Efficacy and Safety of Mibavademab in Adult and Pediatric Patients With Generalized Lipodystrophy

• Mibavademab (Drug), also known as REGN4461: Administered as per the protocol
• Placebo (Drug): Administered as per the protocol

Primary outcomes

• Change in Hemoglobin A1c (HbA1c) [Through 36 weeks of exposure to mibavademab]: Part A
• Percent change in fasting Triglycerides (TG) [Through 36 weeks of exposure to mibavademab]: Part A
• Occurrence of Treatment Emergent Adverse Events (TEAEs) [Up to 15 months]: Part B
• Severity of TEAEs [Up to 15 months]: Part B
• Concentrations of total mibavademab in serum [Up to 15 months]: Part B

Secondary outcomes

• Change in HbA1c compared to placebo [From baseline to week 20]: Part A
• Change in HbA1c compared to placebo [From week 56 to week 64]: Part A
• Change in HbA1c [From baseline to week 52]: Part B
• Percent change in fasting TG compared to placebo [From baseline to week 20]: Part A
• Percent change in fasting TG compared to placebo [From week 56 to week 64]: Part A
• Percent change in fasting TG [From baseline to week 52]: Part B
• Occurrence of HbA1c <7% [At week 20]: Part A
• Occurrence of HbA1c <7% [Through 36 weeks of exposure to mibavademab]: Part A
• Occurrence of HbA1c <6.5% [At week 20]: Part A
• Occurrence of HbA1c <6.5% [Through 36 weeks of exposure to mibavademab]: Part A
• Occurrence of fasting TG <500 mg/dL [At week 20]: Part A
• Occurrence of fasting TG <500 mg/dL [Through 36 weeks of exposure to mibavademab]: Part A
• Occurrence of fasting TG <200 mg/dL [At week 20]: Part A
• Occurrence of fasting TG <200 mg/dL [Through 36 weeks of exposure to mibavademab]: Part A
• Occurrence of fasting TG <150 mg/dL [At week 20]: Part A
• Occurrence of fasting TG <150 mg/dL [Through 36 weeks of exposure to mibavademab]: Part A
• Percent change in Liver Fat Content (LFC) [From baseline to week 20]: Part A
• Percent change in Liver Fat Content (LFC) [From pre-mibavademab exposure to week 56]: Part A
• Change in liver volume [From baseline to week 20]: Part A
• Change in liver volume [From pre-mibavademab exposure to week 56]: Part A
• Change in fasting glucose [From baseline to week 20]: Part A
• Change in fasting glucose [Through 36 weeks of exposure to mibavademab]: Part A
• Change in fasting glucose [From week 56 to week 64]: Part A
• Change in total daily insulin dose [From baseline to week 20]: Part A
• Change in total daily insulin dose [Through 36 weeks of exposure to mibavademab]: Part A
• Change in total daily insulin dose [From week 56 to week 64]: Part A
• Change in total daily insulin dose [From baseline to week 52]: Part B
• Concentrations of total mibavademab in serum [Through Week 72]: Part A
• Occurrence of Anti-Drug Antibodies (ADA) to mibavademab [Through Week 72]: Part A
• Occurrence of ADA to mibavademab [Through Week 60]: Part B
• Magnitude of ADA to mibavademab [Through Week 72]: Part A
• Magnitude of ADA to mibavademab [Through Week 60]: Part B
• Occurrence of TEAEs [Through Week 72]: Part A
• Severity of TEAEs [Through Week 72]: Part A

Sex: All, ages: 2 Years to any

Key Inclusion Criteria:

1\. Diagnosis of congenital or acquired GLD as defined by Multi-Society Practice Guidelines

For Part A only:

1. Participants ≥2 years of age at screening
2. At least one of the below criteria are fulfilled during screening (measurements can be repeated once during screening period)

   * HbA1c ≥7%
   * Fasting TG ≥500 mg/dL
   * Fasting TG value of ≥300 mg/dL and the presence of another complication of GLD consistent with leptin deficiency (history of diabetes mellitus, hyperphagia, Metabolic Associated Fatty Liver Disease (MAFLD), polycystic ovary syndrome, etc)
3. Weight ≥15 kg at screening
4. Willing and able to provide, or have the treating physician provide, values of HbA1c and fasting TG from at least 6 months prior to screening, as described in the protocol

For Part B only:

1. Participants <12 years of age at screening
2. Weighing ≥7 kg at screening
3. No metabolic criteria for study entry is required, as described in the protocol

Key Exclusion Criteria:

1. Has a current diagnosis of familial or acquired partial lipodystrophy or autoimmune (Type 1) diabetes mellitus
2. Any malignancy, eg, lymphoma, within the past 1 year, prior to screening visit, as described in the protocol
3. eGFR of <30 mL/min/1.73 m2 based on Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) creatinine or Schwartz equation, as applicable, at screening. Assessment can be repeated once
4. History of heart failure hospitalization, diagnosis of a myocardial infarction, stroke, clinically significant arrhythmia, as described in the protocol
5. Treatment with over-the-counter or prescription medications with the intention of weight loss within 3 months prior to the screening visit

For Part A only:

1. Treatment with metreleptin within 3 months of the screening visit
2. Addition or discontinuation of prescription medications or over-the-counter supplements for diabetes and/or dyslipidemia within 3 months prior to the start of the screening period, or changes in the use of these medications, as described in the protocol
3. Significant changes to lifestyle and diet, as described in the protocol
4. Current chronic treatment with high-dose corticosteroids, defined as use of higher than physiologic doses, as described in the protocol

NOTE: Other protocol defined inclusion/exclusion criteria apply.

• Clinical Trial Management, Study director, Regeneron Pharmaceuticals