Clinical trial NCT03651765
Conditions: Obesity Associated With Defects in Leptin-melanocortin Pathway
Keywords: setmelanotide RM-493 obesity leptin-melanocortin melanocortin 4 receptor
Sponsor: Rhythm Pharmaceuticals, Inc.
Start date: 2018-07-15; Completion date: 2025-01-09
Enrollment: 205 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
This was a long-term extension trial to study the safety and tolerability of continued setmelanotide treatment in participants who had completed a previous clinical trial on treatment with setmelanotide for obesity associated with genetic defects upstream of the Melanocortin-4 (MC4) receptor in the leptin-melanocortin pathway.

Detailed description:
The primary objectives of this extension trial were to explore the long-term safety and tolerability of setmelanotide for up to 7 years or until drug was otherwise available through authorized use. Participants entered this protocol immediately upon completion of their index protocol such that dosing of setmelanotide continued without gaps in therapy.

Arms: arm 1: Participants received setmelanotide at the same starting dose as received in the index trials as a Subcutaneous (SC) injection once daily for up to 5.6 years in this extension trial.
Interventions: intervention 1: Setmelanotide
Intervention descriptions: intervention 1: Once daily subcutaneous injection

Protocol documents:
Prot_000.pdf: 
 
 
 
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CLINICAL TRIAL PROTOCOL 
 
Protocol RM-493-022 
Long-Term Extension Trial of Setmelanotide (RM-493) for Patients Who 
Have Completed a Trial of Setmelanotide for the Treatment of Obesity 
Associated with Genetic Defects Upstream of the MC4 Receptor in the Leptin-
Melanocortin Pathway 
This extension trial applies to patients with rare genetic, syndromic, or acquired diseases of 
obesity and obesity potentially related to other abnormalities in the MC4 receptor pathway. 
This trial will be conducted according to the protocol and in compliance with Good Clinical 
Practice, the ethical principles stated in the Declaration of Helsinki, 
and other applicable regulatory requirements. 
IND No.: 
 
EudraCT No.: 2017-005006-35 
 
Trial Sponsor:  
Rhythm Pharmaceuticals, Inc. 
 
 
 
 
Document Date (Version):  
19 June 2023 (8.1) 
 


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SUMMARY OF CHANGES TO THE PROTOCOL 
 
Key changes to the current version 8.1 (19 June 2023) of the protocol from version 8.0 (12 May 
2023) are summarized below. 
 
Key changes to version 8.0 of the protocol apply to changes from both version 
 
 except where noted and are summarized 
below. 


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Typographical and administrative changes were also made to improve the clarity of the 
document. 


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APPROVAL SIGNATURE PAGE 
 
Protocol Title: 
Long-Term Extension Trial of Setmelanotide (RM-493) for 
Patients Who Have Completed a Trial of Setmelanotide for the 
Treatment of Obesity Associated with Genetic Defects Upstream of 
the MC4 Receptor in the Leptin-Melanocortin Pathway 
This extension trial applies to patients with rare genetic, syndromic, or 
acquired diseases of obesity and obesity potentially related to other 
abnormalities in the MC4 receptor pathway. 
Protocol Number: 
RM-493-022 
Document Version: 
Version 8.1  
Document Date: 
19 June 2023  
 
REVIEWED/APPROVED BY:  
 
 
 
Rhythm Pharmaceuticals, Inc. 
 
Signature  
 
Date 
 
 
 
 
 
 
 
 
 


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INVESTIGATOR STATEMENT 
 
Protocol Title: 
Long-Term Extension Trial of Setmelanotide (RM-493) for 
Patients Who Have Completed a Trial of Setmelanotide for the 
Treatment of Obesity Associated with Genetic Defects Upstream of 
the MC4 Receptor in the Leptin-Melanocortin Pathway 
This extension trial applies to patients with rare genetic, syndromic, or 
acquired diseases of obesity and obesity potentially related to other 
abnormalities in the MC4 receptor pathway. 
Protocol Number: 
RM-493-022 
Document Version: 
Version 8.1  
Document Date: 
19 June 2023  
 
I understand that all documentation provided to me by Rhythm Pharmaceuticals, Inc. (Rhythm; 
the sponsor) or its designated representative(s) concerning this trial that has not been published 
previously will be kept in the strictest confidence. This documentation includes the trial protocol, 
Investigator Brochure (IB), case report forms, and other scientific data. 
This trial will not commence without the prior written approval of a properly constituted 
Institutional Review Board/Independent Ethics Committee. No changes will be made to the trial 
protocol without the prior written approval of the sponsor and the Institutional Review 
Board/Independent 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) 


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CLINICAL TRIAL SYNOPSIS 
Sponsor 
Rhythm Pharmaceuticals, Inc. 
Investigational Drug 
Product 
Setmelanotide (RM-493) 
Protocol Number 
RM-493-022 
Protocol Title 
Long-Term Extension Trial of Setmelanotide (RM-493) for Patients 
Who Have Completed a Trial of Setmelanotide for the Treatment of 
Obesity Associated with Genetic Defects Upstream of the MC4 
Receptor in the Leptin-Melanocortin Pathway 
This extension trial applies to patients with rare genetic, syndromic, or 
acquired diseases of obesity and obesity potentially related to other 
abnormalities in the MC4 receptor pathway. 
Clinical Phase/Trial 
Type  
Open-label active treatment extension trial (Phase 2/3) 
Treatment Indication 
Treatment of obesity associated with genetic defects upstream of 
the MC4 receptor (MC4R) in the leptin-melanocortin pathway and 
with obesity related to other abnormalities in the MC4R pathway. 
Objective(s) 
Primary 
• To characterize safety and tolerability of setmelanotide in 
patients who have completed a previous trial on treatment 
with setmelanotide for obesity associated with genetic 
defects upstream of the MC4R in the leptin-melanocortin 
pathway and with obesity related to other abnormalities in 
the MC4R pathway. 
Trial Design 
This is a long-term (treatment for up to 7 years) extension trial 
designed to evaluate the safety and tolerability of continued 


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setmelanotide treatment in patients who have completed a previous 
clinical trial on treatment with setmelanotide for rare genetic, 
syndromic, or acquired diseases of obesity upstream of the MC4R 
in the melanocortin-leptin pathway and other abnormalities of the 
MC4R pathway. 
Patients who complete treatment in a previous trial (index trial) of 
setmelanotide and wish to continue with setmelanotide treatment 
will be considered for eligibility to enter this extension trial. 
Patients (or their legal guardians) will provide informed 
consent/assent to participate in this extension trial, and eligibility 
will be confirmed prior to completion of their index trial.  
Visit 1 of this trial will coincide with the final visit of the index 
trial; see Table 1 for details. Generally, there should be no gaps in 
treatment during the transition from the index trial to this extension 
trial. A gap in treatment between the index trial and extension trial 
may be allowed for individual patients, with approval by the 
sponsor. Patients will begin this extension trial on the same dose of 
setmelanotide that they were taking when they completed their 
index trial. Patients who received double-blind study drug in a 
placebo-controlled index trial will start open-label setmelanotide in 
this trial, with the starting dose from the index trial. The dose 
titration should follow the scheme in the index trial and in 
consultation with the sponsor. 
Patients will be evaluated approximately every 3 months at the trial 
site for adverse events (AEs), concomitant medications, 
 
height (in children), 
 
Additional tests will be completed at longer trial visit intervals.  
Trial Population 
Male and female patients who have completed all critical trial 
evaluations in a previous setmelanotide trial and would benefit from 
continued setmelanotide treatment.  
Number of Patients & 
Trial Centers 
It is anticipated that any patient receiving active therapy from a 
setmelanotide clinical trial and experiencing improvements in 
weight-related parameters could be a candidate for enrollment in 
this extension trial. Based on the number of patients currently 
enrolled or planned for enrolment in current or future setmelanotide 
clinical trials, it is anticipated that up to 500 patients may be 
enrolled in this trial; however, expansion in enrollment may occur if 
additional patients with obesity due to monogenic, syndromic or 
acquired disorders affecting the MC4R pathway are enrolled in 
Phase 2 or Phase 3 clinical trials evaluating setmelanotide. It is 
anticipated that up to 100 centers located worldwide will participate 
in this trial. In the event additional patients are to be enrolled, 
additional sites may be added, as necessary.  


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Inclusion Criteria 
1. Patients aged 2 or older (or aged >2 years as per local 
regulations; only patients aged 12 years or older may be 
enrolled in the trial in Greece; only patients 6 years or older 
may be enrolled in the trial in Germany) who have 
completed participation in a previous setmelanotide clinical 
trial.  
2. If patient received setmelanotide on an open-label basis in a 
previous setmelanotide clinical trial, patient demonstrated 
adequate safety and meaningful clinical benefit (efficacy) in 
the previous setmelanotide trial. Meaningful clinical benefit 
is defined as follows: 
• Patients 18 years of age or younger that have completed 
participation on active drug and demonstrated adequate 
safety and at least 3% BMI reduction or reduction in 
BMI Z-score of 0.2 compared to baseline. 
• Patients over 18 years of age should show reduction of 
3% BMI compared to baseline. 
If the patient participated on a double-blind basis in the 
previous placebo-controlled clinical trial, patient tolerated 
blinded study drug. 
3. Patient and/or parent or guardian is able to communicate 
well with the investigator, to understand and comply with 
the requirements of the trial, and to understand and sign the 
written informed consent/assent. The patient must 
consent/assent to participate in the trial. 
4. Patient must meet one of the following requirements 
regarding contraception: 
• If a female of childbearing potential, defined as fertile, 
following menarche and until becoming post-
menopausal unless permanently sterile (hysterectomy, 
bilateral salpingectomy, or bilateral oophorectomy), 
must use a highly effective form of contraception as 
outlined in Section 6.2.1. 
• If a female of non-childbearing potential, defined as 
permanently sterile (status post hysterectomy, bilateral 
oophorectomy, or bilateral salpingectomy) or post-
menopausal for at least 12 months (and confirmed with a 
screening follicle-stimulating hormone (FSH) level in 


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the post-menopausal laboratory range), contraception is 
not required during the trial.  
− Younger female patients who have not reached 
menarche upon trial entry will be assessed for 
Tanner staging and at first menarche will be required 
to comply with contraception requirements and 
pregnancy testing as outlined in the protocol. 
• If a male with female partner(s) of childbearing potential, 
must agree to a double barrier method if they become 
sexually active during the trial. Furthermore, male patients 
must not donate sperm during and for 90 days following 
their participation in the trial.  
Exclusion Criteria 
1. Pregnant and/or breastfeeding women. 
2. Significant dermatologic findings relating to melanoma or pre-
melanoma skin lesions (excluding non-invasive basal or 
squamous cell lesion), determined as part of a screening 
comprehensive skin evaluation performed by a qualified 
dermatologist. 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 
trial.  
3. Patient is, in the opinion of the investigator, not suitable to 
participate in the trial.  
4. Current, clinically significant disease, if severe enough to 
interfere with the trial and/or would confound the results. Any 
such patients should be discussed with the sponsor prior to 
enrollment in the trial. 
5. Diagnosis of schizophrenia, bipolar disorder or other psychiatric 
disorder that the investigator believes will interfere significantly 
with trial compliance. 
6. A Patient Health Questionnaire-9 (PHQ-9) score of ≥15. 
7. Any suicidal ideation of type 4 or 5 on the Columbia Suicide 
Severity Rating Scale (C-SSRS). Any lifetime history of a 
suicide attempt, or any suicidal behavior since the last visit in 
the index trial. 
Note: Patients who are unable to complete the C-SSRS due to 
significant neurocognitive defects may be enrolled in the trial, 
as long as in the opinion of the investigator there are no clinical 
signs or symptoms of suicidal behavior. 
8. History of significant liver disease or liver injury, or a current 
liver assessment due to abnormal liver tests (as indicated by 
abnormal liver function tests, alanine transaminase [ALT], 


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aspartate transaminase [AST], alkaline phosphatase, or serum 
bilirubin >1.5× the upper limit of normal [ULN] for any of 
these tests) for an etiology other than non-alcoholic fatty liver 
disease (NAFLD). Thus, any underlying etiology besides 
NAFLD, including diagnosed non-alcoholic steatohepatitis 
(NASH), other causes of hepatitis, or history of hepatic cirrhosis 
is exclusionary, but the presence of NAFLD is not exclusionary. 
9. Severe renal dysfunction defined by a glomerular filtration rate 
(GFR) <30 mL/min/1.73 m2 in patients <12 years of age or end 
stage renal disease (GFR <15 mL min/1.73 m2 (see 
Appendix 11.4 for GFR calculation). 
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. 
Trial Procedures 
The safety and tolerability of setmelanotide will be assessed by the 
frequency and severity of AEs as well as changes in physical 
examinations, electrocardiograms (ECGs), vital signs, laboratory 
evaluations, and injection site reactions. 
 
 
 
 
 
 
 
Study Drug and 
Administration 
All study drugs are for investigational use only and are to be used 
only within the context of this protocol. Setmelanotide will be 
supplied by the sponsor. 
 
 
  
Setmelanotide will be administered as a subcutaneous (SC) 
injection once daily. 
Setmelanotide doses and titration steps will follow the index trial 
scheme (Section 5.2). 
Statistical 
Considerations  
A detailed Statistical Analysis Plan will describe all analyses for 
this extension trial.  
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.  




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TABLE OF CONTENTS 
APPROVAL SIGNATURE PAGE .................................................................................................4 
INVESTIGATOR STATEMENT ...................................................................................................5 
CLINICAL TRIAL SYNOPSIS ......................................................................................................6 
LIST OF ABBREVIATIONS ........................................................................................................17 
1. 
INTRODUCTION ......................................................................................................21 
1.1. 
Setmelanotide Background and Clinical Experience .................................................22 
1.1.1. 
Clinical Background and Benefit–Risk Assessment ..................................................23 
2. 
TRIAL OBJECTIVES AND ENDPOINTS ...............................................................23 
2.1. 
Trial Objectives ..........................................................................................................23 
2.1.1. 
Primary Objective .......................................................................................................23 
2.1.2. 
Exploratory Objectives ...............................................................................................24 
2.2. 
Trial Endpoints ...........................................................................................................24 
2.2.1. 
Primary Endpoint ........................................................................................................24 
2.2.2. 
 ................................................................................................24 
3. 
INVESTIGATIONAL PLAN .....................................................................................25 
3.1. 
Overall Design and Plan of the Trial ..........................................................................25 
3.2. 
Justification of the Trial Design .................................................................................26 
3.2.1. 
Rationale for Setmelanotide Administration at Doses Up to 5 mg ............................26 
3.3. 
Patient, Cohort or Trial Termination ..........................................................................27 
3.4. 
Transition into Another Rhythm Trial ........................................................................27 
4. 
TRIAL POPULATION ..............................................................................................28 
4.1. 
Number of Patients .....................................................................................................28 
4.2. 
Patient Selection Criteria ............................................................................................28 
4.2.1. 
Inclusion Criteria ........................................................................................................29 
4.2.2. 
Exclusion Criteria .......................................................................................................30 
4.3. 
Patient Identification and Registration .......................................................................30 
4.4. 
Withdrawal of Patients ...............................................................................................31 
4.5. 
Patients’ Re-entry from Other Trials ..........................................................................33 
5. 
TRIAL TREATMENTS .............................................................................................33 
5.1. 
Study Drugs ................................................................................................................33 
5.2. 
Study Drug Dose and Administration and Dose Adjustments ...................................33 


