Leptin to Treat Lipodystrophy

Lipoatrophic diabetes is a syndrome characterized by insulin resistance in association with a paucity of adipose tissue. Patients with severe lipoatrophy die prematurely, typically from the complications of diabetes or liver disease. Experiments with lipoatrophic mice suggest that the insulin resistance is caused by the lack of adipose tissue. Adipose tissue normally produces leptin, a hormone that increases insulin action. For the last fourteen years, we have been studying the extent to which leptin deficiency causes diabetes in lipoatrophic patients. In fact, in our initial study we have seen nearly 60% amelioration of fasting glucose, triglycerides and free fatty acid levels and about 2% actual decreases from baseline HbA1c levels with 4 months of leptin replacement therapy. This response has continued to be sustained, as we continue to follow patients that have now received leptin replacement therapy for fourteen years.

This is an open-labeled study. The study monitors the safety and efficacy of recombinant methionyl human leptin (A-100) replacement in children and adults. We are looking at the long-term effects of leptin replacement on extended therapy. In this long-term replacement protocol, we will monitor metabolic control (e.g. glucose, insulin, and triglyceride levels) as primary outcome measures. Ancillary studies will evaluate the effect of Metreleptin on other hormonal axes, growth and development and on liver pathology.

We continue to evaluate the efficacy in a broader leptin deficient population of patients with lipodystrophy. Current inclusion criteria in patients greater than or equal to 5 years include female patients with leptin levels < 12 ng/mL and male patients with leptin levels < 8 ng/mL. We continue to seek patients who meet these criteria. In children ages 6 months 5 years, we will use a cut-off leptin level of 6 ng/mL in both genders.

Patients who are greater than or equal to age 5 years will be evaluated every 6 months during the first year of therapy. If no improvements are seen after 6 months of therapy, then the study medication may be increased to 150% of the predicted dose (0.09mg/kg/day for males and girls less than 10 years of age/ 0.12mg/kg/day for females 10 years of age and older) from 6 months to 1 year on therapy. If no improvements are seen after increasing to 150% of the predicted dose, then the study medication will be withdrawn. If the patient shows improvements in his/her metabolic parameters while on leptin, the patient will be invited to continue taking the study medication. The investigators will strive for all patients responding to leptin to bring their metabolic parameters into the normal range. The maximum dose of leptin that will be given is 0.24 mg/kg/day for females 10 and older, and 0.12 mg/kg/day for males and females less than 10 years of age. After the first year of treatment, the patient will be evaluated every 6 months through the second year of treatment, and then the study period will end. After two years of treatment, extending the treatment period on an annual basis will be the decision of the patient, principal investigator and Bristol-Myers Squibb (BMS)/AstraZeneca Pharmaceuticals (AZ). Leptin is supplied by BMS/AZ, and is currently only available through research studies. Neither the NIH nor BMS/AZ can guarantee that leptin will be available indefinitely and/or after the study ends. However, leptin was recently approved by the FDA on February 25, 2014, for use in patients with generalized lipodystrophy.

All patient referrals for acceptance into the protocol, are initiated by the physician/health care provider.

• INCLUSION CRITERIA:

All ethnic groups.

Males and females.

• Age greater than or equal to 6 months.
• Clinically significant lipodystrophy, identified by the study physician during the physical examination as an absence of fat outside the range of normal variation and/or identified as a disfiguring factor by the patient.

Circulating leptin levels less than 12.0 ng/ml in females and less than 8.0 ng/ml in males as measured by Linco assay on a specimen obtained after an overnight fast. In children ages 6 months 5 years, a circulating leptin level of less than 6 ng/mL will be used. Leptin samples will be run through Millipore Laboratories, who use the Linco Assay, which has been the assay previously used to measure leptin levels throughout this study period.

Presence of at least one of the following metabolic abnormalities:

• Presence of diabetes as defined by the 2007 ADA criteria

• Fasting plasma glucose greater than or equal to 126 mg/dL, or
• 2 hour plasma glucose greater than or equal to 200 mg/dL following a 75 gram (1.75gm/kg) oral glucose load, or
• Diabetic symptoms with a random plasma glucose greater than or equal to 200 mg/dl
• Fasting insulin greater than 30 micro units/ml.
• Fasting hypertriglyceridemia greater than 200 mg/dL or postprandially elevated triglycerides greater than 500 mg/dL when fasting is clinically not indicated (e.g. in infants)

-Persons with impaired decision-making capacity and who may be unable to provide informed consent may participate in this study per the discretion of the Principal Investigator.

Exclusion criteria

Pregnant women, women in their reproductive years who do not use an effective method of birth control, and women currently nursing or lactating within 6 weeks of having completed nursing.

Exclusions for underlying diseases likely to increase side effects or hinder objective data collection:

• Known infectious liver disease
• Known HIV infection
• Current alcohol or substance abuse
• Psychiatric disorder impeding competence or compliance
• Active tuberculosis
• Use of anorexiogenic drugs
• Other condition(s) which in the opinion of the clinical investigators would impede completion of the study
• Subjects who have known hypersensitivity to E. Coli derived proteins.
• Subjects with acquired lipodystrophy and a hematologic abnormality such as neutropenia and/or lymphadenopathy