Arrowhead's Plozasiran Reduces Triglycerides, Pancreatitis Events in Phase 3 sHTG Trials

Arrowhead Pharmaceuticals announced topline results from the phase 3 SHASTA-3 and SHASTA-4 studies evaluating plozasiran, an RNA interference therapeutic, in patients with severe hypertriglyceridemia (sHTG).¹ Both trials met their primary endpoint of triglyceride reduction from baseline at month 12 compared with placebo, along with all prespecified secondary endpoints.¹

What did the SHASTA-3 and SHASTA-4 trials find?

Across the 2 global, double-blind, placebo-controlled studies, roughly 750 participants received either 25 mg of subcutaneous plozasiran or placebo once every 3 months.² Median triglyceride reductions reached 79% in SHASTA-3 and 81% in SHASTA-4 at month 12, compared with an approximate 27% reduction in the placebo groups.¹

“We continue to see plozasiran data as best in class with respect to safety, activity, efficacy, and convenience, with dosing only four times per year,” said Christopher Anzalone, PhD, president and CEO of Arrowhead, in a company press release.¹

Did the drug reduce pancreatitis risk?

A pooled analysis of acute pancreatitis (AP) events across both trials showed a statistically significant reduction in both the proportion of patients experiencing at least one AP event (p < .0221) and the total incidence rate of AP events (p < .0077) among plozasiran-treated patients versus placebo.¹ In the overall sHTG population—patients with triglycerides above 500 mg/dL, with or without a prior AP history—cumulative AP events dropped 78% relative to placebo.¹ Among the highest-risk subgroup, patients with triglycerides above 880 mg/dL and a prior AP diagnosis, plozasiran was associated with a 100% reduction in AP events versus placebo.¹

What does the safety profile look like?

Treatment-emergent adverse events were consistent with plozasiran's established safety profile from earlier studies, with no new safety signals reported.¹ Investigators noted no clinically meaningful differences in liver fat content by magnetic resonance imaging proton density fat fraction, no clinically meaningful changes in liver enzymes, no hypersensitivity cases, and no signal for thrombocytopenia.¹ James Hamilton, MD, chief medical officer and head of research and development at Arrowhead, said the results build on prior phase 2 and phase 3 data across moderate hypertriglyceridemia, mixed hyperlipidemia, sHTG, and familial chylomicronemia syndrome (FCS) populations.¹

What are the next steps for plozasiran?

Detailed results from SHASTA-3 (NCT06347003) and SHASTA-4 (NCT06347016) will be presented as a Hot Line late-breaker at the European Society of Cardiology (ESC) Congress in Munich, Germany, on August 30, 2026, followed by a company conference call on August 31.²ˌ³ Arrowhead plans to use data from SHASTA-3, SHASTA-4, and the MUIR-3 study to support a supplemental new drug application to FDA for sHTG before the end of 2026, with additional global regulatory submissions to follow.¹

Plozasiran is already approved in the United States, European Union, China, Australia, and Canada under the brand name Redemplo, as an adjunct to diet for adults with genetically confirmed or clinically diagnosed FCS, the most severe form of sHTG.¹ The therapy works by suppressing hepatic production of apolipoprotein C-III, a protein that raises triglyceride levels by slowing their clearance.¹ Sanofi holds commercialization rights to Redemplo in Greater China, while Arrowhead retains rights elsewhere.¹

References

1. Arrowhead Pharmaceuticals. Arrowhead Pharmaceuticals reports topline results from Phase 3 SHASTA-3 and SHASTA-4 studies of plozasiran in patients with severe hypertriglyceridemia. Press release. Published July 22, 2026. Accessed July 22, 2026. https://ir.arrowheadpharma.com/news-releases/news-release-details/arrowhead-pharmaceuticals-reports-topline-results-phase-3-shasta

2. Study of plozasiran (ARO-APOC3) in adults with severe hypertriglyceridemia (SHASTA-3). ClinicalTrials.gov identifier: NCT06347003. Updated July 15, 2026. Accessed July 22, 2026. https://clinicaltrials.gov/study/NCT06347003

3. Study of plozasiran in adults with severe hypertriglyceridemia (SHASTA-4). ClinicalTrials.gov identifier: NCT06347016. Updated October 24, 2025. Accessed July 22, 2026. https://clinicaltrials.gov/study/NCT06347016