Two Phase 3 Trials of Inclisiran in Patients with Elevated LDL Cholesterol

Abstract

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 cardiovascular disease risk equivalent (ORION-11 trial) who had elevated LDL cholesterol 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 placebo, 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.

<p>Cardiovascular Outcomes and Proprotein Convertase Subtilisin/Kexin Type 9 Inhibitors: Current Data and Future Prospects</p>

“…The safety profile of inclisiran was similar to that of placebo, with no treatmentrelated liver or renal abnormalities, 105,106 although generally mild injection-site adverse events were more frequent with inclisiran than with placebo. 106 The ongoing large (n=15,000 planned) ORION-4 trial in patients with pre-existing ASCVD will determine whether the marked LDL-C reductions shown in these trials will translate to a reduction in CV disease risk (Table 1) (NCT03705234). Primary results from this study, which commenced in October 2018, are expected in December 2024.…”

“…104 A phase 3 program of three placebo-controlled trials of subcutaneous inclisiran injections dosed twice yearly on background maximum tolerated statin therapy, ORION-9 (NCT03397121), ORION-10 (NCT03399370), and ORION-11 (NCT03400800), was completed late in 2019, and regulatory submission was filed with the United States Food and Drug Administration. In patients with heterozygous familial hypercholesterolemia (ORION-9 105 ), ASCVD (ORION-10 106 ), and ASCVD or ASCVD risk equivalents (ORION-11 106 ), compared with placebo, inclisiran significantly reduced LDL-C up to 17 months by 48%, 54%, and 49%, respectively (p<0.001 for all). The safety profile of inclisiran was similar to that of placebo, with no treatmentrelated liver or renal abnormalities, 105,106 although generally mild injection-site adverse events were more frequent with inclisiran than with placebo.…”

“…In patients with heterozygous familial hypercholesterolemia (ORION-9 105 ), ASCVD (ORION-10 106 ), and ASCVD or ASCVD risk equivalents (ORION-11 106 ), compared with placebo, inclisiran significantly reduced LDL-C up to 17 months by 48%, 54%, and 49%, respectively (p<0.001 for all). The safety profile of inclisiran was similar to that of placebo, with no treatmentrelated liver or renal abnormalities, 105,106 although generally mild injection-site adverse events were more frequent with inclisiran than with placebo. 106 The ongoing large (n=15,000 planned) ORION-4 trial in patients with pre-existing ASCVD will determine whether the marked LDL-C reductions shown in these trials will translate to a reduction in CV disease risk (Table 1) (NCT03705234).…”

PCSK9 Variants in Familial Hypercholesterolemia: A Comprehensive Synopsis

“…Compared with the placebo group, the Inclisiran group had no serious adverse reactions. In the subsequent phase III clinical study of Inclisiran, compared with placebo, LDL-C in Inclisiran group was significantly reduced, with the efficacy able to last for more than 18 months ( Raal et al, 2020 ; Ray et al, 2020 ). The introduction of PCSK9 inhibitors is a milestone in the treatment of FH, and Inclisiran provides a new lipid-lowering technology.…”

Progress and prospects of biological approaches targeting PCSK9 for cholesterol-lowering, from molecular mechanism to clinical efficacy

“…Phase III clinical trials, ORION-10 and ORION-11, enrolled 1561 and 1617 patients with atherosclerotic cardiovascular disease or with equivalent risk who had LDL-C level elevated despite receiving statin therapy. A regimen of inclisiran injections on day 1, day 90 and every six months reduced levels of LDL-C by 49.2% to 52.2% compared to placebo as the level was decreased mostly in all patients receiving Inclisiran [115]. However, the total number of any potential benefits on cardiovascular outcomes was too small to conclude, a question that will be tested in ongoing cardiovascular trials.…”