SHASTA-2 and Plozasiran in Severe Hypertriglyceridemia, with Christie Ballantyne, MD

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Christie Ballantyne, MD, discusses data from the SHASTA-2 trial and how it informs the community on the potential of plozasiran in management of severe hypertriglyceridemia.

New data from the American College of Cardiology 2024 (ACC.24) Annual Scientific Sessions offers the cardiology community the latest insights into the effects of plozasiran in patients with severe hypertriglyceridemia.

Results of the phase 2b SHASTA-2 trial, which assessed use of the investigational APOC3-targeted small interfering–RNA (siRNA) therapeutic in patients with fasting triglyceride levels of 500 mg/dL or greater, indicate use was associated with least squares (LS)–mean reductions in triglyceride levels of −57% at 24 weeks, with the significant treatment difference persisting at 48 weeks. Investigators noted these were driven by a placebo-adjusted reduction in APOC3 and more than 90% of patients achieved a fasting triglyceride level less than 500 mg/dL.1

“Promising results presented today at ACC.24 and simultaneously published in JAMA Cardiology showed that treatment with plozasiran in the SHASTA-2 study led to significant and sustained reductions in triglyceride levels below the threshold associated with elevated risk for pancreatitis. These are important and exciting data as patients with severe hypertriglyceridemia currently have limited treatment options,” said principal investigator Daniel Gaudet, MD PhD, Professor of Medicine at Université de Montréal.2

A placebo-controlled, dose-ranging trial, the phase 2b study enrolled its first patients in 2021 and was aimed at assessing the tolerability, efficacy, and dose of plozasiran in patients with fasting triglyceride levels in the range of 500 to 4000 mg/dL on stable lipid-lowering therapy. The trial’s primary outcome of interest was the placebo-adjusted differences in mean percentage of triglyceride change at week 24.1

A total of 229 patients were enrolled in the trial. This cohort had a mean age of 55 years, 78% were men, and 90% were White. Investigators pointed out the mean baseline triglyceride level among the cohort was 897 mg/dL. Per trial protocol, participants were randomized in a 3:1 ratio to 2 subcutaneous doses of plozasiran at 10, 25, or 50 mg or matched placebo on day 1 and at week 12, with follow-up through week 48.1

According to study results, use was associated with dose-dependent placebo-adjusted reductions in triglycerides (primary endpoint) of -49% (P < 0.001), -53% (P < 0.001), and -57% (P < 0.001), driven by placebo-adjusted reductions in APOC3 of -68% (P < 0.001), -72% (P < 0.001), and -77% (P < 0.001) at week 24, after receiving 2 doses of 10 mg, 25 mg, and 50 mg plozasiran, respectively. Investigators highlighted 90.6% of plozasiran-treated patients achieved a triglyceride level of less than 500 mg/dL.1

Investigators pointed out use was associated with dose-dependent increases in LDL-C level, which was significant in patients receiving the 50 mg dose (placebo-adjusted LS-mean increase 60%; 95% CI, 31% to 89%; P < .001). Additionally, apolipoprotein B levels did not increase and non–high-density lipoprotein cholesterol levels decreased significantly at all doses, with a placebo-adjusted change of −20% at the 50 mg dose.1

For more on plozasiran and SHASTA-2, check out our interview with study investigator Christie Ballantyne, MD, chief of Cardiology and Cardiovascular Research at Baylor College of Medicine, from the floor at ACC.24

Relevant disclosures for Ballantyne include Arrowhead, AstraZeneca, Eli Lilly and Company, Abbott Diagnostics, NewAmsterdam, and others.


  1. Gaudet D, Pall D, Watts GF, et al. Plozasiran (ARO-APOC3) for Severe Hypertriglyceridemia: The SHASTA-2 Randomized Clinical Trial. JAMA Cardiol. Published online April 07, 2024. doi:10.1001/jamacardio.2024.0959
  2. Arrowhead Pharmaceuticals Inc. Arrowhead Pharmaceuticals announces New Phase 2 data of plozasiran published in Jama Cardiology and presented at American College of Cardiology 73rd Annual Scientific Session & Expo. Arrowhead Pharmaceuticals Inc. April 7, 2024. Accessed April 8, 2024.