Leptin Receptor Deficiency Obesity
Conditions
Keywords
LEPR deficiency obesity, setmelanotide, RM-493, Leptin receptor, Obesity, Melanocortin 4 receptor
Brief summary
To demonstrate statistically significant and clinically meaningful effects of setmelanotide on percent body weight change in participants with LEPR deficiency obesity due to rare bi-allelic or loss-of function mutations at the end of 1 year of treatment.
Interventions
DRUGSetmelanotide
Once daily subcutaneous injection
DRUGPlacebo
Once daily subcutaneous 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 the LEPR gene, with the loss-of-function (LOF) variant for each allele conferring a severe obesity phenotype. 2. Age 6 years and above. 6+: Germany, Netherlands, UK. 12+: France 3. If adult age ≥18 years, obesity with body mass index (BMI) ≥ 30 kilograms per meters squared (kg/m\^2); if child or adolescent (\< 18 years of age), 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 is 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) post-menopausal for at least 12 months (and confirmed with a screening FSH level in the post-menopausal lab range), or failure to have progressed to Tanner Stage V and/or 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. 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, severe stable restrictive or obstructive lung disease arising because of extreme obesity, evidence of significant heart failure (New York Heart Association \[NYHA\] Class 3 or greater), or oncologic disease, if these were severe enough to interfere with the study and/or would confound the results. 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). 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 milliliter/minute (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. 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 every day (QD) injection regimen. 15. Participants who have been placed in an institution through an official or court order, as well as those who are dependent on the sponsor, Investigator or study site.
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 (responders) after approximately Week 52 (\ 1 year) of treatment were analyzed. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Mean Percent Change From Baseline in Body Weight | Baseline and Week 52 | The mean percent change from baseline in body weight at 52 weeks was analyzed. |
| Mean Percent Change From Baseline in Hunger Score ('Most Hunger') | Baseline and 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. |
| Percentage of Participants Achieving at Least 25% Improvement in Daily Hunger From Baseline | Baseline and 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. |
| Absolute Change From Baseline in Waist Circumference | Baseline and Week 52 | Waist circumference (cm) 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 (responders) after approximately Week 52 (\ 1 year) of treatment were analyzed. |
| Absolute Daily Hunger Reduction Score During the Double-Blind Placebo-Controlled Withdrawal Period | Week 8 of withdrawal period | The absolute score in daily hunger reduction 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 | Baseline and Week 52 | The mean percent change from baseline in body mass index (BMI) was assessed. |
| Change From Baseline in Glucose Parameters | Baseline and Week 52 | Glucose parameters included glucose, glycated hemoglobin (HbA1c) and Oral glucose tolerance test (OGTT). Data is planned to be reported only for change from baseline in glucose levels. |
| Absolute Change in Body Weight (Reversal of Weight Loss) During Double-Blind Placebo-Controlled Withdrawal Period | Baseline and Week 8 of 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. |
Countries
Canada, France, Germany, Netherlands, Reunion, United Kingdom
Participant flow
Recruitment details
Participants were enrolled into the pivotal cohort (11 participants) or supplemental cohort (4 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) | Adverse Event | 1 |
| Open-Label Period (32 Weeks) | Serious Adverse Event | 1 |
Baseline characteristics
| Characteristic | Setmelanotide |
|---|---|
| Age, Categorical <=18 years | 5 Participants |
| Age, Categorical >=65 years | 0 Participants |
| Age, Categorical Between 18 and 65 years | 10 Participants |
| Age, Continuous | 21.67 years STANDARD_DEVIATION 8.52 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 13 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 2 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Asian | 1 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 | 2 Participants |
| Race (NIH/OMB) White | 12 Participants |
| Region of Enrollment Canada | 1 Participants |
| Region of Enrollment France | 6 Participants |
| Region of Enrollment Germany | 4 Participants |
| Region of Enrollment Netherlands | 3 Participants |
| Region of Enrollment United Kingdom | 1 Participants |
| Sex: Female, Male Female | 9 Participants |
| Sex: Female, Male Male | 6 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | 1 / 15 |
| other Total, other adverse events | 15 / 15 |
| serious Total, serious adverse events | 3 / 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 (responders) after approximately Week 52 (\ 1 year) of treatment were analyzed.
