TY - JOUR
T1 - Results from a phase 1 study of nusinersen (ISIS-SMN Rx) in children with spinal muscular atrophy
AU - Chiriboga, Claudia A.
AU - Swoboda, Kathryn J.
AU - Darras, Basil T.
AU - Iannaccone, Susan T.
AU - Montes, Jacqueline
AU - De Vivo, Darryl C.
AU - Norris, Daniel A.
AU - Bennett, C. Frank
AU - Bishop, Kathie M.
N1 - Publisher Copyright:
© 2016 American Academy of Neurology.
PY - 2016/3/8
Y1 - 2016/3/8
N2 - Objective: To examine safety, tolerability, pharmacokinetics, and preliminary clinical efficacy of intrathecal nusinersen (previously ISIS-SMN Rx), an antisense oligonucleotide designed to alter splicing of SMN2 mRNA, in patients with childhood spinal muscular atrophy (SMA). Methods: Nusinersen was delivered by intrathecal injection to medically stable patients with type 2 and type 3 SMA aged 2-14 years in an open-label phase 1 study and its long-term extension. Four ascending single-dose levels (1, 3, 6, and 9 mg) were examined in cohorts of 6-10 participants. Participants were monitored for safety and tolerability, and CSF and plasma pharmacokinetics were measured. Exploratory efficacy endpoints included the Hammersmith Functional Motor Scale Expanded (HFMSE) and Pediatric Quality of Life Inventory. Results: A total of 28 participants enrolled in the study (n 6 in first 3 dose cohorts; n 10 in the 9-mg cohort). Intrathecal nusinersen was well-tolerated with no safety/tolerability concerns identified. Plasma and CSF drug levels were dose-dependent, consistent with preclinical data. Extended pharmacokinetics indicated a prolonged CSF drug half-life of 4-6 months after initial clearance. A significant increase in HFMSE scores was observed at the 9-mg dose at 3 months postdose (3.1 points; p 0.016), which was further increased 9-14 months postdose (5.8 points; p 0.008) during the extension study. Conclusions: Results from this study support continued development of nusinersen for treatment of SMA. Classification of evidence: This study provides Class IV evidence that in children with SMA, intrathecal nusinersen is not associated with safety or tolerability concerns.
AB - Objective: To examine safety, tolerability, pharmacokinetics, and preliminary clinical efficacy of intrathecal nusinersen (previously ISIS-SMN Rx), an antisense oligonucleotide designed to alter splicing of SMN2 mRNA, in patients with childhood spinal muscular atrophy (SMA). Methods: Nusinersen was delivered by intrathecal injection to medically stable patients with type 2 and type 3 SMA aged 2-14 years in an open-label phase 1 study and its long-term extension. Four ascending single-dose levels (1, 3, 6, and 9 mg) were examined in cohorts of 6-10 participants. Participants were monitored for safety and tolerability, and CSF and plasma pharmacokinetics were measured. Exploratory efficacy endpoints included the Hammersmith Functional Motor Scale Expanded (HFMSE) and Pediatric Quality of Life Inventory. Results: A total of 28 participants enrolled in the study (n 6 in first 3 dose cohorts; n 10 in the 9-mg cohort). Intrathecal nusinersen was well-tolerated with no safety/tolerability concerns identified. Plasma and CSF drug levels were dose-dependent, consistent with preclinical data. Extended pharmacokinetics indicated a prolonged CSF drug half-life of 4-6 months after initial clearance. A significant increase in HFMSE scores was observed at the 9-mg dose at 3 months postdose (3.1 points; p 0.016), which was further increased 9-14 months postdose (5.8 points; p 0.008) during the extension study. Conclusions: Results from this study support continued development of nusinersen for treatment of SMA. Classification of evidence: This study provides Class IV evidence that in children with SMA, intrathecal nusinersen is not associated with safety or tolerability concerns.
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U2 - 10.1212/WNL.0000000000002445
DO - 10.1212/WNL.0000000000002445
M3 - Article
C2 - 26865511
AN - SCOPUS:84960517144
SN - 0028-3878
VL - 86
SP - 890
EP - 897
JO - Neurology
JF - Neurology
IS - 10
ER -