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

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

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

Study Overview

• Status: Active, not recruiting
• Conditions: Familial Partial Lipodystrophy; Metabolic Abnormalities
• Intervention / Treatment: Drug: REGN4461; Drug: Matching Placebo

• Study Type: Interventional
• Enrollment (Actual): 20
• Phase: Phase 2

Expanded Access

Available outside the clinical trial. See expanded access record.

Contacts and Locations

• Study Contact: Name: Clinical Trials Administrator; Phone Number: 844-734-6643; Email: clinicaltrials@regeneron.com

Study Locations

• France
  • Paris, France, 75013
    • ICAN, Institute of Cardiometabolism and Nutrition
• Spain
  • Galicia
    • Santiago de Compostela, Galicia, Spain, 15706
      • Complexo Hospitalario Universitario de Santiago-Hospital Médico-Cirúrxico de Conxo
• Turkey
  • Bornova
    • Izmir, Bornova, Turkey, 35100
      • Ege University Faculty of Medicine
• United Kingdom
  • UK
    • Cambridge, UK, United Kingdom, CB2 OQQ
      • Cambridge University Hospitals NHS Foundation Trust
• United States
  • Florida
    • Boca Raton, Florida, United States, 33434
      • Excel Medical Clinical Trials - A Flourish Research Site
  • Maryland
    • Bethesda, Maryland, United States, 20892
      • National Institute Of Health
  • Michigan
    • Ann Arbor, Michigan, United States, 48109
      • University of Michigan
  • Pennsylvania
    • Pittsburgh, Pennsylvania, United States, 15213
      • University of Pittsburgh Medical Center
  • Texas
    • Dallas, Texas, United States, 75390
      • UT Southwestern Medical Center
  • Washington
    • Seattle, Washington, United States, 98109
      • University of Washington

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 16 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

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

What is the study measuring?

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

Collaborators and Investigators

• Sponsor: Regeneron Pharmaceuticals
• Investigators: Study Director: Clinical Trial Management, Regeneron Pharmaceuticals

Study record dates

Study Major Dates

• Study Start (Actual): February 28, 2022
• Primary Completion (Estimated): December 27, 2024
• Study Completion (Estimated): June 27, 2025

Study Registration Dates

• First Submitted: October 12, 2021
• First Submitted That Met QC Criteria: October 12, 2021
• First Posted (Actual): October 22, 2021

Study Record Updates

• Last Update Posted (Actual): December 20, 2023
• Last Update Submitted That Met QC Criteria: December 19, 2023
• Last Verified: December 1, 2023

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Metabolic Diseases; Skin Diseases; Genetic Diseases, Inborn; Lipid Metabolism Disorders; Laminopathies; Lipid Metabolism, Inborn Errors; Skin Diseases, Metabolic; Congenital Abnormalities; Lipodystrophy; Lipodystrophy, Familial Partial
• Other Study ID Numbers: R4461-PLD-20100; 2021-000138-33 (EudraCT Number)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: All Individual Patient Data (IPD) that underlie publicly available results will be considered for sharing
• IPD Sharing Time Frame: Individual anonymized participant data will be considered for sharing once the indication has been approved by a regulatory body, if there is legal authority to share the data and there is not a reasonable likelihood of participant re-identification
• IPD Sharing Access Criteria: Qualified researchers may request access to anonymized patient level data or aggregate study data when Regeneron has received marketing authorization from major health authorities (e.g., Food and Drug Administration (FDA), European Medicines Agency (EMA), Pharmaceuticals and Medical Devices Agency (PMDA), etc) for the product and indication, has the legal authority to share the data, and has made the study results publicly available (eg, scientific publication, scientific conference, clinical trial registry).
• IPD Sharing Supporting Information Type: STUDY_PROTOCOL; SAP; ICF; ANALYTIC_CODE; CSR

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No