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Isis Reports Interim Results from Multiple Dose Study in Children with Spinal Muscular Atrophy

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ISIS PHARMACEUTICALS, INC. LOGO

February 21, 2014

Isis Pharmaceuticals, Inc. today announced top-line results from an ongoing open-label, multiple-dose study of ISIS-SMNRx in children with spinal muscular atrophy (SMA). In this study, ISIS-SMNRx was well tolerated at all dose levels in children with SMA.  Consistent with single-dose observations, time- and dose-dependent increases in muscle function were observed in children treated with multiple doses of ISIS-SMNRx. In addition, results from a recently developed biomarker assay that was designed to measure levels of SMN protein in the cerebral spinal fluid (CSF), showed time- and dose-dependent increases in SMN protein levels in SMA children treated with ISIS-SMNRx from both single- and multiple-dose studies.

“We continue to be encouraged with the tolerability of ISIS-SMNRx we have observed in our clinical studies to date. We are also encouraged that we observed dose- and time-dependent increases in muscle function scores in children with SMA. The consistency of the results between the single-dose and the multiple-dose studies supports our earlier optimism around the single dose study results and gives us further confidence to advance ISIS-SMNRx into a Phase 3 program in children with SMA, which we plan to start later this year,” said B. Lynne Parshall, chief operating officer.

In the interim analysis of this ongoing multiple-dose Phase 1b/2a study, children with Type II or Type III SMA were dosed intrathecally with 3 mg, 6 mg or 9 mg of ISIS-SMNRx.  The 3 mg and 6 mg doses were administered on days 1, 29 and 85.  The 9 mg dose was administered on days 1 and 85.  Muscle function changes were measured using the Hammersmith Functional Motor Scale-Expanded (HFMSE), a validated method to measure changes in muscle function in patients with SMA.  Using this test, dose-dependent increases in muscle function scores were observed in this study.  SMA children in the 3 mg, 6 mg and 9 mg cohorts achieved mean increases in HFMSE scores of 1.5, 2.3 and 3.7 points, respectively, nine months following the first dose of ISIS-SMNRx.  In addition, time-dependent increases in muscle function scores were observed.  Children in the 9 mg cohort achieved mean increases in HFMSE scores of 2.7 and 3.7 points three and nine months after the first dose of ISIS-SMNRx, respectively.  The increases in muscle function scores observed in this study at the three month time point is comparable to the single-dose data presented last year, which showed that children treated with 9 mg of ISIS-SMNRx achieved a mean increase in HFMSE score of 3.1 three months after the single-dose.  All children in the multiple-dose study have completed dosing in the initial three cohorts and the first child has been dosed in the 12 mg cohort.  Isis’ plans to give all children who roll over into an extension study a maintenance dose of 12 mg of ISIS-SMNRx every six months.  To date, ISIS-SMNRx has been well tolerated.  Two serious adverse events (pneumonia and fentanyl-related hypersensitivity) that were not considered drug related were reported.

“A subgroup analysis that combines data from children in both the single- and multiple-dose studies demonstrated a mean 5 point increase in muscle function score in children who received at least 9 mg of ISIS-SMNRx between the ages of two and 10 who did not have severe scoliosis or baseline HFMSE scores at the extreme low or high ends of the scale. These results provide us with valuable insight into determining which children with SMA can achieve increases in Hammersmith scores that best correlate with increases in muscle function,” saidC. Frank Bennett, Ph.D., senior vice president of research.  “Because we saw increases in muscle function scores up to 14 months after treatment in our single-dose study, we will continue to monitor the patients from our multiple dose study who enter the extension study for longer-term changes in muscle function scores.  Given the long half-life of ISIS-SMNRx and the complexity of a process that starts with increasing SMN protein production and ends with improvements in muscle function, it makes sense that the effects of ISIS-SMNRx are both dose and time dependent.”

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