Background: Apolipoprotein C3 (APOC3), a component of triglyceride-rich lipoproteins (TRL), inhibits metabolism of TRLs through both inhibition of lipoprotein lipase (LPL) and reduced liver uptake of TRL remnants. Plozasiran (ARO-APOC3) is a GalNAc-siRNA designed to degrade hepatic APOC3 mRNA transcripts and reduce the production of APOC3 protein with expected reductions in serum triglycerides (TG) and TRL. In a Phase 2b clinical study conducted in 324 patients with mixed dyslipidemia (MD; TG 150-499 mg/dL, LDL-C ≥70 mg/dL or non-HDL-C ≥100 mg/dL), plozasiran doses of 10, 25 and 50 mg administered subcutaneously on Day 1 and Week 12 (1 additional 50 mg cohort on Week 24) during the double-blind period and subsequent Q12/24W dosing in the extension portion demonstrated substantial, dose-dependent and durable reductions in TG and in non-HDL-C and ApoB, two markers of atherogenic lipoproteins, supporting the initiation of a pivotal Phase 3 study with plozasiran in patients with mixed hyperlipidemia.
Methods: Due to the major disconnect between plozasiran’s relatively short plasma exposures and its prolonged pharmacodynamic (PD) effects, its PD effects were best described by a kinetic-pharmacodynamic (K-PD) model. Potential impact of intrinsic and extrinsic factors was evaluated using standard covariate search techniques involving forward addition and backward elimination adjudicated by pre-specified statistical criteria. Model-based dose simulations were conducted to support selecting a Phase 3 dose regimen.
Results: Reductions in APOC3, TG, ApoB and non-HDL-C by plozasiran were well described by a two-step, cascading, indirect-response population K-PD model, in which plozasiran, in the effect compartment (liver), inhibits APOC3 biosynthesis, thereby increasing the rates of clearance of TG and TRLs. Hepatic plozasiran is eliminated with an estimated t1/2 of 84 days in MD subjects, which helps explain its long PD action. Plozasiran IC50 dose was estimated to be 4.8 mg for a patient of median weight. The weight effect on PD was moderate and does not support weight-based dosing. No relevant differences were observed for other covariates including race, hepatic/renal functions, diabetic status and obese categories. A small improvement in non-HDL-C and ApoB reductions was projected for 50 mg vs. 25 mg dose, which are both superior to 10 mg.
Conclusion: The results support selecting 25 mg Q3M dose for a future Phase 3 trial to ascertain the benefit of plozasiran to reduce major adverse cardiovascular events in patients with established or higher risk of developing atherosclerotic cardiovascular diseases (ASCVD). Dose adjustment is not recommended for patients with different demographic characteristics and comorbidities, or background lipid lowering therapies.
