Background: Inclisiran is a novel siRNA therapy that inhibits the synthesis of proprotein convertase subtilisin-kexin type 9 (PCSK9) by targeting the PCSK9 mRNA, consequently, decreases low-density lipoprotein cholesterol (LDL-C).
Objective: To assess the safety, PK and LDL-C lowering effects of inclisiran in the Chinese patients with elevated LDL-C despite treatment with maximally tolerated LDL-C lowering therapies.
Methods: Forty Chinese patients with hypercholesterolemia (LDL-C ≥100 mg/dL) who were on maximally tolerated statin were randomized to receive a single dose of either inclisiran sodium 100 or 300mg s.c. injection (each for 15 patients) or placebo (10 patients). Safety, pharmacokinetics and pharmacodynamics (i.e., PCSK9 and LDL-C levels) were evaluated for up to 90 days after the s.c. injection of study drug.
Results: Following single subcutaneous injections inclisiran sodium at 100 mg or 300 mg, inclisiran has a relative short elimination half-life (T1/2, 6.5 hours). Both plasma PCSK9 and serum LDL-C decreased rapidly and consistently, with the maximal reduction between Day 30 and Day 60; then the decreases of PCSK9 and LDL-C were generally maintained up to 56.4% and 49.6% of 100 mg, 74.9% and 58.3% of 300 mg, respectively, at day 90. All adverse events were mild or moderate in severity, and no discontinuations due to adverse events. There were no serious adverse events being reported.
Conclusions: Inclisiran was generally safe and well tolerated. Single dose of both Inclisiran 100 and 300 mg significantly reduced PCSK9 and LDL-C levels in Chinese patients up to Day 90. The greatest reductions were observed with the 300 mg regimen of Inclisiran.
Trial registration: ClinicalTrials.gov: NCT04774003.
Keywords: ASCVD; Hypercholesterolemia; Inclisiran; Low-density lipoprotein cholesterol (LDL-C); Proprotein convertase subtilisin-Kexin type 9 (PCSK9); siRNA.
Copyright © 2023. Published by Elsevier Inc.