Inclisiran May Lower LDL-C Long-Term in ASCVD

Inclisiran twice annually is well tolerated and associated with a decrease in low-density lipoprotein cholesterol (LDL-C) in patients with atherosclerotic cardiovascular disease (ASCVD) for up to 4 years with no new safety signals, according to study results presented at the National Lipid Association (NLA) Scientific Sessions 2023, held in Atlanta, Georgia, between June 1 and June 4, 2023.

Researchers assessed the long-term efficacy and safety of twice-yearly subcutaneous (SC) inclisiran in patients aged 18 years or older with clinical ASCVD (or high-risk primary prevention) and increased LDL-C despite use of maximally tolerated statins or other oral lipid-lowering therapy. Patient data are from the ORION-3 (ClinicalTrials.gov Identifier: NCT03060577) trial, which is a long-term, open-label extension to the phase 2 ORION-1 study.

ORION-3 included 2 treatment arms, an inclisiran-only arm and a “switching” arm in which patients received SC evolocumab in year 1. The exploratory subgroup analysis only included data of patients with clinical ASCVD.

The primary endpoint in ORION-3 was the percentage change in LDL-C from baseline in ORION-1 to day 210 of ORION-3 (570 days of inclisiran exposure) in the inclisiran-only arm.

The analysis included 253 participants (mean age, 65.0 [SD, 9.3] years; 72.7% men) with clinical ASCVD. The inclisiran-only arm intention-to-treat (ITT) and modified ITT (mITT) populations included 190 and 181 participants, respectively, and the switching arm included 63 participants. A total of 206 patients completed the 4-year study (150 in the inclisiran-only arm and 56 in the switching arm).

The mean percentage decrease in LDL-C from baseline to day 210 in the inclisiran-only arm was 49.5% (95% CI, -53.0 to -45.9; P <.0001). The mean time-averaged decrease in LDL-C during the 4-year study period was 46.2% (95% CI, -49.8 to -42.6). For the switching arm, the time-averaged mean percentage decrease in LDL-C with evolocumab (year 1) was 63.0% (95% CI, -67.2 to -58.9), and for inclisiran (years 2-4) it was 45.2% (95% CI, -50.5 to -39.9).

In the inclisiran-only arm, about 83% of patients met LDL-C levels of less than 70 mg/dL at any point after day 1 of ORION-1, and 74.1% of patients achieved LDL-C levels of less than 55 mg/dL.

Patients in the inclisiran-only arm had a cumulative exposure to inclisiran (ORION-1 through ORION-3) of 794.3 patient-years. In the switching arm, cumulative exposure to inclisiran was 176.8 patient-years (ORION-3).

In the inclisiran-only arm (n=185), 96.2% of patients had 1 or more treatment-emergent adverse event vs 91.9% in the switching arm (n=62). In the inclisiran-only arm, 20.5% of patients had 1 or more drug-related treatment-emergent adverse event vs 29.0% in the switching arm.

Limitations of the study include the small population and potential selection bias owing to the voluntary enrollment of patients from ORION-1. Also, the study is not powered to provide formal efficacy comparisons between evolocumab and inclisiran.

“In this exploratory post-hoc analysis of ORION-3, including patients with clinical ASCVD and elevated LDL-C, twice-yearly health care professional-administered inclisiran provided consistent and effective long-term LDL-C lowering when added to maximally tolerated statins,” the researchers wrote.

Disclosure: This investigation was sponsored by Novartis Pharmaceuticals Corporation. Some of the study authors declared affiliations with biotech, pharmaceutical, and/or device companies. Please see the original reference for a full list of authors’ disclosures.