In a much welcomed sign for researchers, companies and investors alike in the field of nucleic acid-based therapeutics, on 10 August 2018 the US Food and Drug Administration (FDA) approved the use of ONPATTRO™ (patisiran) for the treatment of polyneuropathy caused by hereditary transthyretin-mediated (hATTR) amyloidosis in adults. ONPATTRO™ is a RNA interference (RNAi) therapeutic developed by Alnylam Pharmaceuticals, Inc., containing lipid-encapsulated small interfering RNA (siRNA) molecules that target and silence the mutated transthyretin gene in patients with hATTR amyloidosis.

This is the first RNAi therapeutic approved by the FDA, and represents a coming-of-age for nucleic acid-based therapeutics after what has been a very long and challenging road. Demonstrating the commercial and clinical viability of nucleic acid-based therapeutics, this should also signal a new lease on life for patents and patent applications focused on such molecules.

A long path to success

RNAi is a naturally-occurring cellular process that results in gene silencing. Briefly, and very simply put, double-stranded RNA is processed and broken down into siRNA by an enzyme called Dicer. This siRNA binds to RNA-induced silencing complexes (RISCs) before the siRNA strands guide the RISCs to complementary mRNA, whereupon the mRNA is degraded, resulting in gene silencing. After its discovery by Andrew Fire and Craig Mello in 1998 (for which the scientists were awarded the Nobel Prize for Medicine in 2006), there was much hope and excitement that RNAi would be the next blockbuster class of therapeutic. However, this sentiment was replaced with scepticism and then pessimism over the next decade or so, as the challenges of effectively delivering the RNA molecules to cells became apparent. Several large pharmaceutical companies began pulling out of the field after early and significant investment, choosing instead to focus on the development of small molecule therapeutics. The waning interest in this technology from venture capital funds and big pharma also forced many research institutes and universities to forgo patent protection and commercialisation of RNAi-based inventions generated by their researchers, as they failed to attract financial support.

Alnylam was one of the few companies to remain optimistic and committed to RNAi. They, along with several others, continued working on and improving delivery methods for RNAi. The lipid nanoparticles used in the formulation of ONPATTRO™ facilitate delivery and uptake of the encapsulated siRNA to the liver after infusion, silencing genes expressed in the liver so as to treat liver-associated diseases. A variety of lipid and polymer nanoparticles have been developed and successfully trialled in the clinic, as have various conjugates, such as N-acetylgalactosamine (GalNAc)-siRNA conjugates. It can only be presumed that progress will continue to be made in this area, facilitating the use of RNAi therapeutics for a range of diseases.

Good news for early- and late-stage researchers

Alnylam is now being justly rewarded for its efforts and persistence in driving this technology to the clinic. The first-in-class approval of ONPATTRO™ should also go a long way to boosting the prospects of other groups developing nucleic acid-based therapeutics, including siRNA, miRNA and antisense oligonucleotide (ASO) therapeutics. ONPATTRO™ is part of a growing list of FDA-approved nucleic-acid based therapeutics that also includes Exondys 51™ (eteplirsen; Sarepta Therapeutics Inc.), a phosphorodiamidate morpholino antisense oligonucleotide (PMO) that modulates splicing to treat Duchenne muscular dystrophy (DMD) patients; and Spinraza™ (nusinersen; Biogen Inc.), an ASO that targets the SMN2 gene for the treatment of spinal muscular atrophy. The growing number, and variety, of nucleic acid-based molecules approved for therapeutic use should be a clear signal to shareholders, angel investors, venture capital funds and big pharma alike that this class of therapeutic is worthy of investment.

Late-stage developers with already-identified clinical candidates shouldn't be the only beneficiaries of an increased interest in nucleic acid-based therapeutics. Early-stage researchers identifying new therapeutic targets often begin by targeting genes with inhibitory nucleic acid molecules (e.g. siRNA or ASOs) to demonstrate the therapeutic effect of reducing protein levels. For many research groups, it is not feasible to expand this research to identify small molecules that inhibit the protein. Patent applications filed to protect early-stage research, for example at universities and research institutes, may therefore only enable nucleic acid-based therapies. Where in the past this may have deterred investors such as venture capital funds from supporting ongoing patent protection and commercialisation, the clear signal from regulators and the market is that nucleic acid-based therapeutics are commercially viable and clinically relevant, and are not merely research tools for proof-of-concept studies. We fully expect that these early-stage researchers will begin seeing more support for their efforts.