Inclisiran, a
small interfering RNA, selectively inhibits
proprotein convertase subtilisin/kexin type 9 (PCSK9) synthesis in the liver and has been shown to reduce
low-density lipoprotein cholesterol (
LDL-C) by ≥50% in patients with
hypercholesterolemia receiving maximally tolerated
statins. The toxicokinetic, pharmacodynamic, and safety profiles of
inclisiran when coadministered with a
statin were characterized in cynomolgus monkeys. Six cohorts of monkeys were administered either
atorvastatin (40 mg/kg, reduced to 25 mg/kg during the study, daily, oral gavage),
inclisiran (300 mg/kg every 28 days, subcutaneous administration),
atorvastatin (40/25 mg/kg) and
inclisiran combinations (30, 100, or 300 mg/kg), or control vehicles over 85 days followed by 90 days' recovery.
Inclisiran and
atorvastatin toxicokinetic parameters were similar in cohorts administered either agent alone or in combination.
Inclisiran exposure increased in a dose-proportional manner. At Day 86,
atorvastatin increased plasma PCSK9 levels four-fold from pretreatment levels but did not significantly lower serum
LDL-C levels.
Inclisiran (alone or in combination) reduced PCSK9 (mean decrease 66-85%) and
LDL-C (mean decrease 65-92%) from pretreatment levels at Day 86; levels were significantly lower than the control group (p ≤ .05) and remained decreased during the 90-day recovery. Coadministration of
inclisiran with
atorvastatin resulted in greater reductions in
LDL-C and total
cholesterol compared with either drug alone. No toxicities or adverse effects were observed in any cohort receiving
inclisiran, either alone or in combination. In summary,
inclisiran significantly inhibited PCSK9 synthesis and decreased
LDL-C in cynomolgus monkeys without increasing the risk of adverse effects when coadministered with
atorvastatin.