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.

Novartis acquires The Medicines Company

Deal announced: 24 Nov 2019

Deal value: $9.7 billion

Deal background:

• At the time of the deal, The Medicines Company was developing drugs for cardiovascular disease. Its lead candidate, developed in partnership with Alnylam, was the siRNA-based drug inclisiran, for which phase 3 trial data in patients with atherosclerotic cardiovascular disease (ASCVD) and familial hypercholesterolemia (FH) had shown that it could reduce levels of low-density lipoprotein cholesterol (LDL-C)

• Inclisiran acts by inhibiting the production of the lipid-modulating protein PCSK9, for which there is human genetic evidence that loss-of-function mutations are protective against cardiovascular disease. Two monoclonal antibody therapeutics targeting PCSK9, Amgen's evolocumab and Regeneron/Sanofi's alirocumab, were approved by the FDA in 2015

• Inclisiran was approved by the FDA for patients with ASCVD or heterozygous FH who require additional lowering of LDL-C in December 2021

Novo Nordisk acquires Dicerna Pharmaceuticals

Deal announced: 21 Nov 2021

Deal value: $3.3 billion

Deal background:

• Dicerna Pharmaceuticals focuses on siRNA-based therapeutics, and has developed proprietary platforms that can enable specific targeting to the liver (GalXC) and also to other tissues (GalXC-Plus)

• Novo Nordisk entered a research collaboration with Dicerna Pharmaceuticals in 2019 to discover and develop siRNA-based therapeutics using Dicerna’s GalXC platform, involving an upfront payment of $175 million, an equity investment of $50 million and potential milestones of up to $357.5 million per target

• This collaboration set out to develop therapeutics for cardio-metabolic diseases such as non-alcoholic steatohepatitis, obesity and type 2 diabetes

• At the time it announced the acquisition of Dicerna Pharmaceuticals in 2021, Novo Nordisk expected to initiate clinical development of the first investigational drug from this collaboration in 2022

GlaxoSmithKline (GSK) partners with Arrowhead Pharmaceuticals to develop ARO-HSD for NASH

Deal announced: 22 Nov 2021

Deal value: Arrowhead Pharmaceuticals will receive $120 million upfront and up to $910 million in potential milestones

Deal background:

• Arrowhead Pharmaceuticals is developing a pipeline of siRNA-based therapeutics for various diseases based on its portfolio of RNA chemistries and delivery modes

• The pipeline includes ARO-HSD, which was in a phase 1/2 trial as a potential treatment for patients with liver diseases such as non-alcoholic steatohepatitis (NASH) at the time the deal with GSK was announced

• ARO-HSD inhibits the hepatic production of HSD17B13, an enzyme in the hydroxysteroid dehydrogenase family for which there is human genetic evidence that a loss-of-function mutation could be protective against the development of diseases such as NASH

• Through the deal, GSK will exclusively develop and commercialize ARO-HSD in in all territories except Greater China