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5.2.1. 
Dose Adjustments .......................................................................................................34 
5.3. 
Blinding, Packaging, and Labeling .............................................................................35 
5.3.1. 
Blinding ......................................................................................................................35 
5.3.2. 
Packaging and Labeling ..............................................................................................35 
5.4. 
Duration of Patient Participation ................................................................................35 
5.4.1. 
Commercial Availability of Setmelanotide ................................................................35 
5.5. 
Assessment of Treatment Compliance .......................................................................35 
5.6. 
Study Drug Accountability .........................................................................................36 
5.7. 
Prior and Concomitant Treatment ..............................................................................36 
5.7.1. 
Prohibited Medication and Substances .......................................................................36 
5.7.2. 
Concomitant Procedures .............................................................................................36 
6. 
TRIAL ASSESSMENTS ............................................................................................37 
6.1. 
Overview of Schedule of Assessments .......................................................................37 
6.2. 
Patient Requirements ..................................................................................................43 
6.2.1. 
Contraception and Pregnancy Testing ........................................................................43 
6.2.2. 
Protection from Sun ....................................................................................................44 
6.3. 
Efficacy Measurements ..............................................................................................44 
6.3.1. 
 .........................................................................................................................44 
6.3.2. 
 ..................................................................................................44 
6.3.3. 
 ......................................................................................................44 
6.4. 
Clinical Procedures and Safety Assessments .............................................................45 
6.4.1. 
Informed Consent/Assent ...........................................................................................45 
6.4.2. 
Demographics and Medical History ...........................................................................45 
6.4.3. 
 ..............................................................................................45 
6.4.4. 
 .............................................................................................45 
6.4.5. 
 ..........................................................................................46 
6.4.6. 
Physical Examination/Tanner Staging, Height, and Comprehensive Skin 
Examination ................................................................................................................46 
6.4.7. 
Bone Age Assessment ................................................................................................47 
6.4.8. 
Concomitant Medication Review ...............................................................................47 
6.4.9. 
Vital Signs ..................................................................................................................47 
6.4.10. 
12-Lead Electrocardiogram ........................................................................................47 
6.4.11. 
Clinical Laboratory Tests ...........................................................................................47 


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6.4.11.1. 
Hematology, Clinical Chemistry and Urinalysis ........................................................48 
6.4.12. 
 ................................................................................48 
6.4.13. 
Pediatric Nutritional Assay .........................................................................................49 
6.4.14. 
 ........................................................................................................49 
6.4.15. 
Injection Site Evaluation and Scoring ........................................................................49 
6.4.16. 
Anti-Setmelanotide Antibody (ADA) Measurements ................................................50 
6.4.17. 
 ................................................................................................50 
6.4.17.1. 
 ...................................................................................................50 
6.4.17.2. 
 .......................................................................................50 
6.4.17.3. 
 ........................................................................................51 
6.4.18. 
Diet and Nutritional Counseling .................................................................................53 
6.4.19. 
Adverse Events ...........................................................................................................53 
6.4.20. 
Order of Assessments .................................................................................................53 
7. 
ADVERSE EVENTS ..................................................................................................53 
7.1. 
Definitions, Documentation, and Reporting ...............................................................53 
7.2. 
Procedures for AE and SAE Reporting ......................................................................54 
7.2.1. 
Assessment of Severity, Relationship to Study Drug, and Expectedness ..................55 
7.2.1.1. 
Assessment of Severity ...............................................................................................55 
7.2.1.2. 
Assessment of Relationship ........................................................................................55 
7.2.1.3. 
Assessment of Expectedness ......................................................................................56 
7.3. 
Adverse Events and Risks ..........................................................................................56 
7.3.1. 
Medical Monitoring ....................................................................................................56 
7.4. 
Monitoring of Adverse Events and Period of Observation ........................................56 
7.5. 
Guidelines for Additional Monitoring and Suspension of Dosing for a 
Patient .........................................................................................................................57 
7.5.1. 
Depression or Suicidality ............................................................................................57 
8. 
STATISTICAL PROCEDURES ................................................................................57 
8.1. 
Sample Size Estimation ..............................................................................................57 
8.2. 
Hypotheses ..................................................................................................................58 
8.3. 
Definition of Population(s) for Analysis ....................................................................58 
8.4. 
Statistical Methods ......................................................................................................58 
8.5. 
Statistical Analysis Plan .............................................................................................59 
9. 
ADMINISTRATIVE REQUIREMENTS ..................................................................59 


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9.1. 
Good Clinical Practice ................................................................................................59 
9.2. 
Ethical Considerations ................................................................................................59 
9.3. 
Patient Information and Informed Consent/Assent ....................................................59 
9.4. 
Patient Confidentiality ................................................................................................60 
9.5. 
Protocol Compliance ..................................................................................................60 
9.6. 
Trial Conduct During the COVID-19 (Coronavirus) Pandemic .................................60 
9.7. 
Data Management .......................................................................................................61 
9.7.1. 
Data Handling .............................................................................................................61 
9.7.2. 
Computer Systems ......................................................................................................61 
9.7.3. 
Data Entry ...................................................................................................................61 
9.7.4. 
Medical Information Coding ......................................................................................61 
9.7.5. 
Data Validation ...........................................................................................................61 
9.8. 
Direct Access to Source Data .....................................................................................61 
9.9. 
Source Document/Case Report Form Completion .....................................................62 
9.10. 
Record Retention ........................................................................................................62 
9.11. 
Liability Insurance ......................................................................................................62 
9.12. 
Publication of Trial Findings and Use of Information ................................................62 
10. 
REFERENCES ...........................................................................................................64 
11. 
APPENDICES ............................................................................................................66 
11.1. 
Injection Site Evaluations ...........................................................................................66 
11.2. 
Guidance for Monitoring Potential Treatment-Related Dermatological 
Changes and Suggested Criteria for Discontinuation of Dosing ................................67 
11.3. 
Guidance for Monitoring Potential Treatment-Related Penile Erections and 
Suggested Criteria for Discontinuation of Dosing ......................................................69 
11.4. 
Assessment of Renal Function ....................................................................................69 
11.4.1. 
Modification of Diet in Renal Disease (MDRD) Equation ........................................69 
11.4.2. 
Bedside Schwartz Equation ........................................................................................69 
11.5. 
Considerations for Reducing Pain and Distress in the Pediatric Population ..............69 
11.6. 
Guidance on Study Conduct During the COVID-19 (Coronavirus) Pandemic ..........71 
 


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LIST OF TABLES 
Table 1: 
Schedule of Assessments ............................................................................................38 
 


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LIST OF ABBREVIATIONS 
Abbreviation 
Definition 
ADA 
Anti-drug (i.e., setmelanotide) antibody 
AE 
Adverse event 
ALT 
Alanine transaminase 
ARC 
Arcuate nucleus of the hypothalamus 
AS 
Alström syndrome 
AST 
Aspartate transaminase 
BBS 
Bardet-Biedl syndrome 
BBSx 
Bardet-Biedl syndrome-associated genes 
BMI 
Body mass index 
BP 
Blood pressure 
bpm 
Beats per minute 
BUN 
Blood urea nitrogen 
CFR 
Code of Federal Regulations  
CMHL 
Combined medial hypothalamic lesion 
CO2 
Carbon dioxide 
COVID-19 
Coronavirus disease 2019 
CPK 
Creatine phosphokinase 
CRA 
Clinical research associate 
CRF 
Case report form 
CRO 
Contract research organization 


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Abbreviation 
Definition 
C-SSRS 
Columbia Suicide Severity Rating Scale 
CTCAE 
Common Terminology Criteria for Adverse Events 
DSM-III 
Diagnostic and Statistical Manual of Mental Disorders Third Edition 
EC50 
Half maximal effective concentration 
ECG 
Electrocardiogram 
eCRF 
Electronic case report form 
ET 
Early termination 
FSH 
Follicle-stimulating hormone 
GCP 
Good clinical practice 
GFR 
Glomerular filtration rate 
GGT 
Gamma-glutamyl transpeptidase  
HbA1c 
Glycated hemoglobin 
HO 
Hypothalamic obesity 
HR 
Heart rate 
IB 
Investigator Brochure 
ICH 
International Council for Harmonisation 
IEC 
Independent Ethics Committee 
IRB 
Institutional Review Board 
IUD 
Intrauterine device 
 
 
Ki 
Inhibitory constant 
LDH 
Lactate dehydrogenase 
LEP 
Leptin hormone 
LEPR 
Leptin receptor  
MC4R 
Melanocortin-4 receptor 
MedDRA 
Medical Dictionary for Regulatory Activities 
MHP 
Mental health professional 


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Abbreviation 
Definition 
MSH 
Melanocyte stimulating hormone 
MTII 
Melanotan II 
NAFLD 
Non-alcoholic fatty liver disease 
NASH 
Non-alcoholic steatohepatitis 
NDA 
New Drug Application 
NHLBI 
National Heart, Lung, and Blood Institute 
PCSK1 
Proprotein Convertase Subtilisin/Kexin Type 1 
POMC 
Pro-opiomelanocortin 
PPL 
POMC/PCSK1/LEPR 
RSI 
Reference safety information 
SAE 
Serious adverse event 
SAP 
Statistical analysis plan 
SC 
Subcutaneous 
SF-10 
10-Item Short Form Health Survey for Children 
SH2B1 
SH2B Adaptor Protein 1 
SMS 
Smith-Magenis syndrome 
SOA 
Schedule of assessments 
SRC1 
Steroid receptor coactivator-1 
T4 
Thyroxine 
TSH 
Thyroid-stimulating hormone 
ULN 
Upper limit of normal 
US 
United States 
UV 
Ultraviolet 
VMN 
Ventromedial nucleus of the hypothalamus 


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Abbreviation 
Definition 
WOCBP 
Woman of childbearing potential 
 


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1. 
INTRODUCTION 
Rhythm (the sponsor) is focusing the development of setmelanotide as a treatment for patients 
with rare genetic, syndromic, or acquired diseases of obesity due to specific genetic defects that 
impact the functioning of the melanocortin-4 receptor (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 body weight and appetite. Genetic or acquired 
defects in the MC4R pathway and other abnormalities of the MC4R pathway cause hyperphagia, 
an insatiable hunger, leading to severe and early-onset obesity. 
The focus of setmelanotide development is on hyperphagia and obesity arising from lack of 
activation of MC4Rs and lack of “downstream signaling” due to genetic variants or other 
impairments “upstream” of the MC4R. By activating the MC4R with setmelanotide (a MC4R 
agonist), signaling occurs in the “downstream” portion of the pathway, and thereby 
setmelanotide is hypothesized to provide compelling and persistent efficacy on the regulation of 
appetite and body weight.  
Human genetics studies have identified several diseases that are the result of genetic defects 
affecting the MC4R pathway, for example, syndromes or variants of the following genes: 
• Pro-opiomelanocortin (POMC) 
• Proprotein Convertase Subtilisin/Kexin Type 1 (PCSK1) 
• Leptin receptor (LEPR)/leptin hormone (LEP) 
• Bardet-Biedl syndrome (BBS) 
• Alström syndrome (AS) 
• Smith-Magenis syndrome (SMS) 
• SH2B Adaptor Protein 1 (SH2B1), including 16p11.2 deletion 
• Nuclear receptor coactivator-1 (NCOA1), also referred to as steroid receptor 
coactivator 1 (SRC1) 
• MC4R 
Central melanocortin signaling is the central element of energy homeostasis (Holland 2019). 
Somewhat similar to patients with genetic variants in the MC4R pathway, in patients with 
hypothalamic lesions, leptin signaling is often disturbed and as a result melanocortin signaling is 
reduced (Enriori 2016; Roth 1998; Roth 2010; Patel 2002; Shaikh 2008). Imaging studies in 
humans and rodent models show that lesions of the ventromedial nucleus of the hypothalamus 
(VMN) and the region of the arcuate nucleus (ARC), are more often associated with hyperphagia 
and excessive weight gain (Ahmet 2006; DeVile 1996; Roth 2011; Daousi 2005; Holmer 2010; 
Elfers 2011). 
Hypothalamic obesity (HO) is a form of severe obesity that arises from mechanical hypothalamic 
lesions/insults (e.g., tumors, tumor resections, radiotherapy treatment). Lesions of the 
hypothalamus can derive from various types of tumors (craniopharyngiomas, gliomas, pituitary 
adenomas, hamartomas) as well as from the surgeries and radiotherapies for the treatment of the 
tumor itself. Patients with HO display a higher degree of hyperleptinemia and hyperinsulinemia 


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when compared to individuals with normal body mass indexes (BMIs). Alpha-melanocortin 
stimulating hormone (α-MSH) can be detectable in blood, and its levels can change depending 
on different energy states (Enriori 2016); however, in patients with craniopharyngioma or post-
surgical treatment for it, α-MSH levels are significantly reduced (Roth 2010; Roth 2011). 
Reduced serum α-MSH levels suggest melanocortin pathway deficiency, which might explain 
lower energy expenditure in peripheral tissues due to reduced fat and muscle fatty acid oxidation 
(Roth 2010; Roth 2011; An 2007).  
In a rat model of “combined medial hypothalamic lesion” (CMHL rat model) for HO 
(Roth 2011), Roth et al found that the characteristic metabolic changes of human HO were 
recapitulated when the lesion included the rat ARC. In this rat model, α-MSH levels are reduced 
(Roth 2011), similar to patients with craniopharyngioma (Roth 2010).  
Additionally, an MC3/4 receptor agonist, melanotan II (MTII) 1 mg/kg/day administered 
intraperitoneally over a period of 14 days, resulted in a robust reduction of weight gain in CMHL 
rats without rebound/tachyphylaxia (Roth 2012). Preclinical and clinical findings offer a 
rationale for a novel melanocortin treatment also in patients with HO to compensate for and 
potentiate defective leptin signaling.  
Overall, nonclinical and clinical data demonstrate that setmelanotide restores normal hunger, 
satiety, and energy expenditure regulation, leading to profound reduction of excess weight, in 
essence as a form of “replacement therapy”. Setmelanotide is authorized for marketing in the 
United States (US), Great Britain (GB), Israel, the European Union (EU),and Canada in adult 
and pediatric patients 6 years of age and older with obesity due to POMC, PCSK1, or LEPR 
(PPL) deficiency (USPI 2022; EU SmPC 2022; MHRA SmPC 2021; Israel PPI 2022; Product 
Monograph 2023). Additionally, setmelanotide is also approved in the US, EU, and Canada to 
treat chronic weight management in adult and pediatric patients 6 years of age or older with 
monogenic or syndromic obesity due to BBS (USPI 2022, SmPC 2022, Product Monograph 
2023). The clinical testing and regulatory approval of setmelanotide in certain countries have 
established its therapeutic value. This trial will continue to explore the long-term safety and 
tolerability of setmelanotide in patients who have successfully completed a prior index trial of 
setmelanotide. Trial participation may continue for up to 7 years or until setmelanotide is 
otherwise available through authorized use, or unless there is not a clinically meaningful 
treatment effect.  
Patients may enter this trial immediately upon completion of their index trial such that dosing of 
setmelanotide continues without gaps in therapy, if possible. Patients may also enter this trial 
from the extension phases of any prior index trial. Efforts should be made to have the last visit of 
a prior index trial or an index trial extension phase and the initial visit of this long-term extension 
trial occur on the same day, if possible. 
An index trial is defined as any setmelanotide trial in which a patient participated prior to 
enrollment in this extension trial.  
1.1. 
Setmelanotide Background and Clinical Experience 
Setmelanotide is an 8-amino acid, cyclic peptide that binds with high affinity (inhibitory constant 
[Ki] = 2.1 nM) to the human MC4R and is efficient in activating MC4R (50% effective 
concentration [EC50] = 0.27 nM). 


