The Wait is Finally Over

For some time now, I’ve been fascinated by how the RNAi Therapeutics sentiment cycle has been progressing in 3-year intervals.  Before I left off for my baby-break, I referred to 2014-17 as The Wait. The Wait was a reference to the ‘market’ having been convinced by early clinical data that RNAi can bring about deep and sustained gene knockdowns in WoMan, but that the ultimate clinical utility and subsequent commercial value remained to be proven.

We are now on the cusp of finding out with results from the registrational phase III study of the TTR-lowering Patisiran in familial amyloidotic polyneuropathy (FAP) imminent.

The wind is clearly in RNAi’s back with supporting developments in the related oligonucleotide therapeutics and, indeed, drug regulatory spaces.  In particular, the successful commercial launches of splice modulators EXONDYS51 (for Duchenne muscular dystrophy) and SPINRAZA (for spinal muscular atrophy) and promising phase III data from the triglyceride-lowering Volanesorsen (gene target: ApoCIII) should have removed the long-held doubt that oligonucleotides can be clinical practice-changing and profitable drugs.  And boy, are EXONDYS51 and SPINRAZA changing the clinical practice of two devastating, previously orphan diseases!

Equally important, drug regulation is strongly moving infavor of patient choice and access.  As a result, we are going to see many more drug candidates benefiting from accelerated approval pathways similar to EXONDYS51.  A number of RNAi Therapeutics programs such as Givosiran by Alnylam (àmetabolite ALA lowering as reasonably predictive endpoint) and DCR-PHXC by Dicerna (àoxalate lowering) are poised to benefit from this development.

But let’s not get ahead of ourselves and await the Patisiran APOLLO study outcome for which sponsor Alnylam has guided a ‘late September/summer’ read-out.  Drug development is full of surprises, so despite all the data* pointing towards a positive outcome, a number of variables (e.g. steroid use, lipid nanoparticle delivery) remain unknown in how they impact overall outcomes.  I for one will breathe a big sigh of relief should Patisiran be able to overcome this Make-or-Break event for RNAi Therapeutics.

 *

à positive open-label extension data from phase II Patisiran;

à positive phase III data from IONS-TTRRx targeting same gene and indication;

à the high roll-over rate into the open-label extension) indicating a positive outcome