ORION-4 Trial of siRNA Inclisiran

Inclisiran is a small interfering RNA (siRNA), which inhibit the production of PCSK9 in the liver. Unlike PCSK9 inhibitors which require monthly or biweekly injections, Inclisiran need be given only once in 6 months as a subcutaneous injection. It is capable of reducing LDL cholesterol by 50% in those receiving maximal LDL-C lowering therapy. ORION-3 was an open-label extension study of phase 2 ORION-1 trial for a period of 4 years. It showed sustained reductions in LDL cholesterol and PCSK9 concentrations and was well tolerated [1]. ORION-4 Trial of Inclisiran has recruited 16,124 patients from the United Kingdom and United States of America. It is a placebo controlled randomized controlled trial and participants are asked to remain in the study for five years. Recruitment was completed by 30 September 2023.

As per the information available at ClinicalTrials.gov, the inclusion criteria were history or evidence of at least one of prior myocardial infarction, prior ischemic stroke or peripheral artery disease as evident by prior lower extremity artery revascularization or aortic aneurysm repair. Minimum age was 40 years for males and 55 years for females. There was a large list of exclusion criteria like acute coronary syndrome within the past 4 weeks, coronary revascularization procedure planned within next 6 months, known liver disease, current or planned renal dialysis or transplantation. According to a TCTMD news item, ORION-4 is expected to be completed in 2026.

Reference

1. Ray KK, Troquay RPT, Visseren FLJ, Leiter LA, Scott Wright R, Vikarunnessa S, Talloczy Z, Zang X, Maheux P, Lesogor A, Landmesser U. Long-term efficacy and safety of inclisiran in patients with high cardiovascular risk and elevated LDL cholesterol (ORION-3): results from the 4-year open-label extension of the ORION-1 trial. Lancet Diabetes Endocrinol. 2023 Feb;11(2):109-119. doi: 10.1016/S2213-8587(22)00353-9. Epub 2023 Jan 5. PMID: 36620965.