Pro-opiomelanocortin (POMC) Deficiency Obesity
Conditions
Keywords
POMC deficiency obesity, PCSK1 deficiency obesity, Setmelanotide, RM-493, Obesity, Melanocortin 4 receptor, MC4R pathway
Brief summary
To demonstrate statistically significant and clinically meaningful effects of setmelanotide on percent body weight change in participants with pro-opiomelanocortin (POMC) deficiency or proprotein convertase subtilisin/kexin type 1 (PCSK1) deficiency obesity due to rare biallelic or loss-of function mutations at the end of 1 year of treatment.
Interventions
DRUGSetmelanotide
Once daily SC injection
DRUGPlacebo
Once daily SC injection
Sponsors
Rhythm Pharmaceuticals, Inc.
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Masking description
During the 8 week double-blind placebo-controlled withdrawal period, participants received 4 weeks of daily setmelanotide and 4 weeks of daily placebo. Participants, investigators, and sites remained blinded as to when placebo treatment was administered.
Intervention model description
Open-label with an 8 week Double-Blind Placebo-Controlled Withdrawal Period
Eligibility
Sex/Gender
ALL
Age
6 Years to No maximum
Healthy volunteers
No
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 6 years and above. 3. If adult age ≥ 18 years, obesity with body mass index (BMI) ≥ 30 kilograms per square meter (kg/m\^2); if child or adolescent, obesity with BMI ≥ 95th 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, after being informed about the study. 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 follicular stimulating hormone \[FSH\] level in the post-menopausal lab range), or have delayed pubertal development and failure to have achieved menarche, 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 participants 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. Participants 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. 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. 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. 9. History or close family history (parents or siblings) of skin cancer or melanoma, or participant 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. 11. Participant 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 every day (QD) injection regimen.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Participants Who Reached ≥10% Weight Loss Threshold After 1 Year (Pivotal Cohort) | Week 52 | The percentage of participants who met the ≥ 10% weight loss threshold after approximately Week 52 (\ 1 year) of treatment were analyzed. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Mean Percent Change From Baseline in Body Weight at Week 52 | Baseline, Week 52 | The mean percent change from baseline in body weight at 52 weeks was analyzed. |
| Mean Percent Change From Baseline in Hunger Score (Worst Most Hunger in 24 Hours) at Week 52 | Baseline, Week 52 | The mean percent change in hunger scores for participants ≥12 years of age with leptin receptor (LEPR) deficiency obesity in treatment with setmelanotide was evaluated. Hunger score ranged from 0 - 10 on a Likert-type scale; 0 = not hungry at all and 10 = hungriest possible. On the Daily Hunger Questionnaire, each of the 3 items (average hunger, most/worst hunger, and morning hunger) was scored separately and averaged on a weekly basis. The weekly average hunger score of the daily worst (most) hunger score in 24 hours is the hunger score used to assess this study endpoint. |
| Percentage of Participants Who Achieved at Least 25% Improvement in Daily Hunger From Baseline | Baseline, Week 52 | The percentage of participants (≥12 years of age) achieving a ≥25% improvement from baseline in hunger score at Week 52 (i.e., after treatment with setmelanotide for 52 weeks at the therapeutic dose) was assessed. Hunger ranged from 0 - 10 on a Likert-type scale; 0 = not hungry at all and 10 = hungriest possible. On the Daily Hunger Questionnaire, each of the 3 items (average hunger, most/worst hunger, and morning hunger) was scored separately and averaged on a weekly basis. The weekly average hunger score of the daily worst (most) hunger score in 24 hours is the hunger score used to assess this study endpoint. |
