CONFERENCE UPDATE: ESC 2023

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

CARDIOLOGY
17 Nov 2023

STUDY DESIGN

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

FINDINGS

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
Safety:
  • 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.
Related Articles

Long-term safety of inclisiran among high-risk CVS patients demonstrated in a pooled safety analysis

Inclisiran is a first-in-class small interfering ribonucleic acid (siRNA) targeting hepatic proprotein convertase subtilisin/kexin type 9 (PCSK9) and lowering low-density lipoprotein-cholesterol (LDL-C).1 Administered subcutaneously at a dose of 284mg initially, at 3 months, and every 6 months there
CARDIOLOGY
17 Apr 2023

A local case sharing: earlier evolocumab for better long-term outcomes in patients with established ASCVD

Atherosclerotic cardiovascular disease (ASCVD) continuesto be a leading cause of morbidity and mortality worldwide,with over 17.9 million people dying from cardiovascular (CV)diseases annually.1,2 Given the fact that the recurrent riskis high among patients with established ASCVD, secondarypreventio
CARDIOLOGY
09 Feb 2023