Leptin to Treat Lipodystrophy

This study will evaluate the safety and effectiveness of leptin replacement therapy in patients with lipodystrophy (also called lipoatrophy). Patients have a total or partial loss of fat cells. They also lack the hormone leptin, which is produced by fat cells. The leptin deficiency usually causes high blood lipid (fat) levels and insulin resistance that may lead to diabetes. Patients may have hormone imbalances, fertility problems, large appetite, and liver disease due to fat accumulation. Patients age greater than or equal to 6 months with significant lipodystrophy may be eligible for this study. Participants will be admitted to the NIH Clinical Center for 10 days for the following studies before beginning 12 months of leptin therapy: Insulin tolerance test Ultrasound of the liver and, if abnormalities are found, possibly liver biopsies. Fasting blood tests Resting metabolic rate Magnetic resonance imaging of the liver and other organs, and of muscle and fat. Pelvic ultrasound in women to detect ovarian cysts. Estimation of body fat Oral glucose tolerance test Intravenous glucose tolerance test Appetite level and food intake Hormone function tests Questionnaires to assess activity and mood 24-hour urine collections Additional studies may include blood tests for genetic studies of lipodystrophy, a muscle biopsy to study muscle proteins involved in regulating energy expenditure before and after leptin replacement, and examination of a surgical specimen (if available) to study molecules that may be involved in energy storage and use. When the above tests are completed, leptin therapy begins. The drug is injected under the skin twice a day for 4 months and then once a day, if feasible. The dose is increased at the 1- and 2-month visits. Follow-up visits at 1, 2, 4, 6, 8 and 12 months after therapy starts include a physical examination, blood tests and a meeting with a dietitian. At the end of 12 months, all baseline studies described above are repeated. Patients record their symptoms weekly throughout the study. Those with diabetes measure their blood glucose levels daily before each meal and at bedtime.

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.

Lipoatrophic Diabetes, Diabetes Mellitus, Hypertriglyceridemia, NASH, Lipodystrophy, Leptin, Diabetes

subcutaneous metreleptin injections in one to two daily doses ranging from 0.06 to 0.24 mg/kg per day.

Percentage of Glycosylated Hemoglobin at Baseline, 6 Months, and 12 Months on Treatment With Metreleptin

Percentage of glycosylated hemoglobin at Baseline, 6 months, and 12 months on treatment with metreleptin

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

Burant CF, Sreenan S, Hirano K, Tai TA, Lohmiller J, Lukens J, Davidson NO, Ross S, Graves RA. Troglitazone action is independent of adipose tissue. J Clin Invest. 1997 Dec 1;100(11):2900-8. doi: 10.1172/JCI119839.

Moitra J, Mason MM, Olive M, Krylov D, Gavrilova O, Marcus-Samuels B, Feigenbaum L, Lee E, Aoyama T, Eckhaus M, Reitman ML, Vinson C. Life without white fat: a transgenic mouse. Genes Dev. 1998 Oct 15;12(20):3168-81. doi: 10.1101/gad.12.20.3168.

Cao H, Hegele RA. Nuclear lamin A/C R482Q mutation in canadian kindreds with Dunnigan-type familial partial lipodystrophy. Hum Mol Genet. 2000 Jan 1;9(1):109-12. doi: 10.1093/hmg/9.1.109.

Meral R, Malandrino N, Walter M, Neidert AH, Muniyappa R, Oral EA, Brown RJ. Endogenous Leptin Concentrations Poorly Predict Metreleptin Response in Patients With Partial Lipodystrophy. J Clin Endocrinol Metab. 2022 Mar 24;107(4):e1739-e1751. doi: 10.1210/clinem/dgab760.

Nguyen ML, Sachdev V, Burklow TR, Li W, Startzell M, Auh S, Brown RJ. Leptin Attenuates Cardiac Hypertrophy in Patients With Generalized Lipodystrophy. J Clin Endocrinol Metab. 2021 Oct 21;106(11):e4327-e4339. doi: 10.1210/clinem/dgab499.

Sekizkardes H, Cochran E, Malandrino N, Garg A, Brown RJ. Efficacy of Metreleptin Treatment in Familial Partial Lipodystrophy Due to PPARG vs LMNA Pathogenic Variants. J Clin Endocrinol Metab. 2019 Aug 1;104(8):3068-3076. doi: 10.1210/jc.2018-02787.

Brown RJ, Meehan CA, Cochran E, Rother KI, Kleiner DE, Walter M, Gorden P. Effects of Metreleptin in Pediatric Patients With Lipodystrophy. J Clin Endocrinol Metab. 2017 May 1;102(5):1511-1519. doi: 10.1210/jc.2016-3628.

Kassai A, Muniyappa R, Levenson AE, Walter MF, Abel BS, Ring M, Taylor SI, Biddinger SB, Skarulis MC, Gorden P, Brown RJ. Effect of Leptin Administration on Circulating Apolipoprotein CIII levels in Patients With Lipodystrophy. J Clin Endocrinol Metab. 2016 Apr;101(4):1790-7. doi: 10.1210/jc.2015-3891. Epub 2016 Feb 22.

Chan JL, Koda J, Heilig JS, Cochran EK, Gorden P, Oral EA, Brown RJ. Immunogenicity associated with metreleptin treatment in patients with obesity or lipodystrophy. Clin Endocrinol (Oxf). 2016 Jul;85(1):137-49. doi: 10.1111/cen.12980. Epub 2016 Feb 2.

Diker-Cohen T, Cochran E, Gorden P, Brown RJ. Partial and generalized lipodystrophy: comparison of baseline characteristics and response to metreleptin. J Clin Endocrinol Metab. 2015 May;100(5):1802-10. doi: 10.1210/jc.2014-4491. Epub 2015 Mar 3.

Christensen JD, Lungu AO, Cochran E, Collins MT, Gafni RI, Reynolds JC, Rother KI, Gorden P, Brown RJ. Bone mineral content in patients with congenital generalized lipodystrophy is unaffected by metreleptin replacement therapy. J Clin Endocrinol Metab. 2014 Aug;99(8):E1493-500. doi: 10.1210/jc.2014-1353. Epub 2014 Jul 29.

Joseph J, Shamburek RD, Cochran EK, Gorden P, Brown RJ. Lipid regulation in lipodystrophy versus the obesity-associated metabolic syndrome: the dissociation of HDL-C and triglycerides. J Clin Endocrinol Metab. 2014 Sep;99(9):E1676-80. doi: 10.1210/jc.2014-1878. Epub 2014 Jun 13.

Kamran F, Rother KI, Cochran E, Safar Zadeh E, Gorden P, Brown RJ. Consequences of stopping and restarting leptin in an adolescent with lipodystrophy. Horm Res Paediatr. 2012;78(5-6):320-5. doi: 10.1159/000341398. Epub 2012 Sep 4.

Chan JL, Lutz K, Cochran E, Huang W, Peters Y, Weyer C, Gorden P. Clinical effects of long-term metreleptin treatment in patients with lipodystrophy. Endocr Pract. 2011 Nov-Dec;17(6):922-32. doi: 10.4158/EP11229.OR.

Chong AY, Lupsa BC, Cochran EK, Gorden P. Efficacy of leptin therapy in the different forms of human lipodystrophy. Diabetologia. 2010 Jan;53(1):27-35. doi: 10.1007/s00125-009-1502-9. Epub 2009 Sep 2.