title: Results from a phase 1 study of nusinersen (ISIS-SMN(Rx)) in children with spinal muscular atrophy.
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.
  
  
  METHODS
  This study provides Class IV evidence that in children with SMA, intrathecal nusinersen is not associated with safety or tolerability concerns.
authors: 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.
authors: Claudia A
authors: CA
authors: Chiriboga
authors: 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.
authors: Kathryn J
authors: KJ
authors: Swoboda
authors: 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.
authors: Basil T
authors: BT
authors: Darras
authors: 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.
authors: Susan T
authors: ST
authors: Iannaccone
authors: 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.
authors: Jacqueline
authors: J
authors: Montes
authors: 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.
authors: Darryl C
authors: DC
authors: De Vivo
authors: 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.
authors: Daniel A
authors: DA
authors: Norris
authors: 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.
authors: C Frank
authors: CF
authors: Bennett
authors: 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.
authors: Kathie M
authors: KM
authors: Bishop
mesh_terms: D000293:Adolescent; D002648:Child; D002675:Child, Preschool; D015331:Cohort Studies; D004305:Dose-Response Relationship, Drug; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D007278:Injections, Spinal; D008297:Male; D009134:Muscular Atrophy, Spinal / Q000175:diagnosis* / Q000188:drug therapy*; D009841:Oligonucleotides / Q000008:administration & dosage*
chemical_list: D009841:Oligonucleotides; C000590926:nusinersen