Efficacy of Metreleptin Therapy in the Treatment of Fatty Liver Disease Associated with Partial Lipodystrophy

Presentation Number: OR09-4
Date of Presentation: April 4th, 2017

Nevin Ajluni*, Rasimcan Meral, Adam H Neidert, Diana Rus, Rita Hench, Thomas L Chenevert, Barbara McKenna, Frank DiPaola, Hari Conjeevaram and Elif A Oral
University of Michigan, Ann Arbor, MI


Partial lipodystrophy (PL) is associated with metabolic complications of diabetes, dyslipidemia and NASH (non-alcoholic steatohepatitis) with variable degree of residual body fat and leptinemia. The precise efficacy of leptin therapy in PL is not known. We aimed to evaluate the effect of leptin therapy on lipodystrophy-associated NASH in PL and sought to determine if baseline leptin predicted clinical response. 23 patients (18 female, 5 male, ages 12-64) with PL without a prerequisite of leptin deficiency were enrolled in this open-label study. Of 23 patients, 22 had biopsy-proven NASH on baseline transcutaneous liver biopsy and received at least one dose of metreleptin (Aegerion Pharmaceuticals, Cambridge MA, in development for PL). Primary outcomes were determined as NAS (NAFLD activity score) and NASH score, which incorporates fibrosis scores, obtained from histopathological evaluation of liver biopsy specimens using a modified NASH Clinical Research Network scoring system at baseline and after 1 year of subcutaneous metreleptin therapy. An important secondary outcome was the percentage of patients with histological response defined as a decrease in total NASH score of ≥ 2 without an increase in fibrosis to this degree. Other metabolic parameters including HbA1c, triglycerides, liver fat via MRI using DIXON method and body composition using DEXA were also obtained as other secondary measures. Leptin levels at baseline were measured using a commercial ELISA (Millipore, Billerica, MA which typically gives values higher than the traditional Linco RIA assay). The 22 patients (age 12-64, median age 41.5, 5 male /17 female) who received at least one dose of the drug had the following metabolic parameters at baseline: HbA1c: 8.7 ± 1.8 % (reference 4.2-5.6%), triglyceride levels 1102 ± 1773 mg/dl (reference <150 mg/dl), body fat % 31.0 ± 9.8 and liver fat 12.4 ± 6.5%. Of these, 18 completed one year of treatment. Mean ± SD NAS scores in the completers decreased with the 12-month treatment from 5 ± 1 at baseline to 4 ± 1 at 1 year (p=0.0002) and total NASH scores decreased from 6 ± 2 at baseline to 5 ± 2 (p=0.0079). Liver fat as measured by MR Dixon method was also significantly lowered from 13.3 ± 6.6 % at baseline to 8.4 ± 5.2 % at 12 months (p=0.0014). Nine patients (50%) had a histological response with a mean decrease of 2 ± 1 in NAS and a reduction of 49 ± 26 % from baseline in liver fat (p=0.0047). Responders had a baseline leptin level of 14.5 ± 8.5 ng/ml compared to 25.0 ± 12.8 ng/ml in the non-responder group (p=0.0539). We conclude that in PL, metreleptin therapy had a variable effect on lipodystrophy-associated NASH. Half of our patients had a histological response with meaningful improvement in NASH scores (as well as NAS) on liver biopsy after 1 year of treatment. A lower baseline leptin level tended to predict histological response. Further investigations to identify a biomarker of response are underway.


Disclosure: EAO: Advisory Group Member, Aegerion Pharmaceuticals, Principal Investigator, AegerionPharmaceuticals, Investigator, Aegerion Pharmaceuticals, Advisory Group Member, Akcea Therapeutics, Principal Investigator, Ionis pharmaceuticals, Author, Boehringer Ingelheim, Advisory Group Member, Thera, Principal Investigator, GI dynamics. Nothing to Disclose: NA, RM, AHN, DR, RH, TLC, BM, FD, HC