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1.1.1. 
Clinical Background and Benefit–Risk Assessment 
Nonclinical and clinical data generated to date with setmelanotide described in the Investigator 
Brochure (IB) provide meaningful information to support the benefit–risk assessment for the 
proposed use of setmelanotide in the current trial, a long-term extension trial for clinical 
evaluation of long-term treatment of obesity associated with genetic defects in the leptin-
melanocortin pathway upstream of the MC4R and other abnormalities of the MC4R pathway.  
The current clinical development program for setmelanotide is focused on rare monogenic forms 
of early-onset, severe obesity, including POMC deficiency obesity, LEPR deficiency obesity, 
and other genetic forms of early-onset, severe obesity with involvement of the leptin-MC4R 
pathway in their pathogenesis, including epigenetic obesity, PPL heterozygous obesity, and 
potentially other genetic and/or syndromic forms of obesity, and other abnormalities of the 
MC4R pathway, such as HO.  
Informative clinical data from the initial phases of these trials in patients with early-onset severe 
obesity due to rare bi-allelic mutations in the POMC and LEPR genes, as well as BBS, are 
available and were published or presented at scientific meetings. The evolving profile of weight-
related and hunger symptom reduction demonstrated with chronic setmelanotide treatment is 
important to consider, as these findings inform the overall benefit–risk consideration of 
setmelanotide.  
In adult patients who tolerate the 3 mg QD dose level, if additional effect on 
 
 is desired in the current trial, a higher QD dose can be administered at the investigator’s 
discretion and in consultation with the sponsor. The dose can be increased up to 4 mg QD, in 
patients with an absolute weight of >50 kg, and up to 5 mg QD in adult patients with an absolute 
weight of >60 kg. These dose levels have been investigated previously in trial RM-493-026. 
Adult patients exposed to these higher dose levels should be monitored closely via additional 
unscheduled visits or telephone calls to assess safety and tolerability. For patients who escalate 
to 4 or 5 mg QD, the dose level should be reduced to 3 mg and 4 mg if their absolute weight 
decreases to ≤50 kg and ≤60 kg, respectively. The maximum dose of setmelanotide is limited by 
absolute body weight (kg) in order to maintain exposure to excipients in the setmelanotide 
formulation at a lower level than those currently approved for other commercially available 
medicinal products (see Section 3.2 for further details).  
Overall, the expected benefit–risk assessment supports continued evaluation of setmelanotide in 
these rare patient populations with high unmet medical needs.  
Refer to the Investigator Brochure for data regarding setmelanotide administration at doses up to 
5 mg. 
2. 
TRIAL OBJECTIVES AND ENDPOINTS 
2.1. 
Trial Objectives 
2.1.1. 
Primary Objective 
• To characterize safety and tolerability of setmelanotide in patients who have 
completed a previous trial on treatment with setmelanotide for obesity associated with 


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genetic defects upstream of the MC4R in the leptin-melanocortin pathway or with 
obesity related to other abnormalities in the MC4R pathway. 
2.1.2. 
Exploratory Objectives 
2.2. 
Trial Endpoints 
2.2.1. 
Primary Endpoint 
The safety and tolerability of setmelanotide, as assessed by the frequency and severity of AEs, as 
well as changes in physical examinations, vital signs, laboratory evaluations, and injection site 
reactions.  
2.2.2. 
 


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3. 
INVESTIGATIONAL PLAN 
3.1. 
Overall Design and Plan of the Trial 
This is an extension trial of up to an additional 7 years duration for patients who have completed 
a previous trial of setmelanotide for rare genetic, syndromic, or acquired diseases of obesity 
upstream of the MC4R in the melanocortin-leptin pathway and other abnormalities of the MC4R 
pathway. Since continued assessments of the safety and efficacy of setmelanotide are the same in 
this extension trial regardless of the disease studied in the index trial, all patients can be followed 


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in this single extension trial. Nevertheless, the analysis of each sub-population will be performed 
separately with the ability to combine data from the original index trial and this extension trial on 
a disease-specific basis. 
For patients who qualify and provide consent, the trial will start immediately on the completion 
of their index protocol such that there are no gaps in treatment, if possible. Efforts should be 
made to have the last visit of a prior index trial or an index trial extension phase and the initial 
visit of this long-term extension trial to occur on the same day, if possible.  
Patients will be assessed in the clinic approximately every 3 months for vital signs, AEs, 
concomitant medications, 
 height (in children), 
 
Safety laboratory samples will be collected at each visit and additional assessments will be done 
on a yearly basis. In general assessments will be less frequent and burdensome than was required 
in their index protocol.  
Unscheduled clinic and/or telephone visits may be added at the discretion of the investigator to 
follow any changes in dose or adverse event, as required. 
3.2. 
Justification of the Trial Design 
Setmelanotide may be administered chronically; therefore, it is important to evaluate its long-
term safety and efficacy. 
Assessments of vital signs, AEs, 
, height (in children), 
 
 conducted approximately every 3 months along with selected less frequent assessments 
should be adequate to achieve these goals. Since eligibility and trial assessments in this extension 
trial are the same regardless of which index protocol the patient completed, the objective of long-
term follow-up for each sub-population cohort can be achieved within this single extension 
protocol. When desired, data from individual index protocols can be combined with data 
obtained in this extension protocol to evaluate the safety and efficacy of the entire setmelanotide 
exposure of a single patient or group of patients with a specific disease within the MC4R 
pathway. 
The trial has been designed for continued administration of setmelanotide in patients who have 
demonstrated benefits from receiving setmelanotide in a previous index trial. Patients who 
received setmelanotide on an open-label basis in the index trial will begin this extension trial on 
the same dose of setmelanotide they were taking when they completed their index trial, unless 
tolerability or safety reasons justify a dose decrease, or if additional potential clinical effect is 
desired on 
 a dose increase is justified; setmelanotide doses >5 mg are not 
permitted. Patients who participated in a placebo-controlled index trial will start open-label 
setmelanotide in this trial with the starting dose from the index trial, based on the patient’s age 
and weight. Dose titration should follow the scheme in the index trial and in consultation with 
the sponsor. 
3.2.1. 
Rationale for Setmelanotide Administration at Doses Up to 5 mg 
While the target dose of setmelanotide is 3 mg QD, nonclinical and clinical data support dose 
escalation up to 5 mg QD in adult patients in this trial. For additional information, see 
Section 5.2.1 and the IB.  




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At the conclusion of the other setmelanotide trial, the patient may transition back into this 
extension trial, again with the patient’s written informed consent, at the discretion of the 
investigator and sponsor, if continuation of setmelanotide treatment is considered beneficial and 
the patient continues to be eligible for the extension trial. In such cases, the patient will resume 
the extension trial at the time point/visit at which he or she was at prior to transition to the other 
trial. Furthermore, after transition back into this extension trial, the patient is to receive 
setmelanotide at the same dose as they had received prior to transition to the other trial, unless 
the dose needs to be reduced due to tolerability reasons or in case a dose increased is required for 
potential additional efficacy needs, at the investigator’s discretion. If at the time the patient 
completes the other setmelanotide trial, setmelanotide becomes commercially available for an 
indication for which that patient qualifies, the patient will not be eligible to re-enter this 
extension trial. 
If a patient transitions to another setmelanotide clinical trial before completing the ET visit in 
this extension trial, but does not transition back into this extension trial, the patient will not 
complete the ET visit or follow-up in the extension trial. 
If feasible, patients are to have no interruption in setmelanotide treatment between this extension 
trial and the other setmelanotide trial. If an interruption in treatment is necessary due to 
administrative reasons, every effort is to be made to minimize the duration of the interruption 
and interruptions >21 days are not permissible without prior approval from the sponsor.  
If a patient in this extension trial elects to transition to another setmelanotide clinical trial, then 
any screening assessments performed as part of the Screening visit in the other setmelanotide 
clinical trial within 30 days of the Transition Visit in this extension trial need not be repeated.  
4. 
TRIAL POPULATION 
4.1. 
Number of Patients 
It is anticipated that any patient participating in a setmelanotide clinical trial could be a candidate 
for enrollment in this extension trial. Based on the number of patients currently enrolled or 
planned for enrolment in setmelanotide clinical trials, it is anticipated that up to 500 patients may 
be enrolled in this trial; however, expansion in enrollment may occur if additional patients with 
obesity due to monogenic, syndromic or acquired disorders affecting the MC4R pathway are 
enrolled in Phase 2 or Phase 3 clinical trials evaluating setmelanotide. It is anticipated that up to 
100 centers located worldwide will participate in this trial. In the event additional patients are to 
be enrolled, additional sites may be added, as necessary. 
4.2. 
Patient Selection Criteria 
The specific inclusion and exclusion criteria for enrolling patients in this trial are presented in the 
section below. As these patients are ultra-rare, any criteria not fulfilled will be reviewed with the 
sponsor. Assuming no severe health concerns, a joint determination will be made regarding the 
acceptability of enrolling patients not fulfilling all criteria on a case-by-case basis. Any 
exceptions to the inclusion and exclusion criteria will be documented in writing and approved by 
responsible sponsor medical personnel prior to dosing the patient. 


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4.2.1. 
Inclusion Criteria 
1. Patients aged 2 or older (or aged >2 years as per local regulations; ; only patients aged 
12 years or older may be enrolled in the trial in Greece; only patients 6 years or older 
may be enrolled in the trial in Germany) who have completed participation in a previous 
setmelanotide clinical trial.  
2. If patient received setmelanotide on an open-label basis in a previous setmelanotide 
clinical trial, patient demonstrated adequate safety and meaningful clinical benefit 
(efficacy) in the previous setmelanotide trial. Meaningful clinical benefit is defined as 
follows: 
• Patients 18 years of age or younger that have completed participation on active drug 
and demonstrated adequate safety and at least 3% BMI reduction or reduction in BMI 
Z-score of 0.2 compared to baseline. 
• Patients over 18 years of age should show reduction of 3% BMI compared to 
baseline. 
If the patient participated in a double-blind basis in the previous placebo-controlled 
clinical trial, patient tolerated blinded study drug. 
3. Patient and/or parent or guardian is able to communicate well with the investigator, to 
understand and comply with the requirements of the trial, and to understand and sign the 
written informed consent/assent. The patient must consent/assent to participate in the 
trial. 
4. Patient must meet one of the following requirements regarding contraception: 
• If a female of childbearing potential, defined as fertile, following menarche and until 
becoming post-menopausal unless permanently sterile (hysterectomy, bilateral 
salpingectomy, or bilateral oophorectomy), must use a highly effective form of 
contraception as outlined in Section 6.2.1. 
• If a female of non-childbearing potential, defined as permanently sterile (status post 
hysterectomy, bilateral oophorectomy, or bilateral salpingectomy) or post-
menopausal for at least 12 months (and confirmed with a screening follicle-
stimulating hormone (FSH) level in the post-menopausal laboratory range), 
contraception is not required during the trial.  
− Younger female patients who have not reached menarche upon trial entry will be 
assessed for Tanner staging and at first menarche will be required to comply with 
contraception requirements and pregnancy testing as outlined in the protocol. 
• If a male with female partner(s) of childbearing potential, must agree to a double 
barrier method if they become sexually active during the trial. Furthermore, male 
patients must not donate sperm during and for 90 days following their participation in 
the trial. 


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4.2.2. 
Exclusion Criteria 
1. Pregnant and/or breastfeeding women. 
2. Significant dermatologic findings relating to melanoma or pre-melanoma skin lesions 
(excluding non-invasive basal or squamous cell lesion), determined as part of a screening 
comprehensive skin evaluation performed by a qualified dermatologist. 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 trial.  
3. Patient is, in the opinion of the investigator, not suitable to participate in the trial.  
4. Current, clinically significant disease, if severe enough to interfere with the trial and/or 
would confound the results. Any such patients should be discussed with the sponsor prior 
to enrollment in the trial. 
5. Diagnosis of schizophrenia, bipolar disorder, personality disorder or other Diagnostic and 
Statistical Manual of Mental Disorders (DSM-III) disorders that the investigator believes 
will interfere significantly with trial compliance. 
6. A Patient Health Questionnaire-9 (PHQ-9) score of ≥15. 
7. Any suicidal ideation of type 4 or 5 on the C-SSRS. Any lifetime history of a suicide 
attempt, or any suicidal behavior since the last visit in the index trial. 
Note: Patients who are unable to complete the C-SSRS due to significant neurocognitive 
defects may be enrolled in the trial, as long as in the opinion of the investigator there are 
no clinical signs or symptoms of suicidal behavior. 
8. History of significant liver disease or liver injury, or a current liver assessment due to 
abnormal liver tests (as indicated by abnormal liver function tests, alanine transaminase 
[ALT], aspartate transaminase [AST], alkaline phosphatase, or serum bilirubin >1.5× the 
upper limit of normal [ULN] for any of these tests) for an etiology other than non-
alcoholic fatty liver disease (NAFLD). Thus, any underlying etiology besides NAFLD, 
including diagnosed non-alcoholic steatohepatitis (NASH), other causes of hepatitis, or 
history of hepatic cirrhosis is exclusionary, but the presence of NAFLD is not 
exclusionary. 
9. Severe renal dysfunction defined by a glomerular filtration rate (GFR) 
<30 mL/min/1.73 m2 in patients <12 years of age or end stage renal disease (GFR 
<15 mL min/1.73 m2 (see Appendix 11.4 for GFR calculation). 
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. 
4.3. 
Patient Identification and Registration 
Patients who complete treatment in a previous trial of setmelanotide (i.e., index trial) and wish to 
continue with setmelanotide treatment will be considered for eligibility to enter this extension 
trial. Patients who are candidates for enrollment into the trial will be evaluated for eligibility by 


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the investigator to ensure that the inclusion and exclusion criteria have been satisfied and that the 
patient is eligible for participation in this clinical trial.  
All patients enrolled in the trial will be assigned a unique 9-digit number which will be a 
combination of the last 2-digits of the current protocol number (RM-493-022), the last 2-digits of 
the index protocol number (RM-493-XXX), the 2-digit site number, and a sequential 3-digit 
patient number, which will be used to identify patients throughout their participation in the trial. 
Patient numbers will be assigned sequentially starting at 001 (i.e., the first patient enrolled from 
index Protocol RM-493-012 at Site 10 would be assigned Number 22-12-10-001). Once a patient 
number has been assigned, it cannot be reused. 
Note that patient numbers may be modified to identify those patients who transition from this 
extension trial into another setmelanotide clinical trial and, as applicable, transition back into the 
extension trial. However, the patient number will enable tracking the patient across both clinical 
trials. 
4.4. 
Withdrawal of Patients 
Patients will be informed that they have the right to withdraw from the trial at any time for any 
reason, without prejudice to their medical care. Patients withdrawn from the trial should 
discontinue trial treatment and complete the ET visit assessments as per the SOA (Table 1). 
Per Section 3.3, the sponsor has elected to terminate the investigation of the MC4R gene cohort; 
therefore, patients with MC4R gene variants should be withdrawn from the trial. Exceptions will 
be made to allow patients that have displayed reductions from baseline of their index trial in 
 
 These patients can continue to receive setmelanotide treatment and participate in trial 
assessments provided they continue to demonstrate this threshold of clinical response at every 
visit thereafter.  
To be eligible for continued treatment after one year on setmelanotide, all other patients have to 
display evidence of meaningful clinical benefit via 
 treatment effect or other 
assessments. The length of setmelanotide treatment will be calculated by adding the time the 
patient received setmelanotide treatment in the index trial plus the time that the patient received 
setmelanotide in the current extension trial.  
The below criteria for withdrawal of setmelanotide treatment apply to all patients, with the 
exception of those identified as having meaningful clinical benefit–risk ratio at the investigator’s 
discretion:  


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 Withdrawal Criteria: 
• AEs, which justify treatment or trial withdrawal. For specific predefined events, 
additional monitoring and guidance for the investigator is provided in Section 7.5 
and Appendices 11.2 and 11.3. 
• Non-adherence to study drug regimen or protocol requirements. 
• Non-compliance with instructions or failure to return for follow-up. 
• IMCIVREE is available through authorized use for the patient’s indication. 
• The patient becomes pregnant during the trial. 
The sponsor may choose to discontinue investigation of a particular indication or genetic 
cohort/variants at any time; therefore, continued participation of patients for that indication or 
genetic cohort/variants will be addressed at that time. 
If a patient is withdrawn or discontinued from the trial, the primary reason for withdrawal or 
discontinuation from the trial is to be recorded in the source documents/case report form (CRF).  
All patients withdrawn prior to completing the treatment period should be strongly encouraged to 
complete the ET visit as outlined in the Schedule of Assessments (SOA) (Table 1 in Section 6), 
even if they are no longer receiving study drug. (Refer to Section 3.4 for information regarding 
completion of the Termination Visit for patients who transition into another setmelanotide 
clinical trial.) 
In case of discontinuation, all AEs should be followed as described in Section 7.4; any skin AEs 
should continue to be followed, if at all feasible, for up to ~90 days to confirm near, or complete 
resolution (as has been shown in previous trials).  
The sponsor will provide support for patient and caregiver travel, will make available visiting 
home health care professionals, and other necessary logistical support to ease the burden on the 
patient and to facilitate compliance with the trial procedures.  


