Physicians' Academy for Cardiovascular Education

Long-term efficacy and safety data of PCSK9 siRNA in patients with high CV risk and elevated LDL-c

News - Sep. 4, 2023

ORION-8: Long-term efficacy and safety of twice-yearly inclisiran in high cardiovascular risk patients

Presented at the ESC Congress 2023 by: R. Scott Wright, MD - Rochester, MN, USA

Introduction and methods

Inclisiran is a siRNA therapeutic that targets PCSK9 synthesis and lowers LDL-c levels by approximately 52%. The ORION-3 trial demonstrated that LDL-c lowering with twice-yearly inclisiran after starting doses in patients with high CV risk is maintained over 4 years without any new safety signals. In large phase 3 trials of the ORION program, the efficacy and safety of inclisiran vs. placebo has been studied up to 18 months. The ORION-8 trial was a long-term extension with up to 3 years follow-up in high CV risk patients who participated in one of the three phase 3 studies or ORION-11 or in ORION-3. The aim of the study was to assess the long-term efficacy, safety and tolerability of inclisiran.

A total of 3275 patients were enrolled in ORION-8 (1513 patients were from the inclisiran group of ORION-9/10/11, 1478 patients were from the placebo group of ORION-9/10/11, and 284 patients were from the inclisiran group of ORION-3). Safety data was available for 3274 patients. A total of 2446 patients completed 3 years of treatment. Of the patients enrolled in ORION-8, 82.7% had established ASCVD, 17.3% had an ASCVD risk equivalent, and 33.7% had T2D. The mean (±SD) LDL-c was 2.92 (±1.20) mmol/L. The cumulative exposure of inclisiran was over 12,000 patients-years. The longest exposure was 6.84 years, and 25% of patients had an exposure of over 4.45 years.

The primary endpoints were: (1) the proportion of patients achieving pre-specified LDL-c goals at end of the study; (2) and safety. The prespecified lipid goals were <1.8 mmol/L (<70 mg/dL) for patients with ASCVD and <2.6 mmol/L (<100 mg/dL) for patients with ASCVD risk equivalent. The secondary endpoint was percent change in LDL-c from baseline to end of the study.

Main results

Efficacy outcomes

Safety outcomes


In the overall study population of ORION-8, 78.4% of patients on inclisiran achieved the pre-specified lipid goal at the end of the study, with a mean reduction in LDL-c of 49.4%. The safety profile of inclisiran in ORION-8 was similar to the previous studies of the ORION program. ‘’ORION-8 provides additional evidence to support the long-term efficacy, safety and tolerability of inclisiran in patients with high cardiovascular risk and elevated LDL-c’’, says R. Scott Wright.

- Our reporting is based on the information provided at the ESC Congress 2023 -

Watch a video with R. Scott Wright about this study

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