A randomized, double blind, placebo-controlled, phase II clinical trial studying the effect of a novel protein proprotein convertase subtilisin/kexin type 9 (PCSK9) synthesis inhibitor (inclisiran) on serum low density lipoprotein cholesterol (LDL-C) levels has shown that twice a year subcutaneous injections of inclisiran leads to a sustained dose-dependent reduction in serum LDL-C levels over a period of 1 year.
The results from 360 days follow-up of the trial led by Dr. Kausik K. Ray (Imperial Centre for Cardiovascular Disease Prevention, Department of Primary Care and Public Health, Imperial College London) were published in JAMA Cardiology in its September 2019 issue. The ORION-1 trial enrolled 501 participants (65% men) with a history of atherosclerotic cardiovascular disease (ASCVD) with LDL-C greater than 70 mg/dL with a baseline of 128 mg/dl. Patients with ASCVD risk equivalents such as type II diabetes or familial hypercholesterolemia (6%) with LDL-C greater than 100 mg/dl were also included in the study. Patients were randomized to either receive a single dose of 200 mg, 300 mg or 500 mg of inclisiran at day 1 and compared to normal saline administration as placebo; the other assignment strategy randomized participants to either receive 2 doses of inclisiran sodium, 100 mg, 200 mg or 300 mg, or placebo on day 1 and day 90. The primary efficacy end point was the change in LDL-C levels from baseline to day 180 reported as a percentage. In order to study the sustained effect of various doses of inclisiran on LDL reductions, participants whose LDL-C had not returned to within 20% of their change from baseline had additional monthly follow-up visits until this level had been reached up to a maximum of 360 days (48.3% to 65% participants for single dose group and 55.9% to 83.1% for 2-dose group). The investigators found out that the single dose group achieved reductions in LDL-C levels ranging from 29.5% to 38.7% at day 360 (p < 0.001), while the 2-dose group achieved reductions in LDL-C that ranged from 29.9% to 46.4% at day 360 (p < 0.001). Furthermore, the largest reductions in LDL-C were found with the 2-dose regimen using 300 mg of inclisiran. The investigators also collected data concerning the reductions in serum PCSK9 levels (mean 428 ng/ml) subsequent to inclisiran dosing. The mean reduction in PCSK9 levels over 1 year ranged from 44.5% to 55.9% with a single dose and from 43.1% to 60.5% with 2 doses of inclisiran. According to the authors, this reduction in PCSK9 translated into significant reductions in LDL-C levels of participants.
Interestingly, inclisiran, which is designed as a small interfering RNA inhibiting the synthesis of PCSK9, was able to persistently reduce serum LDL-C levels despite an infrequent dosing schedule (twice a year subcutaneous injections). This is in contrast to other PCSK9 inhibitors such as monoclonal antibodies e.g. alirocumab and evolocumab which require 12 to 26 injections annually in order to maintain LDL-C lowering effect. These robust data underscore the selection of a six monthly maintenance dose of 300 mg in Phase III trials (ORION-9, ORION-10, ORION-11), which are now in advanced stages of preparation. The Phase III LDL-C lowering trials in 3,500 patients, which are designed to form the basis for inclisiran approval in the United States and Europe, are expected to test the starting dose of 300 mg given on Day-1 and Day-90, followed by a maintenance dose of 300 mg given every six months for up to 18 months.
The 360-day follow-up results of the ORION-1 trial has some limitations, the first being that the placebo group was followed till day 210, therefore a direct comparison to the placebo group at day 360 was not possible. Secondly, patients who had their LDL-C levels return to within 20% of their baseline were not followed beyond day 210, which decreases the number of participants in the analysis.