Oligonucleotide Therapeutics for Spinal Muscular Atrophy Impresses in Clinical Study

In addition to the continued validation of RNAi in Man, the other big winner of 2013 in the field of oligonucleotide therapeutics was single-strand phosphorothioate chemistry in the CNS.  Today, ISIS Pharmaceuticals announced clinical data from the most prominent candidate in that effort, namely ISIS-SMNRx for spinal muscular atrophy (SMA), a genetic muscle-wasting disease.  Following intrathecal administration of the splice modulating oligonucleotide, time- and dose-dependent improvements were observed not only in muscle function, but also in SMN protein production (biomarker), thus laying the foundation for an accelerated approval pathway.

In the open-label phase Ib/IIa study in ~30 children with the ‘less severe’ form of type II and III SMA, functional improvements of 1.5, 2.3, and 3.7 points on the HFMSE scale were seen at the 3mg (3 doses), 6mg (3 doses), and 9mg (2 doses) cohorts, respectively.  The changes were thus largely consistent with results from a previous similar, but single-dose phase I study where a 3.1 point increase could be observed at the 9mg dose.

Despite the generally positive news, the data raise a number of questions.  For example, optimal dosing frequency remains uncertain as there were similar functional improvements regardless of whether a single dose had been given or 2-3 doses.  This could have been due to the  long half-life of the drug and the time it takes from SMN protein production (as a  result of the splice modulation) to impacting motor neuron function.  Similarly, in the prior phase I study no positive changes in HFMSE scores were observed at the 3mg and 6mg doses whereas in the present study, improvements were reported.  Clearly, larger patient numbers are required  to settle on the optimal dose, and in fact this dose may not have been reached yet (note: a 12mg cohort has been initiated and children from the phase Ib/IIa trial are allowed to roll over to an additional dose of 12mg).

Case for accelerated approval?

Possibly foreseeing such issues due to small patient numbers, ISIS Pharmaceuticals and BiogenIdec recently developed an assay that allows them to measure SMN protein abundance in the cerebral spinal fluid (CSF).  It is the results from these measurements that provide a strong case for why ISIS-SMNRx should be made available (pending the 12mg results) before a larger phase III study will have been completed.  This is because the functional improvements were accompanied by increases in the SMN protein which also were dose-dependent with a more than doubling of SMN protein at 9mg.

In SMA, the SMN1 protein is missing due to mutations.  The therapeutic approach of ISIS-SMNRx takes advantage of the fact that humans have a pretty much identical gene to SMN1, SMN2.  The problem with SMN2, however, is that only ~10% of its precursor messenger RNAs is spliced into a functional SMN protein due to a difference in essentially just one nucleotide in exon 7.  The severity of the disease, i.e. whether somebody belongs to type I (most severe), type II, type III, or type IV of the disease depends on the copy number of SMN2 genes: 2 copies in type I, ~3 copies in type II and III, and at least 4 copies in type IV.

Therefore, doubling the protein output for type II and III patients (the patient population in the present phase Ib/IIa study) would appear to put the children into the type IV category in terms of protein output (correponding to ~6 SMN2 copies).  In contrast to type I-III, type IV results in no differences in life-expectancy and only in rare cases causes patients to be wheelchair-bound late in life.  

Severe disease of high unmet need, strong biomarker data with highly suggestive functional results, all dose-proportional…the ingredients for an accelerated approval. 

Just in: ISISis reporting preliminary data from a parallel multi-dose phase II study in the most severe, infant form of SMA (type I).  Although small in numbers, the fact that the 4 babies at the starting 6mg dose are still alive and without permanent respiratory support at an average age of 12.5 months appears to be much better than expected.  According to natural history data, you would have expected 2 babies either dead or on permanent ventilation by month 10.  

And finally...the ISIS-SMNRx results increase the value of Marina Biotech's CRN chemistry.  This chemistry competes with the ISIS 2'MOE chemistry employed in ISIS-SMNRx and appears to be of higher potency/affinity, but much less defined safety.