Arrowhead Pharmaceuticals has announced long-term efficacy and safety data from a two-year long Open-Label Extension (OLE) study of investigational plozasiran supporting its potential as therapeutic solution for a diverse spectrum of patients with hypertriglyceridemia (HTG).

The data were presented by Dr Christie M Ballantyne, MD, Professor, Baylor College of Medicine, member of the Texas Heart Institute, Baylor, and principal investigator of the two-year OLE study, during an oral presentation at the American College of Cardiology 75th Annual Scientific Session & Expo (ACC.26) in New Orleans and published in the American Journal of Preventive Cardiology.

“With a new therapy, it is always important to see longer-term data to better understand both efficacy and safety. In a long-term Open-Label Extension study, plozasiran treatment was associated with dramatic and meaningful reductions in TGs. In addition, the lack of any acute pancreatitis events during two years of treatment in a patient population that includes those at high risk was particularly reassuring. These data reinforce the importance of APOC3 silencing as a central mechanism in promoting triglyceride clearance. The study provides promising evidence that plozasiran treatment may lead to durable, sustained reductions in triglycerides and atherogenic lipoproteins across the hypertriglyceridemia spectrum,” said Dr Ballantyne.

Plozasiran is designed to reduce the hepatic production of apolipoprotein C-III (APOC3) through targeted RNA interference. APOC3 is a key regulator of triglyceride metabolism that inhibits both lipoprotein lipase (LPL)-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.

The ACC.26 presentation builds on positive findings from two phase-IIb double-blind, placebo-controlled studies of plozasiran: SHASTA-2, conducted in adults with severe hypertriglyceridemia (sHTG), 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.

During the two-year OLE, patients saw median reductions in their triglycerides by -83 percent in sHTG patients from SHASTA-2 and -67 percent in HTG patients from MUIR with favourable reductions in remnant cholesterol and non-HDL-cholesterol.

In both studies, the majority of patients achieved TG levels below thresholds for Acute Pancreatitis (AP) risk or below normal thresholds. Ninety six percent of sHTG patients achieved TGs below 500 mg/dL and 63 percent achieved TGs below 150 mg/dL, a threshold associated with an increased risk of ASCVD. Ninety three percent of HTG patients achieved TGs below 150 mg/dL. These findings support the potential of plozasiran as a promising approach for managing patients with moderate-to -severe HTG phenotypes who are at risk of AP and potentially other cardiometabolic comorbidities.

Plozasiran demonstrated a consistent long-term safety and tolerability profile across both sHTG and HTG 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 (TEAEs) included diabetes, COVID-19, upper respiratory tract infection and back pain, consistent with prior studies; HbA1c levels remained stable. In SHASTA-2, mean placebo-adjusted liver fat content, as assessed by MRI-PDFF, did not change significantly over time with 25 mg plozasiran treatment.

“We’re pleased with the consistent, positive clinical results we’re seeing with plozasiran across the spectrum of hypertriglyceridemias and we’re excited about what this could mean for patients. In the four months since its FDA approval for treating FCS, plozasiran is already making a meaningful difference for the FCS community, and we believe it has the potential to become an important therapy for people living with severe hypertriglyceridemia as well. These advances, enabled by our innovative TRiM platform, reflect our commitment to developing targeted RNAi therapeutics to silence genes associated with cardiometabolic disorders as well as serious diseases in numerous tissue types throughout the body,” said Christopher Anzalone, PhD, President and CEO, Arrowhead.

The company is on schedule to complete the SHASTA-3, SHASTA-4 and MUIR-3 phase-III clinical studies, its global phase-III 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 (sNDA) to the US FDA by year-end 2026. Arrowhead also plans to seek regulatory approval with additional global regulatory authorities thereafter.