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4.5. 
Patients’ Re-entry from Other Trials 
Patients that have left the current trial to enter other setmelanotide trials might re-enter the 
current trial upon discussion with the sponsor. 
If a patient decides to withdraw consent from another setmelanotide trial, they might not be able 
to re-enter the current trial unless the reason for ET was due to a tolerability issue with a 
different setmelanotide formulation. All the other circumstances will be discussed with the 
sponsor on a case-by-case basis and supporting documentation justifying re-entry should be 
provided by the investigator. 
5. 
TRIAL TREATMENTS 
5.1. 
Study Drugs 
All study drugs are for investigational use only and are to be used only within the context of this 
protocol. Setmelanotide will be supplied by the sponsor. 
 
  
Setmelanotide is a clear, colorless to slightly opalescent solution essentially free of visible 
particulates. Setmelanotide will be administered as a subcutaneous (SC) injection once daily.  
All unopened study drug must be kept in a secure, limited-access storage area at a temperature 
between 2°C to 8°C. Setmelanotide is stable at room temperature for a short time period that will 
allow patients to transport study drug home; ice packs and cooler bags will be provided for 
patients and caregivers who will travel long distances from the clinic. Patients will be 
encouraged to proceed directly home after clinic visits in which study drug is dispensed in order 
to minimize the amount of time the study drug is exposed to potentially elevated temperatures. 
Once at home, the unopened study drug must be stored in the patient’s refrigerator. Opened 
study drug may be stored at room temperature for up to 30 days. 
A separate pharmacy manual with specific instructions for the management of study drug will be 
provided to the investigative site. 
5.2. 
Study Drug Dose and Administration and Dose Adjustments 
Study Drug Dose at Trial Entry:  Patients who received setmelanotide on an open-label basis in 
the index trial will begin this extension trial on the same dose of setmelanotide they were taking 
when they completed their index trial, unless tolerability or safety reasons justify a dose 
decrease. Patients who received double-blind study drug in a placebo-controlled index trial will 
start open-label setmelanotide in this trial with the starting dose from the index trial. The dose 
titration should follow the scheme in the index trial and in consultation with the sponsor. 
Study Drug Administration: Trial patients will receive open-label setmelanotide by SC injection 
once daily (administered in the morning). Patients and/or their caregivers (including home health 
practitioners) will be responsible for all procedures associated with study drug administration at 
all times, i.e., drawing up, and self-administering the study drug once daily. Patients should be 




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5.3. 
Blinding, Packaging, and Labeling 
5.3.1. 
Blinding 
This trial is open-label so there is no blinding.  
5.3.2. 
Packaging and Labeling 
Open-label setmelanotide will be supplied by the sponsor. 
Packaging and labeling will be prepared to meet all regulatory requirements. 
5.4. 
Duration of Patient Participation 
The duration of patient participation in this extension trial is up to 7 years. Patients may continue 
setmelanotide treatment under this protocol until they become eligible for commercially 
available setmelanotide, until any applicable trial cohorts are stopped, or if any AEs require 
treatment discontinuation. The end of the trial will be defined as the last patient's last visit. 
Patients may be offered the opportunity to participate in other setmelanotide clinical trials (see 
Section 3.4).  
5.4.1. 
Commercial Availability of Setmelanotide 
Patient participation in this long-term extension trial will conclude once setmelanotide receives 
marketing authorization indicated for the patient’s condition and is available for commercial use 
in the region. The sponsor will notify a clinical site once commercial product is available for any 
applicable patient. 
Once this occurs and the patient has access to authorized setmelanotide, the patient will complete 
an ET visit in person as soon as possible. This will be considered the final trial visit for this 
patient. The assessments outlined in the SOA for the ET visit should be performed and the 
patient will return all remaining study drug to the site. A follow-up telephone call may be 
conducted to follow-up on any new or ongoing AEs from this final visit. This telephone call will 
mark the end of participation in the trial for this patient. 
In the event that a patient has opted to access commercial setmelanotide treatment and is due for 
another trial visit prior to assuring commercial drug access, then the patient should be discussed 
with the sponsor. With sponsor approval, the next planned trial visit may occur as per the SOA to 
minimize gaps in treatment if needed. 
5.5. 
Assessment of Treatment Compliance 
In order to evaluate the safety, tolerability, and efficacy of the study drug, it is critical that 
patients receive study drug as directed. All used study drug vials will be collected to assess 
compliance with the protocol. 
Patients and/or caregivers will record any missed doses in the trial diary.  


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If a patient does not receive the entire dose of study drug, the amount administered will be 
recorded in the study diary. In addition, the reason(s) for the altered dose is to be recorded in 
source documents and the CRF. 
5.6. 
Study Drug Accountability 
The investigator is responsible for study drug accountability, reconciliation, and record 
maintenance (i.e., receipt, reconciliation, and final disposition records) at the trial site. 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 at the trial site. 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 trial site, and return to the sponsor (or disposal of the drug, if approved by the 
sponsor) will be maintained by the trial site. These records will adequately document that the 
patients were provided the doses as specified in the protocol and should reconcile all study drug 
received at the trial site from the sponsor. Reasons for departure from the expected dispensing 
regimen must also be recorded. Accountability records will include dates, quantities, batch/serial 
numbers, expiration dates (if applicable), and patient numbers. The sponsor or its designee will 
review drug accountability records at the trial site during monitoring visits. 
All unused and used study drug will be returned by patients and retained at the trial site until 
inventoried by the monitor. All used, unused or expired study drug will be returned to the 
sponsor or designee or if authorized, disposed of at the trial site and documented.  
5.7. 
Prior and Concomitant Treatment 
5.7.1. 
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 as possible patients with these ultra-rare 
conditions to participate in the trial without prohibition of concomitant medications. 
Patients who enter this trial from an index trial may continue all current medications as 
prescribed. 
All concomitant medications should be kept at a stable dose throughout the course of the trial, 
unless a dose change is necessary to treat an AE. If any new medication for weight loss or a 
 agonist is started prior to or during the extension trial, the 
sponsor should be informed. 
5.7.2. 
Concomitant Procedures 
Concomitant procedures conducted during the trial, including those used to treat AEs, are to be 
reported on the CRF. 


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6. 
TRIAL ASSESSMENTS 
6.1. 
Overview of Schedule of Assessments 
The SOA to be conducted is depicted in Table 1.  
Any patient withdrawing from the trial will complete the ET visit, if possible.  
Discussion of this trial with the patient should occur prior to completion of their index trial and 
attempts should be made to minimize gaps/discontinuation of setmelanotide during transition 
from their index trial to this extension trial. Visit 1 of this trial will coincide with the final visit 
from the index trial, if possible. Visit procedures from the last visit of the index trial and the first 
visit of the extension trial are not intended to be duplicated. Thus, any repeat assessments do not 
need to be conducted and data from the last visit of the index trial will be used as V1 data in this 
trial as applicable. Patients will begin this extension trial on the same dose of setmelanotide that 
they were taking when they completed their index trial.  
In order to provide flexibility to the patient and trial staff for the number of clinic visits, the 
actual scheduling of clinic visits can allow flexibility in timing of visits.  
The actual scheduling and timing of clinic visits is flexible to accommodate the patient and trial 
staff. The SOA depicts the weeks visits are to be scheduled and in some cases, multiple visits are 
to be scheduled within a range of weeks.  
The investigators will adhere to the site-specific blood volume limits for safety laboratory and 
 analyses to ensure minimal distress to the pediatric patients 
(Appendix 11.5). Due to the age of the children, it may not be possible to collect blood samples 
for all laboratory tests at every trial visit. After enrollment, if blood sample collection for all 
laboratory tests is not possible, then the samples should be collected in the following descending 
order of priority:  
1. safety laboratory tests,  
2. anti-setmelanotide antibodies (ADA),  
3. 
 
4. glycated hemoglobin (HbA1c), 
5. 
, 
6. 
 
7. laboratory assessments indicative of nutritional status (e.g., albumin). 
If it is not possible to collect the safety laboratory samples on 2 consecutive visits, the patient 
should be discussed with the sponsor. Refer to the Laboratory Manual for the volumes of blood 
to be collected.  










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18 If bone age was assessed in the index trial, bone age X-rays of the hand with magnified views will be continued in this trial for continued monitoring of 
pediatric patients through sexual maturation to adulthood, or until bone epiphyseal plate fusion and maturation are complete, as per routine pediatric 
evaluation for growth and bone development in patients with underlying endocrine disorders. 
 
 
21 Any patient with a positive ADA will be followed ~every 3 months after detection until titers resolve or return to baseline. Note that in pediatric patients, 
samples for ADA as well as 
 should be collected as feasible/permissible by local regulations. 
22 Adverse events will be recorded from the time a patient provides informed consent/assent. AEs occurring after dosing on Day 1 will be considered treatment-
emergent AEs in the current trial. 
23 For pediatric (age 2-11 years) patients only, Nutritional Counseling and Monitoring may be performed by an appropriate dietician or nutritionist (or 
equivalent), at the investigator’s discretion, to ensure that pediatric patients have adequate nutritional/dietary intake to maintain proper growth and 
development. Additional laboratory assessments indicative of nutritional status may be monitored, as appropriate (e.g., albumin). 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
26  In the event that a patient is completing this trial but continuing treatment with setmelanotide, then this follow-up visit may be converted to a telephone call. 
In that case, the site should document any new AEs and follow-up on any ongoing AEs; remaining study drug should be returned to site, no other activities 
are required (see Section 5.4.1).  
27 Investigators may be asked by the sponsor to perform a chart review and a detailed analysis and collection of the clinical history of certain patient populations 
(e.g., selected based on indication, genetics, age group, duration of participation in the current trial [e.g., at least 6 months]). Patients or their legal guardians 
must provide written informed consent/assent to participate in this substudy. Refer to Section 6.4.1 for details. 
28 Certain patient populations (e.g., selected based on indication, genetics, age group, duration of participation in the current trial [e.g., at least 6 months]), may be 
offered the opportunity to participate in a substudy involving a patient/caregiver survey. Patients or their legal guardians will be required to provide written 
informed consent/assent to participate in this substudy. Refer to Section 6.4.1 for details. 
 


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6.2. 
Patient Requirements 
6.2.1. 
Contraception and Pregnancy Testing 
In animal reproduction trials, setmelanotide was not teratogenic at doses >10 times higher than 
3 mg. No evidence of embryo-fetal toxicity was observed. Pre- and postnatal development trials 
in rats showed no adverse setmelanotide-related effects. Please refer to the IB for additional 
information. 
Female patients of childbearing potential must not be pregnant and must have a negative 
pregnancy test result at each visit.  
Furthermore, it is imperative that all trial patients adhere to the contraception requirements as 
outlined below.  
Women of childbearing potential (WOCBP), defined as fertile, following menarche and until 
becoming post-menopausal unless permanently sterile (hysterectomy, bilateral salpingectomy, or 
bilateral oophorectomy), must use a highly effective form of contraception throughout the trial 
and for 90 days following the trial. Highly effective forms of contraception include:  
• Combined (estrogen and progestogen) hormonal contraception associated with 
inhibition of ovulation (oral, intravaginal, or transdermal)  
• Progestogen-only hormonal contraception associated with inhibition of ovulation 
(oral, injectable, implantable)  
• Intrauterine device (IUD) 
• Intrauterine hormone-releasing system  
• Bilateral tubal occlusion  
• Vasectomized partner (provided that the vasectomized partner is the sole sexual 
partner of the WOCBP, and the vasectomized partner has received medical 
assessment of surgical success)  
• Sexual abstinence, only if it is the preferred and usual lifestyle of the patient 
Women not of childbearing potential, defined as permanently sterile (status post hysterectomy, 
bilateral oophorectomy, or bilateral salpingectomy) or post-menopausal for at least 12 months 
(and confirmed with a screening FSH level in the post-menopausal range) do not require 
contraception during the trial.  
Younger female patients who are not sexually mature at trial entry will be assessed for Tanner 
staging and required to comply with contraception and pregnancy testing requirements at first 
menarche. 
Male patients with female partner(s) of childbearing potential must agree to use contraception 
(e.g., if they have not had a vasectomy then should either (a) abstain from reproductive sexual 
intercourse or (b) use a single barrier method in combination with a female partner using a highly 
reliable method (i.e., hormonal or IUD) if they become sexually active during the trial and for 
90 days following the trial. Male patients must not donate sperm for 90 days following their 
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If a pregnancy should occur while a male or female patient is on study drug, the pregnancy will 
be followed up on to determine birth and neonatal outcomes.  
6.2.2. 
Protection from Sun 
Skin hyperpigmentation, or tanning, was observed in the cynomolgus monkey toxicology trials, 
and the human trials. These events were reversible upon cessation of study drug. However, it is 
still uncertain if exposure to sunlight might exacerbate the tanning effects of setmelanotide. 
Therefore, patients are advised to use sunscreen and/or to wear protective clothing to avoid 
excessive exposure of their skin to sunlight and to avoid sun-tanning. 
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, self-tanning 
lotions, etc.). 
6.3. 
Efficacy Measurements 
6.3.1. 
 
6.3.2. 
 
6.3.3. 
 
 
  
 
 
 
 
 
 
 
 


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6.4. 
Clinical Procedures and Safety Assessments 
6.4.1. 
Informed Consent/Assent 
A complete description of the trial is to be presented to each potential patient or parent/legal 
guardian and signed and dated informed consent/assent is to be obtained before any trial specific 
procedures are performed.  
6.4.2. 
Demographics and Medical History 
A brief recent medical history will be obtained on Day 1 (Visit 1) prior to first dose of drug to 
assess continued trial eligibility and adherence to inclusion/exclusion criteria.  
Information relating to demographics and a detailed medical history will be available and should 
be cited and cross-referenced from the original (index) clinical trial for each patient. Thus, a 
complete medical history along with demographic data will not be required for patients at V1. 
Key data to be recorded in the source document and CRF include the patient’s identification 
number from the prior setmelanotide trial, gender, race, age and year of birth and concomitant 
medication use.  
6.4.3. 
 
6.4.4. 
 


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6.4.5. 
 
 
 
6.4.6. 
Physical Examination/Tanner Staging, Height, and Comprehensive Skin 
Examination 
Physical Examinations 
A complete physical examination will be conducted yearly. 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, neurologic examination, and a skin examination. If unexpected clinically significant 
skin abnormalities are noted the patient should be referred to the dermatologist. Abbreviated 
physical examinations may be conducted at all other time points. 
All physical examinations are to be conducted in adequate light.  
Changes from baseline in any physical examination findings identified by the investigator as 
clinically significant must be recorded as an AE on the appropriate CRF. 
Tanner Staging for assessment of pubertal development will be conducted as part of this 
examination yearly, with the exception of females approaching childbearing potential. according 
to the SOA (Table 1). Whenever possible, the same trained health care professional will conduct 
the physical examination and Tanner Staging.  
Height 
Height (cm) will be measured, without shoes, socks, or hats, according to the SOA (Table 1) 
using a wall-mounted stadiometer. Height will be measured at each visit for patients <21 years of 
age and only at V1 for patients ≥21 years of age. All measurements will be done in triplicate at 
each timepoint and recorded to the nearest half cm.  
The stadiometer should be calibrated by site personnel on a daily basis and prior to any height 
assessments. 
Comprehensive Skin Examination 
Each patient will receive a complete, comprehensive skin examination yearly by a dermatologist 
(Table 1).  
The investigator will identify a dermatologist to serve as a consultant for the investigative site. 
Any atypical lesions identified during the index trial should continue to be monitored as 
clinically indicated. The dermatologist will continue to monitor each patient, performing 
comprehensive skin examinations as outlined in the SOA (Table 1).  