| Absolute Change From Baseline in Waist Circumference at Week 52 | Baseline, Week 52 | Waist circumference (centimeters) was measured according to the National Heart, Lung, and Blood Institute (NHLBI) criteria. Waist circumference was measured when participants were fasting at approximately the same time at each visit. The absolute change from baseline in waist circumference was assessed. |
| Percentage of Participants Who Reached ≥10% Weight Loss Threshold After 1 Year (Pivotal + Supplemental Cohort) | Week 52 | The percentage of participants who met the ≥ 10% weight loss threshold after approximately Week 52 (\ 1 year) of treatment were analyzed. |
| Absolute Score in Daily Hunger Reduction During the Double-Blind Placebo-Controlled Withdrawal Period | 8-week withdrawal period (up to ~Week 20) | The absolute score in daily hunger during the double-blind placebo-controlled withdrawal period (≥12 Years of Age) was assessed. Hunger ranged from 0 - 10 on a Likert-type scale; 0 = not hungry at all and 10 = hungriest possible. On the Daily Hunger Questionnaire, each of the 3 items (average hunger, most/worst hunger, and morning hunger) was scored separately and averaged on a weekly basis. The weekly average hunger score of the daily worst (most) hunger score in 24 hours is the hunger score used to assess this study endpoint. Lower scores represent lower hunger, higher scores represent greater hunger. |
| Mean Percent Change From Baseline in Body Mass Index (BMI) at Week 52 | Baseline, Week 52 | The mean percent change from baseline in BMI was assessed. |
| Area Under the Curve (AUC) Change From Baseline in Oral Glucose, Assessed by the Oral Glucose Tolerance Test (OGTT) | Baseline, Week 52 | The AUC change from baseline for the OGTT was assessed. The AUC was calculated by the linear trapezoidal method and includes pre-dose and post-dose assessments. At each visit, oral glucose was captured pre-meal, and post-meal at the following times: 30 minutes, 60 minutes, 90 minutes, and 120 minutes. OGTT was not performed for participants with a diagnosis of Type 1 or Type 2 diabetes. |
| Change From Baseline in Serum Glucose at Week 52 | Baseline, Week 52 | Change from baseline in serum glucose at Week 52 was assessed. |
| Absolute Change in Body Weight (Reversal of Weight Loss) During Double-Blind Placebo-Controlled Withdrawal Period | Baseline, 8-week withdrawal period (up to ~Week 20) | A comparison of weight change was evaluated during the 8 week placebo-controlled withdrawal period for each participant, during which each participant received 4 weeks of placebo and 4 weeks active therapy in a blinded fashion. |
Countries
Belgium, Canada, France, Germany, Spain, United Kingdom, United States
Participant flow
Recruitment details
Participants were enrolled into the pivotal cohort (10 participants) or supplemental cohort (5 participants). Pivotal cohort: Set of participants under study constituted a collection of detailed clinical case reports with a comprehensive baseline and past medical history assessment and complete clinical efficacy, safety and laboratory evaluations conducted for each participant. Supplemental cohort: Any additional participants enrolled were included in supplemental cohort.
Pre-assignment details
At screening, a blood sample was obtained for genotyping for mechanisms considered to be possibly related to the safety or efficacy response to the study medication (e.g., other obesity related genes). Complete physical, relevant bloodwork, and other standard assessments were performed.
