ISIS Wasting No Time to Find Out Clinical Utility of Spinal Muscular Atrophy Drug

Yesterday at the 2014 Annual Academy of Neurology (AAN) meeting, ISIS Pharmaceuticals provided an update (presentation here, press release here) on their splice modulation antisense drug candidate ISIS-SMNRx for the treatment of spinal muscular atrophy (SMA).  The data were largely consistent with those presented about two months ago.  

Disease progression, including deaths in the infant trial, however, dashed hopes that this drug would be on its way to Accelerated Approval.  In light of the small number of subjects (15) in this trial, these events make it difficult to determine the impact of ISIS-SMNRx.  Similarly, the open-label nature of both the infant (type I SMA) and children (type II/III SMA) studies leaves open the possibility that apparent treatment benefits seen in motor-function outcomes could have been a placebo effect.

As a result of these concerns, the company has taken the bold step to run placebo-controlled, blinded pivotal phase III trials in infants and children to ascertain the tantalizing signs of efficacy seen thus far.  Most importantly, the drug more than doubled target therapeutic SMN protein levels (based on measuring surrogate levels in the cerebrospinal fluid) thereby genetically converting type I into type II/III SMA and similarly type II/III into near-healthy status.   In addition, the motor function increases seen were not only clinically relevant, but were also dose-related and hardly, if ever seen in the natural history of the disease.

Clearly, the apparent disease progression in the infant study would seem contrary to this conclusion.  Type I SMA babies have a mere life expectancy of 10 months, whereas type II/III children are faced with only somewhat shortened life expectancies.  The reason for this discrepancy is probably that in a treatment paradigm, SMN protein levels only catch up with type II/III SMA a few months after birth, whereas in normal development the SMN gene is already expressed in the womb.  The fact, however, that in the mouse model of the disease, ISIS-SMNRx restored mice to near-healthy status when given after birth, supports the notion that the drug should be efficacious when given post-delivery.

In the case of the infant study, drug administration commenced around months 4-5.   Considering that rapid functional decline and death occur soon after this in the natural history of the disease, the more optimal use of the drug would be when given starting right after birth.  However, until whole genome sequencing at birth becomes a routine screening tool for genetic disease (it should be routine already in my opinion), such optimal use has to wait for probably another 7-10 years.  Nevertheless, since ISIS-SMNRx seems safe and was shown to successfully address the disease at its root in babies and children- which also means that it could synergize with other future treatments- regulators should consider the full potential of this drug, present and future, when making a decision as to its approvability in 2016/2017.

One thing is clear, ISIS and partner BiogenIdec want to conduct the most rigorous trials possible to do ISIS-SMNRx justice when it could have taken the present data and pressed for accelerated approval in type I SMA largely based on the increases in SMN protein.  Knowing the real benefit of a drug can only benefit SMA patients and their families, and as we have found out in the case of Sarepta and DMD, the timelines ultimately do not have to be that different.