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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 ET Visit, the patient may be asked to 
return for additional follow-up assessments to document progress towards resolution. 
6.4.7. 
Bone Age Assessment 
If bone age was assessed in the index trial, bone age X-rays of the hand with magnified views 
will be continued in this extension trial for continued monitoring of pediatric patients through 
sexual maturation to adulthood, or until when bone epiphyseal plate fusion and maturation is 
complete, as per routine pediatric evaluation for growth and bone development in patients with 
underlying endocrine disorders. X-rays will be assessed for bone age at the site by an appropriate 
individual, and scans maintained for transmission to a central reading facility, if deemed 
necessary. Bone age assessments will be performed via X-ray according to the SOA (Table 1). 
6.4.8. 
Concomitant Medication Review 
A review of concomitant medications will be conducted at V1 and at every trial visit. Any 
medications taken by trial patients will be recorded in source documents and on the appropriate 
CRF. 
6.4.9. 
Vital Signs 
Vital signs include BP (mmHg), HR (bpm), respiratory rate (RR, in breaths/minute) and body 
temperature (°C). All vital signs will be obtained in the sitting position following at least 
5 minutes of rest each time they are measured according to the SOA (Table 1). Vital signs should 
be obtained prior to blood draws whenever possible. All measurements, except body 
temperature, will be taken in triplicate, approximately 2 minutes apart.  
BP and HR will be performed using the same methodology throughout the trial (manual or 
automated) and should be taken in the non-dominant arm throughout the trial. Special attention 
should be paid to ensure the appropriate cuff size is used in this patient population.  
Repeat measures and more frequent monitoring can be implemented for significant increases in 
BP or HR.  
To allow for a BP reading at the time of 
 sampling, the patient should be instructed not 
to take the study drug on trial days when vital signs are to be measured in the clinic. 
6.4.10. 
12-Lead Electrocardiogram 
Single 12-lead ECGs will be performed following a period of at least 5 minutes of rest in the 
supine position according to the SOA (Table 1). The investigator will read and interpret the 
ECG. In the case of an abnormal ECG, the investigator might contact a cardiologist as a 
consultant at his/her local institution.  
6.4.11. 
Clinical Laboratory Tests 
Clinical safety laboratory tests are to be performed by the local laboratory until central laboratory 
services become available. Patients are to be fasting for at least 8 hours and labs are to be drawn 
prior to dosing, but after measurement of vital signs.  


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All clinically significant laboratory abnormalities will be followed-up by repeat testing and 
further investigated according to the judgment of the investigator.  
In certain situations, it may not be feasible to complete all blood draws scheduled for a specific 
visit (e.g., a younger patient, or difficulty with phlebotomy). In this situation, the investigator 
may use his/her discretion to determine which laboratory tests are completed. Laboratory tests 
should be prioritized in the following manner:  
1. safety laboratory tests,  
2. anti-drug antibodies (ADA),  
3. 
,  
4. glycated hemoglobin (HbA1c), 
5. 
  
6. 
 
 
7. laboratory assessments indicative of nutritional status (e.g., albumin). 
Any patient who does not complete all blood draws as described in the SOA (Table 1) on 
2 consecutive visits should be discussed with the sponsor. 
Specific tests are described below.  
6.4.11.1. Hematology, Clinical Chemistry and Urinalysis 
Hematology: 
Complete blood count with platelet count and standard indices will be obtained. 
Chemistry: 
Sodium, potassium, chloride, CO2, albumin, total protein, glucose, blood urea nitrogen (BUN), 
creatinine, uric acid, AST, ALT, gamma-glutamyltranspeptidase (GGT), creatine phosphokinase 
(CPK), alkaline phosphatase, total bilirubin, direct bilirubin, lactate dehydrogenase (LDH), 
calcium, and phosphorus will be obtained.  
 and HbA1c 
 
 HbA1c will also be collected. Blood samples will need 
to be collected when the patient is in the fasted state.  
Urinalysis: 
pH, glucose, protein, ketones, bilirubin, blood, urobilinogen, specific gravity, nitrite, and 
leukocytes by dipstick analysis or machine urinalysis will be measured. Urine microscopic 
examination will be performed if positive findings on dipsticks warrant further examination.  
6.4.12. 
  
 
 


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6.4.13. 
Pediatric Nutritional Assay 
For pediatric patients (age 2 to 11 years) only, Nutritional Counseling and Monitoring may be 
performed by a qualified dietician or nutritionist (or equivalent) to ensure that pediatric patients 
have adequate nutritional/dietary intake to maintain proper growth and development. Additional 
laboratory assessments indicative of nutritional status may be performed, at the investigator’s 
discretion, in case of rapid and conspicuous weight loss (e.g., albumin) (Bharadwaj 2016). In this 
occurrence, the investigator should inform the sponsor who may request additional assessments.  
6.4.14. 
  
 
 
 
 
 
  
 
 
 
  
 
 
 
 
 
6.4.15. 
Injection Site Evaluation and Scoring 
Injection sites will be carefully inspected, evaluated and scored during the trial period. The 
injection site evaluation will include identification and measurement of areas of erythema, 


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edema, and induration, as well as the presence of localized pain, tenderness and itching. A 
sample injection site evaluation form is included in Appendix 11.1. 
In addition, unscheduled evaluations may also be recorded as warranted by clinical conditions, 
including in the interval between scheduled visits.  
6.4.16. 
Anti-Setmelanotide Antibody (ADA) Measurements 
Blood samples for measurement of anti-setmelanotide antibodies will be collected at each visit. 
Any patient with a positive titer will be followed ~ every 3 months after detection until 
resolution or return to baseline.  
6.4.17. 
  
6.4.17.1. 
 
6.4.17.2. 
 


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6.4.17.3. 
 


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6.4.18. 
Diet and Nutritional Counseling 
For adolescent and adult patients, no special dietary counseling will be part of this trial, but 
patients will be counseled to adhere to a calorie reduced diet, at the discretion of the investigator.  
For pediatric patients (age 2-11 years), nutritional counseling and monitoring may be performed 
by a qualified dietician or nutritionist (or equivalent), at the investigator’s discretion, according 
to the SOA (Table 1), to ensure that pediatric patients have adequate nutritional/dietary intake to 
maintain proper growth and development. Additional laboratory assessments indicative of 
nutritional status may be monitored as appropriate (e.g., albumin).  
6.4.19. 
Adverse Events 
Each patient must be carefully monitored for the development of any AEs throughout the trial 
from V1 through the patient’s last 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 trial 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 (CTCAE) 
grading system.  
Complete details on AE monitoring are provided in Section 7. 
6.4.20. 
Order of Assessments 
When scheduled at the same timepoint, the order of procedures should be as follows: obtain vital 
signs, perform 12-lead ECG, followed by blood draws (at the specified time point, if applicable). 
Adjustments may be made depending upon specific circumstances. Questionnaires are to be 
completed before the morning meal and study drug administration; they may be performed 
before or after blood draws and/or 12-lead ECGs. 
7. 
ADVERSE EVENTS 
Monitoring of adverse events (AEs) will be conducted throughout the trial. AEs will be recorded 
in the CRFs from V1 through the patient’s last visit, as indicated in Table 1. AEs that occur after 
the start of study drug administration will be considered treatment-emergent adverse events. Any 
AEs that are reported as ongoing at the time of the subject’s final visit in their index trial, will be 
recorded as pre-existing condition on the trial AE logs. Serious adverse events (SAEs) will be 
recorded through the patient’s last 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).  
7.1. 
Definitions, Documentation, and Reporting 
An 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 


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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 or suspected adverse reaction 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 trial period, but 
planned prior to trial entry are not considered AEs if the illness or disease existed 
before the patient was enrolled in the trial, provided that it did not deteriorate in an 
unexpected manner during the trial (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. 
7.2. 
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 trial 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 trial 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 1 comprehensive event. 
All SAEs that occur during the course of the trial must be reported by the investigator to the 
sponsor or designee 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. An SAE Report Form will be completed and sent to the sponsor within 24 hours. The 
information collected will include patient number, a narrative description of the event, and an 


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assessment by the investigator as to the severity of the event and relatedness to study drug. All 
SAEs must also be entered into the CRFs. Follow-up information on the SAE may be requested 
by the sponsor or its designee. 
Sites will submit all SAE Report Forms within 24 hours via email or fax to the address below: 
 
 
If there are serious, unexpected adverse drug reactions associated with the use of the study drug, 
the sponsor or designee will notify the appropriate regulatory agency/agencies and all 
participating investigators on an expedited basis. It is the responsibility of the investigator to 
promptly notify the IRB/IEC where required of the IRB/IEC of all unexpected serious adverse 
drug reactions involving risk to human patients.  
7.2.1. 
Assessment of Severity, Relationship to Study Drug, and Expectedness 
For both serious and non-serious AEs, the investigator must determine both the severity of the 
event and the relationship of the event to study drug administration. Only those injection site 
reactions and laboratory abnormalities considered clinically significant by the investigator will 
be recorded as AEs. Expectedness will be evaluated by the sponsor. 
7.2.1.1. 
Assessment of Severity 
Intensity of AEs including clinically significant treatment-emergent laboratory abnormalities, 
injection site reactions and potential systemic reactions will be graded according to the CTCAE 
Version 4.0. 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). 
Adverse events not listed by the CTCAE, including hyperpigmentation, will be graded as 
follows: 
• 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. 
7.2.1.2. 
Assessment of Relationship 
Relationship to of an AE 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 or the temporal relationship is such that study drug would not have had 
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• 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. 
7.2.1.3. 
Assessment of Expectedness 
The reference safety information (RSI) for this trial will be within the current IB. The sponsor 
will be responsible for assessment of expectedness for all AEs to determine regulatory reporting 
requirements. An unexpected AE is one that is not listed within the RSI of the IB. 
7.3. 
Adverse Events and Risks 
Overall, setmelanotide has been generally well-tolerated in previous trials. The most common 
adverse reactions have been injection site reactions, skin hyperpigmentation, nausea, headache, 
diarrhea, abdominal pain, back pain, fatigue, vomiting, depression, upper respiratory tract 
infection, and spontaneous penile erection. The investigator (or a covering clinician) will be 
available at all times to trial participants in the event of a clinical emergency. This availability 
and how to reach the investigators in an emergency will be clearly communicated orally and in 
writing to trial participants. All trial interventions will be provided free of cost.  
Please refer to the current IB for a comprehensive summary of the AEs reported to date.  
7.3.1. 
Medical Monitoring  
The medical monitoring for the trial may be delegated to a medical monitor supplied by the 
Contract Research Organization (CRO) managing the operational conduct of this trial. The 
investigator has overall responsibility for the integrity of the trial and participant safety at their 
site. This information, as well as any other unanticipated problems involving risks to patients or 
others, will also be reported to the applicable regulatory authorities in accordance with regulatory 
requirements. 
7.4. 
Monitoring of Adverse Events and Period of Observation 
AEs will be recorded on the CRFs starting from V1 up to and including the patient’s last visit. 
SAEs and deaths will be recorded on the CRFs starting from the time the ICF is signed and 
continuing through the patient’s last 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 trial, which the investigator considers to 
be related to study drug, must be reported to the sponsor or designee. 


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7.5. 
Guidelines for Additional Monitoring and Suspension of Dosing for a 
Patient 
Patients will be monitored carefully during the treatment period during onsite clinic visits as well 
as periodic telephone calls made to the patients by the trial staff. In the event a patient is 
withdrawn from treatment due to an AE, the patient should be encouraged to complete the ET 
Visit in order to monitor the event to resolution and obtain additional protocol defined safety 
assessments. 
Specific guidelines for dermatological events and penile erections are provided in the 
Appendices (Section 11, Appendix 11.2, and Appendix 11.3). At all times, this guidance is 
subject to the clinical judgment of the investigator and trial consultants (if applicable).  
The investigator will notify the Medical Monitor in the event any trial participant fulfills any of 
the criteria defined in the appendices noted above, or undergoes additional monitoring for any of 
the events defined herein. 
Male and female sexual function and hyperpigmentation will be monitored throughout the trial 
using specific CRF pages. 
7.5.1. 
Depression or Suicidality 
A patient should be referred to a mental health provider (MHP) if he/she has: 
 
• Any suicidal behavior. 
 
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. Any event necessitating referral to an MHP is to be reported as an AE. 
If a patient’s psychiatric disorder can be adequately treated with psychotherapy and/or 
pharmacotherapy, then the patient, at the discretion of the MHP, should be continued in the trial. 
Any elevation in 
 should be evaluated to determine whether it meets 
the criteria for reporting as an AE. 
8. 
STATISTICAL PROCEDURES 
This section describes the plans for analysis. Details of the statistical analysis will be described 
in the Statistical Analysis Plan (SAP) and the final clinical trial report. 
8.1. 
Sample Size Estimation 
The primary objective of this trial is to evaluate long-term safety and tolerability in patients with 
various rare genetic, syndromic, or acquired forms of obesity impacting the MC4R pathway after 
completing planned setmelanotide treatment in a previously completed index protocol. All 
patients who complete an index protocol and meet eligibility criteria can enroll in this trial. Thus, 
sample size estimation and power analyses are not relevant. 


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Given the rarity of these genetic and acquired diseases of the MC4R pathway, estimated power 
for exploratory endpoints such as expected 
 
will not be provided, and efficacy will be only summarized. 
8.2. 
Hypotheses 
Setmelanotide continues to be safe and well tolerated throughout this extension protocol. 
Setmelanotide leads to a clinically relevant reduction of body 
 endpoints and long-
term maintenance of weight-related improvements in each population of patients with rare 
genetic, syndromic, or acquired diseases of obesity (each population analyzed separately). 
8.3. 
Definition of Population(s) for Analysis 
This protocol includes a variety of patient populations who are included as a matter of 
administrative convenience (each population is so rare this protocol anticipates a small number 
of patients in each population). Each sub-population may be analyzed separately as ≥2 patients 
are enrolled, and complete at least 6 additional months of treatment.  
8.4. 
Statistical Methods 
Statistical methods, populations and approaches to missing data will be outlined in the SAP.  
As these patient populations are extremely rare, efforts will be made to keep all patients in the 
trial, and all data collected, even if outside of visit windows, will be included in all analyses of 
endpoints. No missing data will be imputed, analyses will be carried out on all available data. 
With respect to the exploratory endpoints, no adjustment for multiplicity will be included for the 
many patient populations in this trial as these different populations are included in this trial only 
for administrative convenience. 
AEs will be coded by using the most current version of Medical Dictionary for Regulatory 
Activities (MedDRA) and summarized by system organ class and preferred term for the number 
and percent of AEs reported, the number of patients reporting each AE, and the number of 
patients with any AE. 
Analyses of AEs will be performed for those events that are considered treatment-emergent, 
where treatment-emergent is defined as any AE with onset after the administration of study drug 
through the end of the trial, specifically, 30 days after the last dose of setmelanotide, or any event 
that was present at baseline but worsened in severity or was subsequently considered drug-
related by the investigator through the end of the trial. 
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. 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. 




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The patient or his/her guardian or legal representative must provide written informed 
consent/assent any time the informed consent form/assent form is updated during the course of 
the trial. Patients must be informed of and provide consent/assent to the most current version of 
the informed consent form(s) (ICFs) during their participation in the trial, and a copy of the 
ICF(s) must be provided to the patient or their legally authorized representative. 
9.4. 
Patient Confidentiality 
In order to maintain patient privacy, all source documents/CRFs, study drug accountability 
records, trial reports and communications will identify the patient by the assigned patient 
number. The investigator will grant monitor(s) and auditor(s) from the sponsor or its designee 
and regulatory authority/authorities 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. 
9.5. 
Protocol Compliance 
The investigator will conduct the trial in compliance with the protocol provided by the sponsor, 
and given approval/favorable opinion by the IRB/IEC and the appropriate regulatory 
authority/authorities. Modifications to the protocol should not be made without agreement of 
both the investigator and the sponsor. 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 patients. The IRB/IEC may provide, if applicable regulatory 
authority/authorities permit, expedited review and approval/favorable opinion for minor 
change(s) in ongoing trials that have the approval /favorable opinion of the IRB/IEC. The 
sponsor or designee will submit all protocol modifications to the regulatory authority/authorities 
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 the sponsor, if circumstances permit, to discuss the planned 
course of action. Any departures from the protocol must be fully documented in the source 
documents/CRF. 
9.6. 
Trial Conduct During the COVID-19 (Coronavirus) Pandemic 
The worldwide Coronavirus Disease 2019 (COVID-19) pandemic may impact the conduct of 
clinical trials due to the challenges from quarantines, site closures, travel limitations, and other 
considerations if site personnel or trial participants become potentially exposed to or infected 
with COVID-19. To assure the safety of trial participants, maintain compliance with GCP, and 
minimize risks to trial integrity, if necessary, in consultation with the sponsor, the method of 
assessment may be changed (e.g., paper assessments replaced by electronic assessments). In 
addition, site visits may be replaced with telephone, internet-based video‑conferencing 
applications, or home visits by qualified health care professionals. Normal procedures, as 
detailed in this protocol, will be resumed as soon as possible thereafter. 
More detailed guidance on trial conduct during the COVID-19 pandemic is provided in 
Appendix 11.6.  


