Arrowhead's global Phase III SHASTA-3 and SHASTA-4 trials of plozasiran met primary and all prespecified secondary endpoints, delivering median triglyceride reductions of 79% and 81% at 12 months versus ~27% for placebo. A pooled analysis showed statistically significant reductions in acute pancreatitis (p<0.0221 and p<0.0077), including a 78% reduction in patients with TG >500 mg/dL and a 100% reduction in a very high-risk subgroup. Safety was consistent with prior studies with no new signals. Full results will be presented at ESC 2026 and a US sNDA is planned before year-end.
Plozasiran Slashes Triglycerides and Dramatically Reduces Pancreatitis Risk in Phase III SHASTA Trials
Participants in SHASTA-3 and SHASTA-4 received 25mg of plozasiran via subcutaneous injection every three months. Credit: YURIMA / Shutterstock.com.
Arrowhead Pharmaceuticals has reported topline results from the global, randomized, double-blind, placebo-controlled Phase III SHASTA-3 and SHASTA-4 trials of plozasiran for severe hypertriglyceridaemia (sHTG).
Both trials met their primary endpoint, showing substantially greater triglyceride reductions with plozasiran versus placebo. Participants received 25 mg of plozasiran by subcutaneous injection every three months. At 12 months, median triglyceride reductions were 79% in SHASTA-3 and 81% in SHASTA-4, compared with approximately 27% in the pooled placebo arms.
Significant Reduction In Acute Pancreatitis
A pre-planned pooled analysis demonstrated a statistically significant reduction in acute pancreatitis among plozasiran-treated patients (p<0.0221 for event rates; p<0.0077 for total incidence rates). In the broader cohort with baseline triglycerides >500 mg/dL, plozasiran was associated with a 78% reduction in cumulative acute pancreatitis events versus placebo. In the highest-risk subgroup (triglycerides >880 mg/dL and prior acute pancreatitis), the combined analysis observed a 100% reduction in events for patients receiving plozasiran.
Safety And Tolerability
The safety and tolerability profile of plozasiran in SHASTA-3 and SHASTA-4 was consistent with prior studies. Treatment-emergent adverse events aligned with earlier findings and no new safety signals emerged. There were no statistically significant differences between plozasiran and placebo in mean liver fat content or adverse changes in liver enzymes; no cases of hypersensitivity or thrombocytopenia were reported.
James Hamilton, Arrowhead's Chief Medical Officer and Head of R&D, said:
These findings highlight the potential of plozasiran as a promising therapy for patients across the spectrum of severe hypertriglyceridaemia.
Arrowhead plans to present the full dataset from SHASTA-3 and SHASTA-4 at the European Society of Cardiology (ESC) Congress on 30 August 2026, and intends to pursue marketing authorisations in multiple countries, starting with a supplemental New Drug Application (sNDA) in the United States before year-end.
Reporting originally by Clinical Trials Arena (a GlobalData brand).
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