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.

Abstract

Background and Aims: Individuals with severe hypertriglyceridemia have an increased acute pancreatitis (AP) risk. Current treatments fail to lower TGs below a threshold that exposes patients to the risk of AP. Plozasiran, a hepatocyte-targeted siRNA reduces circulating TGs by interfering with the production of APOC3, a key regulator of TG metabolism. Method(s): SHASTA-2, a randomized, placebo-controlled, Phase 2b study (NCT04720534) evaluated efficacy and safety of plozasiran in patients with SHTG. Eligible patients (n=229), randomized 3:1, received a total of 2 doses (SQ 10, 25, or 50 mg plozasiran) or matched placebo on Day 1 and at Wk12 and followed through Wk48. The primary endpoint was percent change from baseline in fasting TGs at Wk24. Mixed model repeated measure (MMRM) approaches were used for statistical modeling. Result(s): Plozasiran produced LS mean reductions in APOC3 of -78% and TGs of -74% at Wk24 (p<0.0001). Reductions in APOC3 and TGs were -48% and -58% respectively at Wk48 (p <0.0001). The majority, 78% of patients achieved TGs <500 mg/dL by Wk48 vs >90% at Wk24. Durable reductions in other lipoprotein parameters (remnant cholesterol, non-HDL-C, ApoB) were also observed through Wk48. No significant increase in adverse events were reported in plozasiran treated patients. All SAEs were mild to moderate in severity (grade 1-3) and no SAEs led to discontinuation or death. Conclusion(s): Plozasiran produced highly durable TG reductions below the threshold associated with elevated AP risk. Key atherogenic lipoprotein parameters also improved. The safety profile was favorable at all doses. These data support initiation of pivotal studies of plozasiran for the treatment of SHTG.Copyright © 2024