ARWR Plozasiran: 78% Pancreatitis Cut, Presses Ionis

Arrowhead Pharmaceuticals (ARWR) presented full 12-month data from the Phase 3 SHASTA-3 and SHASTA-4 trials of plozasiran (REDEMPLO) in severe hypertriglyceridemia (sHTG) at the European Society of Cardiology Congress on August 30, and the numbers sharpen its pitch against Ionis’ already-approved Tryngolza (olezarsen).

Plozasiran, a quarterly RNAi shot, cut triglycerides by a median 79% in SHASTA-3 and 81% in SHASTA-4 at month 12 (p<0.0001). More than 90% of treated patients reached triglycerides below 500 mg/dL, the threshold for pancreatitis risk, and more than half fell below 150 mg/dL. Across the pooled studies, plozasiran reduced acute pancreatitis events by 78% (relative risk 0.22, p=0.008), a 4.1% absolute cut equal to one event prevented for every 24 patients treated for a year. In the highest-risk subgroup, triglycerides above 500 mg/dL plus a prior pancreatitis, the reduction reached 91%, preventing one event for every three patients treated.

Both drugs lower triglycerides by suppressing APOC3, a liver protein that slows the body’s breakdown of fat-carrying particles, but through different chemistries: plozasiran is a small-interfering RNA, Tryngolza an antisense drug. The market is large. More than 3 million people in the US have sHTG, including about 1 million at high risk of the acute pancreatitis attacks that can mean repeated hospitalizations.

Arrowhead’s safety case is the story. Serious treatment-emergent adverse events ran 8.3% for plozasiran versus 10% for placebo, discontinuations were 1.4%, and there were no meaningful liver-enzyme or hepatic-fat changes, a contrast to Tryngolza’s liver-enzyme warnings. One wrinkle: worsening glycemic control appeared in 14.3% of treated patients versus 8.7% on placebo, though average HbA1c stayed stable. Three deaths, two cardiovascular and one leukemia, were judged unrelated to the drug.

The caveat is that these are cross-trial comparisons, and analysts read the two drugs’ efficacy as similar. Arrowhead’s differentiation rests on quarterly dosing (versus Tryngolza’s monthly) and safety, not on a bigger triglyceride number. Tryngolza won FDA approval for sHTG in June 2026 and booked $32 million in first-half US sales. The voucher cost an estimated $75 million to $110 million but can shorten FDA review from ten months to six. The stock sits near $84.91. Arrowhead plans an sNDA for the broader sHTG population before year-end, using the Priority Review Voucher it bought in August to speed review, after the plozasiran SHASTA-3/4 topline results in July. Read the full data announcement.

What to watch next: the year-end sNDA filing, which starts the head-to-head with Tryngolza for the sHTG market in earnest.