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9.7. 
Data Management 
9.7.1. 
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 electronic 
CRF (eCRF) system with source documents. All corrections or changes made to any trial 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. 
9.7.2. 
Computer Systems 
Data will be processed using a validated computer system conforming to regulatory 
requirements. 
9.7.3. 
Data Entry 
Data must be recorded using the eCRF system as the trial is in progress. All trial site personnel 
must log into the system using their secure user name and password in order to enter, review, or 
correct trial data. These procedures must comply with Title 21 of the Code of Federal 
Regulations (21 CFR Part 11). All passwords will be strictly confidential. 
9.7.4. 
Medical Information Coding 
For medical information, the following thesauri will be used: 
• MedDRA for AEs 
• WHO Drug for concomitant medications 
9.7.5. 
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. 
9.8. 
Direct Access to Source Data 
The trial will be monitored by the sponsor or its designee. Monitoring will be performed by a 
representative of the sponsor (site monitor) and will include 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). 


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All unused study drug and other trial materials are to be returned to the sponsor or designee after 
the clinical phase of the trial has been completed (see Section 5.6). 
Regulatory authorities, the IRB/IEC, and/or the sponsor’s clinical quality assurance group or 
designee may request access to all source documents, CRFs, and other trial 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. 
9.9. 
Source Document/Case Report Form Completion 
Source documents/CRFs will be completed for each trial 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/CRFs should indicate the patient’s 
participation in the trial and should document the dates and details of trial procedures, AEs, and 
patient status. 
The investigator, or designated representative, should complete the source document/CRFs as 
soon as possible after information is collected, preferably on the same day that a trial patient is 
seen for an examination, treatment, or any other trial 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/CRFs to endorse the recorded data.  
9.10. 
Record Retention 
The investigator will maintain all trial records according to ICH-GCP and applicable regulatory 
requirement(s). Records will be retained for at least 2 years after the last marketing application 
approval or 2 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 responsibility of keeping the trial records, custody must be transferred to a person willing to 
accept the responsibility. The sponsor must be notified in writing if a custodial change occurs. 
9.11. 
Liability Insurance 
The sponsor 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. 
9.12. 
Publication of Trial Findings and Use of Information 
All information regarding setmelanotide supplied by the sponsor to the investigator is privileged 
and confidential information. The investigator agrees to use this information to accomplish the 
trial and will not use it for other purposes without consent from the sponsor. It is understood that 
there is an obligation to provide the sponsor with complete data obtained during the trial. The 
information obtained from the clinical trial will be used towards the development of 
setmelanotide and may be disclosed to regulatory authority/authorities, other investigators, 
corporate partners, or consultants as required. 


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It is the intention of the sponsor and the academic investigators to publish the results of this trial 
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. 


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10. 
REFERENCES 
Ahmet A, Blaser S, Stephens D, Guger S, Rutkas JT, Hamilton J. Weight gain in 
craniopharyngioma--a model for hypothalamic obesity. J Pediatr Endocrinol Metab. 
2006;19:121-7. 
An JJ, Rhee Y, Kim SH, et al. Peripheral effect of alpha-melanocyte-stimulating hormone on 
fatty acid oxidation in skeletal muscle. J Biol Chem. 2007;282:2862-70. 
Aponte Y, Atasoy D, Sternson SM. AGRP neurons are sufficient to orchestrate feeding behavior 
rapidly and without training. Nat Neurosci. 2011; 14:351-5.  
Bharadwaj S, Ginoya S, Tandon P, et al. Malnutrition: laboratory markers vs nutritional 
assessment. Gastroenterol Rep (Oxf). 2016;4(4):272-80. 
Daousi C, Dunn AJ, Foy PM, MacFarlane IA, Pinkney JH. Endocrine and neuroanatomic 
features associated with weight gain and obesity in adult patients with hypothalamic damage. 
Am J Med. 2005;118:45-50. 
DeVile CJ, Grant DB, Hayward RD, Stanhope R. Growth and endocrine sequelae of 
craniopharyngioma. Arch Dis Child. 1996;75:108-14. 
Elfers C, Ralston M, Roth CL. Studies of different female rat models of hypothalamic obesity. J 
Pediatr Endocrinol Metab 2011;24:131-7. 
Enriori PJ, Chen W, Garcia-Rudaz MC, et al. alpha-Melanocyte stimulating hormone promotes 
muscle glucose uptake via melanocortin 5 receptors. Mol Metab 2016;5:807-22. 
Holland J, Sorrell J, Yates E, et al. A brain-melanocortin-vagus axis mediates adipose tissue 
expansion independently of energy intake. Cell Rep. 2019;27:2399-410 e6. 
Holmer H, Pozarek G, Wirfalt E, et al. Reduced energy expenditure and impaired feeding-related 
signals but not high energy intake reinforces hypothalamic obesity in adults with childhood onset 
craniopharyngioma. J Clin Endocrinol Metab. 2010;95:5395-402. 
Kuhnen P, Krude H, Biebermann H. Melanocortin-4 receptor signalling: importance for weight 
regulation and obesity treatment. Trends Mol Med. 2019;25:136-48. 
Liu T, Kong D, Shah BP, et al. Fasting activation of AgRP neurons requires NMDA receptors 
and involves spinogenesis and increased excitatory tone. Neuron. 2012;73:511-22. 
NHLBI. The practical guide identification, evaluation, and treatment of overweight and obese in 
adults. NIH Publication No. 00-4084, October 2000. 
Patel L, Cooper CD, Quinton ND, et al. Serum leptin and leptin binding activity in children and 
adolescents with hypothalamic dysfunction. J Pediatr Endocrinol Metab. 2002;15:963-71. 
Rhythm Pharmaceuticals. IMCIVREE (setmelanotide). Israel Ministry of Health. 
https://israeldrugs.health.gov.il/#!/byDrug. Accessed 23 February 2023.  
Rhythm Pharmaceuticals. IMCIVREE (setmelanotide) Package Insert. U.S. Food and Drug 
Administration. https://www.accessdata.fda.gov/drugsatfda_docs/label/2022/213793s001lbl.pdf. 
Revised June 2022. Accessed 27 April 2023.  


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Rhythm Pharmaceuticals. IMCIVREE (setmelanotide) Summary of Product Characteristics. 
European Medicines Agency. https://www.ema.europa.eu/en/documents/product-
information/imcivree-epar-product-information_en.pdf. 2022. Accessed 27 April 2023.  
Rhythm Pharmaceuticals. IMCIVREE (setmelanotide) Summary of Product Characteristics. 
Medicines and Healthcare Products Regulatory Agency. 
https://mhraproducts4853.blob.core.windows.net/docs/f16add661be8255e158d0ac3513692fdf5d
91b6d. Revised December 2021. Accessed 13 August 2022. 
Rhythm Pharmaceuticals. IMCIVREE Product Monograph. Health Canada, 2023. 
Roth C, Wilken B, Hanefeld F, Schroter W, Leonhardt U. Hyperphagia in children with 
craniopharyngioma is associated with hyperleptinaemia and a failure in the downregulation of 
appetite. Eur J Endocrinol. 1998;138:89-91. 
Roth CL, Elfers CT, Morton GJ. A Model of Disturbed Weight Regulatory Pathways in 
Hypothalamic Obesity Abstract NIH NIDDK Scientific Workshop- Rare Syndromic Body Fat 
Disorders, March 1 and 2, 2012.  
Roth CL, Enriori PJ, Gebhardt U, et al. Changes of peripheral alpha-melanocyte-stimulating 
hormone in childhood obesity. Metabolism. 2010;59:186-94. 
Roth CL, Gebhardt U, Muller HL. Appetite-regulating hormone changes in patients with 
craniopharyngioma. Obesity (Silver Spring). 2011;19:36-42. 
Schwartz GJ, Muñoz A, Schneider MF, Mak RH, Kaskel F, Warady BA, Furth SL. New 
equations to estimate GFR in children with CKD. J Am Soc Nephrol. 2009 Mar;20(3):629-37. 
Shaikh MG, Grundy RG, Kirk JM. Hyperleptinaemia rather than fasting hyperinsulinaemia is 
associated with obesity following hypothalamic damage in children. Eur J Endocrinol. 
2008;159:791-7. 
Yang Y, Atasoy D, Su HH, Sternson SM. Hunger states switch a flip-flop memory circuit via a 
synaptic AMPK-dependent positive feedback loop. Cell. 2011;146:992-1003.  




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11.2. 
Guidance for Monitoring Potential Treatment-Related 
Dermatological Changes and Suggested Criteria for Discontinuation 
of Dosing 
In clinical trials conducted with setmelanotide, skin hyperpigmentation (tanning), primarily 
noted on sun exposed areas, was reported during the first 7-14 days of treatment at clinical doses. 
In Phase 1/2 clinical studies, hyperpigmentation appeared uniform, and in most instances, 
returned to baseline within 30 days of discontinuing study drug. Some patients also noted 
changes in hair color as well. Facial hyperpigmentation on the muzzle and periorbital region was 
seen in the 14-day, 28-day, and 13-week toxicology studies in cynomolgus monkeys, with 
improvement or resolution seen by the end of the recovery period.  
The investigator will identify a dermatologist to serve as a consultant for the investigative site. 
The dermatologist will receive training in trial procedures and the effects of setmelanotide prior 
to evaluating patients.  
Each patient will receive a complete, comprehensive dermatology examination during V1, prior 
to any setmelanotide treatment. Photographs of any specific lesions at baseline are suggested, 
and any worrisome lesions should be considered for biopsy prior to trial start. The dermatologist 
will continue to monitor each patient, performing comprehensive skin examinations as outlined 
in the SOA. The findings of the dermatological examinations will be captured as part of the trial 
information for each patient. Photographs of lesion progression using standard dermatological 
procedures, or even if captured by a hand-held camera, should be considered, to record changes 
in skin condition. 
While standard dermatological photographs do not robustly capture changes in skin color or hue 
(which require very carefully controlled standard conditions and lighting), sites that may have 
such equipment should discuss this with the sponsor to determine if their equipment meets the 
rigorous standards for following patients over time. If the sponsor and investigator both agree 
that such testing can be performed, sites are encouraged to do so with the careful monitoring by 
the sponsor. It is expected that few sites (and patients) will have the necessary facilities.  
The dermatologist will also serve as a consultant for the investigative site in the event a patient 
reports changes to their skin, including skin tanning, or darkening of existing, or the appearance 
of new, pigmented skin lesions. These events are expected, and were observed in other 
setmelanotide clinical studies, but may require dermatological evaluation outside of the SOA. 
In the event of skin tanning, the patient should generally remain on treatment, with continued 
monitoring, or at more frequent intervals as deemed appropriate by the investigator and/or 
dermatologist.  
In the event of darkening skin lesions, or the presence of a new pigmented skin lesion, the 
investigator can refer the patient to the dermatologist for an evaluation. If clinically indicated, the 
lesion may be biopsied, otherwise careful monitoring is recommended and the patient should 
remain on study drug.  
Any biopsies must be evaluated by a trained dermatopathologist, and biopsy reports must be part 
of the trial information for each patient.  


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While it is not expected that patients will discontinue drug as a result of skin or lesion darkening, 
in some cases it is possible this course will be indicated in some circumstances. If so, experience 
in the clinical trials demonstrates the changes in lesions reverse upon cessation of study drug, so 
if a lesion continues to darken or change after study drug has been discontinued, careful 
consideration should be given for further dermatological evaluation or biopsy. If drug is 
discontinued, all patients with clinically indicated lesions are to be followed by the dermatologist 
until progress towards resolution of the event (up to ~60-90 days after last dosing, if needed). 
 
 


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11.3. 
Guidance for Monitoring Potential Treatment-Related Penile 
Erections and Suggested Criteria for Discontinuation of Dosing 
Male patients will be instructed to immediately report any non-erotic erections lasting for more 
than 30 minutes, or a painful erection of any duration, to the investigator. 
As previously noted, penile erections in males are effects associated with MC4R agonism, and 
have been seen in setmelanotide clinical studies. However, occurrence of these events does not 
appear to correlate with dose and duration of dosing, as the number of events did not increase 
with dose or duration of dosing. These events have been intermittent usually lasting less than 
20 minutes, painless, and resolved without intervention. Some patients have had a series of such 
erections over a multi-hour interval, with intermittent flaccidity. If a patient reports a painless, 
non-erotic continuous erection of more than 1-hour duration, they will be instructed to urgently 
contact the investigator, and based on investigator judgment, study drug injection is to be 
immediately discontinued. If after study drug discontinuation the event does not resolve, further 
treatment may be provided as clinically indicated. 
Erections lasting more than 4 hours or painful erections of shorter duration are of serious 
concern, especially since the presence of pain may connote localized penile ischemia. No painful 
or prolonged erections have been reported in setmelanotide clinical studies, however, in the 
event one is reported, study drug injection is to be stopped immediately and an examination of 
the patient performed by the investigator; alternatively, the patient should be instructed to seek 
emergent medical care.  
11.4. 
Assessment of Renal Function 
11.4.1. 
Modification of Diet in Renal Disease (MDRD) Equation 
In patients, ≥18 years of age, the Modification of Diet in Renal Disease (MDRD) 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) 
11.4.2. 
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 centimeters) / creatinine in mg/dL 
11.5. 
Considerations for Reducing Pain and Distress in the Pediatric 
Population 
Although the study procedures and assessments required per protocol are classified as “No or 
Minimal Risk” (with the exception of DXA, which is classified as “Minor Increase over Minimal 
Risk”) according to the 2008 Guidance Document “Ethical Considerations for Clinical Trials on 
Medicinal Products Conducted with the Paediatric Population”, considerations for reducing pain 
in distress in participants younger than 18 years of age are suggested below. 
• The clinical trial may only be conducted if it subjects the person concerned to as little 
burden and other foreseeable risks as possible. 


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• Physical and emotional pain should be prevented as much as possible, and effectively 
treated when unavoidable. 
• In order to minimize pain, distress, and fear, facilities should be appropriate to 
childcare, and the personnel should be trained to look after children and supervised by 
experienced health care professionals. Staff should be trained to communicate with 
both parents (or legal representative) and children. Generally, this would assume non-
adult patients are being studied at experienced pediatric centers.  
• For most procedures, the child should always be accompanied by a trial-related staff 
member who could provide reassurance. At the sign of distress and/or dissent the 
procedure should be stopped; a short pause to allow the child to feel in control, 
further explanation and an assessment of the situation may be needed to reassure the 
child, or to decide to definitely abandon the procedure at the discretion of the 
investigator. 
• In all situations, investigations/interventions should be limited to the minimum 
required for obtaining valid data and performed using size-/age-appropriate material 
and devices, including limiting in advance the number of attempts for sampling. 
• Study drug injections should only be performed by parents (or home health care 
professionals), unless the child is of suitable age and competency, and desires the 
ability to do so. 
• Although almost all study procedures are classified as low risk (with the exception of 
DXA, which is classified as “minor increase over minimal risk”), risk should be 
continuously monitored and assessed by appropriate personnel.  
• For assessments in which there is a psychological component measures should be 
taken to minimize distress. For example, Tanner Staging assessments could utilize a 
diagram for the child to point to and indicate what stage they currently are, vs. having 
to have an examination without clothes. 
A comment on benefit–risk:  risk is very low, from procedures and/or known safety profile of the 
drug (both clinically and toxicologically, where large margins and preliminary data from juvenile 
tox studies have not identified any new or concerning safety concerns), and based on treatment 
experience in several forms of rare genetic, syndromic, or acquired diseases of obesity impacting 
the MC4R pathway, there is the possibility of major benefit. 
 


