Arrowhead Pharmaceuticals Reports Strong Long-Term Data for Plozasiran in Hypertriglyceridemia

Arrowhead Pharmaceuticals has presented new long-term efficacy and safety data for plozasiran across a spectrum of hypertriglyceridemia at the American College of Cardiology's 75th Annual Scientific Session and Expo. Patients with severe hypertriglyceridemia achieved an 83% median reduction in triglycerides, with 96% of patients achieving triglyceride levels below 500 mg/dL, a threshold associated with increased risk of acute pancreatitis. No adjudicated acute pancreatitis events occurred in any patient receiving plozasiran during the 2-year Phase 2b Open-Label Expansion Study.

Favorable and durable improvements in atherogenic lipoproteins, including remnant cholesterol, non-HDL cholesterol, and ApoB, were observed, with a safety profile consistent with earlier trials. During the two-year open-label extension, patients saw median reductions in their triglycerides by -83% in severe hypertriglyceridemia patients from the SHASTA-2 study and -67% in hypertriglyceridemia patients from the MUIR study with favorable reductions in remnant cholesterol and non-HDL-cholesterol.

In both studies, the majority of patients achieved triglyceride levels below thresholds for acute pancreatitis risk or below normal thresholds. 96% of severe hypertriglyceridemia patients achieved triglycerides below 500 mg/dL and 63% achieved triglycerides below 150 mg/dL, a threshold associated with increased risk of atherosclerotic cardiovascular disease. 93% of hypertriglyceridemia patients achieved triglycerides below 150 mg/dL.

Plozasiran demonstrated a consistent long-term safety and tolerability profile across both severe hypertriglyceridemia and hypertriglyceridemia patient populations, with stable glycemic parameters, no clinically meaningful differences in routine clinical laboratory measurements, and no new safety signals. Common treatment-emergent adverse events included diabetes, COVID-19, upper respiratory tract infection, and back pain, consistent with prior studies; HbA1c levels remained stable.

The ACC.26 presentation builds on positive findings from two Phase 2b double-blind, placebo-controlled studies of plozasiran: SHASTA-2, conducted in adults with severe hypertriglyceridemia, and MUIR, which enrolled patients with hypertriglyceridemia, both of which demonstrated short-term efficacy and safety. With the same patient populations, the company initiated an extension phase in which both groups received plozasiran 25 mg quarterly via subcutaneous injections.

Plozasiran is designed to reduce the hepatic production of apolipoprotein C-III through targeted RNA interference. APOC3 is a key regulator of triglyceride metabolism that inhibits both lipoprotein lipase-dependent and LPL-independent pathways involved in triglyceride catabolism and clearance, leading to elevated triglyceride levels. Individuals with genetic loss-of-function variants in APOC3 typically have markedly lower triglyceride levels and a reduced risk of atherosclerotic cardiovascular disease.

Arrowhead is on schedule to complete the SHASTA-3, SHASTA-4, and MUIR-3 Phase 3 clinical studies, the company's global Phase 3 clinical studies designed to support regulatory submissions for marketing approval of plozasiran for the treatment of severe hypertriglyceridemia, in mid-2026 and intends to submit a supplemental New Drug Application to regulatory authorities.

Severe hypertriglyceridemia is characterized by triglyceride levels greater than 500 mg/dL, with the most severe form being familial chylomicronemia syndrome where triglycerides typically exceed 880 mg/dL. Severe hypertriglyceridemia significantly increases the risk of acute pancreatitis, which can often include recurrent attacks requiring repeat hospital admissions and worsening outcomes.