Leptin analog shows promise as lipodystrophy treatment

Therapy with a synthetic analog of the hormone leptin has been shown to have a positive effect on patients with partial lipodystrophy-associated nonalcoholic steatohepatitis, according to researchers at Michigan Medicine in Ann Arbor, MI, who presented their findings at the Endocrine Society's 99th Annual Meeting and Expo (ENDO 2017) in Orlando, FL.

Results showed that patients with a lower baseline leptin level had a higher response rate after 1 year of treatment.

“Fatty liver, or excess fat building up in the liver, is a common metabolic disturbance seen in patients with lipodystrophy,” according to Elif Oral, MD, associate professor of endocrinology at Michigan Medicine, and principal investigator of the study. “The underlying metabolic disturbances seen in this patient population can be difficult to manage with traditional therapies.”

Patients with partial lipodystrophy who were enrolled in the study underwent two liver biopsies—one at the beginning of the trial and one after 1 year of treatment with metreleptin, a pharmaceutical manufactured by Novelion Therapeutics’ subsidiary. The participants’ NASH score, which measures progression of fatty liver disease, and NAS score, which measures progression of non-alcoholic fatty liver disease, were recorded.

Of the 23 patients enrolled in the study, 22 were treated with at least one dose of metreleptin at baselines. Eighteen patients completed treatment after 1 year. Those patients’ NASH scores improved from a mean of 6 at baseline (moderate to advanced disease) to a mean of 5. NAS scores in these patients also improved from a mean of 5 to a mean of 4 after 1 year. These changes were noted to be statistically significant.

“About half of the patients had scores that lowered by two points or more, which is clinically significant in patients with this disease,” said Dr. Oral. “Generally, that type of drop is only seen with 10% or more sustained weight loss in the common form of fatty liver disease, which usually only occurs with metabolic surgery.”

Patients who saw an improvement of 2 points or greater had a lower baseline leptin level (14.5 ng/mL) when compared with non-responders (25 ng/mL). In addition, some patients saw reductions in glucose control and lipid levels, but these were not statistically significant. The most frequently reported adverse events in the study were upper respiratory infections, hypoglycemia, and diarrhea.

“The liver disease at baseline is quite significant among the patients in this study, which showed a significant degree of inflammation and fibrosis, even in the absence of liver test abnormalities,” according to Nevin Ajluni, MD, assistant professor of endocrinology at Michigan Medicine and the presenting author of the study. “This highlights the importance of screening for this complication.”

Lipodystrophy is a group of rare diseases that involve the selective loss of fat tissue from the body. Affected patients may have severe insulin resistance, elevated blood lipid levels, and fatty liver.

Generalized lipodystrophy causes fat loss throughout the entire body, and partial lipodystrophy typically causes fat loss in the arms, legs, head, and torso, and fat accumulation in the neck, face, and intra-abdominal areas of the body. Metreleptin was approved by the Food and Drug Administration in 2014 to treat generalized lipodystrophy, but has not been approved to treat partial lipodystrophy.

The open-label study was funded by the NIH.