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.
2 comments:
Isis also provided updates for ISIS-SMN Rx at the 2014 annual meeting of the American Academy of Neurology.
"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."
Was pleased to see you emphasize potential synergies with other future treatments given that fmsa.org just posted a press release on the initiation of a Phase I Clinical Trial of Systemic AAV9-Delivered SMN 1 Gene For type 1 Spinal Muscular Atrophy (see link below).
Since the two drugs are employing different mechanisms aimed at increasing SMN protein expression, I'm hopeful that they can both advance to the point of being tested in combination.
http://www.fsma.org/LatestNews/index.cfm?ID=8172&TYPE=1150
Post a Comment