Participants by arm
| Arm | Count |
|---|---|
| Setmelanotide Participants received titrated doses of setmelanotide once daily, by SC injection during titration period for 2 - 12 weeks. Thereafter, participants continued setmelanotide at their specific therapeutic dose for an additional 10 weeks during the open label treatment period. Participants who achieved at least a 5 kg weight loss (or at least 5% weight loss if baseline body weight was \<100 kg) at the end of the open label treatment period, continued into the 8-week double-blind withdrawal period and received 4 weeks setmelanotide and 4 weeks placebo. Following the withdrawal period, participants entered open label treatment period and received setmelanotide to complete approximately 52 weeks (\
1 year) of treatment at a therapeutic dose. | 15 |
| Total | 15 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Open-Label Period (10 Weeks) | Lack of Efficacy | 1 |
| Open-Label Period (10 Weeks) | Protocol Violation | 1 |
| Open-Label Period (32 Weeks) | Lost to Follow-up | 1 |
Baseline characteristics
| Characteristic | Setmelanotide |
|---|---|
| Age, Continuous | 17.20 years STANDARD_DEVIATION 7.02 |
| Age, Customized < 12 years | 5 Participants |
| Age, Customized ≥ 12 years | 10 Participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 2 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 11 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 2 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 7 Participants |
| Race (NIH/OMB) White | 8 Participants |
| Region of Enrollment Belgium | 2 Participants |
| Region of Enrollment Canada | 1 Participants |
| Region of Enrollment France | 2 Participants |
| Region of Enrollment Germany | 7 Participants |
| Region of Enrollment Spain | 2 Participants |
| Region of Enrollment United States | 1 Participants |
| Sex: Female, Male Female | 6 Participants |
| Sex: Female, Male Male | 9 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | 0 / 15 |
| other Total, other adverse events | 15 / 15 |
| serious Total, serious adverse events | 6 / 15 |
Outcome results
Primary
Percentage of Participants Who Reached ≥10% Weight Loss Threshold After 1 Year (Pivotal Cohort)
The percentage of participants who met the ≥ 10% weight loss threshold after approximately Week 52 (\ 1 year) of treatment were analyzed.
Time frame: Week 52
Population: Full Analysis Set (FAS) population included participants who received any of the study drug injections and had at least one baseline assessment (included those who did and did not demonstrate ≥ 5 kg weight loss or 5% of body weight if weight was \< 100 kg at baseline over the 12-week open-label treatment period, and proceeded into the double-blind, placebo-controlled withdrawal period). Participants in pivotal cohort were included in the analysis.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Setmelanotide (Entire Study) | Percentage of Participants Who Reached ≥10% Weight Loss Threshold After 1 Year (Pivotal Cohort) | 80.0 percentage of participants |
p-value: <0.0001Exact binomial test
Secondary
Absolute Change From Baseline in Waist Circumference at Week 52
Waist circumference (centimeters) was measured according to the National Heart, Lung, and Blood Institute (NHLBI) criteria. Waist circumference was measured when participants were fasting at approximately the same time at each visit. The absolute change from baseline in waist circumference was assessed.
Time frame: Baseline, Week 52
Population: Participants in the DUS population with available data were analyzed. Participants in pivotal and supplemental cohort were included in the analysis.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Setmelanotide (Entire Study) | Absolute Change From Baseline in Waist Circumference at Week 52 | Baseline | 115.48 centimeters | Standard Deviation 17.92 |
| Setmelanotide (Entire Study) | Absolute Change From Baseline in Waist Circumference at Week 52 | Change at Week 52 | -17.51 centimeters | Standard Deviation 9.112 |
Comparison: Model based summary statistics from longitudinal mixed analysis of variance model with fixed effect for visit, baseline waist circumference and random effect for participant, one sided p-value from model.p-value: <0.000190% CI: [-21.27, -14.88]Longitudinal mixed analysis of variance
Secondary
Absolute Change in Body Weight (Reversal of Weight Loss) During Double-Blind Placebo-Controlled Withdrawal Period
A comparison of weight change was evaluated during the 8 week placebo-controlled withdrawal period for each participant, during which each participant received 4 weeks of placebo and 4 weeks active therapy in a blinded fashion.
Time frame: Baseline, 8-week withdrawal period (up to ~Week 20)
Population: Participants in the DUS population with available data were analyzed. Participants in pivotal and supplemental cohort were included in the analysis.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Setmelanotide (Entire Study) | Absolute Change in Body Weight (Reversal of Weight Loss) During Double-Blind Placebo-Controlled Withdrawal Period | Change after 4 weeks of therapy: Setmelanotide | -2.8 kilograms | Standard Deviation 2.41 |
| Setmelanotide (Entire Study) | Absolute Change in Body Weight (Reversal of Weight Loss) During Double-Blind Placebo-Controlled Withdrawal Period | Change after 4 weeks of therapy: Placebo | 6.2 kilograms | Standard Deviation 3.87 |
Secondary
Absolute Score in Daily Hunger Reduction During the Double-Blind Placebo-Controlled Withdrawal Period
The absolute score in daily hunger during the double-blind placebo-controlled withdrawal period (≥12 Years of Age) was assessed. Hunger ranged from 0 - 10 on a Likert-type scale; 0 = not hungry at all and 10 = hungriest possible. On the Daily Hunger Questionnaire, each of the 3 items (average hunger, most/worst hunger, and morning hunger) was scored separately and averaged on a weekly basis. The weekly average hunger score of the daily worst (most) hunger score in 24 hours is the hunger score used to assess this study endpoint. Lower scores represent lower hunger, higher scores represent greater hunger.
