Two back-to-back phase 3 trials — SHASTA-3 and SHASTA-4 — have delivered striking results for plozasiran (Redemplo, Arrowhead Pharmaceuticals), a small interfering RNA (siRNA) therapy targeting APOC3, a key regulator of triglyceride metabolism. In 757 patients with severe hypertriglyceridemia (triglycerides ≥500 mg/dL), four quarterly subcutaneous injections of plozasiran 25 mg over one year reduced triglyceride levels by 79–81% compared with just 27% in the placebo groups — with effects visible as early as 3 months.

Beyond lipid lowering, plozasiran also dramatically cut the risk of acute pancreatitis, a potentially life-threatening complication of severe hypertriglyceridemia. In the highest-risk subgroup — patients with prior pancreatitis and triglycerides ≥880 mg/dL — plozasiran achieved a 100% reduction in pancreatitis events. Arrowhead plans to file a supplemental NDA with the FDA by year's end. These results complement those of olezarsen (Tryngolza, Ionis), an antisense oligonucleotide also targeting APOC3 that received FDA approval in June 2026 for severe hypertriglyceridemia.

By the Numbers:

• 79–81% reduction in triglycerides with plozasiran vs. 27% with placebo
• 78% reduction in acute pancreatitis event frequency (NNT = 24 over 1 year)
• 100% reduction in pancreatitis events in the highest-risk subgroup (prior pancreatitis + TG ≥880 mg/dL)
• 50% of plozasiran patients achieved normal triglyceride levels vs. 6% on placebo
• 14% of plozasiran patients experienced worsening glycemic control (vs. 9% placebo)

Why it matters: For patients with severe hypertriglyceridemia — a condition poorly managed by existing therapies — two APOC3-targeting drugs now offer dramatic, sustained triglyceride reduction and meaningful protection against acute pancreatitis. Experts say this marks a new evidence bar for the field, though questions remain about prescribing thresholds and long-term cardiovascular outcomes.