SHASTA trials show substantial triglyceride reductions with plozasiran

Plozasiran treatment resulted in substantial reductions in triglyceride levels in patients with severe hypertriglyceridemia after one year, according to results presented in a Hot Line session today at ESC Congress 2026 and published simultaneously in the New England Journal of Medicine.

Severe hypertriglyceridemia is characterized by highly elevated blood triglyceride levels. Severe hypertriglyceridemia significantly increases the risk of acute pancreatitis, which can often include recurrent attacks requiring repeat hospital admissions.

Presenter, Professor Gerald Watts from the University of Western Australia, Perth, Australia, pointed out that currently available therapeutic approaches for severe hypertriglyceridemia are often insufficient to lower triglyceride levels and prevent acute pancreatitis.

Plozasiran is an RNA interference therapeutic designed to reduce production of apolipoprotein C-III (APOC3), a key regulator of triglyceride metabolism and clearance. Given encouraging results in other trials we investigated the efficacy and safety of plozasiran in two phase III trials in patients with severe hypertriglyceridemia."

Professor Gerald Watts, University of Western Australia

SHASTA-3 and SHASTA-4 were double-blind trials conducted across 24 countries. Participants were eligible if they had triglyceride levels of 500 mg/dL or greater. Patients were randomised (2:1) to receive four quarterly subcutaneous injections of plozasiran 25 mg or placebo over a one-year period. In total, 757 patients were included, who had a mean age of 53 years and 22% were women.

Regarding the primary endpoint, treatment with plozasiran led to median triglyceride reductions at month 12 of 79% and 81%, in SHASTA-3 and SHASTA-4, respectively, vs. a placebo reduction of approximately 27% in each trial.

Across the trial populations, cumulative acute pancreatitis events were reduced by 78% in patients treated with plozasiran vs. placebo. In a subset of patients with triglycerides above 880 mg/dL and a prior history of acute pancreatitis, a 100% reduction in acute pancreatitis events was observed with plozasiran vs. placebo.

Plozasiran demonstrated a favorable safety and tolerability profile, with no clinically meaningful differences in routine clinical laboratory measurements, including liver enzymes. Treatment-related adverse events that led to study discontinuation occurred in 1.4% of patients treated with plozasiran and 0.8% of patients receiving placebo.

Professor Watts concluded, "Results from the SHASTA-3 and SHASTA-4 studies build on the positive results from other plozasiran trials across various patient populations, including those with the most severe form of hypertriglyceridemia, familial chylomicronemia syndrome. These findings highlight the potential of plozasiran as a promising therapy for patients across the spectrum of severe hypertriglyceridemia."