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NEWS FROM THE AAN ANNUAL MEETING: Antisense Therapy for Spinal Muscular Atrophy Moves Toward Phase 3 Trials

Robinson, Richard

doi: 10.1097/01.NT.0000451836.03713.d4
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Two Phase 2 trials of intrathecal delivery of Isis-SMNRx, an antisense molecule, in infants and children showed that the treatment reached neurons throughout the spinal cord and motor cortex, increased expression of the survival motor neuron protein, and improved functional measures over several months.

PHILADELPHIA—Antisense therapy for spinal muscular atrophy (SMA) is moving toward Phase 3 trials, based on positive results from two Phase 2 trials of intrathecal delivery in infants and children. The trials showed that the treatment reached neurons throughout the spinal cord and motor cortex, increased expression of the survival motor neuron (SMN) protein, and improved functional measures over several months. While the trials were small and the drug was given open label, researchers hope these results may translate into clinical benefits for SMA patients.

In humans, virtually all SMN protein is made by the SMN1 gene. SMA occurs when two defective copies of SMN1 are inherited. Humans also possess two or three copies of the SMN2 gene, but these are mutated, leading to improper splicing and the production of mostly truncated, functionless protein. The little functional SMN protein made from SMN2 is insufficient to compensate for loss of SMN1. Milder SMA phenotypes are associated with having more copies of the SMN2 gene.

The antisense molecule delivered in the two trials, called Isis-SMNRx, targets the SMN2 mutation to correct the splicing error, increasing the level of functional SMN protein.

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Richard Finkel, MD, chief of neurology at Nemours Children's Hospital in Orlando, FL, led the study of infants with Type 1 SMA. In infants with only two copies of SMN2, the median age at death or transition to full-time ventilator support is 10.5 months, and by 18 months, almost all children will meet one of these endpoints, he explained.

The trial enrolled both male and female infants who were age 7 months or younger and who were not hypoxemic at screening. Patients received either 6 mg or 12 mg of drug by lumbar puncture without sedation, at days 1, 15, 85, and 253, followed by a planned 36 weeks of follow-up. The study is ongoing, and results reported at the meeting were those available as of April 7, 2014.

To date, four patients have been enrolled in the low-dose group and 11 in the high-dose group. The mean age at symptom onset in both groups was seven weeks, with enrollment occurring between 18 and 21 weeks. All patients have two copies of the SMN2 gene, except for one patient in the high-dose group who has three copies.

“The treatment has been well tolerated,” Dr. Finkel said, with most adverse events mild or moderate, and none considered drug-related. All serious adverse events, including respiratory infections, are so far attributable to disease progression.

At the time of the presentation, all patients in the low-dose group had received at least the first three doses and underwent follow-up at 92 days, and thus were evaluated for efficacy. One child in this cohort had died of accidental causes, and one progressed to require a respirator. The median age of the group at the time of either an event or April 7 was 14 months. In the high-dose cohort, seven patients met efficacy evaluation criteria. One had died, and one required a respirator. The median age was 9.6 months.

One autopsy was performed, which showed uptake of the drug into lumbar, thoracic, and cervical regions of the spinal cord, and in cortical motor neurons.

Preliminary efficacy measures suggest that treatment may be having an effect, Dr. Finkel said. Clinical change was measured on the CHOP-INTEND, a 16-item, 64-point scale of infant motor function. Type 1 SMA infants typically never exceed a score of 40 on the CHOP-INTEND, and decline by about 1.25 points per year. In the study, two infants receiving the low dose declined over nine months, and two improved. In the high-dose group, over three months, one remained at baseline, and six improved, with a mean improvement from baseline of 8.3 points. Some of these infants scored above 40 at the latest evaluation.

Additionally, Dr. Finkel said, compound muscle action potentials performed on ulnar and peroneal nerves remained stable or increased in most patients. Nine of the 11 patients also improved on achievement of motor milestones, as measured on the Hammersmith Neonatal Neurologic Assessment, with several patients increasing their ability to control their heads and sit upright with support.

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A second study of similar design in Type 2 SMA was led by Claudia Chiriboga, MD, MPH, an associate professor of clinical neurology at Columbia University in New York. The 25 patients, ages 2 to 15, received by lumbar puncture three ascending doses over three months of up to 9 mg of Isis-SMNRx, with six months follow-up after the final dose. A 12 mg treatment arm is currently being enrolled, but no data are available yet.

Dr. Chiriboga reported that the treatment was well tolerated, with no safety concerns. She and her team found a dose-dependent increase in scores on the Hammersmith scale, improvements on both the six-minute walk test and tests of upper limb function, and a dose-dependent increase in SMN protein within the CSF. However, she noted, the patient numbers were small and not amenable to statistical analysis.

It is unclear what, if any, effect treatment is having on the neurodegenerative process at the heart of SMA, according to Dr. Chiriboga. Neither is it known what a chronic dosing strategy would be, should the treatment prove successful in Phase 3 trials. Animal data suggest the most acute need for SMN is during development, and in conditional expression models, turning the gene off in adulthood leads to symptoms only after a long delay, suggesting that intermittent dosing in adulthood might be possible.

Frank Bennett, PhD, of Isis Pharmaceuticals, indicated that the company is currently planning a Phase 3 trial, which may be ready to proceed before the end of the year, and is expected to last for 15 months.

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While the results are preliminary and only in small numbers of patients, “There are no dark clouds” in the data, according to John Kissel, MD, FAAN, professor of neurology and director of the Division of Neuromuscular Medicine at Ohio State University.

“One major accomplishment is that Dr. Finkel and colleagues showed it is possible to do a therapy trial in Type 1 infants,” Dr. Kissel said, given the course of the disease and the difficulty of assessing outcomes. The normal fluctuations in this population make it difficult to interpret these short-term functional results, and more follow-up will be needed to understand the significance of the improvements presented “but I think there is enough encouraging data to suggest they should continue to go forward.”

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•. AAN Annual Meeting Abstract: Results of a phase 2 open-label study of ISIS-SMNRx in patients with infantile (Type 1) spinal muscular atrophy:
    •. For more Neurology Today coverage of spinal muscular atrophy, go to
      •. For studies of spinal muscular atrophy published in Neurology, go to
        © 2014 American Academy of Neurology