In patients with atherosclerotic cardiovascular disease (ASCVD) or ASCVD risk equivalents and elevated LDL-C despite maximum tolerated dose of statins, the addition of subcutaneous inclisiran was associated with a substantial reduction in LDL-C at 18 months, according to findings from the Phase 3 ORION-11 study presented by Kausik Kumar Ray, MD, FACC, Sept. 2 at ESC Congress 2019. 

Using a dosing schedule to evaluate a twice yearly maintenance program, participants were randomized to subcutaneous inclisiran sodium 300 mg (n=810) or placebo (n=807) administered at Day 1, Day 90 and then every six months (Day 270 and Day 450). Inclisiran is a small interfering RNA (siRNA) targeting PCSK9.

Among the 1,617 participants (median age, 65 years; 28 percent women) from seven countries randomized into the study, most had established ASCVD (87 percent). Of the participants who had an ASCVD risk equivalent (12 percent of population), 7 percent had a 10-year ASCVD risk >20 percent and 1.7 percent had heterozygous familial hypercholesterolemia. The mean baseline LDL-C was 107 mg/dL in the intervention arm and 104 mg/dL in the placebo arm.  Most patients (95 percent) were on a high-intensity statin about 6 percent and 8 percent of the intervention and placebo arms were on ezetimibe.

Results showed that for the primary endpoint of percent change in LDL-C from baseline to Day 510 there was a 49 percent reduction with inclisiran and a 4 percent increase with placebo, for a 54 percent between-group difference (p<0.00001). For the other primary endpoint of time-averaged percent change in LDL-C from Day 90 to Day 540, the between-group difference was 50 percent (p<0.00001).

The safety profile of inclisiran was similar with placebo, with a similar rate of treatment-emergent adverse and serious events in both groups. Injection-site adverse events were higher with inclisiran (38 vs. 4 with placebo) but most were mild and none were persistent. No differences were seen between the groups for treatment-related liver function, kidney function, muscle discomfort or platelet toxicity.

Looking at adverse cardiovascular events in an exploratory endpoint analysis, 63 patients (7.8 percent) in the inclisiran group vs. 83 patients (10.3 percent) in the placebo group experienced a prespecified cardiovascular endpoint. In the inclisiran and placebo groups, respectively, the rate of cardiovascular death was similar (1.1 percent and 1.2 percent), but the rate of fatal or nonfatal myocardial infarction and stroke was lower (1.5 percent vs. 3.7 percent) and this was primarily driven by a lower rate of fatal or nonfatal myocardial infarction (1.2 percent vs. 2.7 percent).

An open-label extension study of patients who have completed Phase 3 studies in the ORION program will eventually provide more data on the longer-term safety of inclisiran.

Keywords: ESC 19, ESC Congress, RNA, Small Interfering, Hyperlipoproteinemia Type II, Maximum Tolerated Dose, Blood Platelets, Sodium, Atherosclerosis, Myocardial Infarction, Stroke, Myalgia, Liver

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