TRIAL SUCCESS

Arrowhead's plozasiran cuts triglycerides 79% and pancreatitis events in Phase 3

SHASTA-3 hit its primary endpoint and every prespecified secondary endpoint, setting up a U.S. sNDA filing by year-end for severe hypertriglyceridemia.

SHASTA-3 met its primary endpoint, cutting fasting triglycerides by a median 79% at month 12 versus roughly 27% with placebo, and also met all prespecified secondary endpoints including a statistically significant reduction in acute pancreatitis.

By AppliedXLJuly 22, 2026Trial NCT06347003

Executive Summary

Arrowhead Pharmaceuticals reported that its Phase 3 severe hypertriglyceridemia trial met its primary endpoint with a triglyceride reduction well ahead of placebo, and also cleared every prespecified secondary endpoint, including a reduction in acute pancreatitis events.
The result extends a mechanism already approved for a narrower, more severe lipid disorder into a much larger population defined by high triglycerides alone, setting up a near-term U.S. regulatory filing.
The APOC3-silencing class now has one approved entrant and several late-stage RNA-based rivals, so replication of an already-established effect size, not discovery of a new mechanism, is the relevant bar this readout had to clear.
The trial's completion landed after its most recently stated window, a pattern consistent with several primary-completion-date revisions logged over the study's life, though enrollment held flat against target.

The result

Arrowhead Pharmaceuticals, Inc. announced topline results on July 22, 2026 for SHASTA-3 (NCT06347003), a 446-patient Phase 3 trial testing plozasiran against placebo in adults with severe hypertriglyceridemia. The trial's registered primary endpoint was percent change in fasting serum triglycerides from baseline to month 12 compared to placebo. Plozasiran, dosed subcutaneously at 25 mg once every three months, produced a median triglyceride reduction of 79% at month 12 versus approximately 27% for placebo, and the trial met all prespecified secondary endpoints. A companion Phase 3 study, SHASTA-4, produced a similar 81% median reduction in the same readout window. NCT06347003+1

Probability of Success

Endpoint Met96%

Completes97%

Clinical Significance73%

Regulatory94%

The pancreatitis signal

In a pre-planned pooled analysis across SHASTA-3 and SHASTA-4, plozasiran reduced the rate of patients experiencing at least one acute pancreatitis event (p<0.0221) and the total incidence rate of pancreatitis events (p<0.0077) versus placebo. In the broad study population, defined as triglycerides above 500 mg/dL with or without prior pancreatitis history, cumulative pancreatitis events fell 79% in treated patients. In the highest-risk subset, patients with triglycerides above 880 mg/dL and a prior pancreatitis history, plozasiran treatment showed a 100% reduction in pancreatitis events versus placebo, a small-subgroup finding that nonetheless reinforces the primary triglyceride result in the population where pancreatitis risk is greatest. Arrowhead

Safety

Arrowhead reported a favorable safety and tolerability profile consistent with plozasiran's prior studies, with no new safety signals, no clinically meaningful differences in liver enzymes or liver fat content by MRI-PDFF, no hypersensitivity cases, and no thrombocytopenia signal. James Hamilton, Arrowhead's chief medical officer, said the results "build upon the promising results from prior Phase 2 and Phase 3 studies across various patient populations". Chief Executive Christopher Anzalone said the company now begins "the process of seeking regulatory approval in multiple global geographies," with a U.S. supplemental NDA filing planned before year-end. Arrowhead

Regulatory and competitive frame

Plozasiran is already approved as REDEMPLO for familial chylomicronemia syndrome, a narrower and more severe form of hypertriglyceridemia, following the PALISADE study, and the FDA granted plozasiran Breakthrough Therapy designation for severe hypertriglyceridemia in December 2025. This SHASTA-3 filing would extend that mechanism into the broader severe hypertriglyceridemia population. The APOC3-silencing field includes Ionis Pharmaceuticals' olezarsen, which is in Phase 3 testing in the same indication, along with volanesorsen and earlier-stage APOC3 programs from Ikaria Bioscience, Regeneron, and CorrectSequence. Historical Phase 3 readouts in this target-indication pairing have so far all met their primary endpoints, with no terminations recorded in the class to date. Arrowhead

Operational context

The trial's registered primary completion date moved twice, from July 2026 to June 1, 2026, and then to June 12, 2026, while enrollment held flat at its 446-patient target after an early adjustment from 405. The topline readout landed on July 22, 2026, after the sponsor's most recently stated H1-2026 data window had closed. Detailed results are scheduled for presentation as a Hot Line Late Breaker at the European Society of Cardiology Congress on August 30, 2026, with a company call the following day. NCT06347003+1

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