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

  • Kucher, Klaus MD
  • Johns, Donald MD
  • Maier, Doris MD
  • Abel, Rainer MD
  • Badke, Andreas MD
  • Baron, Hagen MD
  • Thietje, Roland MD
  • Casha, Steven MD, PhD
  • Meindl, Renate MD
  • Gomez-Mancilla, Baltazar MD, PhD
  • Pfister, Christian PhD
  • Rupp, Rüdiger PhD
  • Weidner, Norbert MD
  • Mir, Anis PhD
  • Schwab, Martin E. PhD
  • Curt, Armin MD

  • 1 Novartis Institutes for BioMedical Research, Basel, Switzerland

    2 Novartis Institutes for BioMedical Research Inc, Cambridge, MA, USA

    3 BG Trauma Center Murnau, Center for Spinal Cord Injury, Murnau, Germany

    4 Trauma Center Bayreuth, Bayreuth, Germany

    5 Eberhard Karls University, Tübingen, Germany

    6 BG Trauma Hospital Hamburg, Hamburg, Germany

    7 University of Calgary, Calgary, Alberta, Canada

    8 BG University Hospital Bergmannsheil, Ruhr-University, Bochum, Germany

    9 McGill University, Montreal, Québec, Canada

    10 Heidelberg University Hospital, Heidelberg, