FPLD is an extreme form of metabolic dyslipidemia and diabetes caused by selective loss of peripheral subcutaneous fat. Currently, there are no approved therapies for this rare cause of diabetes in the U.S. Reductions in circulating levels of the hepatokine ANGPTL3 either by mutations in humans or by targeted drugs in rodents are associated with reductions in triglyceride levels and provide protection from atherosclerosis, making it an attractive target for patients with FPLD and metabolic dyslipidemia. The objective of this proof-of concept, Phase 2, open-label study was to assess the early efficacy and safety of a strategy that targets ANGPTL3 via ISIS-703802 (AKCEA-ANGPTL3-LRx) in patients with FPLD. Four patients with FPLD (3F/1M; age range: 38-47; 1 with LMNA R482Q, 1 with LMNA R584H, and 2 with no causative genetic variant) with diabetes (HbA1c>6.5%) and hypertriglyceridemia (≥ 500 mg/dL or ≥ 200 mg/dL for patients meeting genetic or family history criteria) were included. Patients received the study drug at a subcutaneous dose of 20 mg weekly for 26 weeks. Primary endpoint was the percent change in serum triglycerides from baseline to week 27. All other endpoints were also analyzed at week 27. Treatment resulted in a 60±26 (mean±SD) % reduction in triglycerides from a baseline of 818±432 mg/dL. Consistent with antisense reduction of ANGPTL3 mRNA, circulating ANGPTL3 levels were lowered by 55±10%. Treatment was also associated with 51±27% reduction in circulating apoC3 levels, 64±24% reduction in total VLDL and chylomicron triglycerides, and 18±15% reduction in total cholesterol. In addition, HbA1c showed a modest mean absolute reduction of 0.2±1.0 % The drug was well tolerated and there were no new safety signals observed. Although a small study, these results suggest that targeting ANGPTL3 in patients with FPLD could successfully address metabolic dyslipidemia.


M. Foss-Freitas: None. B. Akinci: Advisory Panel; Self; Aegerion Pharmaceuticals, Regeneron Pharmaceuticals. Research Support; Self; Gemphire Therapeutics Inc. Speaker’s Bureau; Self; AstraZeneca, Boehringer Ingelheim Pharmaceuticals, Inc., Eli Lilly and Company, Novartis AG, Novo Nordisk A/S, Sanofi-Aventis, Servier. A.H. Neidert: None. R.P. Hench: None. M. Swaidan: None. E.A. Oral: Consultant; Self; Aegerion Pharmaceuticals, Akcea Therapeutics, Regeneron Pharmaceuticals. Research Support; Self; Aegerion Pharmaceuticals, Akcea Therapeutics, Gemphire Therapeutics Inc., GI Dynamics Inc., Regeneron Pharmaceuticals.


Ionis Pharmaceuticals, Inc.; Akcea Therapeutics

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