BACKGROUND

Inclisiran inhibits hepatic synthesis of proprotein convertase subtilisin–kexin type 

9. Previous studies suggest that inclisiran might provide sustained reductions in

low-density lipoprotein (LDL) cholesterol levels with infrequent dosing.

METHODS

We enrolled patients with atherosclerotic cardiovascular disease (ORION-10 trial) 

and patients with atherosclerotic cardiovascular disease or an atherosclerotic car-

diovascular disease risk equivalent (ORION-11 trial) who had elevated LDL choles-

terol levels despite receiving statin therapy at the maximum tolerated dose. Patients 

were randomly assigned in a 1:1 ratio to receive either inclisiran (284 mg) or pla-

cebo, administered by subcutaneous injection on day 1, day 90, and every 6 months 

thereafter over a period of 540 days. The coprimary end points in each trial were 

the placebo-corrected percentage change in LDL cholesterol level from baseline to 

day 510 and the time-adjusted percentage change in LDL cholesterol level from 

baseline after day 90 and up to day 540.

RESULTS

A total of 1561 and 1617 patients underwent randomization in the ORION-10 and 

ORION-11 trials, respectively. Mean (±SD) LDL cholesterol levels at baseline were 

104.7±38.3 mg per deciliter (2.71±0.99 mmol per liter) and 105.5±39.1 mg per 

deciliter (2.73±1.01 mmol per liter), respectively. At day 510, inclisiran reduced LDL 

cholesterol levels by 52.3% (95% confidence interval [CI], 48.8 to 55.7) in the 

ORION-10 trial and by 49.9% (95% CI, 46.6 to 53.1) in the ORION-11 trial, with 

corresponding time-adjusted reductions of 53.8% (95% CI, 51.3 to 56.2) and 49.2% 

(95% CI, 46.8 to 51.6) (P<0.001 for all comparisons vs. placebo). Adverse events 

were generally similar in the inclisiran and placebo groups in each trial, although 

injection-site adverse events were more frequent with inclisiran than with placebo 

(2.6% vs. 0.9% in the ORION-10 trial and 4.7% vs. 0.5% in the ORION-11 trial); 

such reactions were generally mild, and none were severe or persistent.

CONCLUSIONS

Reductions in LDL cholesterol levels of approximately 50% were obtained with 

inclisiran, administered subcutaneously every 6 months. More injection-site adverse 

events occurred with inclisiran than with placebo. (Funded by the Medicines 

Company; ORION-10 and ORION-11 ClinicalTrials.gov numbers, NCT03399370 

and NCT03400800.)