Alnylam Pharmaceuticals, the first company to bring an RNA interference (RNAi) drug to market, has struck an $800 million-plus deal with Regeneron Pharmaceuticals to develop RNAi therapies for eye and central nervous system diseases. The partnership is an important step not only for Alnylam but also for the RNAi field as a whole, which has thus far struggled to make RNA drugs for any organ but the liver.
In the first phase of the collaboration, Regeneron and Alnylam will seek to develop RNAi therapies that knock down, or silence, 30 disease-causing genes. Regeneron will pay Alnylam $400 million up front, buy $400 million worth of its stock, and offer up to $200 million in milestone payments.
Alnylam has been at the forefront of the RNAi field’s successes and disappointments since the company was founded in 2002. Last August, Alnylam’s Onpattro became the first RNAi drug approved for sale in the US.
But developing the right lipid nanoparticle to safely and effectively deliver RNAi drugs was a major hurdle for the firm. After they are injected into the body, lipid nanoparticles congregate predominantly in the liver, leading the company to focus on RNAi drugs that treat liver diseases or block the production of proteins that are primarily manufactured by liver cells.
In fact, the new Regeneron collaboration includes a small program that targets genes in the liver. The duo will test an experimental Regeneron antibody and an experimental Alnylam RNAi therapy to knock down genes in the liver. The companies are already collaborating on RNAi drugs for the liver condition nonalcoholic steatohepatitis.
For the new realms of the eye and central nervous system, it’s not yet clear how Alnylam will deliver RNAi drugs, though both organs will likely require direct injections.
A class of gene-blocking drugs called antisense oligonucleotides—similar, older cousins to RNAi therapies—offers a precedent. These drugs have been safely injected into the gel-like vitreous fluid of the eye to treat viral infections. And Biogen’s antisense oligonucleotide Spinraza, currently the only therapy to treat a childhood neurodegenerative disease called spinal muscular atrophy, requires multiple injections into the spinal fluid every year.
In addition to lipid nanoparticles, RNAi therapies for the liver need a liver-homing chemical tag called N-acetylgalactosamine. The tag is appended to the RNAi molecules and recognized by receptors on specific kinds of liver cells, which then engulf the drugs so they can exert their gene-silencing powers inside cells.
Alnylam’s plans for getting RNA drugs into the brain may rely on a similar mechanism. A presentation at a Cold Spring Harbor Laboratory conference last month indicated that the company is using a ligand to help get its therapies into the brain cells of rodents and monkeys, but it didn’t provide any clues to the ligand’s molecular makeup. The preliminary results indicated RNAi’s potential for knocking down a gene linked to amyotrophic lateral sclerosis (ALS). Alnylam suggested that the same gene-silencing trick could be applied to other brain conditions, including Alzheimer’s, Parkinson’s, and Huntington’s.
Regeneron and Alnylam aren’t disclosing any targets for their eye and brain programs yet, but Alnylam predicts it will be filing investigational new drug applications for one to two eye or nervous system conditions every year beginning in 2020.
In a separate announcement, Sanofi says it is wrapping up a rare disease research agreement it struck with Alnylam when it made a $700 million investment in the company in 2014. The more than 10.5 million shares of Alnylam stock that Sanofi owns are now valued at roughly $1 billion. The two firms will continue developing two RNAi drugs: fitusiran for hemophilia and vutrisiran for transthyretin-mediated amyloidosis. They will also advance an undisclosed rare disease program.