAL] For manual measurements, place the manometer at eye level, sufficiently close 
to read the calibration markings on the gauge or column. 
3. Select the appropriately sized cuff. The proper cuff size should be used on the non-
dominant arm throughout the study. Bladder width should be at least 40% of arm 
circumference; bladder should be at least 80% of arm circumference. 
4. [MANUAL] Locate the brachial artery along the inner upper arm by palpation. 
5. Wrap the cuff smoothly and snugly around the arm, centering the bladder over the brachial 
artery. The lower margin should be 2.5 cm above the antecubital space. (Do not rely on cuff 
marking; find the center by folding the bladder in half.) 
6. For manual measurements:  
a. Determine the level for maximal inflation by observing the pressure at which the radial 
pulse is no longer palpable as the cuff is rapidly inflated (palpated systolic) and by 
adding 30 mm Hg. 
b. Rapidly and steadily deflate the cuff. Then wait 15 to 30 seconds before re-inflating. 
c. For manual measurements, position the stethoscope over the palpated brachial artery 
below the cuff at the antecubital fossa. Earpieces should point forward. The bell head of 
the stethoscope should be applied with light pressure, ensuring skin contact at all points. 
Heavy pressure may distort sounds. 
d. Rapidly and steadily inflate the cuff to the maximal inflation level as determined in Step 
f. 
e. Release the air in the cuff so that the pressure falls at a rate of 2 to 3 mm per second. 

Protocol Amendment 10 
 
RM-493-014 
Rhythm Pharmaceuticals, Inc. 
75 of 87 
Confidential 
 
  
 
f. Note the systolic pressure at the onset of at least two consecutive beats (Phase 1 
Korotkoff sounds). Blood pressure levels should always be recorded in even numbers 
and read to the nearest 2 mm Hg mark on the manometer. 
g. Record the diastolic pressure at the cessation of the Korotkoff sounds (Phase V). Listen 
for 10 to 20 mm Hg below the last sound heard to confirm disappearance, and then 
deflate the cuff rapidly and completely. 
7. For automatic measurement: 
a. Take automatic measurements and record. 
8. Record the patient’s position and the arm used for the measurement. 
9. Wait 2 minutes before repeating the pressure measurement in the same arm to permit the 
release of blood trapped in the arm veins. 
10. Note that all three readings at each timepoint should be captured on the case report form, as 
well as the average.  
11. For each patient, the method used for BP determinations (manual or automatic) should be 
used throughout the study. In addition, the same size cuff should be used throughout. Care 
should be taken to make all measurements in the same position (sitting) for all 
measurements.  
Rounding Rules for Blood Pressure Measurements 
Blood pressure readings will be recorded to the nearest even mm Hg. Do not round off to the nearest 
5 or 10 mm Hg BP reading. Therefore, a 142/94 reading should not be reported as 140/95, but 
should be reported as 142/94. 
When calculating the means (average) of the readings, the following rules should be used: 
If the value is XX.1 to XX.4, it should be rounded down (example: A diastolic mean of 97.2 would 
be recorded as 97, as would a mean of 97.4). 
If the value is XX.5 or greater it should be rounded up (example: A diastolic mean of 97.5 would be 
recorded as 98, as would a mean of 97.9). 
The mean of the readings may be an odd number. 
Special Pitfalls and Problems 
The Auscultatory Gap 
[MANUAL] In some subjects, particularly in patients with hypertension, the sounds heard over the 
brachial artery when the cuff pressure is high disappear as the pressure is reduced and then reappear 
at some lower level. This early, temporary disappearance of sound is called the auscultatory gap and 
occurs during the latter part of Phase I and Phase II. Because this gap may extend over a range as 
great as 40 mm Hg, one may seriously underestimate the systolic pressure or overestimate the 
diastolic pressure, unless its presence is excluded by first palpating for disappearance of the radial 
pulse as the cuff pressure is raised. 

Protocol Amendment 10 
 
RM-493-014 
Rhythm Pharmaceuticals, Inc. 
76 of 87 
Confidential 
 
  
 
Effect of Arm Position 
The pressure in the arm increases as the arm is lowered from the level of the (phlebostatic axis); 
conversely, raising the arm above this position lowers the pressure measurement. The effect is 
largely explained by hydrostatic pressure or by the effect of gravity on the column of blood. 
Therefore, when measuring indirect blood pressure, the patient’s arm should be positioned so that 
the location of the stethoscope head (preferably the bell or its equivalent) is at the level of the heart. 
This location of the heart is arbitrarily taken to be at the junction of the fourth intercostal space and 
the lower left sternal border. When the patient is seated, placing the arm on a nearby tabletop a 
little above waist level will result in a satisfactory position.  
Large Arm Size  
Falsely elevated indirect pressure measurements may be obtained in patients with increased arm 
girth if the standard-sized bladder and technique are used. This is caused by the use of bladders that 
are too small, with subsequent excessive loss of cuff pressure through the thick, compressible soft 
tissues of the large arms. This problem may be minimized by using a bladder width that is 40 to 
50% of measured arm circumference. In individuals with moderately large arm size, a large adult 
cuff (32 to 42 cm wide) will usually be adequate, but a larger cuff (38-50 cm) should be available, if 
necessary. 

Protocol Amendment 10 
 
RM-493-014 
Rhythm Pharmaceuticals, Inc. 
78 of 87 
Confidential 
 
  
 

Protocol Amendment 10 
 
RM-493-014 
Rhythm Pharmaceuticals, Inc. 
79 of 87 
Confidential 
 
  
 

Protocol Amendment 10 
 
RM-493-014 
Rhythm Pharmaceuticals, Inc. 
80 of 87 
Confidential 
 
  
 

Protocol Amendment 10 
 
RM-493-014 
Rhythm Pharmaceuticals, Inc. 
81 of 87 
Confidential 
 
  
 

Protocol Amendment 10 
 
RM-493-014 
Rhythm Pharmaceuticals, Inc. 
82 of 87 
Confidential 
 
  
 

Protocol Amendment 10 
 
RM-493-014 
Rhythm Pharmaceuticals, Inc. 
83 of 87 
Confidential 
 
  
 

Protocol Amendment 10 
 
RM-493-014 
Rhythm Pharmaceuticals, Inc. 
84 of 87 
Confidential 
 
  
 
APPENDIX H. CREATININE CLEARANCE ESTIMATE 
In patients ≥18 years of age, the Modification of Diet in Renal Disease Equation should be used as 
follows:  
GFR = 175 x (creatinine in mg/dL)-1.154 x (age in years)-0.203 x (0.742 if female) x (1.210 if African 
American) 
 

Protocol Amendment 10 
 
RM-493-014 
Rhythm Pharmaceuticals, Inc. 
85 of 87 
Confidential 
 
  
 
APPENDIX I. BEDSIDE SCHWARTZ EQUATION 
In patients <18 years of age, the Bedside Schwartz Equation should be used as follows: 
GFR (mL/min/1.73 m²) = (0.41 × height in centimetres) / creatinine in mg/dL 

Protocol Amendment 10 
 
RM-493-014 
Rhythm Pharmaceuticals, Inc. 
86 of 87 
Confidential 
 
  
 

Protocol Amendment 10 
 
RM-493-014 
Rhythm Pharmaceuticals, Inc. 
87 of 87 
Confidential