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: Terminated
• Conditions: Familial Partial Lipodystrophy; Metabolic Abnormalities
• Intervention / Treatment: Drug: REGN4461; Drug: Matching Placebo

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

Contacts and Locations

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 (Türkiye)
  • Bornova
    • Izmir, Bornova, Turkey (Türkiye), 35100
      • Ege University Faculty of Medicine
• 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

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 14 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 From Baseline to Week 12 in Fasting Serum Triglyceride (TG) (Cohort A)	Percentage change in fasting serum TG was reported for participants with elevated baseline fasting TG (> 200 mg/dL) and with baseline leptin < 8.0 ng/mL (Cohort A).	Baseline to week 12
Change From Baseline to Week 12 in Hemoglobin A1c (HbA1c) (Cohort A)	Change in HbA1c was reported for participants with elevated baseline HbA1c (> 7.0%) and with baseline leptin < 8.0 ng/mL (Cohort A).	Baseline to week 12

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Percent Change From Baseline to Week 12 in Fasting Serum TG (Cohorts B and A + B)	Percent change in fasting serum TG was reported for participants with elevated baseline fasting TG (>200 mg/dL) in Cohort B and Cohorts A + B.	Baseline to week 12
Change From Baseline to Week 12 in HbA1c (Cohorts B and A + B)	Change in HbA1c was reported for participants with elevated baseline HbA1c (>7.0%) in Cohort B and Cohorts A + B.	Baseline to week 12
Percent Change From Baseline to Weeks 12 and 24 in Fasting Serum TG (Study Arm 1)	Percent change in fasting serum TG was reported for participants in Study Arm 1.	Baseline, Week 12, Week 24
Percent Change From Baseline to Weeks 12 and 24 in Fasting Serum TG (Study Arm 2)	Percent change in fasting serum TG was reported for participants in Study Arm 2.	Baseline, Week 12, Week 24
Change From Baseline to Weeks 12 and 24 in HbA1c (Study Arm 1)	Change from baseline in HbA1c was reported for participants in Study Arm 1.	Baseline, Week 12, Week 24
Change From Baseline to Weeks 12 and 24 in HbA1c (Study Arm 2)	Change from baseline in HbA1c was reported for participants in Study Arm 2.	Baseline, Week 12, Week 24
Change From Baseline to Weeks 12 and 24 in Fasting Glucose (Study Arm 1)	Change from baseline in fasting glucose was reported for participants in Study Arm 1.	Baseline, Week 12, Week 24
Change From Baseline to Weeks 12 and 24 in Fasting Glucose (Study Arm 2)	Change from baseline in fasting glucose was reported for participants in Study Arm 2.	Baseline, Week 12, Week 24
Percent Change From Baseline to Weeks 12 and 24 in Liver Fat Magnetic Resonance Imaging-derived Proton Density Fat Fraction (MRI-PDFF) (Study Arm 1)	Percent change from baseline in MRI-PDFF was reported for participants with baseline MRI-PDFF ≥8.5% in Study Arm 1.	Baseline, Week 12, Week 24
Percent Change From Baseline to Weeks 12 and 24 in Liver Fat MRI-PDFF (Study Arm 2)	Percent change from baseline in MRI-PDFF was reported for participants with baseline liver fat MRI-PDFF ≥8.5% in Study Arm 2.	Baseline, Week 12, Week 24
Change From Baseline to Weeks 12 and 24 on the Daily Lipodystrophy Hunger Questionnaire - Highest Hunger Score	The daily lipodystrophy hunger questionnaire was developed to assess hunger related behaviors among patients with lipodystrophy. The highest hunger score asked participants to rate their highest hunger that day on a scale from 0 to 4, with higher scores representing the higher perceived hunger. A negative change from baseline indicated a reduction in perceived hunger.	Baseline, Week 12, Week 24
Change From Baseline to Weeks 12 and 24 on the Daily Lipodystrophy Hunger Questionnaire - Lowest Hunger Score	The daily lipodystrophy hunger questionnaire was developed to assess hunger related behaviors among patients with lipodystrophy. The lowest hunger score asked participants to rate their lowest hunger that day on a scale from 0 to 4, with higher scores indicating higher perceived hunger. A negative change from baseline score indicated a reduction in perceived lowest hunger.	Baseline, Week 12, Week 24
Change From Baseline to Weeks 12 and 24 on the Daily Lipodystrophy Hunger Questionnaire - Felt Hungry Score	The daily lipodystrophy hunger questionnaire was developed to assess hunger related behaviors among participants with lipodystrophy. The felt hungry score asked how much time participants felt hunger that day on a scale from 0 to 4, with higher scores indicating more time feeling hungry. A negative change from baseline score indicated a reduction in time spent feeling hungry.	Baseline, Week 12, Week 24
Change From Baseline to Weeks 12 and 24 on the Daily Lipodystrophy Hunger Questionnaire - Fullness Score	The daily lipodystrophy hunger questionnaire was developed to assess hunger related behaviors among patients with lipodystrophy. The fullness score asked participants to rate how often they felt full after eating that day on a scale from 0 to 4, with higher scores indicating higher feeling of fullness. A negative change from baseline indicated a reduced feeling of fullness.	Baseline, Week 12, Week 24
Number of Participants With Treatment-emergent Adverse Events (TEAEs)		Up to Day 169
Concentrations of REGN4461 in Serum		Weeks 0, 1, 2, 3, 4, 5, 6, 9, 12, 13, 14, 15, 16, 17, 18, 21, 28, 32 and 36. Weeks 0 and 12 collected pre- and post-dose. All other time points were only pre-dose.
Number of Participants With Treatment-emergent Anti-drug Antibody (ADA) Response		Up to Day 281

Collaborators and Investigators

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

Publications and helpful links

Helpful Links

• A Plain Language Summary is available on TrialSummaries.com

Study record dates

Study Major Dates

• Study Start (Actual): February 28, 2022
• Primary Completion (Actual): December 13, 2023
• Study Completion (Actual): April 18, 2024

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 (Estimated): October 16, 2025
• Last Update Submitted That Met QC Criteria: October 8, 2025
• Last Verified: August 1, 2025

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Laminopathies; Genetic Diseases, Inborn; Metabolic Diseases; Skin Diseases; Lipid Metabolism Disorders; Lipid Metabolism, Inborn Errors; Skin Diseases, Metabolic; Congenital, Hereditary, and Neonatal Diseases and Abnormalities; Nutritional and Metabolic Diseases; Skin and Connective Tissue Diseases; 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