RNAi scores big wins

    November was a big month for Alnylam Pharmaceuticals’ siRNA platform. On November 20, Alnylam gained FDA approval for Givlaari (givosiran), an aminolevulinate synthase inhibitor, for treating adults with acute hepatic porphyria. Four days later, Novartis swooped on The Medicines Company with a $9.7 billion buyout offer, prompted by the progress of inclisiran, an siRNA-based inhibitor of proprotein convertase subtilisin/kexin type 9 (PCSK9), which The Medicines Company developed under license from Alnylam. Taken together, the two drugs are further evidence of the rapid maturation of the siRNA modality, which Alnylam has pioneered. With the cholesterol-lowering inclisiran, Novartis thinks it has a blockbuster drug on its hands, based on its estimate of 50 million patients in the main Western markets with excessively high low-density lipoprotein cholesterol (LDL-C) levels despite being on current standard-of-care medications. Novartis has remained tight-lipped about pricing, but to gain widespread adoption inclisiran will need to cost far lower than the two approved antibody-based PCSK9 inhibitors, Sanofi/Regeneron’s Praluent (alirocumab) and Amgen’s Repatha (evolocumab). Novartis has plenty of scope to undercut its rivals, given inclisiran’s low and infrequent dose schedule, its small-molecule-like production costs and its lack of cold-chain distribution or storage requirements. FDA approval is expected in late 2020. The economics of Givlaari are radically different from those of inclisiran, as it addresses a patient population of about 3,000 people in the United States and Europe. After discounts, it will cost about $442,000 on an annual basis, but only if it delivers the same benefits observed in clinical trials, in which it reduced porphyria attacks by an average of 70% as compared with placebo. Givlaari represents Alnylam’s second drug approval, after Onpattro (patisiran) for treating hereditary transthyretin-mediated amyloidosis in August 2018. Significantly, both Givlaari and inclisiran employ N-acetylgalactosamine conjugation, a highly efficient liver-targeting delivery system. Targeting siRNA drugs to other organs remains a work in progress.

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    RNAi scores big wins. Nat Biotechnol 38, 4 (2020). https://doi.org/10.1038/s41587-019-0384-8

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