Pharma industry interest in therapeutics that harness RNA interference (RNAi) is on the up again. Following the first report of small interfering RNAs (siRNAs) that exploit this endogenous gene silencing mechanism to reduce the levels of target proteins in human cells two decades ago, major companies invested heavily in the technology platform. But setbacks related in particular to delivery issues led to the retreat of most of these companies from the area between 2010 and 2015.
Persistence from pioneer companies in the field kept it alive (Nat. Rev. Drug Discov. 21, 12–13; 20221). One of these, Alnylam, was rewarded with the first approval of an siRNA-based drug—patisiran for hereditary transthyretin-mediated amyloidosis—by the US Food and Drug Administration (FDA) in 2018. Since then, a string of pharma companies have re-entered the field through partnerships and acquisitions, including some focusing on cardiovascular and metabolic disease indications (see deal snapshots).
Novartis was at the front of the pack, with its $9.7 billion acquisition of The Medicines Company and its siRNA-based phase 3 candidate inclisiran in 2019. Inclisiran targets PCSK9, an exemplar of a genetically validated target: loss-of-function mutations in humans reduce levels of low-density lipoprotein cholesterol (LDL-C) and protect against heart disease. Its investment came to fruition when inclisiran gained FDA approval in 2021 to lower levels of LDL-C in patients with atherosclerotic cardiovascular disease and heterozygous familial hypercholesterolemia.
Other large companies have also joined in. Novo Nordisk announced its $3.3 billion purchase of Dicerna Pharmaceuticals in 2021, building on a 2019 deal to develop siRNA-based drugs for diseases such as non-alcoholic steatohepatitis (NASH). And soon after, GlaxoSmithKline inked a deal potentially worth more than $1 billion with Arrowhead Pharmaceuticals to develop its siRNA-based therapy ARO-HSD, a phase 2/3 candidate for NASH.