Plozasiran meets primary endpoint in two phase III trials for severe hypertriglyceridemia

Topline data from SHASTA-3 and SHASTA-4 showed median triglyceride reductions of up to 81%, while a pooled analysis found fewer acute pancreatitis events with the quarterly siRNA therapy, according to Arrowhead Pharmaceuticals.

Arrowhead Pharmaceuticals, Inc. (Pasadena, CA) has reported topline results from two phase III trials evaluating plozasiran in adults with severe hypertriglyceridemia (sHTG), according to a recent press release.¹ Plozasiran, an siRNA therapy directed against apolipoprotein C-III (APOC3) messenger RNA, is already approved as Redemplo for adults with familial chylomicronemia syndrome but remains investigational for the broader sHTG population.

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Severe hypertriglyceridemia is generally characterized by fasting triglyceride levels above 500 mg/dL and is associated with an increased risk of acute pancreatitis, particularly as triglyceride levels rise. Treatment options capable of producing substantial and sustained triglyceride reductions remain limited.

Plozasiran is designed to reduce hepatic production of apolipoprotein C-III, a regulator of triglyceride-rich lipoprotein metabolism. It is administered by subcutaneous injection once every three months.

SHASTA-3 (NCT06347003) and SHASTA-4 ( NCT06347016) were global, phase III, double-blind, placebo-controlled studies evaluating plozasiran in adults with sHTG.^2,3 Across the two studies, approximately 750 participants were randomized to receive four quarterly doses of plozasiran 25 mg or placebo over 12 months.

Both trials met their primary endpoint of change in fasting triglyceride levels from baseline to month 12 compared with placebo. Median triglyceride levels fell by 79% from baseline in SHASTA-3 and by 81% in SHASTA-4, compared with an approximately 27% reduction among placebo recipients, according to Arrowhead.¹

The company also reported that both studies met all prespecified secondary endpoints. In a preplanned pooled analysis of SHASTA-3 and SHASTA-4, plozasiran significantly reduced both the proportion of patients experiencing at least one acute pancreatitis event and the total incidence rate of acute pancreatitis events compared with placebo.¹

Across the overall study population, which included patients with triglyceride levels above 500 mg/dL with or without a history of acute pancreatitis, cumulative pancreatitis events were reduced by 78% with plozasiran. Arrowhead reported no acute pancreatitis events among treated patients in a high-risk subgroup with triglyceride levels above 880 mg/dL and a previous history of pancreatitis, corresponding to a 100% reduction relative to placebo. Exact event numbers have not yet been released.

Arrowhead said the overall safety and tolerability profile was consistent with earlier plozasiran studies, with no new safety signals identified. There were no reported cases of hypersensitivity or evidence of a thrombocytopenia signal, and no clinically meaningful adverse changes in liver enzymes. A prespecified MRI-PDFF analysis found no statistically significant difference in mean liver fat content between plozasiran and placebo. Detailed trial-level safety findings have not yet been disclosed.

Arrowhead intends to use data from SHASTA-3 , SHASTA-4, and the related MUIR-3 study to support regulatory submissions for the broader sHTG indication, beginning with a supplemental new drug application to the FDA before the end of 2026.

Detailed results are scheduled to be presented during a Hot Line late-breaking session at the European Society of Cardiology Congress in Munich on August 30, 2026. Publication of the complete findings is also planned.

The topline findings suggest that quarterly plozasiran may produce substantial triglyceride reductions and could lower the risk of acute pancreatitis in adults with sHTG. However, assessment of the magnitude and clinical relevance of the pancreatitis findings will require the complete dataset, including absolute event numbers and study-specific results.

References

1. Arrowhead Pharmaceuticals, Inc. Arrowhead Pharmaceuticals Reports Topline Results from Phase 3 SHASTA-3 and SHASTA-4 Studies of Plozasiran in Patients with Severe Hypertriglyceridemia. Press release. July 22, 2026.