Familial chylomicronemia syndrome is rare and affects about one in one million people. It features defective or deficient lipoprotein lipase activity, very high triglycerides, and recurrent pancreatitis. Apoprotein C3 blocks LPL activity and drives severe hypertriglyceridemia. Researchers have focused on targeting Apo C3 pharmacologically. We now have an antisense inhibitor of hepatic Apo C3 mRNA called volanesorsen.
This phase 3 double blind randomized trial shows that volanesorsen lowers Apo C3 and triglycerides remarkably. Apo C3 drops by about 25.7 mg/dL and triglycerides fall by about 1700 mg/dL, which reflects an eighty percent reduction. Low platelets and injection site reactions occurred more often with volanesorsen than placebo. The study focused on triglyceride lowering, but reduced pancreatitis risk is also expected.
These findings matter because they add another pathway for lowering very high triglycerides. Hypertriglyceridemia is common in metabolic syndrome and acts as an independent cardiovascular risk factor. I expect antisense inhibitor technology will soon be tested in metabolic syndrome, insulin resistance, prediabetes, and diabetes, since these conditions are far more common than familial chylomicronemia syndrome.
About Dr. Gerti Tashko, MD
Dr. Gerti Tashko, MD, is an endocrinologist in Montgomery County, Maryland. He is uniquely quadruple board-certified in endocrinology, lipidology, hypertension, and obesity medicine. His practice delivers root-cause-focused metabolic and endocrine care, available virtually and in person. He uses advanced diagnostics, personalized nutrition, and preventive medicine to improve long-term health.
N E J M, RCT, August 2019
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 APO C3 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.
Primary endpoint was the percentage change in fasting triglyceride levels from baseline to 3 months.
RESULTS
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.
CONCLUSIONS
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.