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11.6. 
Guidance on Study Conduct During the COVID-19 (Coronavirus) 
Pandemic 
Coronavirus disease 2019 (COVID-19) could impact the conduct of this clinical study for several 
reasons, including: self-isolation/quarantine by patients and study-site personnel; travel 
restrictions/limited access to public places, including hospitals; and reassignment of site 
personnel to critical tasks. 
In accordance with recent health authority guidance, the sponsor is providing temporary 
considerations for study conduct in the event of disruption of the study. This guidance does not 
supersede any local or government requirements or the clinical judgment of the investigator. If at 
any time a patient’s safety is considered to be at risk, study intervention will be discontinued, and 
study follow-up will be conducted. 
If COVID restrictions are imposed on or by the study site and the site cannot fully carry out 
normal operations, the following measures are recommended on a temporary basis during the 
COVID-19 pandemic:  
• Where possible, every effort should be made to complete all protocol-required 
assessments. In place of a required site visit, a qualified healthcare provider could 
perform study-related procedures as per the SOA (Table 1) via a home visit, including 
but not limited to collection of body weight, vital signs, physical examinations, 
electrocardiograms (ECGs), recording of adverse events (AEs), collection of blood 
and urine samples. Most efficacy assessments could potentially be done off site. 
investigators should use their clinical judgment to determine whether a patient can 
continue study treatment in the absence of on-site clinic visits, or consider 
alternatives such as temporary treatment interruption or study discontinuation. 
• All protocol-required assessments missed due to COVID restrictions should be 
documented in detail within the patients’ source documents and should be clearly 
designated as “COVID-19 RELATED”. It must be documented if a site visit is 
instead conducted remotely. Source documentation should detail how each 
assessment was collected (e.g., remote vs. on-site, central vs. local laboratory, vital 
signs taken at home by caregiver vs. delegated in-home nursing). 
• If applicable, discontinuations of study interventions and withdrawal from the study 
due to disruption of study conduct by the pandemic should be documented with the 
prefix “COVID-19 RELATED” in the case report form (CRF). 
COVID-19 Infection in Study Patients: 
There is currently no available data suggesting that patients treated with setmelanotide should 
have treatment interrupted during the COVID-19 pandemic. If a patient develops symptoms 
associated with coronavirus infection, it is recommended to confirm the diagnosis using locally 
approved laboratory kits and report it to the local health authorities, as required. Patients with 
positive test results for SARS-COV-2 should have this recorded as an AE, and if hospitalized, 
this should be reported as a serious adverse event (SAE). 

SAP_001.pdf: 
 
 
STATISTICAL ANALYSIS PLAN 
PROTOCOL RM-493-022 
Long Term Extension Trial of Setmelanotide (RM-493) for Patients who have 
Completed a Trial of Setmelanotide for the Treatment of Obesity Associated 
with Genetic Defects Upstream of the MC4 Receptor in the Leptin-
melanocortin Pathway 
 
Protocol Number: 
Protocol Version and Date: 
RM-493-022 
Amendment 7:  12 May 2023 
Amendment 6:  09 November 2022 
Amendment 5:  05 August 2021 
Amendment 4:  16 October 2019 
Amendment 3:  15 October 2018 
Amendment 2:  14 May 2018 
Amendment 1:  12 April 2018 
Original:  09 January 2018 
Name of Test Drug: 
Setmelanotide (RM-493, Melanocortin-4 Receptor Agonist) 
Phase: 
Open-label Active Treatment Extension Trial 
Methodology: 
Long-term extension trial  
Sponsor: 
Rhythm Pharmaceuticals, Inc. 
500 Boylston Street 
Boston, MA 02116, USA 
Tel: (857) 264-4282 
Fax: (857) 264-4299 
Sponsor Representative: 
 
 
Rhythm Pharmaceuticals, Inc. 
Analysis Plan Date: 
28 June 2024 
Analysis Plan Version: 
Version 2.0  
 




Rhythm Pharmaceuticals, Inc. 
Statistical Analysis Plan, Protocol RM-493-022 
June 28, 2024 Version 2.0 
 
CONFIDENTIAL  
 
Page 3 of 30 
 
TABLE OF CONTENTS 
Section 
Page 
1. 
Information from the Study Protocol ............................................................................ 7 
1.1. 
Introduction ........................................................................................................ 11 
1.2. 
Study Objectives................................................................................................. 11 
1.2.1. 
Primary Objective ................................................................................. 11 
1.2.2. 
Exploratory Objectives ......................................................................... 11 
1.3. 
Study Design ....................................................................................................... 11 
1.3.1. 
Synopsis of Study Design ..................................................................... 11 
1.3.2. 
Stopping Rules and Unblinding ............................................................ 14 
1.3.3. 
Randomization Methodology ............................................................... 14 
1.4. 
Study Procedures ............................................................................................... 14 
1.4.1. 
Primary Endpoint .................................................................................. 20 
1.4.2. 
 .......................................................................... 20 
2. 
Subject populations ........................................................................................................ 21 
2.1. 
Population Definitions ....................................................................................... 21 
2.2. 
Protocol Violations ............................................................................................. 21 
3. 
General Statistical Methods .......................................................................................... 22 
3.1. 
Sample Size Justification ................................................................................... 22 
3.2. 
General Methods ................................................................................................ 22 
3.3. 
Computing Environment................................................................................... 22 
3.4. 
Baseline Definitions ............................................................................................ 22 
3.5. 
Methods of Pooling Data ................................................................................... 23 
3.6. 
Adjustments for Covariates .............................................................................. 23 
3.7. 
Multiple Comparisons/Multiplicity .................................................................. 23 
3.8. 
Subpopulations ................................................................................................... 23 
3.9. 
Data from Index Studies .................................................................................... 23 
3.10. Withdrawals, Dropouts, Loss to Follow-up ..................................................... 23 
3.11. Missing, Unused, and Spurious Data ............................................................... 24 
3.12. Visit Windows..................................................................................................... 24 
3.13. Interim Analyses ................................................................................................ 24 
3.14. Final Analyses..................................................................................................... 24 


Rhythm Pharmaceuticals, Inc. 
Statistical Analysis Plan, Protocol RM-493-022 
June 28, 2024 Version 2.0 
 
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Page 4 of 30 
 
4. 
Study Analyses ............................................................................................................... 25 
4.1. 
Subject Disposition............................................................................................. 25 
4.2. 
Demographics and Disease Characteristics ..................................................... 25 
4.3. 
Exploratory Evaluations ................................................................................... 25 
4.3.1. 
 ................................................................................................... 25 
4.3.2. 
 ....................................................................................................... 25 
4.3.3. 
 ................................. 26 
4.3.4. 
.................................................................................................. 26 
4.3.5. 
 ............................................................................ 27 
4.3.6. 
................................................................................ 27 
4.3.7. 
 and HbA1c....................................................................... 27 
4.3.8. 
 ..................................... 27 
4.3.9. 
 .............................................. 28 
4.3.10. 
 ............................. 28 
4.3.11. 
.......................................................................... 28 
4.4. 
 ........................................................................... 29 
4.5. 
Safety Evaluations .............................................................................................. 29 
4.5.1. 
Study Drug Exposure ............................................................................ 29 
4.5.2. 
Adverse Events ..................................................................................... 29 
4.5.3. 
Injection Site Evaluations ..................................................................... 29 
4.5.4. 
Laboratory Data .................................................................................... 30 
4.5.5. 
Concomitant Medications and Procedures ........................................... 30 
4.5.6. 
12-Lead Electrocardiogram .................................................................. 30 
4.5.7. 
Quantitative Skin Color Measurement ................................................. 30 
4.5.8. 
Bone Age Assessment .......................................................................... 30 
4.5.9. 
 .................................................................. 31 
4.5.10. 
Vital Signs............................................................................................. 31 
4.5.11. 
Physical Exam and Comprehensive Skin Examination ........................ 31 
4.5.12. 
Anti-RM Antibody ................................................................................ 31 
5. 
Changes to Planned Analyses ....................................................................................... 32 
6. 
References ....................................................................................................................... 33 
7. 
Appendix ......................................................................................................................... 34 
 


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TABLES INCLUDED IN THE TEXT 
Section 
Page 
Table 1-1: 
Index Studies Currently Included in RM-493-022 ............................................................ 9 
Table 1-2: 
Schedule of Assessments ................................................................................................. 14 
 
 


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LIST OF ABBREVIATIONS AND DEFINITION OF TERMS 
Abbreviation 
Definition 
AE 
Adverse event 
AESI 
Adverse event of special interest 
ALT 
Alanine aminotransferase 
AST 
Aspartate aminotransferase 
BP 
Blood pressure 
CO2 
Carbon dioxide 
CRF 
Case report form 
CTCAE 
Common Terminology Criteria for Adverse Events 
ECG 
Electrocardiogram 
HbA1c 
glycated hemoglobin 
HR 
Heart rate 
IWQOL-Lite 
Impact of Weight on Quality of Life-Lite Questionnaire 
LDH 
Lactic dehydrogenase 
LEPR 
Leptin Receptor 
MC 
Melanocortins 
MedDRA 
Medical Dictionary for Regulatory Activities 
MHP 
Mental health provider 
PedsQL 
Pediatric quality of life 
PHQ-9 
Patient Health Questionnaire 9 
POMC 
Pro-opiomelanocortin 
PT 
Preferred term 
SAE 
Serious adverse event 
SAP 
Statistical analysis plan 
SF-36 
36-item Short Form health survey 
SOA 
Schedule of assessments 
SOC 
System organ class 


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1. 
INFORMATION FROM THE STUDY PROTOCOL 
1.1. 
Introduction  
This document presents the statistical analysis plan (SAP) for Study RM-493-022, Long Term 
Extension Trial of Setmelanotide (RM-493) for Patients Who Have Completed a Trial of 
Setmelanotide for the Treatment of Obesity Associated with Genetic Defects Upstream of the 
MC4 Receptor in the Leptin-Melanocortin Pathway. The SAP is based upon protocol version 
8.0, dated 12 May 2023. 
This SAP is designed to outline the methods to be used in the analysis of study data in order to 
answer the study objectives.  Populations for analysis, data handling rules, statistical methods, 
and formats for data presentation are provided. The statistical analyses and summary tabulations 
described in this SAP will provide the basis for the results sections of the clinical study report 
(CSR) for this trial. 
1.2. 
Study Objectives  
1.2.1. 
Primary Objective 
The primary objective of the study is to characterize safety and tolerability of setmelanotide in 
subjects who have completed a previous trial on treatment with setmelanotide for obesity 
associated with genetic defects upstream of the MC4R in the leptin-melanocortin pathway or 
with obesity related to other abnormalities in the MC4R pathway.  
1.2.2. 
Exploratory Objectives 
1.3. 
Study Design 
1.3.1. 
Synopsis of Study Design 
This is a long-term extension study of up to an additional 7 years duration beyond the index trial 
for patients who have completed a previous study on treatment with setmelanotide for rare 


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genetic, syndromic, or acquired diseases of obesity upstream of the MC4R in the melanocortin-
leptin pathway and other abnormalities of the MC4R pathway.  
Since continued assessments of the safety and efficacy of setmelanotide are the same in this extension 
protocol regardless of the index protocol, all patients can be followed consistently in this single extension 
protocol. The index trials relevant to this study are identified in Table 1-1.Eligible and consenting 
patients start in the extension trial immediately on the completion of their index protocol 
(ideally, Visit 1 of this trial will coincide with the final visit of the index trial) in order to limit 
gaps in treatment.  
 
Patients are assessed approximately every 3 months for adverse events (AEs), concomitant 
medications, 
 height (in children), 
 
 
Patients enrolled in this extension trial may exit the trial to participate in other setmelanotide 
clinical trials. At the conclusion of the other setmelanotide trial, the patient may transition back 
into this extension trial. In such cases, the patient resumes the extension trial at the time 
point/visit at which he or she was at prior to transition to the other trial. Furthermore, after 
transition back into this extension trial, the patient receives setmelanotide at the same dose as 
they had received prior to transition to the other trial, unless the dose needs to be reduced due to 
tolerability reasons or in cases where a dose increase is required for potential additional efficacy 
needs at the investigator’s discretion.  
 


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Table 1-1 
Index Studies Currently Included in RM-493-022 
Study 
Identifier 
Study 
Phase 
Number of 
Subjects  who 
participated in 
Extension Trial 
Diagnosis of Subjects 
 
 
 
 
011 
2 
9 
Genetic disorder of obesity 
012 
3 
13 
Early Onset POMC/PCSK1 Deficiency Obesity 
014 
2 
119 
Genetic disorder of obesity 
015 
3 
12 
LEPR Deficiency Obesity 
023 
3 
38 
BBS and AS 
030 
2 
14 
Hypothalamic Obesity 
034 
2 
1 
Genetic disorder of obesity 
Abbreviations: AS=Alstrom Syndrome; BBS= Bardet-Biedl Syndrome; LEPR = Leptin Receptor; POMC = Pro-opiomelanocortin.   
Note: Patients in RM-493-037 were previously enrolled in one of the index studies and RM-493-022 prior to entering the RM-493-037; patients were eligible to reenroll in RM-
493-022 after participation in the RM-493-037. These patients are analyzed according to their index trial.   
 


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1.3.2. 
Stopping Rules and Unblinding 
This study is open label so there is no blinding.  All blinded index trials have been completed 
and are unblinded for analysis of RM-493-022.   
A specific gene cohort or the whole trial may be terminated, if in the opinion of the investigator 
(at a participating site) or Rhythm (for the whole study), there is sufficiently reasonable cause. 
The terminating party will provide written notification documenting the reason for termination 
to either the investigator or Rhythm. Circumstances that may warrant termination include, but 
are not limited to: 
 Determination of unexpected, significant, or unacceptable risk to subjects 
 Failure to enter subjects at an acceptable rate 
 Insufficient adherence to protocol requirements 
 Insufficient complete and/or evaluable data 
 Plans to modify, suspend or discontinue the development of the study drug 
 Lack of clinical efficacy 
1.3.3. 
Randomization Methodology 
As this is a single arm, open-label study, there will be no randomization in this trial. 
1.4. 
Study Procedures 
The schedule of assessments, as outlined in the study protocol, is provided in Table 1-2.  
In order to provide flexibility to the subject and study staff for the number of clinic visits, the 
actual scheduling of clinic visits can allow flexibility in timing of visits. 
 








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measured at each visit for patients <21 years of age. Height 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 half cm. The stadiometer should be calibrated by site personnel on a daily basis prior to height assessment. 
6 A comprehensive skin evaluation will be performed yearly by a dermatologist. As part of the physical examination at each visit, the investigator will note any significant skin 
abnormalities and refer the patient to the dermatologist if necessary. 
 
 
8 Prior to study drug administration. 
 
 
 
 
10 Study drug is administered by patients/caregivers beginning the morning of Day 1 and for the duration of dosing. (If the index study drug is administered on the last day of the 
index trial/Day 1 of the current trial, then study drug administration in the current trial will begin on Day 2.) Patients/caregivers will draw up and self-administer/administer 
the drug QD in the morning. On days with clinic visits, the patients/caregivers will administer the drug in the clinic in the presence of the clinical staff to ensure proper 
technique. Patients/caregivers will return all used vials to the clinic when they visit (the number recorded) and both clinic administered study drug, as well as outpatient 
study drug administration will be recorded in a trial diary. In patients aged ≥18 years who tolerate the 3 mg QD dose level for at least 6 months, if additional effect on 
 
 is desired per the patient individual needs, a higher QD dose can be administered at the investigator’s discretion and in consultation with the sponsor; the 
dose can be escalated to 3.5 mg and, if tolerated, it can be escalated by an additional 0.5 mg every second week, until reaching the maximum dose of 5 mg QD in adult 
patients with on absolute body weigh >60 kg. The maximum dose level is 4 mg in patients with an absolute weight of >50 kg. These dose levels have been investigated 
previously in trial RM-493-026. Patients exposed to these dose levels should be monitored closely via additional unscheduled visits or telephone calls to assess safety and 
tolerability. For patients who escalated to 4 or 5 mg QD, the dose level should be reduced to 3 mg and 4 mg if their absolute weight decreases to ≤50 kg and ≤60 kg, 
respectively. This is due to the excipients content in the setmelanotide formulation (see study protocol for details). 
11 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 unscheduled evaluations may also be recorded as warranted by clinical conditions, including in the interval between 
scheduled visits. 
12 All vital signs are to be obtained in the sitting position following at least 5 minutes of rest. All measurements, except body temperature, will be taken in triplicate, approximately 
2 minutes apart. When possible, BP should be taken in the non-dominant arm throughout the trial, using the same methodology (automated or manual). Vital signs should be 
obtained prior to blood draws whenever possible. 
13 A single 12-lead ECG will be performed in the supine position following a period of at least 5 minutes of rest. 
14 Safety laboratory tests will include: CBC with platelet count and standard indices, chemistry panel (includes sodium, potassium, chloride, CO2, albumin, total protein, glucose, 
BUN, creatinine, uric acid, AST, ALT, GGT, CPK, alkaline phosphatase, total bilirubin, direct bilirubin, LDH, calcium, phosphorus), urinalysis (pH, glucose, protein, 
ketones, bilirubin, blood, urobilinogen, specific gravity, nitrite, and leukocytes) with microscopic analysis if positive findings on dipsticks warrant further examination. 
Fasting samples (8-hour minimum) are required at all timepoints where feasible. Fasting lipid panel and HbA1c will also be included. 
 
