The investigational drug plozasiran reduced triglyceride levels significantly without causing any significant safety concerns in patients with severely elevated triglyceride levels at risk for developing acute pancreatitis, according to results from the SHASTA 2 study presented during a Late-Breaking Clinical Trial session at ACC.24.

The double-blind, phase 2b, placebo-controlled, dose-ranging trial tested the effectiveness and safety of plozasiran as an add-on to existing lipid-lowering treatment in patients with severe hypertriglyceridemia. A total of 229 patients (55 years old, 78% men, 90% White) were enrolled in eight countries. The majority of enrolled patients had at least three of the following risk factors: elevated risk for or history of cardiovascular disease, diabetes, low HDL-C and high body mass index.

Patients were randomized to one of four groups. Three groups received two injections of plozasiran at one of three doses (10 mg, 25 mg or 50 mg); the fourth group received two injections of a placebo. The first injection was given on day one and the second at week 12.

The study's primary endpoint was the percentage change in fasting triglyceride levels from study entry to 24 weeks. Secondary endpoints included the percentage change in ApoC3 at 24 weeks and every four weeks from baseline through 48 weeks and in fasting triglyceride levels every four weeks through 48 weeks. All patients were followed for 36 weeks after the second dose.

At 24 weeks, the average reduction in triglyceride levels in plozasiran-treated patients was 74%, compared with 17% in placebo-treated patients.

At 48 weeks, the average reduction was 58% in patients who received the highest doses of plozasiran compared with 7% for those in the placebo group. The average reduction in ApoC3 was 78% for plozasiran-treated patients vs. 1% for the placebo group at 24 weeks. At 48 weeks, ApoC3 levels were reduced by 48% on average among patients receiving the highest doses of plozasiran, whereas ApoC3 levels increased 4% in the placebo group.

Of note, at 24 weeks, over 90% of patients who received the higher doses of plozasiran saw their triglyceride levels fall to <500 mg/dL, the commonly accepted threshold for an increase in risk for pancreatitis. At 48 weeks, 77% of patients still had triglyceride levels <500 mg/dL. More than 50% of patients on higher doses achieved triglyceride levels <150 mg/dL at 24 weeks.

"Plozasiran produced significant reductions in triglyceride levels below the threshold associated with elevated risk for pancreatitis, with a favorable safety profile," said Daniel Gaudet, MD, PhD, the study's lead author. "These data support the initiation of pivotal studies of plozasiran for the treatment of severe hypertriglyceridemia."