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Neurology. 2016 Mar 8;86(10):890-7. doi: 10.1212/WNL.0000000000002445. Epub 2016 Feb 10.

Results from a phase 1 study of nusinersen (ISIS-SMN(Rx)) in children with spinal muscular atrophy.

Author information

1
From the Departments of Neurology (C.A.C., J.M., D.C.D.) and Rehabilitative and Regenerative Medicine (J.M.), Columbia University, New York, NY; Department of Neurology (K.J.S.), University of Utah, Salt Lake City; Department of Neurology (B.T.D.), Boston Children's Hospital, Boston, MA; Department of Pediatrics (S.T.I.), University of Texas Southwestern Medical School, Dallas; and Ionis Pharmaceuticals, Inc. (formerly Isis Pharmaceuticals, Inc.) (D.A.N., C.F.B., K.M.B.), Carlsbad, CA. cac3@cumc.columbia.edu.
2
From the Departments of Neurology (C.A.C., J.M., D.C.D.) and Rehabilitative and Regenerative Medicine (J.M.), Columbia University, New York, NY; Department of Neurology (K.J.S.), University of Utah, Salt Lake City; Department of Neurology (B.T.D.), Boston Children's Hospital, Boston, MA; Department of Pediatrics (S.T.I.), University of Texas Southwestern Medical School, Dallas; and Ionis Pharmaceuticals, Inc. (formerly Isis Pharmaceuticals, Inc.) (D.A.N., C.F.B., K.M.B.), Carlsbad, CA.

Abstract

OBJECTIVE:

To examine safety, tolerability, pharmacokinetics, and preliminary clinical efficacy of intrathecal nusinersen (previously ISIS-SMNRx), 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.

PMID:
26865511
PMCID:
PMC4782111
DOI:
10.1212/WNL.0000000000002445
[Indexed for MEDLINE]
Free PMC Article
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