Plozasiran Cuts Triglycerides By 80% in SHASTA-3/4 Trials

Plozasiran, an RNA interference (RNAi) therapeutic targeting apolipoprotein C-III (APOC3), reduced triglyceride levels by approximately 80% at 1 year in patients with severe hypertriglyceridemia, according to results from the phase 3 SHASTA-3 and SHASTA-4 trials presented in a Hot Line session at the European Society of Cardiology (ESC) Congress 2026 in Munich, Germany.¹ A significant reduction in acute pancreatitis events accompanied the triglyceride-lowering effect.¹

Plozasiran already carries US Food and Drug Administration approval as Redemplo for familial chylomicronemia syndrome (FCS), granted in November 2025 based on the phase 3 PALISADE trial.² SHASTA-3 and SHASTA-4 extend testing of the agent to a broader severe hypertriglyceridemia population, defined by triglyceride levels of 500 mg/dL or greater, rather than requiring a genetically confirmed or clinically diagnosed FCS.

Severe hypertriglyceridemia significantly increases the risk of acute pancreatitis, which can often include recurrent attacks requiring repeat hospital admissions, and Watts noted currently available therapeutic approaches are often insufficient to lower triglyceride levels and prevent this complication.¹

Gerald Watts, MD, PhD, presenter and professor at the University of Western Australia, Perth, Australia, explained the mechanism behind the therapy. "Plozasiran is an RNA interference therapeutic designed to reduce production of apolipoprotein C-III (APOC3), a key regulator of triglyceride metabolism and clearance," Watts said. "Given encouraging results in other trials, we investigated the efficacy and safety of plozasiran in two phase III trials in patients with severe hypertriglyceridaemia."

SHASTA-3 and SHASTA-4 Trial Design and Efficacy Results

SHASTA-3 and SHASTA-4 were double-blind trials conducted across 24 countries.¹ Participants were eligible if they had triglyceride levels of 500 mg/dL or greater and were randomized (2:1) to receive four quarterly subcutaneous injections of plozasiran 25 mg or placebo over a 1-year period.¹ The trials included 757 patients with a mean age of 53 years, and 22% were female.¹

For the primary endpoint, treatment with plozasiran led to median triglyceride reductions at month 12 of 79% in SHASTA-3 and 81% in SHASTA-4, compared with a placebo reduction of approximately 27% in each trial.¹ Across the trial populations, cumulative acute pancreatitis events were reduced by 78% with plozasiran versus placebo.¹ In a subset of patients with triglycerides above 880 mg/dL and a prior history of acute pancreatitis, a 100% reduction in acute pancreatitis events was observed with plozasiran versus placebo.¹

Plozasiran Safety and the Broader APOC3-Targeting Landscape

Plozasiran demonstrated a favorable safety and tolerability profile, with no clinically meaningful differences in routine clinical laboratory measurements, including liver enzymes, compared with placebo. Treatment-related adverse events leading to study discontinuation occurred in 1.4% of patients treated with plozasiran and 0.8% of patients receiving placebo.¹

"Results from the SHASTA-3 and SHASTA-4 studies build on the positive results from other plozasiran trials across various patient populations, including those with the most severe form of hypertriglyceridaemia, familial chylomicronaemia syndrome," Watts said. "These findings highlight the potential of plozasiran as a promising therapy for patients across the spectrum of severe hypertriglyceridaemia."

Plozasiran is one of 2 APOC3-directed RNA therapeutics approved for FCS, alongside olezarsen, an antisense oligonucleotide approved in December 2024 under the brand name Tryngolza. Unlike olezarsen, which is dosed monthly, plozasiran is administered quarterly, reflecting a difference in RNA-targeting approach between the 2 agents.⁴

References

1. European Society of Cardiology. Plozasiran significantly reduces triglyceride levels in patients with severe hypertriglyceridaemia. Published August 30, 2026. Accessed August 30, 2026.

2. Watts GF, Rosenson RS, Hegele RA, et al. Plozasiran for managing persistent chylomicronemia and pancreatitis risk. N Engl J Med. 2025;392(2):127-137. doi:10.1056/NEJMoa2409368

3. Ballantyne CM, Vasas S, Azizad M, et al. Plozasiran, an RNA interference agent targeting APOC3, for mixed hyperlipidemia. N Engl J Med. 2024;391:899-912.

4. Ionis Pharmaceuticals, Inc. TRYNGOLZA (olezarsen) approved in U.S. as first-ever treatment for adults living with familial chylomicronemia syndrome as an adjunct to diet. Published December 19, 2024. Accessed August 30, 2026. https://ir.ionis.com/news-releases/news-release-details/tryngolzatm-olezarsen-approved-us-first-ever-treatment-adults