2. Academic Validation
  3. First-in-Man Intrathecal Application of Neurite Growth-Promoting Anti-Nogo-A Antibodies in Acute Spinal Cord Injury

First-in-Man Intrathecal Application of Neurite Growth-Promoting Anti-Nogo-A Antibodies in Acute Spinal Cord Injury

  • Neurorehabil Neural Repair. 2018 Jun;32(6-7):578-589. doi: 10.1177/1545968318776371.
Klaus Kucher 1,  Donald Johns 2,  Doris Maier 3,  Rainer Abel 4,  Andreas Badke 5,  Hagen Baron 5,  Roland Thietje 6,  Steven Casha 7,  Renate Meindl 8,  Baltazar Gomez-Mancilla 1 9,  Christian Pfister 1,  Rüdiger Rupp 10,  Norbert Weidner 10,  Anis Mir 1,  Martin E Schwab 11,  Armin Curt 12
Affiliations

Affiliations

  • 1 1 Novartis Institutes for BioMedical Research, Basel, Switzerland.
  • 2 2 Novartis Institutes for BioMedical Research Inc, Cambridge, MA, USA.
  • 3 3 BG Trauma Center Murnau, Center for Spinal Cord Injury, Murnau, Germany.
  • 4 4 Trauma Center Bayreuth, Bayreuth, Germany.
  • 5 5 Eberhard Karls University, Tübingen, Germany.
  • 6 6 BG Trauma Hospital Hamburg, Hamburg, Germany.
  • 7 7 University of Calgary, Calgary, Alberta, Canada.
  • 8 8 BG University Hospital Bergmannsheil, Ruhr-University, Bochum, Germany.
  • 9 9 McGill University, Montreal, Québec, Canada.
  • 10 10 Heidelberg University Hospital, Heidelberg, Germany.
  • 11 11 University of Zurich, Zurich, Switzerland.
  • 12 12 Balgrist University Hospital, Zurich, Switzerland.
PMID: 29869587 DOI: 10.1177/1545968318776371
Abstract

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.

Keywords

clinical trial; neuronal plasticity; paraplegia; regeneration; spinal cord injuries; tetraplegia.

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