RNA interference is hitting the market - Alnylam’s success heralds a new era for RNAi therapeutics


By Josephine Pepper - Writer, Science Entrepreneur Club

It has been a bumpy ride for RNA interference-based therapeutics. The protein-silencing phenomenon that shot into the spotlight with its 2006 Nobel Prize fell (aptly) quiet thereafter, suffering clinical disappointments and losing high-profile backing. But it is back with a bang: the first RNAi drug was FDA approved in August and a number of Big Pharma companies are striking deals with developers. Does this mark a watershed moment for RNAi therapeutics?

Alnylam’s RNAi drug, Onpattro. Source: Drug Development Technology

Alnylam’s RNAi drug, Onpattro. Source: Drug Development Technology

RNA interference was first noted in petunia plants in 1990 when scientists added double-stranded (ds) RNA encoding a purple pigment to already-purple flowers. Instead of the deepening of colour they anticipated, the petals turned white. The same counter-intuitive phenomenon later appeared in nematode worms and has since proven to be universal.

It arises from a protective cellular response to short 20-25 nucleotide dsRNA molecules which commonly appear while a cell is infected with a virus. The cytoplasmic RNA-induced silencing complex (RISC) binds such ribonucleotides – known as silencing siRNAs— processing them to single-stranded molecules that can bind to any complementary mRNA and prevent their translation to a protein product. Other forms of RNAi – including microRNA (miRNA), short hairpin RNA (shRNA), and Dicer-substrate siRNA (dsiRNA) – exhibit a similar effect, but it is siRNA that has garnered the most commercial attention.

Its discovery generated huge hype, spurring research into potential applications from agricultural sprays (to trigger ripening or eradicate pests) to contraception (switching off a sperm-binding protein expressed on eggs). And its therapeutic promise is massive: here is a potential drug which does not rely on protein binding, meaning previously untargetable proteins can now be nipped in the bud; a drug that can easily circumvent the mutational escape which generates drug resistance or tolerance in infections and cancers; and a drug that bypasses the ethical and social pitfalls of genetic modification.

But progress has been slower than anticipated. One major technical stumbling block is the inherent instability of RNA. It is rapidly broken down in the blood. While this is ideal for agricultural applications (since concerns for human safety are minimised), complex delivery strategies must be developed for therapeutic application. Some of those explored include chemical modification of the ribonucleotides and specialised delivery vesicles including lipoproteins and viral capsules.

siRNA cellular mechanism. Source:  Michelson Medical Research Foundation

siRNA cellular mechanism. Source: Michelson Medical Research Foundation

Nevertheless, by 2016 more than twenty RNAi-based drugs were in clinical trials, and in August 2018 the FDA granted approval for Onpattro, the first RNAi therapeutic. Developed by Alnylam Pharmaceuticals, Onpattro combats a rare but lethal form of amyloidosis (the build-up of amyloid deposits in tissue). It is packaged in acutely engineered lipid nanoparticles which travel straight to the liver – ideal for Onpattro’s action, but solving no problems for other diseases which require a non-hepatic site of delivery.

Another challenge for RNAi drugs is their expense: Alnylam spent $2 billion getting an RNAi therapeutic to market. Other companies may face even greater pay-outs since Alnylam holds exclusive rights to one of two key patents in the field and shares in the other. Other biotech companies license with Alnylam for legal protection and easy access to the tech. In the absence of profit earnings, RNAi-based companies generate income through licensing fees and legal leverage surrounding the use of the IP. Alnylam’s influence is so great that CEO John Maraganore has stated, “We think anyone developing synthetic RNAs will need to license our IP.” They defended this view in litigation concerning Onpattro against Silence Therapeutics, which was settled late last year. Alnylam currently has a further six drugs in late-stage trials.

Big Pharma is taking note. In the last 6 months there has been a wave of licensing deals struck between RNAi biotechs and giants including Amgen, Eli Lilly and Johnson & Johnson. We can read this as reflecting a boom in confidence in the technology and perhaps expect to see far more RNAi drugs hitting the market in the near future.

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