Volanesorsen, an antisense oligonucleotide to apolipoprotein C-III, increases lipoprotein lipase activity and lowers triglycerides in partial lipodystrophy.

Background: Partial lipodystrophy (PL) syndromes involve deficiency of adipose tissue, causing severe insulin resistance and hypertriglyceridemia. Apolipoprotein C-III (apoC-III) is elevated in PL and is thought to contribute to hypertriglyceridemia by inhibiting lipoprotein lipase (LPL).

Objective: We hypothesized that volanesorsen, an antisense oligonucleotide to apoC-III, would decrease apoC-III, increase LPL activity, and lower triglycerides in PL.

Methods: Five adults with PL enrolled in a 16-week placebo-controlled, randomized, double blind study of volanesorsen, 300 mg weekly, followed by 1-year open label extension.

Results: Within-subject effects of volanesorsen before and after 16 weeks of active drug are reported due to small sample size. From week 0 to 16, apoC-III decreased from median (25, 75 %ile) 380 (246, 600) to 75 (26, 232) ng/mL, and triglycerides decreased from 503 (330, 1040) to 116 (86, 355) mg/dL while activation of LPL by subjects' serum increased from 21 (20, 25) to 36 (29, 42) nEq/mL*min. Although, A1c did not change, peripheral and hepatic insulin sensitivity (glucose disposal and suppression of glucose production during hyperinsulinemic clamp) increased and palmitate turnover decreased. After 32-52 weeks of volanesorsen, liver fat decreased. Common adverse events included injection site reactions and decreased platelets.

Conclusions: In PL, volanesorsen decreased apoC-III and triglycerides, in part through an LPL dependent mechanism, and may improve insulin resistance and hepatic steatosis.