Time frame: 8-week withdrawal period (up to ~Week 20)
Population: Participants in the DUS population with available data were analyzed. Participants in pivotal and supplemental cohort were included in the analysis.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Setmelanotide (Entire Study) | Absolute Score in Daily Hunger Reduction During the Double-Blind Placebo-Controlled Withdrawal Period | Setmelanotide | 4.5 units on a scale | Standard Deviation 2.57 |
| Setmelanotide (Entire Study) | Absolute Score in Daily Hunger Reduction During the Double-Blind Placebo-Controlled Withdrawal Period | Placebo | 6.7 units on a scale | Standard Deviation 2.22 |
Secondary
Area Under the Curve (AUC) Change From Baseline in Oral Glucose, Assessed by the Oral Glucose Tolerance Test (OGTT)
The AUC change from baseline for the OGTT was assessed. The AUC was calculated by the linear trapezoidal method and includes pre-dose and post-dose assessments. At each visit, oral glucose was captured pre-meal, and post-meal at the following times: 30 minutes, 60 minutes, 90 minutes, and 120 minutes. OGTT was not performed for participants with a diagnosis of Type 1 or Type 2 diabetes.
Time frame: Baseline, Week 52
Population: Participants in the SAS population with available data were analyzed. Participants in pivotal and supplemental cohort were included in the analysis.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Setmelanotide (Entire Study) | Area Under the Curve (AUC) Change From Baseline in Oral Glucose, Assessed by the Oral Glucose Tolerance Test (OGTT) | Baseline | 951.900 minutes*millimoles/liter (min*mmol/L) | Standard Deviation 464.9342 |
| Setmelanotide (Entire Study) | Area Under the Curve (AUC) Change From Baseline in Oral Glucose, Assessed by the Oral Glucose Tolerance Test (OGTT) | Change at Week 52 | -35.284 minutes*millimoles/liter (min*mmol/L) | Standard Deviation 442.6334 |
Secondary
Change From Baseline in Serum Glucose at Week 52
Change from baseline in serum glucose at Week 52 was assessed.
Time frame: Baseline, Week 52
Population: Participants in the SAS population with available data were analyzed. Participants in pivotal and supplemental cohort were included in the analysis.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Setmelanotide (Entire Study) | Change From Baseline in Serum Glucose at Week 52 | Baseline | 6.606 mmol/L | Standard Deviation 5.0024 |
| Setmelanotide (Entire Study) | Change From Baseline in Serum Glucose at Week 52 | Change at Week 52 | -1.527 mmol/L | Standard Deviation 1.9374 |
Secondary
Mean Percent Change From Baseline in Body Mass Index (BMI) at Week 52
The mean percent change from baseline in BMI was assessed.
Time frame: Baseline, Week 52
Population: Participants in the DUS population with available data were analyzed. Participants in pivotal and supplemental cohort were included in the analysis.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Setmelanotide (Entire Study) | Mean Percent Change From Baseline in Body Mass Index (BMI) at Week 52 | -27.32 percent change | Standard Deviation 8.971 |
Comparison: Model based summary statistics from longitudinal mixed analysis of variance model with fixed effect for week, baseline BMI and random effect for participant, one sided p-value from model.p-value: <0.000190% CI: [-30.6, -24.29]Longitudinal mixed analysis of variance
Secondary
Mean Percent Change From Baseline in Body Weight at Week 52
The mean percent change from baseline in body weight at 52 weeks was analyzed.
