Sustained LDL-c-lowering with long-term treatment with PCSK9 siRNA
Long-term efficacy and safety of inclisiran in patients with high cardiovascular risk and elevated LDL cholesterol (ORION-3): results from the 4-year open-label extension of the ORION-1 trial
Introduction and methods
Small-interfering ribonucleic acid (siRNA)-based therapies against PCSK9 have emerged as an alternative method to lower LDL-c, which require substantial less injections than therapy with PCSK9 monoclonal antibodies. The siRNA-therapeutic inclisiran reduces hepatic PCSK9 production resulting in reduced circulating PCSK9 levels [1-2]. Twice-yearly administration of inclisiran from second dose onwards was studied up to 18 months in the ORION-9, ORION-10, and ORION-11 trials [3-5].
Aim of the study
The authors investigated the long-term efficacy and safety of twice-yearly inclisiran in patients with high CV risk and elevated LDL-c.
ORION-3 was a 4-year open label extension study of the 1-year, phase 2 ORION-1-trial. ORION-1 was a multicenter, double-blind, placebo-controlled, dose-finding study with subcutaneous injections of inclisiran in patients at high risk of ASCVD or high-risk primary prevention and elevated LDL-c concentrations despite maximally tolerated statins or other LDL-lowering therapies, or with documented statin intolerance . Patients that were treated with inclisiran in ORION-1 received twice-yearly 300 mg subcutaneous inclisiran sodium throughout ORION-3 (inclisiran-only arm, n=290), whereas patients in the placebo group in ORION-1 first started with subcutaneous evolocumab 140 mg every 2 weeks until day 360 and thereafter transitioned to subcutaneous 300 mg inclisiran sodium subcutaneously twice-yearly for the remainder of ORION-3 (switching arm, n=92). Inclisiran was administrated by a health care professional, whereas evolocumab was self-administered. 233 patients in the inclisiran-only arm and 80 patients in the switching arm completed the full 4-year study period.
The primary endpoint was the percentage change in LDL-c from baseline of ORION-1 to day 210 of ORION-3 in the inclisiran-only arm (total observational period of approximately 570 days after first inclisiran exposure). Secondary endpoints were changes in LDL-c and PCSK9 levels over 4 years in each arm, and long-term safety and tolerability.
- In the inclisiran-only arm, LDL-c levels were significantly reduced at day 210 compared to the baseline (reduction of 47.5%; 95%CI: 50.7 to 44.3; P<0.0001).
- These reductions in LDL-c levels were maintained throughout the study period (changes in LDL-c levels varied between -34.3% to -53.8%; overall 4-year time-averaged reduction of 44.2% with 9 injections).
- The levels of non-HDL-c and apoB were reduced throughout the study period in the inclisiran-only arm (changes varied between -41.7% and -30.0%, and -40.4% and -26.5%, respectively).
- LDL-c concentrations of 2.6 mmol/L were achieved in most patients (93%). 79% of patients achieved LDL-c concentrations of <1.8 mmol/L and 63% of patients achieved LDL-c concentrations of <1.3 mmol/L.
- In the switching arm, evolocumab reduced LDL-c levels by 47.8% to 65.7%, with a time-averaged reduction of 61.0% (95%CI: -64.5 to -57.4) through 25 injections. After switching, the time-averaged 3-year reduction in LDL-c by inclisiran was 45.3% (95%CI: -49.7 to -40.9) through 7 injections.
- Treatment-emergent adverse events possibly related to study medication occurred in 28% of patients in the inclisiran-only arm and in 25% of patients in the switching arm. These adverse events were mostly related to the drug administration. An increase in hepatic enzymes that was possibly related to study medication was detected in 3 patients (3%) in the switching arm.
- Treatment-emergent serious adverse events possibly related to study medication were reported in 3 patients (1%) in the inclisiran-only arm and in 1 patient (1%) in the switching arm. This included an exacerbated tachycardia; acute cholecystitis in a patient with gallstones; hepatic fibrosis in a patient with fatty liver disease; and an increase in ALT and AST in a patient with hepatitis C and high alcohol intake.
- 10% of patients in the inclisiran-only arm experienced a hepatic event, whereas 9% of patients in the switching arm experienced such an event.
This study demonstrates that twice-yearly administration of inclisiran is well tolerated in patients, and provided sustained reductions in LDL-c, non-HDL-c, and apoB over a period of 4 years. In contrast to LDL-c lowering with PCSK9 monoclonal antibodies, much less injections are needed with an siRNA therapeutic.