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

• In the overall study population, 78.4% of patients achieved the pre-specified lipid goals at the end of the study. The pre-specified lipid goal was achieved by 79.4% of patients with established ASCVD (n=2205), and by 74.3% of patients with ASCVD risk equivalent (n=526).
• The percent change in LDL-c from baseline to the end of the study was -49.4% across the whole study population. The degree in LDL-c lowering was consistent across whole duration of the study. The change in LDL-c was -51.0% (95%CI: -52.2 to -49.9) in patients with established ASCVD and -42.4% (95%CI: -45.0 to -39.9) in patients with ASCVD risk equivalent.

Safety outcomes

• 2548 patients (77.8%) had an adverse event. The most common adverse events were COVID-19 (n=453, 13.8%), inadequate control of DM (n=229, 7.0%), hypertension (n=22, 7.0%), and DM (n=206, 6.35%).
• 297 patients (9.1%) had an adverse events related to study drug, which included adverse events at injection site (n=176, 5.4%), hepatic event (n=11 patients, 0.3%), new onset of worsening of diabetes (n=37, 1.1%), and MACE (n=11, 0.3%).
• 989 patients (30.2%) had a serious adverse event. Serious adverse events with highest occurrence were CAD (n=64, 2.0%), COVID-19 (n=49, 1.5%), and acute MI (44 patients, 1.3%).
• 165 patients (5.0%) had a fatal serious adverse event.
• 80 patients (2.4%) had an adverse event leading to discontinuation of study treatment.
• During the follow-up period, 172 patients (5.1%) had detectable anti-drug antibodies, and 57 patients (1.7%) had persistent anti-drug antibodies response. However, the presence of anti-drug antibodies did not impact efficacy or safety of inclisiran.

Conclusion

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