Time frame: Baseline, Week 52
Population: Designated Use Set (DUS) analysis population consisted of participants who received any of the study drug injections, demonstrated ≥ 5 kg weight loss or 5% of body weight if weight was \<100 kg at baseline over the 12-week open-label treatment period, and proceeded into the double-blind, placebo-controlled withdrawal period. Participants in pivotal and supplemental cohort were included in the analysis.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Setmelanotide (Entire Study) | Mean Percent Change From Baseline in Body Weight at Week 52 | -25.83 percent change | Standard Deviation 9.721 |
Comparison: Model based summary statistics from longitudinal mixed analysis of variance model with fixed effect for visit, baseline body weight and random effect for participant, one sided p-value from model.p-value: <0.000190% CI: [-28.49, -22.98]Longitudinal mixed analysis of variance
Secondary
Mean Percent Change From Baseline in Hunger Score (Worst Most Hunger in 24 Hours) at Week 52
The mean percent change in hunger scores for participants ≥12 years of age with leptin receptor (LEPR) deficiency obesity in treatment with setmelanotide was evaluated. Hunger score ranged from 0 - 10 on a Likert-type scale; 0 = not hungry at all and 10 = hungriest possible. On the Daily Hunger Questionnaire, each of the 3 items (average hunger, most/worst hunger, and morning hunger) was scored separately and averaged on a weekly basis. The weekly average hunger score of the daily worst (most) hunger score in 24 hours is the hunger score used to assess this study endpoint.
Time frame: Baseline, Week 52
Population: Participants in the DUS population with available data were analyzed. Participants in pivotal and supplemental cohort were included in the analysis.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Setmelanotide (Entire Study) | Mean Percent Change From Baseline in Hunger Score (Worst Most Hunger in 24 Hours) at Week 52 | -27.1 percent change | Standard Deviation 28.11 |
Comparison: Model based summary statistics from longitudinal mixed analysis of variance model with fixed effect for week, baseline daily hunger score and random effect for participant, one sided p-value from model.p-value: 0.000590% CI: [-40.58, -14.96]Longitudinal mixed analysis of variance
Secondary
Percentage of Participants Who Achieved at Least 25% Improvement in Daily Hunger From Baseline
The percentage of participants (≥12 years of age) achieving a ≥25% improvement from baseline in hunger score at Week 52 (i.e., after treatment with setmelanotide for 52 weeks at the therapeutic dose) was assessed. Hunger ranged from 0 - 10 on a Likert-type scale; 0 = not hungry at all and 10 = hungriest possible. On the Daily Hunger Questionnaire, each of the 3 items (average hunger, most/worst hunger, and morning hunger) was scored separately and averaged on a weekly basis. The weekly average hunger score of the daily worst (most) hunger score in 24 hours is the hunger score used to assess this study endpoint.
Time frame: Baseline, Week 52
Population: Participants in the FAS population with available data were analyzed. Participants in pivotal and supplemental cohort were included in the analysis.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Setmelanotide (Entire Study) | Percentage of Participants Who Achieved at Least 25% Improvement in Daily Hunger From Baseline | 50.0 percentage of participants |
p-value: 0.0004Exact binomial test
Secondary
Percentage of Participants Who Reached ≥10% Weight Loss Threshold After 1 Year (Pivotal + Supplemental Cohort)
The percentage of participants who met the ≥ 10% weight loss threshold after approximately Week 52 (\ 1 year) of treatment were analyzed.
Time frame: Week 52
Population: FAS Population. Participants in pivotal and supplemental cohort were included in the analysis.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Setmelanotide (Entire Study) | Percentage of Participants Who Reached ≥10% Weight Loss Threshold After 1 Year (Pivotal + Supplemental Cohort) | 85.7 percentage of participants |
p-value: <0.0001Exact binomial test