ORION-1: PCSK9 Synthesis Inhibitor May Reduce LDL Cholesterol in High-Risk Patients
The results of ORION-1 support a phase 3 trial.
NEW ORLEANS — Subcutaneous injection inclisiran reduced LDL cholesterol levels in patients with or at high risk for atherosclerotic cardiovascular disease (ASCVD), according to results of a phase 2 clinical trial presented at the American Heart Association's Scientific Sessions 2016.
Kausik K. Ray, MD, MPhil, of Imperial College of London in the United Kingdom, presented the findings on behalf of the ORION-1 investigators. ORION-1 (ClinicalTrials.gov identifier: NCT02597127) is a phase 2 double-blind, randomized controlled trial comparing 6 different subcutaneous injection dosing regimens of a PCSK9 synthetic double-stranded oligonucleotide (inclisiran; The Medicines Company).
As Dr Ray explained, inclisiran is a PCSK9 synthesis inhibitor which acts via RNA interference and requires only 2 to 3 injections per year vs the anti-PCSK9 monoclonal antibodies which need 12 to 24 injections per year.
ORION-1's primary end point was the percentage change in LDL cholesterol and circulating PCSK9 levels at 180 days. Secondary end points included LDL cholesterol levels at 90 days and PCSK9 levels over time plus safety and tolerability.
A total of 501 patients were randomly assigned to 1 of 6 treatment arms (average age: 63 years; 48.1% with ASCVD; 14.2% with diabetes). More than 80% were taking statins at the study entry and 28.1% were on ezetimibe with a baseline LDL cholesterol of 128 mg/dL.
A mean 51% reduction in LDL cholesterol was seen in the group assigned to the 300-mg dose; a 57% reduction was seen in the group assigned to 2 doses of 300 mg. Additionally, side effects including elevated liver and muscle enzymes, myalgia, and injection site skin reactions were mild.
Dr Ray concluded that inclisiran's profile has the potential to ensure adherence and positively affect cardiovascular outcomes. These results should support a phase 3 clinical trial.
Disclosures: Dr Ray has received research grants from Sanofi, Regeneron, Pfizer, MSD as well as honoraria from Takeda, Boehringer Ingelheim, Cipla, and AstraZeneca, among others. Dr Ray also serves as a consultant for The Medicines Company, among others. Other investigators reported financial relationships with Amgen, Janssen, Pfizer, Sanofi, The Medicines Company, MSD, Merck, and Regeneron, among others.
- Ray KK, Landmesser U, Leiter LA, et al; on behalf of the ORION-1 Investigators. LBCT.03: Insights from new therapeutic trials for lipids. ORION-1. Inclisiran inhibits PCSK9 synthesis by RNA interference. Planned interim analysis of a multi-center randomized controlled dose-finding trial. Presented at: American Heart Association's Scientific Sessions 2016; November 12-16, 2016; New Orleans, LA.