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

Area of Science:

• Cardiovascular Medicine
• Pharmacology

Background:

• Inclisiran targets hepatic synthesis of proprotein convertase subtilisin-kexin type 9 (PCSK9).
• Prior research indicated potential for sustained low-density lipoprotein (LDL) cholesterol reduction with infrequent inclisiran administration.

Purpose of the Study:

• To evaluate the efficacy and safety of inclisiran in patients with atherosclerotic cardiovascular disease (ASCVD) or equivalent risk.
• To assess LDL cholesterol reduction in patients with elevated levels despite maximally tolerated statin therapy.

Main Methods:

• Two randomized, placebo-controlled trials (ORION-10 and ORION-11) enrolled patients with elevated LDL cholesterol.
• Participants received subcutaneous inclisiran (284 mg) or placebo on day 1, day 90, and every 6 months for 540 days.
• Coprimary endpoints assessed placebo-corrected LDL cholesterol change from baseline to day 510 and time-adjusted change from day 90 to day 540.

Main Results:

• Inclisiran achieved significant LDL cholesterol reductions: 52.3% in ORION-10 and 49.9% in ORION-11 at day 510.
• Time-adjusted reductions were 53.8% and 49.2%, respectively (P<0.001 vs. placebo).
• Adverse events were similar between groups, with more frequent, generally mild injection-site reactions in the inclisiran group.

Conclusions:

• Inclisiran demonstrated substantial LDL cholesterol lowering (approx. 50%) with a convenient every-6-month subcutaneous dosing regimen.
• The treatment was associated with a higher incidence of mild injection-site adverse events compared to placebo.