Daniel Gaudet, MD, PhD: Contextualizing Plozasiran Data from SHASTA-2, Upcoming MUIR Data

In recent years, movement in the therapeutic pipeline have ushered in a new era of management for dyslipidemia—an area where, for years, there was an extreme level of unmet need.

Although a significant level of unmet need still exists for many forms of dyslipidemia, continued progress in the aforementioned therapeutic pipeline offer promise of impacting abnormal levels of various lipids and lipid particles, including triglycerides and Lp(a). At the American College of Cardiology 2024 (ACC.24) Annual Scientific Session, the cardiovascular community received further insight into 1 of these agents: plozasiran.

The investigational APOC3-targeted small interfering–RNA therapeutic from Arrowhead Pharmaceutical was examined in the SHASTA-2 trial, which included 229 patients with severe hypertriglyceridemia already receiving lipid-lowering therapy. Results of the study suggested use of plozasiran appeared to be well-tolerated and was associated with consistent and sustained reductions in triglyceride levels.¹

In this video interview, SHASTA-2 principal investigator Daniel Gaudet, MD, PhD, professor of Medicine at Université de Montréal, explains the significance of the trial, what the community will learn about plozasiran in the upcoming MUIR trial, and what questions surrounding the agent will require a phase 3 program to answer.

SHASTA-2

The phase 2b SHASTA-2 trial was a placebo-controlled, dose-ranging study, aimed to evaluate the tolerability, efficacy, and optimal dosage of plozasiran in patients with fasting triglyceride levels of 500 to 4000 mg/dL on stable lipid-lowering therapy.¹

Among 229 patients (mean age 55, 78% men, 90% White) randomized to 10, 25, or 50 mg or matched placebo, receiving plozasiran was associated with dose-dependent, placebo-adjusted reductions in triglycerides (-57% with plozasiran 50 mg; P <.001), with 90.6% of plozasiran-treated achieving levels under 500 mg/dL. Results also indicated, plozasiran induced significant reductions in APOC3 levels, but also dose-dependent increases in LDL-C, particularly at the 50 mg dose. Investigators noted apolipoprotein B levels remained stable during the trial and non–HDL-c levels decreased significantly across all doses.¹

MUIR

At the upcoming European Atherosclerosis Society (EAS) 2024 meeting, the cardiology community will receive further insight into the effects of plozasiran from another phase 2 trial: MUIR. A phase 2b trial assessing the same doses of plozasiran or matched placebo therapy, the MUIR trial enrolled 353 patients with mixed dyslipidemia, which was defined as having fasting triglycerides of 150 to 499 mg/dL and either an LDL-C of 70 mg/dL or greater or non-HDL-C of 100 mg/dL or greater.²

Designed as a 48-week trial, interim 24-week results were presented at the American Heart Association 2023 Scientific Sessions by Christie Ballantyne, MD, chief of Cardiology and Cardiovascular Research at Baylor College of Medicine. At AHA 2023, data presented by Ballantyne indicated use of plozasiran was associated with significantly decreased APOC3 up to 80%, with these reductions occurring in a dose-dependent manner (P <.0001).²

Further analysis suggested least squares (LS) mean triglycerides were significantly reduced by 52 to 64% (P <.0001). Additionally, the LS mean atherogenic lipoproteins were reduced by up to 27% for non-HDL-C, 19% for apolipoprotein B, and 55% for remnant cholesterol.²

Final data from the MUIR trial will be presented by Christie Ballantyne, MD, at EAS 2024 on Tuesday, May 28, 2024.

Relevant disclosures of interest for Gaudet include Arrowhead Pharmaceuticals, AstraZeneca, Boehringer Ingelheim, Eli Lilly, Novo Nordisk, New Amsterdam Pharma, and others.

References:

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. Vasas S, Azizad M, Clifton P, et al. ARO-APOC3, an Investigational RNAi Therapeutic, Silences APOC3 and Reduces Atherosclerosis-Associated Lipoproteins in Patients With Mixed Dyslipidemia: MUIR Study Results. Presented at: American Heart Association (AHA) Scientific Sessions 2023. November 11 - 13, 2024. Philadelphia, PA.