Arrowhead Pharmaceuticals, Inc. (Nasdaq: ARWR) reported topline results from two pivotal Phase III trials of plozasiran in severe hypertriglyceridemia, data that could expand the drug's use well beyond the ultra-rare genetic disease for which it is already approved. The California-based company said the SHASTA-3 and SHASTA-4 studies both hit their primary endpoint and showed a statistically significant reduction in acute pancreatitis events. For a company whose only approved product currently serves a population estimated at roughly 6,500 patients in the US, positive results in the much larger severe hypertriglyceridemia population would transform the molecule into a mainstream cardiometabolic drug.
SHASTA-3 and SHASTA-4 are global, double-blind, placebo-controlled trials that together randomized approximately 750 adults with severe hypertriglyceridemia — defined as fasting triglycerides above 500 mg/dL — to four quarterly doses of 25 mg plozasiran or placebo. At month 12, plozasiran produced median triglyceride reductions of 79% and 81% in the two studies, respectively, compared with roughly 27% for placebo. Arrowhead also reported a statistically significant reduction in acute pancreatitis events across the pooled study population, with what it described as a 100% reduction among high-risk patients, though the company did not disclose the underlying p-value or confidence intervals in the topline release. Safety findings were consistent with plozasiran's existing profile with no new signals, and particularly no meaningful change in liver fat on MRI-PDFF imaging or in liver enzymes. Arrowhead has consistently emphasized a clean liver profile as a differentiator. Full efficacy and safety data will be presented as a Hot Line late-breaker at the European Society of Cardiology Congress in Munich on August 30.
Plozasiran silences production of apolipoprotein C-III, a liver-derived protein that normally slows the breakdown and clearance of triglyceride-rich lipoproteins. By reducing apoC-III through RNA interference, the drug allows lipoprotein lipase to clear those particles more efficiently, driving triglycerides down. The mechanism is the same one underlying plozasiran's existing approval: the drug is marketed as Redemplo in the US, EU, China, Australia and Canada as an adjunct to diet for adults with familial chylomicronemia syndrome, a rare genetic disorder representing the most extreme end of the hypertriglyceridemia spectrum.
Arrowhead intends to file a supplemental new drug application with the FDA before the end of 2026, drawing on data from SHASTA-3, SHASTA-4 and the related MUIR-3 study, which enrolled patients with more moderate hypertriglyceridemia. The company has already built commercial infrastructure around Redemplo's FCS launch, including a dedicated patient support program and a pricing model designed to hold steady across indications — a structure explicitly built in anticipation of this broader sHTG approval.