In the Journals

Apolipoprotein C-III inhibitor reduces triglycerides

Patients with hypertriglyceridemia treated with an antisense inhibitor of apolipoprotein C-III synthesis exhibited prolonged and dose-dependent reductions in triglycerides, according to results of a phase 2 study.

In the double blind, dose-ranging trial, researchers randomly assigned 85 patients with severe or uncontrolled hypertriglyceridemia to placebo or volanesorsen (Isis Pharmaceuticals), at a dose ranging from 100 mg to 300 mg once a week for 13 weeks. All patients also were receiving stable fibrate therapy and had baseline fasting triglyceride levels of 225 mg/dL to 2,000 mg/dL (mean, 376 mg/dL) or were not receiving any other treatment and had baseline fasting triglyceride levels of 350 mg/dL to 2,000 mg/dL (mean, 581 mg/dL).

In the monotherapy group, 16 patients received placebo and 41 received the investigational therapy. In the fibrate plus volanesorsen group, eight patients received placebo and 20 received the investigational therapy.

Change to levels of apolipoprotein C-III from baseline was the primary outcome. At baseline, the mean apolipoprotein C-III level was 22.8 mg/dL in the monotherapy group vs. 17.6 mg/dL in the fibrate/volanesorsen group. The researchers noted dose-dependent, persistent decreases in apolipoprotein C-III in both the monotherapy group (range, 40% decrease with 100 mg to 79.6% with 300 mg vs. 4.2% increase with placebo; P < .001) and in the fibrate/volanesorsen group (range, 60.2% decrease with 200 mg to 70.9% with 300 mg vs. 2.2% decrease with placebo; P < .001).

Triglycerides also were decreased in a dose-dependent fashion across the treatment groups. In the monotherapy group, patients assigned the highest dose exhibited a 70.9% decrease in triglycerides vs. a 20.1% increase among those assigned placebo (P < .001). In the fibrate/volanesorsen group, patients assigned the highest dose exhibited a 64% decrease in triglycerides vs. a 7.7% decrease among those assigned placebo (P < .01).

HDL levels were increased with the 300-mg dose of volanesorsen vs. placebo in both the monotherapy group (45.7% increase vs. 0.7%; P < .001) and the fibrate/volanesorsen group (51.8% vs. 5.9%; P < .01).

The researchers observed no safety issues related to volanesorsen during the study. Ten percent of patients assigned volanesorsen discontinued treatment due to adverse events, but discontinuation did not appear to be linked to dosage, the researchers wrote.

“Selective antisense inhibition of [apolipoprotein C-III] synthesis provides evidence for a causal relationship between [apolipoprotein C-III] and triglyceride metabolism,” the researchers concluded. “The results of our study support the continued development of [volanesorsen] for the treatment of patients who remain at risk for CV events and pancreatitis because of very high triglyceride levels.” – by Adam Taliercio

Disclosure: Isis Pharmaceuticals supported the study.

Patients with hypertriglyceridemia treated with an antisense inhibitor of apolipoprotein C-III synthesis exhibited prolonged and dose-dependent reductions in triglycerides, according to results of a phase 2 study.

In the double blind, dose-ranging trial, researchers randomly assigned 85 patients with severe or uncontrolled hypertriglyceridemia to placebo or volanesorsen (Isis Pharmaceuticals), at a dose ranging from 100 mg to 300 mg once a week for 13 weeks. All patients also were receiving stable fibrate therapy and had baseline fasting triglyceride levels of 225 mg/dL to 2,000 mg/dL (mean, 376 mg/dL) or were not receiving any other treatment and had baseline fasting triglyceride levels of 350 mg/dL to 2,000 mg/dL (mean, 581 mg/dL).

In the monotherapy group, 16 patients received placebo and 41 received the investigational therapy. In the fibrate plus volanesorsen group, eight patients received placebo and 20 received the investigational therapy.

Change to levels of apolipoprotein C-III from baseline was the primary outcome. At baseline, the mean apolipoprotein C-III level was 22.8 mg/dL in the monotherapy group vs. 17.6 mg/dL in the fibrate/volanesorsen group. The researchers noted dose-dependent, persistent decreases in apolipoprotein C-III in both the monotherapy group (range, 40% decrease with 100 mg to 79.6% with 300 mg vs. 4.2% increase with placebo; P < .001) and in the fibrate/volanesorsen group (range, 60.2% decrease with 200 mg to 70.9% with 300 mg vs. 2.2% decrease with placebo; P < .001).

Triglycerides also were decreased in a dose-dependent fashion across the treatment groups. In the monotherapy group, patients assigned the highest dose exhibited a 70.9% decrease in triglycerides vs. a 20.1% increase among those assigned placebo (P < .001). In the fibrate/volanesorsen group, patients assigned the highest dose exhibited a 64% decrease in triglycerides vs. a 7.7% decrease among those assigned placebo (P < .01).

HDL levels were increased with the 300-mg dose of volanesorsen vs. placebo in both the monotherapy group (45.7% increase vs. 0.7%; P < .001) and the fibrate/volanesorsen group (51.8% vs. 5.9%; P < .01).

The researchers observed no safety issues related to volanesorsen during the study. Ten percent of patients assigned volanesorsen discontinued treatment due to adverse events, but discontinuation did not appear to be linked to dosage, the researchers wrote.

“Selective antisense inhibition of [apolipoprotein C-III] synthesis provides evidence for a causal relationship between [apolipoprotein C-III] and triglyceride metabolism,” the researchers concluded. “The results of our study support the continued development of [volanesorsen] for the treatment of patients who remain at risk for CV events and pancreatitis because of very high triglyceride levels.” – by Adam Taliercio

Disclosure: Isis Pharmaceuticals supported the study.