BACKGROUND: Familial chylomicronemia syndrome is a rare genetic disorder that is 
caused by loss of lipoprotein lipase activity and characterized by 
chylomicronemia and recurrent episodes of pancreatitis. There are no effective 
therapies. In an open-label study of three patients with this syndrome, 
antisense-mediated inhibition of hepatic APOC3 mRNA with volanesorsen led to 
decreased plasma apolipoprotein C-III and triglyceride levels.
METHODS: We conducted a phase 3, double-blind, randomized 52-week trial to 
evaluate the safety and effectiveness of volanesorsen in 66 patients with 
familial chylomicronemia syndrome. Patients were randomly assigned, in a 1:1 
ratio, to receive volanesorsen or placebo. The primary end point was the 
percentage change in fasting triglyceride levels from baseline to 3 months.
RESULTS: Patients receiving volanesorsen had a decrease in mean plasma 
apolipoprotein C-III levels from baseline of 25.7 mg per deciliter, 
corresponding to an 84% decrease at 3 months, whereas patients receiving placebo 
had an increase in mean plasma apolipoprotein C-III levels from baseline of 1.9 
mg per deciliter, corresponding to a 6.1% increase (P<0.001). Patients receiving 
volanesorsen had a 77% decrease in mean triglyceride levels, corresponding to a 
mean decrease of 1712 mg per deciliter (19.3 mmol per liter) (95% confidence 
interval [CI], 1330 to 2094 mg per deciliter [15.0 to 23.6 mmol per liter]), 
whereas patients receiving placebo had an 18% increase in mean triglyceride 
levels, corresponding to an increase of 92.0 mg per deciliter (1.0 mmol per 
liter) (95% CI, -301.0 to 486 mg per deciliter [-3.4 to 5.5 mmol per liter]) 
(P<0.001). At 3 months, 77% of the patients in the volanesorsen group, as 
compared with 10% of patients in the placebo group, had triglyceride levels of 
less than 750 mg per deciliter (8.5 mmol per liter). A total of 20 of 33 
patients who received volanesorsen had injection-site reactions, whereas none of 
the patients who received placebo had such reactions. No patients in the placebo 
group had platelet counts below 100,000 per microliter, whereas 15 of 33 
patients in the volanesorsen group had such levels, including 2 who had levels 
below 25,000 per microliter. No patient had platelet counts below 50,000 per 
microliter after enhanced platelet-monitoring began.
CONCLUSIONS: Volanesorsen lowered triglyceride levels to less than 750 mg per 
deciliter in 77% of patients with familial chylomicronemia syndrome. 
Thrombocytopenia and injection-site reactions were common adverse events. 
(Funded by Ionis Pharmaceuticals and Akcea Therapeutics; APPROACH Clinical 
Trials.gov number, NCT02211209.).