Plozasiran Reduces Triglycerides, ApoC3 in Phase 2b SHASTA-2 Trial

Daniel Gaudet, MD
Credit: American College of Cardiology

Use of plozasiran, an APOC3 inhibiting therapy from Arrowhead Pharmaceuticals, was associated with least squares mean reductions in triglyceride levels by 74% at 24 weeks, according to the SHASTA-2 trial.

Presented as a late-breaker at the American College of Cardiology 2024 (ACC.24) Annual Scientific Sessions, the trial, which included more than 200 patients with severe hypertriglyceridemia, provides evidence supporting the initiation of pivotal trials for plozasiran, according to lead investigator Daniel Gaudet, MD, PhD.^1,2

“Plozasiran produced significant reductions in triglyceride levels below the threshold associated with elevated risk for pancreatitis, with a favorable safety profile,” said Gaudet, a professor of medicine at the University of Montreal.² “These data support the initiation of pivotal studies of plozasiran for the treatment of severe hypertriglyceridemia.”

Although it does not receive the same attention as LDL-C or HDL, the role of triglycerides in cardiovascular risk and development of pancreatitis has become increasingly evident in contemporary literature. According to Arrowhead Pharmaceuticals, plozasiran a GalNAc-bound RNA interference that targets APOC3 mRNA within the cytoplasm of hepatocytes, which enables the liver to increase its clearance of triglycerides and other fats.^1,2

Prior to the SHASTA-2 trial, the phase 2 MUIR trial provided the community with insight into the effects of the agent. In this trial, which included people with mixed dyslipidemia who had fasting triglycerides between 150-499 mg/dL and either LDL-cholesterol greater than 70 mg/dL or non-HDL-cholesterol greater 100 mg/dL, receipt of 2 doses was associated with a 64% reduction in triglycerides, a 54% reduction in remnant cholesterol, a 19% reduction in apolipoprotein B (ApoB), a 27% reduction in non-HDL-cholesterol, and a 51% increase in HDL-cholesterol.³

The phase 2 SHASTA trial was a randomized, placebo-controlled, phase 2b study aimed at assessing the safety and efficacy of plozasiran in patients with severe hypertriglyceridemia, which was defined as fasting triglyceride levels greater than 500 mg/dL. Patients included in the trial were randomized in a 3:1 ratio to receive a total of 2 doses of 10, 25, or 50 mg plozasiran or matched placebo on day 1 and at week 12 of the trial.¹

Overall, 229 patients from 8 countries 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 approximately 900 mg/dL and most had a least 3 of the following risk factors: elevated risk for or history of cardiovascular disease, diabetes, low HDL-C, and elevated body mass index.¹

The primary outcome of SHASTA-2 was the percentage change in fasting triglyceride levels from baseline to week 24. The trial included multiple secondary endpoints of interest, including percentage change in ApoC3 at 24 weeks and every four weeks from baseline through 48 weeks and in fasting triglyceride levels every four weeks through 48 weeks.¹

Results of the primary outcome analysis indicated people receiving plozasiran experienced a mean reduction in triglyceride levels of 74% by week 24 compared to 17% among the placebo group (P < .0001). Secondary outcome analyses revealed a mean ApoC3 reduction of 78% with plozasiran through 24 weeks compared to just 1% among the placebo arms.¹

Investigators also pointed out those using the highest doses of plozasiran experienced a mean reduction in ApoC3 levels of 48% compared to 4% in the placebo group. When assessing patients reaching triglyceride targets of less than 500 mg/dL, investigators found more than 90% of patients of patients receiving plozasiran achieved a fasting triglyceride level less than 500 mg/dL at week 24, with 77% still having a triglyceride level of less than 500 mg/dL.¹

“From the patients’ standpoint, the possibility that in the near future there could be an agent that safely and effectively lowers severely elevated triglyceride levels and reduces or eliminates the risk of developing pancreatitis is extraordinary,” Gaudet added.²

References:

1. Gaudet D, Pall D, Watts G, et al. Plozasiran (ARO-APOC3), An Investigational RNAi Therapeutic, Demonstrates Profound And Durable Reductions In APOC-3 And Triglycerides (TG) In Patients With Severe Hypertriglyceridemia (SHTG), SHASTA-2 Final Results. Presented at: American College of Cardiology (ACC.24) Annual Scientific Session. April 6 – 8, 2024. Atlanta, GA.
2. American College of Cardiology. Plozasiran Reduces Triglyceride Levels by 74% at 24 Weeks. American College of Cardiology. Published April 7, 2024. Accessed April 7, 2024.
3. Arrowhead Pharmaceuticals Inc. Arrowhead presents New phase 2 data on plozasiran and zodasiran at AHA 2023. Arrowhead Pharmaceuticals Inc. November 13, 2023. Accessed April 7, 2024. https://ir.arrowheadpharma.com/news-releases/news-release-details/arrowhead-presents-new-phase-2-data-plozasiran-and-zodasiran-aha.