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RNAi hits another rut

RNA interference (RNAi) company Alnylam Pharmaceuticals has discontinued one of its lead programmes, halting the development of phase III candidate revusiran due to an “imbalance of mortality”. The discontinuation was a blow to the trailblazing RNAi company, re-raising concerns in some quarters about the future of RNAi platforms.

Alnylam's revusiran is a modified oligonucleotide conjugate that silences transthyretin (TTR) mRNA via the RNA-induced silencing complex (RISC). It was in phase III trials for hereditary ATTR amyloidosis with cardiomyopathy, a rare and life-threatening disease that is caused by the accumulation of misfolded TTR. Following reports of worsening peripheral neuropathy with the drug, the company unblinded the safety data: it found no evidence of drug-related neuropathy, but did find an increased risk of mortality.

The jury is now out on whether RNAi toxicity might affect Alnylam's entire platform. But, after assessing the safety of its other lead compound, patisiran, the company has decided to keep trials of this drug ongoing. Patisiran also silences TTR mRNA, and is in phase III trials for ATTR amyloidosis with polyneuropathy. Before the revusiran setback, Alnylam planned to file patisiran for FDA approval next year.

Key differences between patisiran and revusiran include the formulation and route of administration of the siRNA oligonucleotides. Subcutaneously administered revusiran consists of an siRNA that is conjugated to a N-acetylgalactosamine (GalNAc) ligand, using a first-generation chemistry. Intravenously administered patisiran consists of an siRNA that is encapsulated in a lipid nanoparticle. Alnylam has six other RNAi programmes in the clinic, all of which use a second-generation version of the GalNAc chemistry. The company has also licensed RNAi drugs to several partners.

RNAi-based companies have been on a roller-coaster ride over the past decade. Merck, Roche, Pfizer, Abbott and Novartis all invested heavily in the field, only to subsequently drop out. But Sanofi signed a US$700 million deal with Alnylam in 2014 for access to their technology, and Roche re-entered the space that same year with its acquisition of Santaris Pharma. In September, Amgen partnered with Arrowhead Pharmaceuticals to develop RNAi therapies for cardiovascular diseases.

Arrowhead Pharmaceuticals and Arbutus BioPharma also have siRNA-based drugs in the clinic.


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Mullard, A. RNAi hits another rut. Nat Rev Drug Discov 15, 738 (2016).

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