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

Lipids in Health and Disease

Victoria J. Bartlett¹  Ewa Karwatowska-Prokopczuk¹  Eunju Hurh¹  Baris Akinci²  Elif A. Oral³  Adam Neidert³  Maria C. Foss-Freitas³ 

[1] Akcea Therapeutics, Inc, Boston, MA, USA;Division of Metabolism, Endocrinology & Diabetes and Caswell Diabetes Institute, University of Michigan, Ann Arbor, MI, USA;Dokuz Eylul University, İzmir, Turkey;Metabolism, Endocrinology and Diabetes, Department of Internal Medicine, Michigan Medicine, University of Michigan, Caswell Diabetes Institute, 2800 Plymouth Road, North Campus Research Complex, 25-3696, 48109-2800, Ann Arbor, MI, USA;Division of Metabolism, Endocrinology & Diabetes and Caswell Diabetes Institute, University of Michigan, Ann Arbor, MI, USA;Metabolism, Endocrinology and Diabetes, Department of Internal Medicine, Michigan Medicine, University of Michigan, Caswell Diabetes Institute, 2800 Plymouth Road, North Campus Research Complex, 25-3696, 48109-2800, Ann Arbor, MI, USA;

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

DOI  :  10.1186/s12944-021-01589-4

来源: Springer

【 摘 要 】

BackgroundFamilial 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.MethodsThis 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).ResultsBaseline 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.ConclusionsAlthough limited, these results suggest that targeting ANGPTL3 with vupanorsen could address several metabolic abnormalities in patients with FPLD.

【 授权许可】

CC BY