Familial chylomicronemia syndrome is rare. Its prevalence is about 1 in 1 million. It is characterized by defective or deficient lipoprotein lipase (LPL) enzyme, severely high triglycerides, and recurrent pancreatitis. Apoprotein C3 antagonizes LPL activity leading to hypertriglyceridemia. Much effort has been done to target Apo C3 pharmacologically. Now we have an anti-sense inhibitor to the hepatic Apo C3 mRNA, called volanesorsen.
This phase 3, double-blind randomized clinical trial shows that volanesorsen lowers both Apo C3 and triglycerides remarkably. Apo C3 is decreased by 25.7 mg/dL and triglycerides by about 1700 mg/dL (Δ80% reduction). Low platelet count and injection site reactions were seen more commonly with volanesorsen than placebo. Although the study was designed to evaluate changes in triglyceride levels, clinical outcomes (pancreatitis) are also expected to improve.
Study findings are of major importance as it provides us with another tool and pathway of lowering elevated triglycerides. Hypertriglyceridemia, commonly found in patients with metabolic syndrome, is a well-established independent risk factor for cardiovascular events. I anticipate that the antisense inhibitor technology will also be tested in patients with metabolic syndrome, insulin resistance, prediabetes, and diabetes; as these conditions are far more prevalent than familial chylomicronemia syndrome.
N E J M
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 APO C3 mRNA with volanesorsen led to decreased plasma apolipoprotein C-III and triglyceride levels.
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.
Primary endpoint was the percentage change in fasting triglyceride levels from baseline to 3 months.
Patients receiving volanesorsen had a decrease of 25.7 mg/dL in mean plasma apolipoprotein C-III levels from baseline, corresponding to an 84% decrease at 3 months, whereas patients receiving placebo had an increase of 1.9 mg/dL in mean plasma apolipoprotein C-III levels from baseline, 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/dL, whereas patients receiving placebo had an 18% increase in mean triglyceride levels, corresponding to an increase of 92.0 mg/dL (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 <750 mg/dL.
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 <100,000/uL, whereas 15 of 33 patients in the volanesorsen group had such levels, including 2 who had levels <25,000 per microliter.
No patient had platelet counts below 50,000/uL after enhanced platelet-monitoring began.
Volanesorsen lowered triglyceride levels to <750 mg/dL in 77% of patients with familial chylomicronemia syndrome.
Thrombocytopenia and injection-site reactions were common adverse events.