Long-term efficacy and tolerability of inclisiran sustained in ORION-8, the 3-year OLE study, among patients with high CV risk

17 Nov 2023


Inclisiran is a small interfering ribonucleic acid (siRNA) therapeutic, which offers a 52% reduction in low-density lipoprotein cholesterol (LDL-C) after only 18 months of treatment among patients with high cardiovascular (CV) risks.1 Previous phase 3 studies such as ORION-9, ORION-10, and ORION-11 had already established the efficacy and safety of the drug but data on its long-term use was only investigated in the phase 2 open-label extension (OLE) study ORION-3.1 Therefore, much of inclisiran’s extended effect remains unexplored in the clinical setting. At the ESC 2023 Congress,  Dr. Scott R. Wright presented the results of ORION-8, a 3-year OLE to a pooled population of multiple phase 2 and phase 3 trials.1

The ORION-8 study assessed the long-term efficacy and tolerability of inclisiran in patients with atherosclerotic cardiovascular disease (ASCVD) or ASCVD risk equivalent as defined by being in the high-risk primary prevention category.1 The study incorporated patients from the ORION-3, ORION-9, ORION-10, and ORION-11 trials, enrolling a total of 3,274 patients with 82.7% of them having established ASCVD and the rest being ASCVD risk equivalent.¹ During the 3-year study period, patients received inclisiran injections twice a year, resulting in a cumulative inclisiran exposure of 12,109.3 patient-years.1 The primary endpoints for this OLE included the proportion of patients achieving pre-specified LDL-C goals (ASCVD: <1.8mmol/L; ASCVD risk equivalent: <2.6mmol/L) at the end of study and safety.¹ The percentage change in LDL-C from baseline to the end of study served as the secondary endpoint.1


Primary endpoint:
  • The primary endpoint was the proportion of patients achieving pre-specified LDL-C goals after 3 years of inclisiran treatment1
  • 78.4% of patients had achieved their pre-specified LDL-C goals at the end of study1
  • Among patients with established ASCVD (n=2,205), 79.4% of patients had achieved an LDL-C goal of <1.8mmol/L (<70mg/dL)1
  • Similarly, in the ASCVD risk equivalent cohort (n=526), 74.3% of patients achieved an LDL-C goal of <2.6mmol/L (<100mg/dL)1
Secondary endpoints:
  • The secondary endpoint was the percentage change in LDL-C between baseline and trial periods until the end of study1
  • A 49.4% overall reduction in mean LDL-C levels from baseline was reported at the end of study1
  • The ASCVD cohort attained a 51% (95% CI: -52.2 to -49.9%) reduction in LDL-C from baseline, while a 42.4% (95% CI: -45.0 to -39.9%) reduction in LDL-C was reached for the ASCVD risk equivalent cohort1
  • Overall, the safety profile of inclisiran was tolerable and similar to previous studies1
  • Among the safety population (n=3,274), 77.8% of patients experienced ≥1 adverse events (AE), of which only 9.1% of AEs were inclisiran-related1
  • 30.2% of patients experienced severe AEs (SAEs), with a discontinuation rate of 2.4% and a 5.0% fatal SAE1
  • 5.1% of patients exhibited inclisiran-associated anti-drug antibody (ADA) response with 1.7% of patients exhibiting persistent ADA response. Regardless, the impact of ADA response on the overall efficacy or safety of inclisiran was negligible1


"ORION-8 provides additional evidence to support the  long-term efficacy and tolerability of inclisiran in patients  with high CV risk and elevated LDL-C."

Dr. Scott R. Wright 
Mayo Clinic, 
Rochester, Minnesota, United States

Get access to our exclusive articles.