Study of REGN4461, a Leptin Receptor Agonist Antibody, in Patients With Generalized Lipodystrophy

Study Overview
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Brief Summary
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The primary objectives of the study are to estimate the effects of REGN4461 on glycemic parameters in the subset of patients with elevated baseline hemoglobin A1c levels (HbA1c ≥7%) and to estimate the effects of REGN4461 on fasting triglyceride levels in the subset of patients with elevated baseline fasting triglycerides (TG ≥250 mg/dL). The secondary objectives are to estimate the effects of REGN4461 on a composite endpoint of changes in either HbA1c or fasting TG for all patients, estimate the effects of 3 dose levels of REGN4461 on glycemic parameters and fasting TG, to estimate the effects of REGN4461 on insulin sensitivity, to evaluate the safety and tolerability of REGN4461 and to evaluate the pharmacokinetics (PK) and immunogenicity of REGN4461.

Official Title
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A Randomized, Double-Blind, Placebo-Controlled Study of REGN4461, a Leptin Receptor Agonist Antibody, in Patients With Generalized Lipodystrophy

Conditions
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Generalized Lipodystrophy

Intervention / Treatment
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* Drug: Placebo
* Drug: Low-Dose REGN4461
* Drug: High-dose REGN4461


Participation Criteria
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Eligibility Criteria
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Key Inclusion Criteria: Diagnosis of congenital or acquired generalized lipodystrophy (GLD), as defined in the protocol Presence of one or both of the following metabolic abnormalities at screening: HbA1c ≥ 7% OR Fasting TG ≥250 mg/dL Generally stable diet (based on patient's recall) and medication regimen (that optimizes treatment for their metabolic disease) for at least 3 months prior to the screening visit Key Exclusion Criteria: Treatment with metreleptin within 1 month of the screening visit Treatment with over-the-counter or prescription medications for weight loss within 3 months prior to the screening visit Treatment with oral glucocorticoids >7.5 mg prednisone equivalents per day within 3 months prior to screening visit or plans to begin treatment with oral glucocorticoids >7.5 mg prednisone equivalents per day during the study period History of Human Immunodeficiency Virus (HIV) or HIV seropositivity at screening visit Uncontrolled infection with hepatitis B or hepatitis C infection, or known active tuberculosis at screening Participation in any clinical research study evaluating an Investigational product (IP) or therapy within 3 months and less than 5 half-lives of IP prior to the screening visit. Pregnant or breast-feeding women NOTE: Other protocol defined inclusion/exclusion criteria apply.

Ages Eligible for Study
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Minimum Age: 12 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: Sequential Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Treatment A<br> | Drug: Placebo<br>* Intravenous (IV) infusion loading dose or subcutaneous (SC) injection weekly (QW).<br>Drug: Low-Dose REGN4461<br>* IV infusion loading dose or SC injection QW.<br>Drug: High-dose REGN4461<br>* IV infusion loading dose or SC injection QW.<br>|
| Experimental: Treatment B<br> | Drug: Placebo<br>* Intravenous (IV) infusion loading dose or subcutaneous (SC) injection weekly (QW).<br>Drug: Low-Dose REGN4461<br>* IV infusion loading dose or SC injection QW.<br>Drug: High-dose REGN4461<br>* IV infusion loading dose or SC injection QW.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Absolute change from baseline hemoglobin A1c (HbA1c) | In patients with elevated baseline HBA1c (HbA1c ≥7%) | Week 8 | 
| Absolute change from baseline fasting glucose | In patients with elevated baseline HBA1c (HbA1c ≥7%) | Week 8 | 
| Absolute change from baseline weighted mean glucose (WMG) | In patients with elevated baseline HBA1c (HbA1c ≥7%) | Week 8 | 
| Percent change from baseline fasting triglycerides (TG) | In patients with elevated baseline fasting TG (fasting TG ≥250 mg/dL) | Week 8 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Absolute change in composite endpoint comprising absolute change in either HbA1c or percent change in fasting TG | In all patients | Week 8 | 
| Absolute change in HbA1c from baseline | In all patients | Approximately Week 128 | 
| Percent change in fasting TG from baseline over time | In all patients | Approximately Week 128 | 
| Absolute change from baseline in fasting glucose | In all patients | Approximately Week 128 | 
| Absolute change from baseline in fasting glucose | In patients with elevated baseline HbA1c (HbA1c ≥7%) | Approximately Week 128 | 
| Percent change from baseline in fasting TG | In patients with elevated baseline fasting TG (TG ≥250 mg/dL) | Approximately Week 128 | 
| Absolute change from baseline in HbA1c over time | In patients with elevated baseline HbA1c (HbA1c ≥7%) | Approximately Week 128 | 
| Absolute change from baseline in WMG over time | In all patients | Up to Week 24 | 
| Absolute change from baseline in WMG over time | In patients with elevated baseline HbA1c (HbA1c ≥7%) | Up to Week 24 | 
| Change from baseline in glucose area under the concentration-time curve (AUC0-4) during a mixed meal tolerance test (MMTT) | In all patients | At Week 8, 16 and 24 | 
| Change from baseline in glucose AUC0-4 during a MMTT | In patients with elevated baseline HbA1c (HbA1c ≥7%) | At Week 8, 16 and 24 | 
| Change from baseline in glucose infusion rate per kilogram body mass during hyperinsulinemia-euglycemic clamp (clamp study) | In all patients | At Week 8 and Week 52 | 
| Change from baseline in glucose infusion rate per kilogram body mass during hyperinsulinemia-euglycemic clamp (clamp study) | In patients with elevated baseline HbA1c (HbA1c ≥7%) | At Week 8 and Week 52 | 
| Change from baseline in glucose clearance rate (kITT) during insulin-tolerance test (ITT) | In all patients | At Week 8 and Week 52 | 
| Change from baseline in glucose clearance rate (kITT) during insulin-tolerance test (ITT) | In patients with elevated baseline HbA1c (HbA1c ≥7%) | At Week 8 and Week 52 | 
| Incidence and severity of treatment-emergent adverse events (TEAEs) |  | Approximately Week 128 | 
| Concentrations of total REGN4461 in serum over time |  | Approximately Week 128 | 
| Incidence of anti-drug antibodies (ADA) to REGN4461 over time |  | Approximately Week 128 | 
| Incidence of abnormal weight change |  | Approximately Week 128 | 
| Incidence of vital sign abnormalities |  | Approximately Week 128 | 
| Incidence of 12-lead electrocardiogram (ECG) abnormalities |  | Approximately Week 128 | 
| Incidence of physical examination abnormalities |  | Approximately Week 128 | 
| Incidence of laboratory abnormalities |  | Approximately Week 128 | 
| Concentrations of total soluble leptin receptor (sLEPR) in serum over time |  | Approximately Week 128 |