Date: 2014-02-21
Type of information: Initiation of preclinical development
phase:
Announcement: interim results
Company: Isis Pharmaceuticals (USA)
Product: ISIS-SMNRx (antisense oligonucleotide targeted to the SMN2 gene)
Action
mechanism: antisense oligonucleotide. ISIS-SMNRx is an antisense drug that has been designed to potentially treat all types of childhood SMA by altering the splicing of SMN2 gene, that leads to the increased production of fully functional SMN protein. In January 2012, Isis Pharmaceuticals and Biogen Idec entered into a preferred partner alliance that provides Biogen Idec an option to develop and commercialize ISIS-SMNRx. Under the agreement, Biogen Idec has the option to license ISIS-SMNRx until completion of the first successful Phase 2/3 study.
Disease: spinal muscular atrophy (SMA)
Therapeutic area: Neuromuscular diseases - Rare diseases - Genetic diseases
Country: USA
Trial
details: In 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. (NCT01703988)
Latest
news: * On February 21, 2014, Isis Pharmaceuticals has 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.
In the interim analysis of this ongoing study, 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.
In addition, analysis of CSF samples from both the single dose and the ongoing multiple dose studies demonstrated dose-dependent increases in SMN protein levels over time in patients treated with ISIS-SMNRx. In the single dose study, SMN protein levels more than doubled in the two highest dose cohorts with average increases of approximately 120% and 160% compared to baseline observed approximately 9-14 months after dosing in the 6 mg and 9 mg cohorts, respectively. Similarly, in the multiple dose study, patients in the 9 mg cohort all exhibited a substantial increase in SMN protein levels. At Day 86, SMN protein levels more than doubled with an average increase of 115% compared to baseline.
Isis plans to report additional detail from this study at an upcoming medical conference. \"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.
