The European Union has approved a small interfering RNA (siRNA)-based drug for reducing low-density lipoprotein cholesterol (LDL-cholesterol) in patients with abnormally high blood cholesterol. The go-ahead for Leqvio (inclisiran), announced on 11 December, is an important milestone for Novartis, of Basel, Switzerland, as it attempts to recoup some of the $9.7 billion it spent in acquiring the drug’s developer, The Medicines Company. Leqvio, an N-acetylgalactosamine-conjugated 2′-O-methyl, 2′-H-phosphorothioate oligonucleotide, prevents the mRNA encoding the liver enzyme PCSK9 from being translated into protein. PCSK9, short for proprotein convertase subtilisin/kexin type 9, maintains LDL-cholesterol in circulation by preventing LDL receptors from returning to the plasma membrane after they have bound and internalized an LDL-cholesterol molecule. By targeting and reducing PCSK9, Leqvio boosts such recycling, which encourages further cholesterol uptake from circulation. Two antibody PCSK9 inhibitors have already reached the market: Repatha (evolocumab), marketed by Amgen, and Praluent (alirocumab), from Regeneron Pharmaceuticals. Leqvio has a similar effect to both — it cuts LDL-cholesterol by about 50% — but market observers expect it to dominate because of its small-molecule-like manufacturing costs and its more convenient dosing schedule: Leqvio requires a twice-yearly subcutaneous injection, whereas each of the antibodies requires systemic dosing at either two-week or four-week intervals. Neither antibody has, so far, realized the blockbuster ambitions their developers had attached to them, but Novartis CEO Vas Narasimhan has said that Leqvio could become one of the pharma’s best-selling products. A US approval has been delayed, however, because the FDA has yet to decide whether it will inspect a manufacturing facility in Italy. And it will take several more years before a fuller understanding of the clinical value of Leqvio emerges. A cardiovascular outcomes study, which will evaluate the effect of the drug in reducing death or cardiovascular events, such as heart attack or stroke, will report in 2024.
This is a preview of subscription content, access via your institution