PMID- 29869587
OWN - NLM
STAT- MEDLINE
DCOM- 20190211
LR  - 20190215
IS  - 1552-6844 (Electronic)
IS  - 1545-9683 (Linking)
VI  - 32
IP  - 6-7
DP  - 2018 Jun
TI  - First-in-Man Intrathecal Application of Neurite Growth-Promoting Anti-Nogo-A 
      Antibodies in Acute Spinal Cord Injury.
PG  - 578-589
LID - 10.1177/1545968318776371 [doi]
AB  - BACKGROUND: Neutralization of central nervous system neurite growth inhibitory 
      factors, for example, Nogo-A, is a promising approach to improving recovery 
      following spinal cord injury (SCI). In animal SCI models, intrathecal delivery of 
      anti-Nogo-A antibodies promoted regenerative neurite growth and functional 
      recovery. OBJECTIVE: This first-in-man study assessed the feasibility, safety, 
      tolerability, pharmacokinetics, and preliminary efficacy of the human anti-Nogo-A 
      antibody ATI355 following intrathecal administration in patients with acute, 
      complete traumatic paraplegia and tetraplegia. METHODS: Patients (N = 52) started 
      treatment 4 to 60 days postinjury. Four consecutive dose-escalation cohorts 
      received 5 to 30 mg/2.5 mL/day continuous intrathecal ATI355 infusion over 24 
      hours to 28 days. Following pharmacokinetic evaluation, 2 further cohorts 
      received a bolus regimen (6 intrathecal injections of 22.5 and 45 mg/3 mL, 
      respectively, over 4 weeks). RESULTS: ATI355 was well tolerated up to 1-year 
      follow-up. All patients experienced >/=1 adverse events (AEs). The 581 reported AEs 
      were mostly mild and to be expected following acute SCI. Fifteen patients 
      reported 16 serious AEs, none related to ATI355; one bacterial meningitis case 
      was considered related to intrathecal administration. ATI355 serum levels showed 
      dose-dependency, and intersubject cerebrospinal fluid levels were highly variable 
      after infusion and bolus injection. In 1 paraplegic patient, motor scores 
      improved by 8 points. In tetraplegic patients, mean total motor scores increased, 
      with 3/19 gaining >10 points, and 1/19 27 points at Week 48. Conversion from 
      complete to incomplete SCI occurred in 7/19 patients with tetraplegia. 
      CONCLUSIONS: ATI335 was well tolerated in humans; efficacy trials using 
      intrathecal antibody administration may be considered in acute SCI.
FAU - Kucher, Klaus
AU  - Kucher K
AD  - 1 Novartis Institutes for BioMedical Research, Basel, Switzerland.
FAU - Johns, Donald
AU  - Johns D
AD  - 2 Novartis Institutes for BioMedical Research Inc, Cambridge, MA, USA.
FAU - Maier, Doris
AU  - Maier D
AD  - 3 BG Trauma Center Murnau, Center for Spinal Cord Injury, Murnau, Germany.
FAU - Abel, Rainer
AU  - Abel R
AD  - 4 Trauma Center Bayreuth, Bayreuth, Germany.
FAU - Badke, Andreas
AU  - Badke A
AD  - 5 Eberhard Karls University, Tubingen, Germany.
FAU - Baron, Hagen
AU  - Baron H
AD  - 5 Eberhard Karls University, Tubingen, Germany.
FAU - Thietje, Roland
AU  - Thietje R
AD  - 6 BG Trauma Hospital Hamburg, Hamburg, Germany.
FAU - Casha, Steven
AU  - Casha S
AD  - 7 University of Calgary, Calgary, Alberta, Canada.
FAU - Meindl, Renate
AU  - Meindl R
AD  - 8 BG University Hospital Bergmannsheil, Ruhr-University, Bochum, Germany.
FAU - Gomez-Mancilla, Baltazar
AU  - Gomez-Mancilla B
AD  - 1 Novartis Institutes for BioMedical Research, Basel, Switzerland.
AD  - 9 McGill University, Montreal, Quebec, Canada.
FAU - Pfister, Christian
AU  - Pfister C
AD  - 1 Novartis Institutes for BioMedical Research, Basel, Switzerland.
FAU - Rupp, Rudiger
AU  - Rupp R
AD  - 10 Heidelberg University Hospital, Heidelberg, Germany.
FAU - Weidner, Norbert
AU  - Weidner N
AD  - 10 Heidelberg University Hospital, Heidelberg, Germany.
FAU - Mir, Anis
AU  - Mir A
AD  - 1 Novartis Institutes for BioMedical Research, Basel, Switzerland.
FAU - Schwab, Martin E
AU  - Schwab ME
AD  - 11 University of Zurich, Zurich, Switzerland.
FAU - Curt, Armin
AU  - Curt A
AD  - 12 Balgrist University Hospital, Zurich, Switzerland.
LA  - eng
PT  - Clinical Trial, Phase I
PT  - Journal Article
PT  - Multicenter Study
PT  - Research Support, Non-U.S. Gov't
DEP - 20180605
PL  - United States
TA  - Neurorehabil Neural Repair
JT  - Neurorehabilitation and neural repair
JID - 100892086
RN  - 0 (Immunoglobulin G)
RN  - 0 (Nogo Proteins)
SB  - IM
MH  - Adolescent
MH  - Adult
MH  - Dose-Response Relationship, Drug
MH  - Feasibility Studies
MH  - Female
MH  - Humans
MH  - Immunoglobulin G/administration & dosage/*therapeutic use
MH  - Injections, Spinal
MH  - Male
MH  - Middle Aged
MH  - Nerve Regeneration/*drug effects
MH  - Neurites/*drug effects
MH  - Nogo Proteins/*immunology
MH  - Paraplegia/*drug therapy/etiology
MH  - Quadriplegia/*drug therapy/etiology
MH  - Recovery of Function/drug effects
MH  - Spinal Cord Injuries/*drug therapy
MH  - Treatment Outcome
MH  - Young Adult
OTO - NOTNLM
OT  - clinical trial
OT  - neuronal plasticity
OT  - paraplegia
OT  - regeneration
OT  - spinal cord injuries
OT  - tetraplegia
EDAT- 2018/06/06 06:00
MHDA- 2019/02/12 06:00
CRDT- 2018/06/06 06:00
PHST- 2018/06/06 06:00 [pubmed]
PHST- 2019/02/12 06:00 [medline]
PHST- 2018/06/06 06:00 [entrez]
AID - 10.1177/1545968318776371 [doi]
PST - ppublish
SO  - Neurorehabil Neural Repair. 2018 Jun;32(6-7):578-589. doi: 
      10.1177/1545968318776371. Epub 2018 Jun 5.