Sustained LDL-c lowering with PCSK9 siRNA up to 4 years

Long-term efficacy and safety of inclisiran in patients with high cardiovascular risk and elevated low-density lipoprotein cholesterol (ORION-3): Results from the 4-year open-label extension of the ORION-1 trial

Presented at the AHA Scientific Sessions 2022 by: Prof. Kausik Ray, MD - London, UK

Introduction and methods

Inclisiran is an siRNA therapeutic that inhibits the translation of PCSK9 mRNA in hepatocytes leading to reduction in circulating PCSK9 levels. Three large phase 3 trials with inclisiran have previously shown that a dosing interval at day 1, 90 and 6-monthly thereafter over 18 months reduced placebo-corrected LDL-c levels by 52%. It is however unknown whether twice-yearly dosing of inclisiran results in sustained lowering of LDL-c beyond 18 months, and whether repeated exposes to a siRNA-based approach by inclisiran has additional safety concerns.

The objective of the ORION-3 study was to assess the 4-year long-term efficacy and safety of inclisiran twice a year in patients with high CV risk and elevated LDL-c (despite maximally-tolerated LLT).

The study population was the population of patients who completed the ORION-1 trial. Patients ≥18 years of age with established ASCVD or ASCVD risk equivalent (high-risk primary prevention). 317 Patients who had been on inclisiran (either single or double dose) in ORION-1 were invited to participate in the open-label extension study; 290 patients were enrolled. The 127 patients in the ORION-1 study who had not been exposed to inclisiran were invited to participate, first in the switching arm – evolocumab every 2 weeks for 1 year- and then transitioning to the inclisiran arm in 2 ways -either sequential, where the last dose of evolocumab was 24 days earlier or at the same time at day 360; a total of 92 patients were enrolled.

The primary endpoint was percentage change in LDL-c from baseline of ORION-1 to day 210 of ORION-3 for the inclisiran-only arm.

Main results

Efficacy outcomes

• The mean percentage LDL-c reduction in the inclisiran-only arm at day 210 was 47.5% (95%CI: 44.3 to 50.7, P<0.0001). At year 2, 3 and 4, mean percentage LDL-c reduction were 44.5%, 49.4% and 45.4% respectively resulting in a time-averaged mean percentage reduction of 44.2% with ~8 injections of inclisiran.
• Mean percentage change in PCSK9 levels from ORION-1 baseline ranged between -62.2% to -77.8%.
• 79.2% Of patients reached LDL-c levels <70 mg/dL.
• In addition, non-HDL-c and apoB levels were reduced, with peak reductions of 42% and 37% respectively.

Exploratory analyses

• In the switching arm, time-average mean percentage reduction in LDL-c from ORION-3 baseline after switching to inclisiran to day 1440 (4 years) was 45.3%.

Safety outcomes

• There were no new surprising safety findings; the most common treatment adverse events observed were injection site reactions.

Conclusion

Over 4 years, twice-yearly dosing of inclisiran resulted in effective and sustained reductions in LDL-c by 44.2% from ORION-1 baseline.

Prof. Ray concluded that this study suggests that the siRNA-based therapy of inclisiran with a twice-yearly dosing schedule has a favorable safety and efficacy profile for long-term control of LDL-c levels.

- Our reporting is based on the information provided at the AHA Scientific Sessions 2022 -