-Arrowhead Pharmaceuticals, Inc. presented results from the pivotal Phase 3 SHASTA-3 and SHASTA-4 studies of plozasiran in adults with severe hypertriglyceridemia (sHTG) during a Hot Line Late-Breaking Science session at the European Society of Cardiology (ESC) Congress 2026 in Munich, Germany.

In the highest-risk subgroup, patients with TG above 880 mg/dL and a prior history of AP, there was a 100% reduction in events versus placebo

SHASTA-3 and SHASTA-4 met their primary and all prespecified secondary endpoints and demonstrated deep and durable reductions in triglycerides (TG), with median reductions from baseline of 79% and 81%, respectively at Month 12 (p<0.0001 in both studies). In a prespecified pooled analysis, plozasiran also significantly reduced acute pancreatitis (AP) events across the broad sHTG study population, with greater absolute benefit observed among patients at higher risk of AP. More than 90% of plozasiran-treated patients in both studies achieved TG levels below 500 mg/dL (<5.65 mmol/L) at Month 12, and more than half achieved TG levels below 150 mg/dL (<1.69 mmol/L).

“These SHASTA-3 and -4 results build on the compelling topline data we reported in July and further strengthen our view that plozasiran has the potential to fundamentally change how severe hypertriglyceridemia is treated,” said Christopher Anzalone, Ph.D., President and Chief Executive Officer at Arrowhead. “The depth and consistency of triglyceride lowering across two large pivotal studies are impressive, but what may be most important for patients and physicians is the significant reduction in acute pancreatitis. The benefit was particularly pronounced among patients with a prior history of pancreatitis, a population with substantial ongoing risk. Combined with quarterly dosing and a favorable safety and tolerability profile, we believe these data demonstrate a highly differentiated profile for plozasiran and unequivocally support our plans to seek regulatory approval for the broader sHTG population. Our purchase of a U.S. FDA Priority Review Voucher, announced earlier this month, will potentially accelerate our goal of getting this important new medicine to patients.”

James Hamilton, M.D., MBA, Chief Medical Officer and Head of R&D at Arrowhead, added, “SHASTA-3 and SHASTA-4 enrolled a broad population that reflects the heterogeneity and substantial disease burden seen in patients with severe hypertriglyceridemia. Plozasiran produced deep and durable reductions in triglycerides and other atherogenic lipoproteins, and more than 90% of treated patients achieved triglyceride levels below the severe hypertriglyceridemia threshold at Month 12. Importantly, the reduction in acute pancreatitis events was observed across the pooled population and became increasingly more meaningful in patients at higher risk. We believe the totality of these data provides strong evidence supporting APOC3 reduction in the liver with plozasiran as a potentially important treatment approach for patients with sHTG.”

Arrowhead intends to leverage data from the Phase 3 SHASTA-3, SHASTA-4 and MUIR-3 studies to seek marketing authorization for plozasiran in the broader sHTG population in multiple global geographies, beginning with a planned supplemental New Drug Application (sNDA) with the U.S. Food and Drug Administration (FDA) before the end of 2026. On August 4, 2026, the company announced it had purchased an FDA Priority Review Voucher, which it intends to utilize for this application.

SHASTA-3 and SHASTA-4 Phase 3 Results

SHASTA-3 and SHASTA-4 were global, randomized, double-blind, placebo-controlled Phase 3 studies evaluating plozasiran 25 mg administered subcutaneously once every three months in adults with sHTG. Across the two studies, 757 patients were randomized to receive plozasiran or placebo.

Triglyceride and Lipoprotein Effects

• At Month 12, median TG levels were reduced from baseline by 79% in SHASTA-3 and 81% in SHASTA-4 in patients receiving plozasiran 25 mg (p<0.0001 in each study).
• Among patients with baseline TG ≥880 mg/dL (≥9.94 mmol/L), median TG reductions at Month 12 were 85% in both SHASTA-3 and SHASTA-4.
• At Month 12, 91% and 93% of plozasiran-treated patients in SHASTA-3 and SHASTA-4, respectively, achieved TG levels <500 mg/dL (<5.65 mmol/L), compared with 51% and 50% of placebo-treated patients (p<0.0001 for each comparison).
• 52% and 55% of plozasiran-treated patients in SHASTA-3 and SHASTA-4, respectively, achieved TG levels <150 mg/dL (<1.69 mmol/L), compared with 7.9% and 2.0% of placebo-treated patients (p<0.0001 for each comparison).
• Plozasiran also produced significant reductions in APOC3, remnant cholesterol (VLDL-C) and non-HDL cholesterol.