SMA: ISIS-SMNRx Shows Benefit in Infants, Children

Update (Aug. 1, 2014): The phase 2 infant study of ISIS-SMNRx is now closed to new participants. However, a phase 3 study of this drug has opened. See ISIS-SMNRx to Be Tested in Phase 3 Trial in Infants With SMA.


original story:

Treatment with the experimental drug ISIS-SMNRx in two phase 2 studies in infants and children with spinal muscular atrophy (SMA) has been found to result in functional improvement, encouraging its developer to pursue phase 3 studies in 2014.

A phase 2 trial of ISIS-SMNRx in infants with type 1 SMA has yielded encouraging results, with several of the babies showing improvement on standardized tests of muscle strength and function. The infant study remains open to new participants.

And, a phase 2 trial of ISIS-SMNRx in children 2-15 years old with type 2 and type 3 SMA, now closed to new participants, likewise showed increases in muscle function scores, as well as evidence that the drug was biologically active in spinal fluid.

Biotechnology company Isis Pharmaceuticals, based in Carlsbad, Calif., announced the encouraging results at the 66th annual meeting of the American Academy of Neurology held April 26-May 3, 2014, and in an April 29, 2014, press release. The release provides details of the two studies and future plans for development of ISIS-SMNRx.

Isis has also provided a webcast of the AAN meeting presentation.

The company plans to begin a large-scale, phase 3 study of ISIS-SMNRx in infants with SMA in mid-2014 and a phase 3 study in children with SMA in the second half of 2014. (Details will be publicized when they are available.)


ISIS-SMNRx is an antisense-based compound, designed to alter the way cells interpret the genetic instructions for a protein known as survival motor neuron (SMN). This protein is deficient in SMA because of mutations in both copies of a gene on chromosome 5 known as SMN1.

However, neighboring gene, known as SMN2, codes for a similar protein that is not fully functional. ISIS-SMNRx is designed to target the SMN2 gene instructions and cause them to be "spliced" in a new way. The desired result is production of full-length, fully functional SMN protein.

MDA did not support the ISIS-SMNRx clinical trials, but it supported the laboratory development of this drug through a grant to molecular biologist Adrian Krainer at Cold Spring Harbor (N.Y.) Laboratory.

About the ISIS-SMNRx phase 2 study in infants

As of April 7, 15 babies with type 1 SMA had received multiple injections of ISIS-SMNRx into their spinal fluid — four receiving 6 milligrams per injection and 11 receiving 12 milligrams.

Although the study was not designed to provide evidence of functional improvement, increases in muscle function scores were seen at both dosage levels on the Children's Hospital of Philadelphia Infant Test of Neuromuscular Disorders (CHOP INTEND), which measures strength.

The average increase on the CHOP INTEND for both groups was 5.4 points at the most recent evaluation, while the average increase in the 12-milligram group so far has been 8.3 points.

Improvements were also seen on the Hammersmith Infant Neurological Exam Motor Milestones.

About the ISIS-SMNRx phase 2 trial in children 2-15 years old

In the study of children 2-15 years old with types 2 or 3 SMA (now closed to new participants), children treated with multiple injections of ISIS-SMNRx into their spinal fluid showed increases in muscle function scores on the Hammersmith Functional Motor Scale-Expanded.

Nine months after the first injection, those in a 3-milligram dosage group showed an average increase of 1.5 points; those in a 6-milligram group had an average increase of 2.3 points; and those in a 9-milligram group improved by 3.7 points.

Encouraging preliminary results were also seen in two additional tests of motor function: the distance that could be walked in six minutes (six-minute walk test), and the upper limb module (ULM), which measures arm function.

All children tolerated the drug well.

In addition to the changes in function, samples of spinal fluid taken from children in this trial showed increases in levels of the desire SMN protein over time, with the greatest increase seen in the 9-milligram dose group.

A 12-milligram dose group has now been added to this study but has not yet been evaluated.

"The debilitating progressive muscle weakness observed in children with SMA can vary substantially from child to child and can have a profound effect on their quality of life," said Claudia Chiriboga, associate professor of clinical neurology and clinical pediatrics at Columbia University Medical Center and an investigator on this trial. She added that the "results are encouraging and suggest that ISIS-SMNRx could have the potential to bring benefit to these children."

To participate in the infant study

The infant study of ISIS-SMNRx remains open to those who meet study criteria, which are listed at A Study to Assess the Safety and Pharmacokinetics of ISIS-SMNRx in Infants With Spinal Muscular atrophy. The information can also be reached by entering NCT01839656 in the search box at

Contact Isis Pharmaceuticals at (800) 679-4747 or or the study site nearest you on the list.