In the study in children with SMA, time and dose-dependent increases in muscle function scores, as measured by the Hammersmith Functional Motor Scale-Expanded (HFMSE), were observed in children treated with multiple-doses of ISIS-SMNRx.
Children in the 3 mg, 6 mg and 9 mg cohorts achieved mean increases of 1.5, 2.3 and 3.7 points, respectively nine months following the first dose. Encouraging preliminary results were also observed in two additional functional tests: the six-minute walk test (6MWT), and the upper limb module (ULM) test. In the 6MWT, performed with nine ambulatory children, a mean increase of 22.7 meters was observed at 9 months. In the ULM test, which utilizes a 9 item scale (max score of 18), performed with 10 non-ambulatory children, a mean increase of 2.3 was observed at 9 months. In all children treated with ISIS-SMNRx to date, the drug has been well tolerated at doses as high as 12 mg.
In addition, analysis of cerebral spinal fluid (CSF) samples from children in this study demonstrated dose-dependent increases in SMN protein levels over time in patients treated with ISIS-SMNRx with the maximum effect observed in the 9 mg cohort in which the mean SMN protein level more than doubled by Day 86 from baseline (n=9). Children in the 12 mg cohort have not yet been evaluated. These results are consistent with the increases in SMN protein levels from the single-dose study, in which SMN protein levels more than doubled in the highest dose cohort.
"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. As such, even small increases in muscle function can translate into significant changes in quality of life for these children. The Hammersmith muscle function scoring method is a well-established test that was designed to track the progressive loss of muscle function in children with SMA. Using this test, dose- and time-dependent increases in muscle function scoring in children treated with ISIS-SMNRx have been observed in both the single- and multiple-dose studies. These results are encouraging and suggest that ISIS-SMNRxcould have the potential to bring benefit to these children," said Claudia Chiriboga, M.D., M.P.H., associate professor of clinical neurology and clinical pediatrics at Columbia University Medical Center.
"We continue to be encouraged with the dose- and time-dependent increases in both muscle function scores and SMN protein levels observed in children with SMA treated with ISIS-SMNRx. To date, 54 children with SMA have been treated with a total of 138 doses. Although our studies were not placebo controlled, the consistency of the data supports our optimism that ISIS-SMNRxmay be able to improve the lives of infants and children with SMA and gives us further confidence to advance ISIS-SMNRx into a Phase 3 program," said C. Frank Bennett, Ph.D., senior vice president of research at Isis. "We are on track to start the Phase 3 study in children with SMA later this year."
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