 


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18 If bone age was assessed in the index trial, bone age X-rays of the hand with magnified views will be continued in this trial for continued monitoring of pediatric patients 
through sexual maturation to adulthood, or until bone epiphyseal plate fusion and maturation are complete, as per routine pediatric evaluation for growth and bone 
development in patients with underlying endocrine disorders. 
 
21Any patient with a positive ADA will be followed ~every 3 months after detection until titers resolve or return to baseline. Note that in pediatric patients, samples for ADA as 
well as 
 should be collected as feasible/permissible by local regulations. 
22 Adverse events will be recorded from the time a patient provides informed consent/assent. AEs occurring after dosing on Day 1 will be considered treatment-emergent AEs in 
the current trial. 
23 For pediatric (age 2-11 years) patients only, Nutritional Counseling and Monitoring may be performed by an appropriate dietician or nutritionist (or equivalent), at the 
investigator’s discretion, to ensure that pediatric patients have adequate nutritional/dietary intake to maintain proper growth and development. Additional laboratory 
assessments indicative of nutritional status may be monitored, as appropriate (e.g., albumin). 
 
 
 
 
 
 
 
 
26 In the event that a patient is completing this trial but continuing treatment with setmelanotide, then this follow-up visit may be converted to a telephone call. In that case, the site 
should document any new AEs and follow-up on any ongoing AEs; remaining study drug should be returned to site, no other activities are required (see study protocol). 
27 Investigators may be asked by the sponsor to perform a chart review and a detailed analysis and collection of the clinical history of certain patient populations (e.g., selected 
based on indication, genetics, age group, duration of participation in the current trial [e.g., at least 6 months]). Patients or their legal guardians must provide written 
informed consent/assent to participate in this substudy. Refer to study protocol for details. 
28 Certain patient populations (e.g., selected based on indication, genetics, age group, duration of participation in the current trial [e.g., at least 6 months]), may be offered the 
opportunity to participate in a substudy involving a patient/caregiver survey. Patients or their legal guardians will be required to provide written informed consent/assent to 
participate in this substudy. Refer to study protocol for details. 
 


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1.4.1. 
Primary Endpoint 
The safety and tolerability of setmelanotide will be assessed by the frequency and severity of 
AEs, as well as changes in physical examinations, vital signs, laboratory evaluations, and 
injection site reactions. 
1.4.2. 
 


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2. 
SUBJECT POPULATIONS  
2.1. 
Population Definitions 
 Safety Analysis Population (SAS) – The SAS includes all subjects who received at least 
one dose of treatment in RM-493-022. The safety population will be used for all 
analyses.  
2.2. 
Protocol Violations 
All protocol deviations will be presented in a data listing; major deviations will be indicated. 
Categorization of protocol deviations will be determined by a review of the protocol deviation 
data collected on the case report form (CRF). Determination of major/minor and categorization 
of each protocol deviation type will be made prior to database lock. 
 


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3. 
GENERAL STATISTICAL METHODS 
3.1. 
Sample Size Justification 
The primary objective of this study is to evaluate long term safety and tolerability in subjects 
with various rare genetic, syndromic, or acquired forms of obesity impacting the MC4R 
pathway after completing planned setmelanotide treatment in a previously completed index 
protocol. All subjects who complete an index protocol and meet eligibility criteria can enroll in 
this study. Thus, sample size estimation and power analyses are not relevant. 
Given the rarity of these genetic and acquired diseases of the MC4R pathway, estimated power 
for exploratory endpoints such as expected weight-related improvements and change in hunger 
will not be provided, and efficacy will be only summarized. 
3.2. 
General Methods 
All data listings that contain an evaluation date will contain a relative study day (Rel Day).  Pre-
treatment and on-treatment study days are numbered relative to the day of the first dose of study 
medication which is designated as Day 1.  The preceding day is Day -1, the day before that is 
Day -2, etc.  The last day of study medication is designated with an “L” (e.g., Day 14L).  Post-
treatment study days are numbered relative to the last dose and are designated as Day 1P, 
Day 2P, etc. 
All output will be sorted and labeled according to the International Conference on 
Harmonisation (ICH) recommendations and formatted to the appropriate page size(s). 
Tabulations will be produced for appropriate demographic, baseline, efficacy, pharmacokinetic, 
and safety parameters.  For categorical variables, summary tabulations of the number and 
percentage of subjects within each category (with a category for missing data) of the parameter 
will be presented.  For continuous variables, the number of subjects, mean, median, standard 
deviation (SD), minimum, and maximum values will be presented. . For the reporting of 
descriptive statistics, the mean and median will be reported to 1 decimal place more than the 
source data; the minimum and the maximum values will be presented to the same precision as 
the source data, and SD will be reported to 2 decimal places more than the source data. 
 
3.3. 
Computing Environment 
All descriptive statistical analyses will be performed using SAS statistical software Version 9.4 
(SAS Institute Inc., Cary, NC, USA), unless otherwise noted.  Medical history and adverse 
events will be coded using the Medical Dictionary for Regulatory Activities (MedDRA) Version 
23.0 or later.  Concomitant medications will be coded using the World Health Organization 
(WHO) Drug Dictionary Version September 2023 or later. 
3.4. 
Baseline Definitions 
To assess the temporal dynamics of setmelanotide on weight, BMI, BMI z-score, percent of 
BMI 95th percentile, waist circumference, body composition,  two baseline definitions will be 
utilized: 


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 Extension study baseline will be defined as the last value obtained in the index study 
prior to the first dose of active treatment in the extension study. For subjects with a 
>1 day gap in Setmelanotide treatment between the index study and the extension 
study, the last value obtained prior to first active treatment dose in the extension 
study will be used as the baseline 
 Index study baseline will be defined as the last value obtained prior to the first dose of 
active treatment in the index study. 
For all other parameters, baseline will use the extension study baseline as defined above.   
3.5. 
Methods of Pooling Data 
For safety-related analyses, data will be pooled across index studies and rare genetic disorders 
of obesity and summarized together. For non-safety-related analyses, data will be pooled by rare 
genetic disorder of obesity within study, as applicable, and data will therefore be summarized by 
index study. 
3.6. 
Adjustments for Covariates 
No formal statistical analyses that adjust for possible covariate effects are planned. 
3.7. 
Multiple Comparisons/Multiplicity 
Multiplicity is not of concern for this study with a descriptive interpretation. 
3.8. 
Subpopulations 
No subpopulations have been defined.  
3.9. 
Data from Index Studies 
In general, data from index studies will only be used for identifying index study baseline and the 
extension study baseline, as applicable. Index study data will additionally be used to summarize 
demographic and disease characteristics at time of entry into index study such as age at 
enrollment in index study, country of investigational site, sex, race, ethnicity, gene type, height, 
weight, BMI, and waist circumference.  
3.10. 
Withdrawals, Dropouts, Loss to Follow-up 
Subjects will be followed for the duration of the study, except where: 
 Informed consent is withdrawn and the subject or guardian refuses further follow-up 
(subjects have the right to withdraw consent and discontinue from the study at any 
time, for any reason.) 
 The subject is unable to comply with protocol-defined requirements (non-
adherence/compliance to dosing regimens or visits). 


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 Investigator decision to withdraw subject 
The subject’s reason for, and date of, withdrawal from the study is to be recorded in the CRF. 
Any subject withdrawing from the study will complete the Early Termination Visit, if possible. 
3.11. 
Missing, Unused, and Spurious Data 
In general, no missing data will be imputed for this extension study and analyses will be carried 
out on all available data. Imputation of missing questionnaire data will be applied for the 
derivation of summary scores, dependent on the questionnaire and imputation rules of the 
questionnaire. Questionnaire-specific imputation rules will be outlined in the sections below, as 
applicable. 
3.12. 
Visit Windows 
It is expected that all visits should occur according to the protocol schedule. All data will be 
tabulated per the evaluation visit as recorded on the CRF even if the assessment is outside of the 
visit window. If the evaluation visit is missing in the database but there are data from an 
unscheduled or additional visit that is inside the visit window, the data from the unscheduled or 
additional visit will be used in data summaries. All available data will be listed for each subject.  
3.13. 
Interim Analyses 
No formal interim analyses are planned; however, various data cuts may occur in support of 
regulatory submission such as NDA. The timing of these data cuts and the number of subjects 
included in each analysis will take into account specific requests from regulatory agencies and 
applicable regulatory guidance. The rationale for each analysis will be documented. 
3.14. 
Final Analyses 
A final analysis will be performed when all subjects complete the study, defined as last subject 
last visit. 


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4. 
STUDY ANALYSES 
4.1. 
Subject Disposition 
A tabulation of the disposition of subjects will be presented, including the number enrolled, the 
total time followed since index study baseline and since extension study baseline, the number of 
subjects completing the extension study, the number of subjects discontinuing from the study, 
and the reasons for any subject who discontinued. Disposition will be summarized by index 
study and overall. 
A by-subject data listing of study completion information including the reason for premature 
study withdrawal, if applicable, will be presented.  
4.2. 
Demographics and Disease Characteristics 
Demographics and disease characteristics will be summarized and presented overall and by 
index study. Age at index study enrollment, country of investigational site, height, weight, BMI, 
and waist circumference will be summarized using descriptive statistics (number of subjects, 
mean, standard deviation, median, minimum, and maximum). The number and percentage of 
subjects in each sex, gene type, ethnicity and race category will also be presented.  
Medical history prior to enrollment in index trial and brief medical history collected prior to 
enrollment into extension study will be included in a by-subject listing, with extension study 
medical history flagged in the listing. 
4.3. 
Exploratory Evaluations 
4.3.1. 
 
4.3.2. 
 
  
 
 
  


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Change and percent change from the index trial baseline as well as change and percent change 
from the extension study baseline (as defined in Section 3.4). will be summarized for all patients 
and separately for patients > 18 years of age  .  
A by-subject listing be provided for all subjects. 
4.3.3. 
 
4.3.4. 
 
 
   
 
 
 
 
 
  
 
  


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4.3.5. 
 
 
 
 
  
4.3.6. 
 
 
 
   
4.3.7. 
and HbA1c 
 and HbA1c will be collected according to the SOA (Table 1-2) and will consist of 
 
 and HbA1c. Descriptive statistic summaries of the extension study 
raw, change and percent change from extension study baselines will be presented for each 
measure. By-subject results will be presented in a listing. 
4.3.8. 
 
4.3.8.1. 
  
4.3.8.2. 
 


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4.3.8.3. 
 
4.3.9. 
 
4.3.10. 
 
4.3.11. 
 


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4.4. 
 
 
 
 
4.5. 
Safety Evaluations 
4.5.1. 
Study Drug Exposure 
The duration of exposure in days will be reported for the for both the index + extension studies 
as wells the extension study  only.  The duration of exposure for the extension study will be 
calculated as the extension study last dose date minus the extension first dose date + 1.; the 
duration of exposure for the index + extension studies will be calculated as the sum of the 
extension period duration (as described above) plus the duration of exposure for the index study 
(last dose date – first dose date +1 from index study) .Data will be summarized and listed.  
4.5.2. 
Adverse Events 
All AEs will be coded using the MedDRA coding system (version 25.0 or higher) and displayed 
in tables and in data listings using system organ class (SOC) and preferred term (PT). AE Grade 
assessment will be based on Investigator reporting using the National Cancer Institute Common 
Terminology Criteria for Adverse Events [NCI CTCAE], version 4.03. 
Summarization will focus on incidence of drug product related AEs, treatment-emergent SAEs 
by SOC and PT,   
A by-subject listing for the following AEs that occurred on extension study will also be 
provided: drug product-related AEs, treatment-emergent SAEs, drug product-related SAEs, 
deaths, AEs leading to study withdrawal, and subject deaths. Adverse event listings will be 
sorted by index study.  
4.5.3. 
Injection Site Evaluations 
Injection site evaluations will be measured as shown in the SOA (Table 1-2) and will be 
summarized by visit according to severity (none, mild, moderate, severe) and type of reaction: 
erythema, edema, induration, itching, pain or tenderness, or other reaction. For subjects 
reporting more than one occurrence of the same type of reaction, the most severe reaction will 
be used for the summary.  
A by-subject listing will be provided for all injection site evaluations and will also include 
measurement (if applicable).  
4.5.4. 
Laboratory Data 
Clinical laboratory values will be expressed using the International System of Units (SI). Values 
will be summarized using raw, change and percent change from extension study baseline for 


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each clinical laboratory parameter. Clinical laboratory parameters include hematology, 
chemistry, and urinalysis. 
Shift tables, which will indicate abnormally high or abnormally low changes in laboratory 
parameter grade based on CTCAE criteria from extension study baseline through extension 
study follow-up, will be performed by visit. 
By-subject listings will be provided for all laboratory data collected, including hematology, 
chemistry, urinalysis, and pregnancy tests. 
4.5.5. 
Concomitant Medications and Procedures 
Prior and concomitant medications will be coded using the WHO Drug Dictionary.  
Concomitant medications are those which were ongoing or began after the patient began 
participating in the extension trial.  
The use of concomitant medications during the extension study will be included in a summary 
table. Prior and concomitant procedures will be included in a by-subject data listing.  
Concomitant procedures will be included in a by-subject data listing.  
4.5.6. 
12-Lead Electrocardiogram 
Electrocardiogram results will be summarized in a by-visit shift table, including the number and 
percentage of subjects with normal, abnormal, and clinically significant abnormal results at 
extension study baseline and shift to each extension study visit. 
Electrocardiogram data for each subject, including heart rate, PR interval, QRS interval, QT 
interval, and QTcF interval, as well as the overall interpretation, will be provided in a summary 
table and a data listing. 
4.5.7. 
Quantitative Skin Color Measurement 
Quantitative skin color measurement data will be provided in a by-patient listing.    
4.5.8. 
Bone Age Assessment 
Bone age assessment will be measured as shown in the SOA (Table 1-2) if done in the index 
study. A by-subject listing, including the date of the assessment and result, will be provided as 
available. 
4.5.9. 
 


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4.5.10. 
Vital Signs 
Vital signs will be measured as shown in the SOA (Table 1-2). Aside from those used in 
exploratory evaluation, the raw, change and percent change from extension study baseline of 
additional vital signs of temperature, heart rate, systolic blood pressure, diastolic blood pressure, 
respiratory rate will be summarized descriptively by visit. A by-subject listing of all vital signs 
will be provided.  
4.5.11. 
Physical Exam and Comprehensive Skin Examination 
Physical exams will be measured as shown in the SOA (Table 1-2). Results from each 
component of the physical exam will be provided in shift tables, summarizing the shift from 
extension study baseline by visit. A by-subject listing of all physical exam findings will be 
provided; results of the comprehensive skin examination will be provided in the listing. 
Tanner Staging will be presented in a by-subject listing.  
4.5.12. 
Anti-RM Antibody 
Anti-RM Antibody will be measured as shown in the SOA (Table 1-2). A by-subject listing, 
including the date of the assessment and result, will be provided. 


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5. 
CHANGES TO PLANNED ANALYSES 


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6. 
REFERENCES 
NHLBI. The practical guide identification, evaluation, and treatment of overweight and obese in 
adults. NIH Publication No. 00-4084, October 2000. 
Saris-Baglama R, Dewey C, Chisholm G, et al. (2011). QualityMetric Health Outcomes Scoring 
Software 4.5 User’s Guide. Lincoln, RI: QualityMetric Incorporated. 
Vami, JW. (2017). Scaling and Scoring of the Pediatric Quality of Life Inventory PedsQL. 
Lyon, France: Mapi Research Trust. 
 
 


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7. 
APPENDIX