Next Stop: ISIS-SMNRx for Spinal Muscular Atrophy

In case you were wondering why RNA Therapeutics stocks have been going up and up regardless of the overall markets, it is because it is happening right now: RNA Therapeutics are claiming the role of the 3^rd major drug discovery engine, the most vibrant at that, following small molecules (withering) and recombinant proteins/monoclonal antibodies (running out of target space).  It therefore becomes important to anticipate the next major event on that road which are the results from two separate multi-dose phase II studies of ISIS-SMNRx to be reported sometime over the coming 6 weeks.

ISIS-SMNRx for the treatment of severe, orphan disease spinal muscular atrophy (SMA), a muscle wasting disease, is yet another powerful example of how RNA Therapeutics typically target the root causes of diseases rather than merely covering up their symptoms as drugs so often are designed to do, especially drugs for chronic illnesses. 

In SMA, the SMN1 gene is inactivated due to a mutation.  Luckily, there is another SMN1-like gene, SMN2, and this differs from SMN1 by one nucleotide.  As a result, splicing of SMN2 predominantly generates transcripts lacking an exon which in turn results in inactive SMN proteins.  Only a small fraction of SMN2 is spliced functionally.  By antagonizing a splice silencer element on the SMN2 precursor mRNA, phosphorothioate 2’MOE antisense ISIS-SMNRx redirects splicing towards the active form of SMN thereby rescuing the deficiency underlying SMA.  It is insights like these why you want your kids to study biology.  

Following intriguing phase Ib/IIa results from a small, open-label single-dose study in kids with type II and III SMA (‘moderate’ and ‘less severe’ forms of the disease) which showed dose-related continual functional improvements over 9-14 months, consistent with the long half-life of the oligonucleotide in the CNS, the multi-dose phase II studies aim to confirm that in a larger patient population.  In addition, a second phase II study is conducted in infants with the very severe type I form of the disease which results in nightmarish life expectancies of less than 2 years. 

   

It is the compelling scientific rationale, the 12mg dose, the preclinical efficacy and PK results at even smaller dosages and the tantalizing phase Ib/IIa results described above that you would think that the outcome from these two studies should be positive. 

If they are, expect them to be all over the news and RNA Therapeutics stocks continue their march upwards.

ISIS-SMNRx was discovered by ISIS Pharmaceuticals and is partnered with BiogenIdec.