A Study to Examine the Effects of the Leptin Receptor (LEPR) Agonist Antibody REGN4461 in Adult Patients With Familial Partial Lipodystrophy (FPLD)

Study Overview
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Brief Summary
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Two cohorts are being studied based on leptin levels. Cohort A is composed of patients with baseline leptin <8.0 ng/mL and Cohort B is composed of patients with baseline leptin 8.0 to ≤20.0 ng/mL The primary objectives will be evaluated for patients in Cohort A only: To evaluate the effect of REGN4461 on fasting triglycerides (TG) in patients with elevated baseline fasting TG To evaluate the effect of REGN4461 on hyperglycemia in patients with elevated baseline Hemoglobin A1c (HbA1c) The following secondary objectives of the study will be evaluated for Cohort B and for the combined set of Cohorts A plus B: To evaluate the effect of REGN4461 on fasting TG levels in patients with hypertriglyceridemia To evaluate the effect of REGN4461 on glycemic control in patients with hyperglycemia The following secondary objectives of the study will be evaluated for Cohorts A and B separately, and for the combined set of Cohorts A plus B: To evaluate the effect of REGN4461 on liver fat in patients with hepatic steatosis To evaluate the effect of REGN4461 on hunger To evaluate safety and tolerability of REGN4461 To characterize the concentration profile of REGN4461 over time To assess immunogenicity to REGN4461

Official Title
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A Randomized Double-Blind Placebo-Controlled Study of the LEPR Agonist Antibody REGN4461 for the Treatment of Metabolic Abnormalities in Patients With Familial Partial Lipodystrophy

Conditions
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Familial Partial Lipodystrophy, Metabolic Abnormalities

Intervention / Treatment
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* Drug: REGN4461
* Drug: Matching Placebo


Participation Criteria
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Eligibility Criteria
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Key Inclusion Criteria: Clinical diagnosis of familial partial lipodystrophy as defined in the protocol Fasting leptin level ≤20.0 ng/ml, as determined during the screening period Presence of significant metabolic abnormalities related to glucose and triglycerides (TGs) as defined in the protocol Stable body weight within the 3 months prior to screening (no gain or loss of >5% current weight) Stable diet during the past 3 months defined as no major change in macronutrient composition (eg, starting or stopping diets such as Atkins, Paleo, Vegetarianism, Veganism) No clinically meaningful change in medication regimen in the 3 months prior to screening as defined in the protocol Key Exclusion Criteria: Treatment with metreleptin within 3 months of the screening visit Patients with a diagnosis of generalized lipodystrophy Patients with a diagnosis of acquired lipodystrophy Pregnant or breastfeeding women NOTE: Other protocol defined inclusion/exclusion criteria apply

