Plozasiran for Severe Hypertriglyceridemia and Risk of Pancreatitis.

Authors

Gerald F Watts, Christie M Ballantyne, Agustin Blanco Echevarria, Jamie Smith, Robert S Rosenson, Savitha Subramanian, James Trippi, Norman Lepor, Archna Bajaj, Vladimir Blaha, Russell Scott, Alexis Baass, Ira J Goldberg, Antonio Gallo, Jose Luis Diaz, Manish Saxena, Jianping Li, Rong Zhou, Lalitha Aiyer, Jennifer Hellawell, James Hamilton, Daniel Gaudet, SHASTA-3 and SHASTA-4 Study Groups

Published in

The New England journal of medicine. Volume 395. Issue 18. Pages 1805-1817. Nov 05, 2026.

Abstract

Severe hypertriglyceridemia is associated with an increased risk of acute pancreatitis. Plozasiran, a small interfering RNA targeting APOC3 messenger RNA, lowers triglyceride levels and potentially mitigates the risk of acute pancreatitis.
In two double-blind, placebo-controlled trials, 757 adults with severe hypertriglyceridemia were randomly assigned in a 2:1 ratio to receive plozasiran (25 mg) or placebo at baseline and at months 3, 6, and 9. These trials had identical designs, end points, and analytic plans. The primary end point was the percent change in the fasting plasma triglyceride level from baseline to month 12. Key secondary end points were the percent change in the fasting triglyceride level from baseline to month 10, a fasting triglyceride level of less than 500 mg per deciliter (5.6 mmol per liter) and less than 150 mg per deciliter (1.7 mmol per liter), the percent change in the fasting serum triglyceride level at month 12 for patients with a baseline triglyceride level of 880 mg per deciliter or greater, and changes in remnant cholesterol and non-HDL cholesterol. A pooled analysis addressed adjudicated acute pancreatitis, incidence, and first-event timing.
At month 12, patients in the plozasiran groups had a median triglyceride level that was lower than the baseline level by 79% and 81% in the two trials. These reductions corresponded to a median difference in the plozasiran groups as compared with the placebo groups (placebo-adjusted change) of -45 percentage points (95% confidence interval [CI], -51 to -38) and -47 percentage points (95% CI, -54 to -39). A triglyceride level of less than 500 mg per deciliter at 12 months was reported in 91% and 93% of the patients in the plozasiran groups and in 51% and 50% of those in the placebo groups (P<0.001). The rates of acute pancreatitis were 1 per 100 patient-years with plozasiran and 5 per 100 patient-years with placebo (rate ratio, 0.22; P = 0.008). Adverse events during treatment occurred in 73% of the patients in both the pooled plozasiran and placebo groups.
Among patients with severe hypertriglyceridemia, the use of plozasiran resulted in lower triglyceride levels and a lower risk of acute pancreatitis than placebo at 12 months. (Funded by Arrowhead Pharmaceuticals; SHASTA-3 ClinicalTrials.gov number, NCT06347003; SHASTA-4, NCT06347016.).

PMID:
42981569
Bibliographic data and abstract were imported from PubMed on 05 Nov 2026.

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