K-PD model of Plozasiran in Patients with Severe Hypertriglyceridemia

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 219 patients with severe hypertriglyceridemia (SHTG; TG > 500 mg/dL), plozasiran doses of 10, 25 and 50 mg administered subcutaneously on Day 1 and Week 12 during the double-blind period and subsequent Q12W dosing in the extension portion, demonstrated deep, dose-dependent and long-lasting reductions of serum TG with acceptable safety profiles, supporting the initiation of pivotal Phase 3 studies with plozasiran in patients with SHTG.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 simulations were conducted to support selecting a Phase 3 dose regimen.Results: Reductions in APOC3 and TG from the treatment with 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, and in turn, increases the rate of elimination of TG and thereby lowers its level in serum. Hepatic plozasiran is eliminated with an estimated t1/2 of 70 days in the SHTG patient population, which helps explain its long PD action. The estimated IC50 dose of plozasiran was 3.3 mg, suggesting a high on-target pharmacological potency via the efficient RNAi mechanism of action. There were no factors either intrinsic (e.g., patient’s demographic profiles or baseline values of relevant biomarkers) or extrinsic factors(e.g., concomitant statin use) identified as statistically significant to influence these PD effects of plozasiran. Simulations projected modest peak-to-trough fluctuations with quarterly (Q3M) dosing with similar time-averaged TG reductions over a dosing cycle between 25 mg (81%) and 50 mg (86%) doses, suggesting that 25 mg Q3M is a near PD saturating dose.Conclusion: Modeling results support choosing 25 mg Q3M as a dose to be studied in the Phase 3 trials for SHTG treatment. Dose adjustment is not required for patients with different demographic characteristics, baseline TG levels, or concomitant lipid lowering therapies.Citations: No citation