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Study Arm 1<br>Randomized to placebo for 12 weeks and then crossover to REGN4461 for 12 weeks | Drug: REGN4461<br>* Intravenous (IV) infusion loading dose followed by subcutaneous (SC) injection weekly (QW).<br>* Other names: mibavademab;Drug: Matching Placebo<br>* Intravenous (IV) infusion loading dose followed by subcutaneous (SC) injection weekly (QW).<br>|
| Experimental: Study Arm 2<br>Randomized to receive REGN4461 for 24 weeks | Drug: REGN4461<br>* Intravenous (IV) infusion loading dose followed by subcutaneous (SC) injection weekly (QW).<br>* Other names: mibavademab;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percent change in fasting serum triglyceride (TG) | In patients with elevated baseline fasting TG (fasting TG ≥200 mg/dL) and with baseline leptin <8.0 ng/mL | Baseline to week 12 | 
| Absolute change in hemoglobin A1c (HbA1c) | In patients with elevated baseline HbA1c (>7.0%) and with baseline leptin <8.0 ng/mL | Baseline to week 12 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percent change in fasting serum TG | In patients with elevated baseline fasting TG (>200 mg/dL) Cohort B and Cohorts A+B | Baseline to week 12 | 
| Absolute change in HbA1c | In patients with elevated baseline HbA1c (>7.0%) Cohort B and Cohorts A+B | Baseline to week 12 | 
| Percent change in fasting serum TG | Cohorts A and B separately and Cohorts A+B in Study Arm 1 | Baseline to week 12 | 
| Percent change in fasting serum TG | Cohorts A and B separately and Cohorts A+B in Study Arm 1 | Week 12 to week 24 | 
| Percent change in fasting serum TG from baseline to week 12 compared to the percent change between week 12 and week 24 | Cohorts A and B separately and Cohorts A+B in Study Arm 1 | Week 24 | 
| Percent change in fasting serum TG | Cohorts A and B separately and Cohorts A+B in Study Arm 2 | Baseline to week 24 | 
| Percent change in fasting serum TG after the first 12 weeks of exposure to REGN4461 | Cohorts A and B separately and Cohorts A+B in Study Arm 2 | Baseline to week 12 | 
| Percent change in fasting serum TG after the first 12 weeks of exposure to REGN4461 | Cohorts A and B separately and Cohorts A+B in Study Arm 1 Patients must meet stability criteria | Week 12 to week 24 | 
| Change in HbA1c | Cohorts A and B separately and Cohorts A+B in Study Arm 1 | Baseline to week 12 | 
| Change in HbA1c | Cohorts A and B separately and Cohorts A+B in Study Arm 1 | Week 12 to week 24 | 
| Change in HbA1c from baseline to week 12 compared to change between week 12 and week 24 | Cohorts A and B separately and Cohorts A+B in Study Arm 1 | Week 24 | 
| Change in fasting glucose | Cohorts A and B separately and Cohorts A+B in Study Arm 1 | Baseline to week 12 | 
| Change in fasting glucose | Cohorts A and B separately and Cohorts A+B in Study Arm 1 | Week 12 to week 24 | 
| Change in fasting glucose from baseline to week 12 compared to change between week 12 and week 24 | Cohorts A and B separately and Cohorts A+B in Study Arm 1 | Week 24 | 
| Change in HbA1c | Cohorts A and B separately and Cohorts A+B in Study Arm 2 | Baseline to week 24 | 
| Change in fasting glucose | Cohorts A and B separately and Cohorts A+B in Study Arm 2 | Baseline to week 24 | 
| Change in HbA1c | Cohorts A and B separately and Cohorts A+B in Study Arm 2 | Baseline to week 12 | 
| Change in HbA1c | Cohorts A and B separately and Cohorts A+B in Study Arm 1 Patients must meet stability criteria | Week 12 to week 24 | 
| Change in fasting glucose | Cohorts A and B separately and Cohorts A+B in Study Arm 2 | Baseline to week 12 | 
| Percent change in liver fat magnetic resonance imaging-derived proton density fat fraction (MRI-PDFF) REGN4461 | In patients with baseline liver fat (MRI-PDFF) ≥8.5% Cohorts A and B separately and Cohorts A+B | Baseline to week 12 | 
| Percent change in liver fat (MRI-PDFF) placebo | In patients with baseline liver fat (MRI-PDFF) ≥8.5% Cohorts A and B separately and Cohorts A+B | Baseline to week 12 | 
| Percent change in liver fat (MRI-PDFF) REGN4461 versus placebo | In patients with baseline liver fat (MRI-PDFF) ≥8.5% Cohorts A and B separately and Cohorts A+B | Baseline to week 12 | 
| Percent change in liver fat (MRI-PDFF) | In patients with baseline liver fat (MRI-PDFF) ≥8.5% Cohorts A and B separately and Cohorts A+B in Study Arm 1 | Baseline to week 12 | 
| Percent change in liver fat (MRI-PDFF) | In patients with baseline liver fat (MRI-PDFF) ≥8.5% Cohorts A and B separately and Cohorts A+B in Study Arm 1 | Week 12 to week 24 | 
| Percent change in liver fat (MRI-PDFF) from baseline to week 12 compared to percent change between week 12 and week 24 | In patients with baseline liver fat (MRI-PDFF) ≥8.5% Cohorts A and B separately and Cohorts A+B in Study Arm 1 | Week 24 | 
| Percent change in liver fat (MRI-PDFF) | In patients with baseline liver fat (MRI-PDFF) ≥8.5% Cohorts A and B separately and Cohorts A+B in Study Arm 2 | Baseline to week 24 | 
| Percent change in liver fat (MRI-PDFF) | In patients with baseline liver fat (MRI-PDFF) ≥8.5% Cohorts A and B separately and Cohorts A+B in Study Arm 2 | Baseline to week 12 | 
| Change on the daily lipodystrophy hunger questionnaire | Cohorts A and B separately and Cohorts A+B Patients will complete the PRO assessments daily. The Hunger questionnaire is self-administered and contains 4 items based on a Likert-like scale, where 0 is not hungry at all and 10 is the hungriest possible | Baseline to week 12 | 
| Change on the daily lipodystrophy hunger questionnaire | Cohorts A and B separately and Cohorts A+B | Baseline to week 24 | 
| Incidence and severity of treatment-emergent adverse events (TEAEs) | Cohorts A and B separately and Cohorts A+B | Up to week 40 | 
| Concentrations of REGN4461 in serum over time | Cohorts A and B separately and Cohorts A+B | Up to week 40 | 
| Immunogenicity of REGN4461 over time compared to placebo | Cohorts A and B separately and Cohorts A+B | Up to week 40 |