A recent conversation brought to mind a blog piece I wrote back in early 2011 about the exit of big pharma, en masse, from interfering RNA (RNAi) drug development, with the canning of internal development or strategic partnerships, due in part to the technical challenge of delivering effective quantities of small oligonucleotides and the availability of less rocky paths to targeted therapies, both biologic and small molecule.
RNAi works by throwing a spanner into the cellular mechanism which translates the information encoded by DNA into proteins: small, double stranded pieces of synthetic RNA (siRNAs) bind to messenger RNA to dial down expression of disease-related proteins. Although simple in concept,successful RNAi drug development involves selection of the right mRNA binding sequence, chemical toughening of the double-stranded oligonucleotide so that it resists degradation, and efficient delivery to the target cell. The latter has proven to be the most difficult element and the early promise of lipid-based oligonucelotide delivery has long since evaporated. High hopes are now pinned on carbohydrate conjugate delivery ("GalNac" conjugation), which offers an easier route to liver and other cell types and more patient-friendly dosing.
Fast forwarding from 2011 to the second half of 2017, has enthusiasm for RNAi been rekindled? Well, sort of, although with reservations. Big pharma has, in the main, not changed its collective mind over RNAi, but the remaining exponents (largely small and mid-cap biopharmas) have made significant progress in the clinic and in pre-clinical pipeline expansion.
Leading the pack is Alnylam, with four late-stage (Phase III) candidates, fitusiran, inclisiran and givosiran, indicated in the treatment of the rare genetic disorder hereditary ATTR amyloidosis, hypercholesterolemia, haemophilia and rare bleeding disorders and acute hepatic porphyrias, respectively. Positive Phase II data was recently reported for an open label inclisiran study where haemophilia patients were treated once a month for up to 20 months without safety or tolerability issues.
Alnylam needs continued good news. A higher than expected death rate in the study arm forced the company to abandon late stage development of revusiran, then in evaluation for another form of ATTR-amyloidosis, last October, causing the share price to tank by 50% as investors considered the implications for the rest of the RNAi pipeline. Arrowhead Pharmaceuticals abandoned its clinical RNAi hepatitis B programme after primate deaths occurred in toxicology studies, necessitating a return to the pre-clinical drawing board.
There's nothing to indicate that RNAi drugs have inherent safety issues. Quark Pharmaceuticals and Arbutus Biopharma have not encountered problems with their respective Phase II/III RNAi candidates and Alnylam's analysis of the revusiran data has not uncovered an obvious association between treatment and increased mortality. But, as a 20 year old development platform that has still to produce an a single approved drug, it's not surprising that investors and potential global pharma partners remain largely unconvinced about RNAi technology and are tuned into negative news.
The future of RNAi drug development hangs on Alnylam's patisiran, currently in Phase III development, with top-line data expected in September. Submission of US and/or EU marketing applications before the end of 2017 would go a long way to (re)build confidence in RNAi as a platform. On the other hand, significant delay in regulatory submissions or abandonment of patisiran will impact heavily not only on Alnylam but, perhaps unfairly, its RNAi peers.
Perhaps most galling for those companies that have the kept the faith is that clinical and regulatory success may not translate into sustainable commercial success, as even in the orphan and niche indications being targeted by Alnylam and its peers, RNAi drugs will need to compete with small molecule, monoclonal antibody and antisense oligonucleotide therapies.