TRIAL SUCCESS

Arrowhead's plozasiran cuts triglycerides 81% in Phase 3 SHASTA-4

The RNAi drug also cut acute pancreatitis events, positioning Arrowhead for a U.S. sNDA filing this year against a field of APOC3-targeting rivals still in early trials.

Arrowhead Pharmaceuticals reported that plozasiran met the primary endpoint in the Phase 3 SHASTA-4 trial, cutting median triglycerides 81% versus roughly 27% for placebo at Month 12, and also reduced acute pancreatitis events.

By AppliedXLJuly 22, 2026Trial NCT06347016

Executive Summary

A Phase 3 trial of Arrowhead's RNAi drug plozasiran in severe hypertriglyceridemia met its primary endpoint, cutting triglycerides far beyond the placebo effect, and also reduced acute pancreatitis events across the pooled program.
The result gives Arrowhead a second Phase 3 confirmation of the triglyceride-lowering effect it will use to support a U.S. supplemental filing later this year, building on plozasiran's existing approval in a related, rarer lipid disorder.
Plozasiran now has two positive Phase 3 readouts in this population while direct RNAi and antisense rivals targeting the same protein remain largely in earlier-phase testing, giving Arrowhead the most advanced same-target dataset in hand.
The trial reported no new safety signals and no clinically meaningful liver or platelet findings, consistent with the drug's safety profile from prior studies rather than introducing new tolerability concerns.

The readout

Arrowhead Pharmaceuticals, Inc. reported topline results from SHASTA-4 (NCT06347016), a Phase 3 trial testing plozasiran against placebo in adults with severe hypertriglyceridemia, a condition in which triglyceride levels above 500 mg/dL raise the risk of acute pancreatitis. The trial's registered primary endpoint was percent change in fasting serum triglycerides from baseline to Month 12 compared to placebo. Arrowhead said plozasiran, dosed at 25 mg subcutaneously once every three months, produced a median triglyceride reduction of 81% at Month 12, versus approximately 27% for placebo, and that the trial met all prespecified secondary endpoints. "We continue to see plozasiran data as best in class with respect to safety, activity, efficacy, and convenience," said Christopher Anzalone, President and CEO at Arrowhead. NCT06347016+1

Probability of Success

Endpoint Met96%

Completes96%

Clinical Significance58%

Regulatory88%

The pancreatitis signal

Beyond the lipid endpoint, a pre-planned pooled analysis of SHASTA-3 and SHASTA-4 found a statistically significant reduction in acute pancreatitis events among plozasiran-treated patients, both in the share of patients with at least one event (p<0.0221) and in the total event rate (p<0.0077). In the broader severe hypertriglyceridemia population, cumulative pancreatitis events fell 78% versus placebo, and in the highest-risk subset, patients with triglycerides above 880 mg/dL and a prior pancreatitis history, plozasiran-treated patients had a 100% reduction in events versus placebo. That subgroup result carries real weight because it targets the population where pancreatitis risk, and its consequence, hospitalization, is most acute. Arrowhead

Safety and tolerability

Arrowhead described a favorable safety and tolerability profile, with treatment-emergent adverse events consistent with plozasiran's established profile from prior studies and no new safety signals. There were no statistically significant differences in liver fat content by MRI-PDFF, no clinically meaningful adverse changes in liver enzymes, no hypersensitivity cases, and no thrombocytopenia signal. Full analysis of the safety and efficacy data is ongoing, with detailed results expected as a HOT LINE Late Breaker presentation at the ESC Congress on August 30, 2026, and a company call the following day. Arrowhead

Design and reach

SHASTA-4 was a double-blind, placebo-controlled, quadruple-masked Phase 3 study that enrolled 311 adults, matching its target, across ten countries including the United States, Brazil, Poland, and Argentina. The trial ran under a randomized, two-arm design with the primary completion date moved up one month, from July 1 to June 1, 2026, alongside a minor enrollment update from 300 to 311 in July 2025. Both changes fall within the routine range for a trial of this design, and the primary completion landed close to that guided window. NCT06347016

Regulatory path

Plozasiran, branded REDEMPLO, already carries FDA approval for familial chylomicronemia syndrome, a rarer and more severe form of hypertriglyceridemia, along with Australian approval in the same indication. The FDA granted plozasiran Breakthrough Therapy designation for severe hypertriglyceridemia in December 2025, covering the SHASTA-3, SHASTA-4, and MUIR-3 Phase 3 program. Arrowhead said it will use the SHASTA-3 and SHASTA-4 data, together with the MUIR-3 study, to support a supplemental NDA in the U.S. before the end of 2026, with additional global filings to follow. Arrowhead+1

The competitive field

Plozasiran is not the only RNAi or antisense drug targeting APOC3 in this indication. Ionis Pharmaceuticals' olezarsen (NCT05681351) and volanesorsen (NCT02300233) are also Phase 3 programs against the same target, while earlier-stage entrants include Ikaria Bioscience's RN0361 in Phase 1/2 and Regeneron's ALN-APOC3 in Phase 1. Arrowhead itself runs the closest peer trial, SHASTA-3 (NCT06347003), which read out alongside SHASTA-4 with a comparable 79% median triglyceride reduction at Month 12. Across this target-indication pairing, four completed Phase 3 trials show no terminations, and the field itself has cooled: recent APOC3 trial activity runs at about a quarter the rate of prior years, even as this pairing has produced two straight positive readouts. NCT06347016

This analysis was produced using AI-assisted reporting systems, AppliedXL data, and official public records. These systems undergo editorial review, quality checks, and regular audits by human experts. Errors may still occur, as with any automated system. Always consult the linked primary sources. Read our AI Editorial Policy.