Interim data from the ORION-1 trial suggest inclisiran is both efficacious and safe. These positive interim results should support the further development of inclisiran as a treatment for dyslipidemia. Inclisiran offers patients a more convenient dosing schedule that may allow it to compete with marketed PCSK9 inhibitors when approved.
Interim results from the Phase II ORION-1 trial suggest that the novel proprotein convertase subtilisin/kexin type 9 (PCSK9) synthesis inhibitor is both safe and efficacious. Inclisiran (The Medicines Company/Alnylam Pharmaceuticals/Arbutus Biopharma) is a systemically delivered RNAi therapeutic that inhibits the production of PCSK9. RNAi therapies are a novel class of compounds designed to provide therapeutic benefits by inhibiting the translation of specific proteins. The positive results from this trial should encourage further investigation of this therapeutic approach.
Inclisiran significantly reduced elevated low-density lipoprotein cholesterol (LDL-C) levels in dyslipidemia patients from baseline and met the trial’s primary endpoint. A single 300mg dose of the medication at the beginning of the trial was found to reduce LDL-C levels at day 180 by 43% on average as compared to the patient’s baseline. This reduction in LDL-C was found to be significantly more than the reduction observed in the placebo arm. Additionally, the medication was well tolerated as there were no associated material safety issues.
The ORION-1 trial is a double-blind, placebo-controlled, randomized Phase II study. A total of 501 patients with atherosclerotic cardiovascular disease (ASCVD) or ASCVD-risk equivalents (diabetes and familial hypercholesterolemia) and elevated LDL-C levels, despite taking the maximum tolerated doses of LDL-C-lowering therapies, were enrolled in the trial. Inclisiran (or placebo) was administered in addition to maximum tolerated doses of statin, which the patients were receiving at baseline. The interim analysis presented at the conference was based on data from 189 patients followed for 180 days, while final data collection from the trial is scheduled to be completed by the end of Q4 2016.
It is likely inclisiran will gain approval if the drug demonstrates similar efficacy in its Phase III trial. Once on the market, its convenient dosing schedule may allow the medication to compete with the marketed PCSK9 inhibitors Repatha (evolocumab; Amgen/Astellas) and Praluent (alirocumab; Sanofi/Regeneron) for market share. At the American Heart Association Scientific Session, Dr Ray commented that the Phase III study of inclisiran will likely investigate a 300mg dose of the drug administered two or three times a year. This dosing schedule would put it at a significant advantage compared with Repatha and Praluent, which are administered via subcutaneous injection once weekly or monthly. This dosing advantage would likely lead to especially strong uptake in elderly patients, where it has been shown that repetitive injections can damage and kill blood vessels.