Selective targeting of angiopoietin-like 3 (ANGPTL3) with vupanorsen for the treatment of patients with familial partial lipodystrophy (FPLD): results of a proof-of-concept study

Abstract

Background: Familial partial lipodystrophy (FPLD) is a rare disease characterized by selective loss of peripheral subcutaneous fat, associated with dyslipidemia and diabetes mellitus. Reductions in circulating levels of ANGPTL3 are associated with lower triglyceride and other atherogenic lipids, making it an attractive target for treatment of FPLD patients. This proof-of-concept study was conducted to assess the efficacy and safety of targeting ANGPTL3 with vupanorsen in patients with FPLD.

Methods: This was an open-label study. Four patients with FPLD (two with pathogenic variants in LMNA gene, and two with no causative genetic variant), diabetes (HbA1c ≥ 7.0 % and ≤ 12 %), hypertriglyceridemia (≥ 500 mg/dL), and hepatic steatosis (hepatic fat fraction, HFF ≥ 6.4 %) were included. Patients received vupanorsen subcutaneously at a dose of 20 mg weekly for 26 weeks. The primary endpoint was the percent change from baseline in fasting triglycerides at Week 27. Other endpoints analyzed at the same time point included changes in ANGPTL3, fasting lipids and lipoproteins, insulin secretion/sensitivity, postprandial lipids, and glycemic changes in response to a mixed meal test, HFF measured by MRI, and body composition measured by dual-energy absorptiometry (DEXA).

Results: Baseline mean ± SD fasting triglyceride level was 9.24 ± 4.9 mmol/L (817.8 ± 431.9 mg/dL). Treatment resulted in reduction in fasting levels of triglycerides by 59.9 %, ANGPTL3 by 54.7 %, and in several other lipoproteins/lipids, including very low-density lipoprotein cholesterol by 53.5 %, non-high-density lipoprotein cholesterol by 20.9 %, and free fatty acids (FFA) by 41.7 %. The area under the curve for postprandial triglycerides, FFA, and glucose was reduced by 60 %, 32 %, and 14 %, respectively. Treatment with vupanorsen also resulted in 55 % reduction in adipose tissue insulin resistance index, while other insulin sensitivity indices and HbA1c levels were not changed. Additional investigations into HFF and DEXA parameters suggested dynamic changes in fat partitioning during treatment. Adverse events observed were related to common serious complications associated with diabetes and FPLD. Vupanorsen was well tolerated, and there was no effect on platelet count.

Conclusions: Although limited, these results suggest that targeting ANGPTL3 with vupanorsen could address several metabolic abnormalities in patients with FPLD.

Keywords: Adipose tissue insulin resistance; Angiopoietin-like protein 3; Familial partial lipodystrophy; Mixed meal test; Triglycerides; Vupanorsen.

Fig. 1

Effect of vupanorsen on ANGPTL3 (A), Triglyceride (B), and VLDL-C (C) levels in individual participants over the course of the study. Legend shows the patient number to link individual data from different figures

Fig. 2

Change in insulin resistance indices during the study. A Adipo-IR (adipose tissue insulin resistance index) and B correlation between HOMA-IR (homeostatic model assessment- insulin resistance index) and free fatty acids. Legend shows the patient number to link individual data from different figures

Fig. 3

Postprandial response in the area under the curve (AUC) of triglyceride (A) and free fatty acid (FFA) (B) levels in the individual patients, and mean triglyceride levels from all participants (C) during the mixed meal test at key study time points. Legend shows the patient number to link individual data from different figures. Conversion factor for SI units for triglycerides=0.0113 (mmol/L)

Fig. 4

Change from baseline in hepatic fat fraction (A) and body fat distribution (B, C and D) during the study in individual patients. Legend shows the patient number to link individual data from different figures