Setmelanotide for the Treatment of Early-Onset POMC Deficiency Obesity

Inclusion Criteria:

1. Bi-allelic, homozygous or compound heterozygous (a different gene mutation on each
allele) genetic status for either the POMC or PCSK1 genes, with the loss-of-function
(LOF) variant for each allele conferring a severe obesity phenotype.

2. Age 12 years and above.

3. If adult age ≥18 years, obesity with body mass index (BMI) ≥ 30 kg/m2; if child or
adolescent, obesity with weight > 97th percentile for age on growth chart assessment.

4. Study participant and/or parent or guardian is able to communicate well with the
investigator, to understand and comply with the requirements of the study, and be able
to understand and sign the written informed consent/assent.

5. Female participants of child-bearing potential must agree to use contraception as
outlined in the protocol. Female participants of non-childbearing potential, defined
as surgically sterile (status post hysterectomy, bilateral oophorectomy, or bilateral
tubal ligation) or post-menopausal for at least 12 months (and confirmed with a
screening FSH level in the post-menopausal lab range), do not require contraception
during the study.

6. Male participants with female partners of childbearing potential must agree to a
double barrier method if they become sexually active during the study. Male patients
must not donate sperm during and for 90 days following their participation in the
study.

Exclusion Criteria:

1. Recent intensive (within 2 months) diet and/or exercise regimen with or without the
use of weight loss agents including herbal medications, that has resulted in weight
loss or weight stabilization. Patients may be reconsidered approximately 1 month after
cessation of such intensive regimens.

2. Prior gastric bypass surgery resulting in >10% weight loss durably maintained from the
baseline pre-operative weight with no evidence of weight regain. Specifically,
patients may be considered if surgery was not successful, or resulted in <10% weight
loss compared to pre-operative baseline weight or clear evidence of weight regain
after an initial response to bariatric surgery. All patients with a history of
bariatric surgery must be discussed with, and receive approval from Rhythm prior to
enrollment.

3. 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 study compliance.

4. A Patient Health Questionnaire-9 (PHQ-9) score of ≥ 15.

5. 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 in the
last month.

6. Current, clinically significant pulmonary, cardiac, or oncologic disease, if these
were severe enough to interfere with the study and/or would confound the results. Any
such patients should be discussed with the sponsor prior to inclusion.

7. History of significant liver disease or liver injury, or current liver assessment for
a cause of abnormal liver tests [as indicated by abnormal liver function tests,
alanine transaminase (ALT), aspartate transaminase (AST), alkaline phosphatase, or
serum bilirubin (> 2.0 x 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 will be exclusionary, but
the presence of NAFLD would not be exclusionary.

8. History or presence of impaired renal function as indicated by clinically significant
abnormal creatinine, blood urea nitrogen (BUN), or urinary constituents (e.g.,
albuminuria) or moderate to severe renal dysfunction as defined by the Cockcroft Gault
equation < 30 mL/min (Appendix 11.10).

9. History or close family history (parents or siblings) of skin cancer or melanoma, or
patient history of ocular-cutaneous albinism.

10. Significant dermatologic findings relating to melanoma or pre-melanoma skin lesions,
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 study.

11. Volunteer is, in the opinion of the Study Investigator, not suitable to participate in
the study.

12. Participation in any clinical study with an investigational drug/device within 3
months prior to the first day of dosing.

13. Significant hypersensitivity to study drug.

14. Inability to comply with QD injection regimen.