Protocol Amendment 1 included the following revisions to the original protocol: • Treatment of younger patients with the POMC null genetic deficiency (12 years of age and older). • Adjustment of the initial dose level of setmelanotide and subsequent dose escalation procedure based on results of the first patient. • Revisions to study procedures to include pharmacokinetics (PK) measurement of setmelanotide at a scheduled study visit. • Addition of 24-hour ambulatory blood pressure monitoring (ABPM) to more closely evaluate potential changes in blood pressure and heart rate.

Amendments 2 and 2.1 were not approved by the local CA. All elements of Amendments 2 and 2.1 were therefore included, submitted, and approved in Amendment 3. Protocol Amendment 3 provided the following revisions to the study protocol: •Increased the starting dose of setmelanotide from 0.25 mg to 0.5 mg in the dose titration phase of the study. •Decreased the interval of dose escalations from 2 weeks to 1 week. •Added procedures at the final visit examination after the third phase of the study to accommodate a planned pharmacodynamic analysis. Additional serum samples were intended to permit correlation analysis of setmelanotide PK. •Added a 24-hour blood pressure measurement on the day before the final visit examination. Also, the study was extended to a duration of 1-2 years. If a patient lost sufficient body weight during the first 12 weeks in the study without significant adverse events reported and agreed to provide consent to continue treatment with setmelanotide, they were eligible to participate in an extension phase. The following revisions were included in this amendment to accommodate this extension of setmelanotide treatment: •Extension of treatment duration for 1 year (ability to continue in 1-year increments; with careful monitoring of the vital signs; continuation for another year after confirmation by BfArM (up to a maximum of a total 2-year treatment period). •Regular visits at least every 3 months with the study doctor. •Full safety laboratory evaluations including OGTT, GnRH test every 6 months. •Consultation with a dermatologist every 6 months. •Daily measurements of blood pressure (once daily) at home, and additional blood pressure monitoring at study site visits. •A brief report summarizing the study course to be sent to the CA every 8 weeks.

Protocol Amendment 4 included the following revisions to the original protocol: Based upon promising results demonstrating efficacy and safety in 2 adult POMC deficient patients participating in the study, the study inclusion criteria were revised to include adult LEPR and PCSK1 deficient patients.

Protocol Amendment 5 included the following revisions to the original protocol: The study was amended to allow inclusion of non-adult, adolescent POMC patients 12 years of age and older. In addition, the amendment included the following additional monitoring steps. 1. During the first 3 months of treatment, non-adult patients were to be examined by a paediatrician once a week, and the investigator was to have weekly contact (phone call or clinic visit). 2. The patients were to be seen by the investigator every 4 weeks during the first 3 months. 3. Blood pressure measurements 3 times daily. 4. A brief progress report regarding chronic animal toxicology findings was to be provided by Rhythm Pharmaceuticals every 4 weeks. 5. Patients that entered the extension portion of the study were to be examined by the investigator every 3 months, and laboratory testing (liver function, complete blood count, and metabolic parameters) and dermatological examinations performed. Every 6 months laboratory testing was to include OGTT and GnRH testing.

Protocol Amendment 6.1 included the following revisions. 1. Renamed protocol to clarify this protocol studied a broad range of rare monogenic causes of obesity related to the MC4 pathway. 2. Inclusion of the following obese patient populations with genetic mutations impacting the leptin-melanocortin pathway: • Heterozygous POMC mutations • POMC hypermethylation • Bardet-Biedl syndrome • Alstrom’s Syndrome 3. Based on initial clinical data in an adult LEPR patient, this amendment included non-adult, adolescent LEPR patients (≥12 years of age). 4. Outlined specific entry procedures related to non-adult, adolescent patients (≥12 years of age). 5. Allowed a short period of treatment withdrawal for consenting patients who qualified for inclusion in the extension phase.

Protocol Amendment 7 included the following revisions to the original protocol: This protocol amendment revised the maximum setmelanotide dose level administered to adult patients up to 2.5 mg and revised the weight loss criterion for entering the extension portion of the study from 8 kg to 5 kg of total weight reduction during the initial treatment phase of the study.

Protocol Amendment 8 included the following revisions to the original protocol: This protocol amendment provided for the inclusion of MC4R variant carriers in the study and established a further extension of treatment with setmelanotide beyond 2 years (elongation portion). This amendment also revised the maximum setmelanotide dose level administered to adult patients up to 3.0 mg.

Protocol Amendment 9 included the following revisions to the original protocol: This protocol amendment assigned a subinvestigator and established the previous investigator as the principal investigator. It also expanded eligibility to epigenetic variant non-adult patients (12 years of age and older) and implemented the use of a dosing diary.

Protocol Amendment 10 included the following revisions to the original protocol: A change from single-use vials to multiple-use vials was incorporated into this amendment. Patients received written instructions in addition to injection training.

Protocol Amendment 11 included the following revisions to the original protocol: This amendment provided the rationale for inclusion of non-adult MC4R deficient patients ≥12 years of age.