J Clin Pharmacol. 2026 Apr;66(4):e70190. doi: 10.1002/jcph.70190.
ABSTRACT
Plozasiran (Redemplo), a novel small interfering RNA (siRNA) therapeutic targeting the hepatic biosynthesis of apolipoprotein C-III (APOC3), is approved by the US FDA for treating familial chylomicronemia syndrome (FCS), a disease of rare prevalence that presents with extremely elevated levels of serum triglycerides (TG) leading to a higher risk of acute pancreatitis. Plozasiran is also in Phase 3 development to treat the broader indication of severe hypertriglyceridemia. Population pharmacodynamic (PD) analysis of plozasiran was conducted on serially measured serum APOC3 and TG levels in the FCS patients participating in the pivotal Phase 3 study by employing a cascading kinetic-PD model that described the inhibitory effect of plozasiran on the synthesis of APOC3, which in turn decreases serum TG levels. The estimated IC50 dose of plozasiran was 2.2 mg, demonstrating potent on-target pharmacological activity of plozasiran conferred by its efficient mechanism of action via RNA interference (RNAi). The model-estimated elimination half-life of plozasiran in the liver was 48 days, supporting quarterly dosing (Q3M) for patients’ convenience. Body mass index (BMI) and background TG-lowering therapy were identified as the only statistically significant covariates without clinical importance, and the subcutaneous 25 mg Q3M dose is approved for all adult FCS patients, including those with Asian ethnicity, mild-to-moderate degrees of renal impairment or a mild degree of hepatic impairment. There was no evidence to suggest that the TG-lowering efficacy of plozasiran was significantly different between clinically diagnosed and genetically confirmed FCS patients, and therefore plozasiran treatment is suitable for both genetic and clinically diagnosed FCS patients.
PMID:42003054 | DOI:10.1002/jcph.70190
