Rare Disease Report

Medication for Spinal Muscular Atrophy Showing Benefit in Phase 2 Trial

AUGUST 01, 2015
Ruth J Hickman, MD
Extension data following a Phase 2 study of the drug ISIS-SMNRX continue to show motor benefits for patients with spinal muscular atrophy (SMA).The US Food and Drug Administration has granted orphan drug status and fast track designation to ISIS-SMNRX for the treatment of patients with SMA. Patients enrolled in the Phase 2 open-label, multiple-dose study are continuing to receive treatment in an open-label extension study performed by ISIS Pharmaceuticals.1
SMA is an autosomal recessive muscular disease causing muscle atrophy and weakness. The disease results from a defect in the SMN1 gene, leading to a decrease in its protein, survival motor neuron protein (SMN). This protein is critical for nerve cells in the spinal cord that play an important role in neuromuscular growth. The amount of functional SMN protein that is available correlates with the severity of symptoms. Patients with the most severe form (type I) typically die in infancy. Those with type II have more protein, but have a shortened life span and significant motor impairment. The children with type III have a normal lifespan and less significant motor impairment.1
The drug takes advantage of a closely related gene, SMN2, to help produce more functional SMN protein. This gene normally also codes for SMN protein, but mostly for a short and less functional version. ISIS-SMNRX is a type of “antisense” technology that changes the way the genetic code is interpreted by cells, allowing for larger amounts of normal SMN to be made from the SMN2 gene.1,2
In this current trial, 30 patients with SMA type II or type III received intrathecal doses of the drug every six months. The researchers assessed clinical outcomes using the Hammersmith Functional Motor Scale-Expanded, the 6-minute walk test (for ambulatory patients) and the upper limb module test (for non-ambulatory patients). An evaluation at 9 months revealed mean increases of 3.8 in the Hammersmith scale, 55 meters in the 6-minute walk test, and 2 points on the upper limb module test.1
Just as importantly, the drug continued to show a favorable safety profile. No serious adverse effects were reported in the Phase 2 or extension studies to date. Most adverse effects were only mild to moderate in severity, even with repeated doses of the drug.1
Two separate Phase 3 studies for infant onset and later onset SMA began last year and are still ongoing. The “ENDEAR” study is an ongoing trial of ISIS-SMNRX in infants with type  I SMA who already have symptoms. The “CHERISH” study is currently assessing the drug in children ages 2-12 who have type II SMA. Other trials are also set to begin in 2015, a phase 2 trial in presymptomatic infants (the “NURTURE” trial), as well as a phase 2 trial of children who did not make the age and inclusion requirements for the “ENDEAR” and “CHERISH” studies.1,3
“We observed encouraging results that were consistent with earlier results from our open-label Phase 2 study,” said C Frank Bennett, PhD, senior vice president of research at Isis Pharmaceuticals, in a press release. “Taken together, these data suggest that ISIS-SMNRX could provide benefit to patients with SMA beyond halting their disease progression. The safety and tolerability profile that we have observed across all of our ISIS-SMNRX studies support the ongoing Phase 3 programs in both infants and children with SMA.”1


  1. Isis Pharmaceuticals reports data from ISIS-SMNRx in children with spinal muscular atrophy. ISIS Pharmaceuticals. http://ir.isispharm.com/phoenix.zhtml?c=222170&p=irol-newsArticle&ID=2061208. June 22, 2015. Accessed July 27, 2015.
  2. Wahl M. ISIS-SMNRx to be tested in Phase 3 trial in infants with SMA. Quest. Muscular Dystrophy Association. http://quest.mda.org/news/isis-smnrx-be-tested-phase-3-trial-infants-sma. August 1, 2014. Accessed July 27, 2015.
  3. Isis expands Phase 3 clinical trials. http://www.curesma.org/news/isis-expands-phase-3.html. November 25, 2014. Accessed July 27, 2015.
Black and white photograph of a woman, aged 35 years, suffering from atrophy of the spinal muscles. Photograph shows the patient's inability to stand erect without support. Medical Photographic Library Keywords: St Bartholomew's Hospital Photographic Society. Image courtesy of Wellcome Images and wikimedia commons.

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