Efficacy and Safety of Metreleptin in Patients with Partial Lipodystrophy: Lessons from an Expanded Access Program

Abstract

Objective: Patients with lipodystrophy have severe metabolic abnormalities (insulin resistance, diabetes, and hypertriglyceridemia) that may increase morbidity and mortality. Metreleptin is approved by the United States Food and Drug Administration for treatment of generalized forms of lipodystrophy. We aimed to determine the efficacy and safety of metreleptin among patients with partial lipodystrophy using an expanded-access model.

Methods: Study FHA101 (ClinicalTrials.gov identifier: NCT00677313) was an open-label, expanded-access, long-term clinical effectiveness and safety study in 23 patients with partial lipodystrophy and diabetes and/or hypertriglyceridemia with no prespecified leptin level. Metreleptin was administered subcutaneously at 0.02 mg/kg twice daily (BID) at Week 1, followed by 0.04 mg/kg BID at Week 2. Dose adjustments thereafter were based on patient response (maximum dose of 0.08 mg/kg BID). One-year changes in glycated hemoglobin (HbA1c), fasting plasma glucose, triglycerides, alanine and aspartate aminotransferases, and treatment-emergent adverse events (TEAEs) were evaluated.

Results: HbA1c, fasting plasma glucose, and triglycerides were numerically decreased throughout 1 year, with mean (standard error) changes from baseline of -0.88 (0.62)%, -42.0 (22.4) mg/dL, and -119.8 (84.1) mg/dL, respectively, which were greater among patients with higher baseline abnormalities. Liver enzymes did not worsen, and the most frequently observed TEAEs (≥ 10% incidence) were mild to moderate and included nausea (39.1%), hypoglycemia (26.1%), and urinary tract infections (26.1%)-all reported previously. There were no reports of clinically significant immune-related adverse events or new safety signals.

Conclusions: Our clinical observations document the large heterogeneity and disease burden of partial lipodystrophy syndromes and suggest that metreleptin treatment benefits may extend to patients with partial lipodystrophy. Additional studies are needed to confirm these preliminary findings.

Keywords: Diabetes; Hypertriglyceridemia; Metreleptin; Partial lipodystrophy.

Figure 1

Patients with generalized lipodystrophy and partial lipodystrophy. Left panel: 19-year-old female with acquired generalized lipodystrophy. Right panel: two 40-year-old twin sisters with familial partial lipodystrophy (Patients 20 and 21; Supplemental Table 1), which demonstrates adipose tissue loss in the upper extremities while adipose tissue is preserved in the face and neck.

Figure 2

Study design and treatment algorithm after enrollment. BID, twice daily; D, day; M, month; W, week. *Metreleptin dose titration up to 0.08 mg/kg BID was allowed if there were no improvements in metabolic parameters, and a reduction in target dose was permitted if tolerability became an issue.

Figure 3

Patient disposition and data availability. ALT: Alanine Aminotransferase; AST: Aspartate Aminotransferase; FPG: Fasting Plasma Glucose; HbA1c: Glycated Hemoglobin; TG: Triglycerides

Figure 4

Mean changes from baseline in (A) glycated hemoglobin (HbA1c), (B) fasting plasma glucose (FPG), and (C) triglycerides (TG) in patients with available measurements at each 3-month interval. *Represents the 95% confidence interval (CI) at 12 months.

Figure 5

Mean changes from baseline in (A) ALT and (B) AST in patients with available measurements at each 3-month interval. ALT: Alanine Aminotransferase; AST: Aspartate Aminotransferase. *Represents the 95% confidence interval (CI) at 12 months.