Time frame: Week 52
Population: The full analysis set (FAS) consisted of participants who received any of the study drug injections and at least one baseline assessment (included those who did and did not demonstrate ≥5 kg weight loss or 5% of body weight if weight is \<100 kg at baseline over the initial12-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) | 45.5 percentage of participants |
p-value: 0.0001Clopper-Pearson method
Secondary
Absolute Change From Baseline in Waist Circumference
Waist circumference (cm) 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 and Week 52
Population: DUS population with available data at specified time point. 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 | Baseline | 131.58 Centimeter | Standard Deviation 24.047 |
| Setmelanotide (Entire Study) | Absolute Change From Baseline in Waist Circumference | Change at Week 52 | -9.80 Centimeter | Standard Deviation 6.095 |
p-value: 0.003190% CI: [-14.1, -3.61]ANOVA
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 and Week 8 of withdrawal period
Population: DUS population with available data at specified time point. 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 at Week 4: Setmelanotide | -1.2 Kilogram | Standard Deviation 3.04 |
| Setmelanotide (Entire Study) | Absolute Change in Body Weight (Reversal of Weight Loss) During Double-Blind Placebo-Controlled Withdrawal Period | Change at Week 4: Placebo | 4.9 Kilogram | Standard Deviation 2.82 |
Secondary
Absolute Daily Hunger Reduction Score During the Double-Blind Placebo-Controlled Withdrawal Period
The absolute score in daily hunger reduction 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: Week 8 of withdrawal period
Population: DUS population with available data at specified time point. Participants in pivotal and supplemental cohort were included in the analysis.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Setmelanotide (Entire Study) | Absolute Daily Hunger Reduction Score During the Double-Blind Placebo-Controlled Withdrawal Period | Setmelanotide | 3.4 units on a scale | Standard Deviation 1.63 |
| Setmelanotide (Entire Study) | Absolute Daily Hunger Reduction Score During the Double-Blind Placebo-Controlled Withdrawal Period | Placebo | 6.3 units on a scale | Standard Deviation 2.13 |
Secondary
Change From Baseline in Glucose Parameters
Glucose parameters included glucose, glycated hemoglobin (HbA1c) and Oral glucose tolerance test (OGTT). Data is planned to be reported only for change from baseline in glucose levels.
Time frame: Baseline and Week 52
Population: The Safety Analysis Set (SAS) was defined as all participants who received any study drug injections at least one post-dose safety assessment. Participants 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 Glucose Parameters | Baseline | 5.586 millimole per liter | Standard Deviation 2.374 |
| Setmelanotide (Entire Study) | Change From Baseline in Glucose Parameters | Change at Week 52 | -0.465 millimole per liter | Standard Deviation 1.435 |
Secondary
Mean Percent Change From Baseline in Body Mass Index
The mean percent change from baseline in body mass index (BMI) was assessed.
Time frame: Baseline and Week 52
Population: DUS population with available data at specified time point. 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 | -14.24 Percent change | Standard Deviation 9.096 |
p-value: <0.000190% CI: [-16.8, -11.2]ANOVA
Secondary
Mean Percent Change From Baseline in Body Weight
The mean percent change from baseline in body weight at 52 weeks was analyzed.
Time frame: Baseline and Week 52
Population: The Designated Use Set (DUS) consisted of participants who received any of the study drug injections, demonstrated ≥5 kg weight loss \[or 5% of body weight if weight was \<100 kg at baseline\] during the initial 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 | -12.34 Percent change | Standard Deviation 7.534 |
p-value: <0.000190% CI: [-15.08, -9.66]ANOVA
Secondary
Mean Percent Change From Baseline in Hunger Score ('Most Hunger')
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.
Time frame: Baseline and Week 52
Population: DUS Population. 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 ('Most Hunger') | -42.7 Percent Change | Standard Deviation 27.49 |
p-value: <0.000190% CI: [-56.35, -29.02]ANOVA
Secondary
Percentage of Participants Achieving 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.
Time frame: Baseline and Week 52
Population: FAS population with available data at specified time point. Participants in pivotal and supplemental cohort were included in the analysis.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Setmelanotide (Entire Study) | Percentage of Participants Achieving at Least 25% Improvement in Daily Hunger From Baseline | 71.4 percentage of participants |
p-value: <0.0001Clopper-Pearson method
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 (responders) 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) | 53.3 percentage of participants |
p-value: <0.0001Clopper-Pearson method