A Phase 3, Randomized, Double-Blind, Placebo-Controlled Trial: Multiple Independent Sub-studies of Setmelanotide in Patients with POMC/PCSK1, LEPR, NCOA1 (SRC1) or SH2B1 Gene Variants in the Melanocortin-4 Receptor Pathway

1. Patients must have a pre-identified:
• Heterozygous gene variant in the POMC gene or PCSK1 gene (Substudy035a),
• Heterozygous gene variant in the LEPR gene (Sub-study 035b),
• Homozygous, heterozygous, or compound heterozygous variant in the
NCOA1 (SRC1) gene (Sub-study 035c),
• Homozygous, heterozygous, or compound heterozygous variant in the
SH2B1 gene, or chromosomal 16p11.2 deletion encompassing the SH2B1
gene (Sub-study 035d),
For POMC, PCSK1, LEPR, NCOA1 (SRC1) and SH2B1 gene variants, to be
considered for inclusion, the variant must either:
• Be categorized by a Clinical Laboratory Improvement Amendments
(CLIA)/College of American Pathologists (CAP)/International
Organisation for Standardization (ISO) 15189 -certified laboratory using
ACMG criteria as
a) pathogenic (P); or
b) likely pathogenic (LP); or
c) Variant of uncertain significance (VUS); or FOR POMC, PCSK1
d) and LEPR, in addition to P/LP, only the subcategory of VUS variants
that are suspected to be pathogenic (VUS-SP) will be eligible for
inclusion.
If a patient has 2 or more variants eligible for the trial, she/he will be
assigned to a sub-study according to the following 2 rules:
1) To the highest ACMG pathogenicity category according to the
following hierarchy: P > LP > VUS-SP > VUS (see Appendix 1 for further
examples).
• For example, if a patient carries both a POMC pathogenic (P) variant
and a LEPR VUS-SP variant, the patient will be assigned as a POMC
Pathogenic (P) patient (Sub-study 035a).
2) If the 2 variants have the same ACMG classification, the patient will
be assigned to the sub-study with lower overall frequency of gene
variants according to the following hierarchy (least frequent to most
frequent): LEPR > POMC/PCSK1 > NCOA1 (SRC1) > SH2B1 (see
Appendix 2. for further examples).
For example:
• If a patient carries both a LEPR Pathogenic (P) variant and SH2B1
Pathogenic (P) variant, the patient will be assigned as a LEPR
Pathogenic (P) patient (Sub-study 035b).
See Appendix 3 for genetic testing requirements to be enrolled in the
trial.
2. Between 6 and 65 years of age at the time of provision of informed
consent/assent.
3. Obesity, with reported onset in childhood, and BMI >=30 kg/m2 for
patients >=18 years of age or BMI >=95th percentile for age and gender for
patients 6 to 17 years of age, based on the United States (US) CDC
criteria, at screening.
4. Patient and/or parent or guardian is able to communicate well with
the Investigator, understand and comply with the requirements of the
trial (including once daily [QD] injection regimen and all other trial
procedures), and is able to understand and sign the written informed
consent/assent. Patients who are unable to comply with all trial
procedures due to cognitive limitations or any other reason should not
be enrolled into the trial.
5. Patient and/or parent or guardian reports that the patient
experienced childhood obesity, defined as the patient and/or parent or
guardian reporting that the patient had obesity or was significantly
overweight prior to the age of 6 years old.
Refer to the protocol for inclusion criteria 6, 7, and 8 due character limit.

1. Bariatric surgery or procedure (e.g., gastric bypass/band/sleeve, duodenal
switch, gastric balloon, intestinal barrier, etc.) within the last 6 months.
All patients with a history of bariatric surgery or procedures must be
discussed with, and receive approval from, the Sponsor prior to enrollment.
2. Weight loss >2% in the previous 3 months.
Patients will not be excluded for using regimens for weight maintenance or to
prevent weight gain, such as dietary and/or exercise regimens, or medications,
supplements or herbal treatments (e.g., orlistat, lorcaserin, phentermine,
topiramate, naltrexone, bupropion, Glucagon-like peptide-
1 [GLP-1] receptor agonists, etc.) provided:
• the regimen and/or dose has been stable for at least 3 months prior to
randomization
• the patient has not experienced weight loss >2% during the previous 3 months,
AND
• the patient intends to keep the regimen and/or dose stable throughout the
course of the trial.
3. Documented diagnosis of current unstable major psychiatric disorder(s)
(e.g., major depressive disorder, bipolar disorder, schizophrenia, etc.) or
documented worsening psychiatric condition that required changes in treatment
regimen within
the previous 2 years, or other psychiatric-related risks that the Investigator
believes may interfere with trial compliance or patient
safety.
4. Clinically significant depression or suicidality as defined by: any suicidal
ideation of type 4 or 5 on the Columbia Suicide Severity Rating Scale (C-SSRS)
during Screening, any suicide attempt during the patient's lifetime, or any
suicidal behavior in the last month, or a Patient Health Questionnaire-9
(PHQ-9) score of >=15 during Screening.
5. Current, clinically significant pulmonary, cardiac, endocrine/metabolic,
hepatic or oncologic disease considered severe
enough to interfere with the trial and/or confound the results. Any patient
with a potentially clinically significant disease should be
reviewed with the Sponsor to determine eligibility.
6. HbA1c >10% at Screening.
7. History of significant liver disease other than non-alcoholic fatty liver
disease (NAFLD) or nonalcoholic steatohepatitis (NASH). (Patients with NAFLD or
NASH will not be excluded based on this criterion.)
8. Estimated glomerular filtration rate (eGFR) <30 mL/min/1.73 m2 at Screening.
In patients >=18 years of age the Modification of Diet in Renal Disease (MDRD)
Equation should be used to calculate eGFR. In patients <18 years of age the
Bedside Schwartz Equation should be used to calculate eGFR (see Section 7.2.5).
9. History or close family history (parents or siblings) of melanoma, or
patient history of oculocutaneous albinism.
10. Significant dermatologic findings relating to melanoma or premelanoma skin
lesions (excluding non-invasive basal or squamous cell lesion), determined as
part of a comprehensive skin evaluation performed by the Investigator during
Screening. Any concerning lesions identified during Screening 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.
11. Patient is, in the opinion of the Investigator, not suitable to participate
in the trial.
12. Participation in any clinical trial with an investigational drug/device
within 3 months or 5 half-lives, whichever is longer, prior to the first day of
dosing.
13. Previously enrolled in a clinical trial involving setmelanotide or any
previous exposure to setmelanotide.
14. Hypersensitivity to the active substance or to any of the excipients of the
investigational medicinal products (active and placebo).
15.Females who are, pregnant or breastfeeding, or planning or desiring to
become pregnant during the duration of the trial.
16. Patients with the following gene variations: biallelic BBS (and/or clinical
diagnosis of Bardet-Biedl syndrome [BBS]) or biallelic ALMS1, or any MC4R
variants.
17. Legally protected persons per local regulations (e.g., those that fall
under the L1121-6 article of the Public Health code in France) or other
applicable local laws.