The Effects of Metreleptin in Congenital Leptin Deficiency

An Observational Study of the Effects of Metreleptin in Young Adults With Congenital Leptin Deficiency

This study has been designed to 1) provide access to metreleptin to the only two individuals in the US known to have congenital leptin deficiency (CLD) and 2) explore a variety of unanswered questions about leptin physiology in general and metreleptin therapy in CLD specifically.

The primary study endpoints include the following measures: body composition, measures of hepatic steatosis, measures of insulin sensitivity, and measures of sleep architecture.

Secondary study endpoints include assessment of clock gene expression, body temperature, thyroid function, gonadal function, cognitive function, eating behavior, physical activity, mood, quality of life, and body image.

Study Overview

• Status: Completed
• Conditions: Congenital Leptin Deficiency (Disorder)
• Intervention / Treatment: Drug: Metreleptin

Detailed Description

Congenital leptin deficiency (CLD) is a rare autosomal recessive condition caused by a mutation in the leptin gene (LEP). This mutation leads to a severe deficiency in leptin, a hormone secreted primarily by adipocytes. Leptin is also secreted by gastric mucosal cells, in response to stimuli such as food intake. Leptin has many important physiologic roles, including serving as a signal to the hypothalamus of both long-term (adipocyte) and short-term (gastric) energy storage. Individuals with CLD have hyperphagia and morbid obesity with an onset in early childhood. Hypogonadotropic hypogonadism, insulin resistance, and immune dysfunction are also often observed in patients with CLD but these features can be of varying degrees of severity.

Recombinant human leptin (metreleptin; Myalept®) was approved by the U.S. Food and Drug Administration in 2014 to treat the complications of leptin deficiency in patients with generalized lipodystrophy (GL). Commercial use of metreleptin is restricted to patients with leptin deficiency due to GL. However, ~3 dozen patients worldwide who are known to have congenital leptin deficiency (CLD) have been treated safely and successfully with metreleptin in the investigational setting for two decades. Metreleptin therapy has been shown to reduce hunger and desire to eat in leptin-deficient humans, and significant weight loss is typical.

Some questions remain regarding the pluripotent effects of metreleptin in patients with CLD. Understudied aspects of physiology in these patients include the role of leptin (independent of weight) in insulin sensitivity, hepatic steatosis, and sleep. For each of these areas, there is preliminary evidence from humans or the ob/ob (leptin-deficient) mouse model for a beneficial role of leptin, but important knowledge gaps remain.

• Study Type: Observational
• Enrollment (Actual): 2

Contacts and Locations

Study Locations

• United States
  • Illinois
    • Chicago, Illinois, United States, 60611
      • Northwestern University Feinberg School of Medicine

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 14 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: N/A
• Genders Eligible for Study: All

• Sampling Method: Non-Probability Sample

Study Population

This study will enroll two young adults who have been recently diagnosed with congenital leptin deficiency (homozygous for the pathogenic variant c.398delG in exon 3 of the leptin gene). They have not been previously treated with metreleptin.

Description

Inclusion Criteria:

• Diagnosis of congenital leptin deficiency
• Age 18 years or older
• Must agree to use contraception for the duration of treatment with metreleptin and for 6 months post-treatment completion.

Exclusion Criteria:

• Presence of a clinically significant medical condition that could significantly affect the risk/benefit ratio for metreleptin treatment, as judged by the PI
• Known allergies to E. coli-derived proteins or hypersensitivity to any component of metreleptin treatment

Study Plan

How is the study designed?

Design Details

• Observational Models: Case-Only
• Time Perspectives: Prospective

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
change in hepatic steatosis	ultrasound elastography with dispersion imaging	repeated measures at baseline, 1 week, 1 month, 3 months, 6 months, 12 months, 18 months, 24 months
change in insulin sensitivity	HOMA (fasting labs)	repeated measures at baseline, 1 week, 3 months
change in sleep architecture	polysomnography	repeated measures at baseline, 3 months, 6 months, 12 months
change in body composition	full body DXA	repeatured measures at baseline, 3 months, 6 months, 12 months, 18 months, 24 months

Collaborators and Investigators

• Sponsor: Northwestern University
• Investigators: Principal Investigator: Lisa Neff, MD, Dr.

Study record dates

Study Major Dates

• Study Start (Actual): June 20, 2019
• Primary Completion (Actual): August 13, 2021
• Study Completion (Actual): August 13, 2021

Study Registration Dates

• First Submitted: July 12, 2019
• First Submitted That Met QC Criteria: August 19, 2019
• First Posted (Actual): August 21, 2019

Study Record Updates

• Last Update Posted (Actual): December 30, 2021
• Last Update Submitted That Met QC Criteria: December 10, 2021
• Last Verified: December 1, 2021

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Overnutrition; Nutrition Disorders; Overweight; Body Weight; Obesity; Obesity, Morbid
• Other Study ID Numbers: 00209730

Drug and device information, study documents

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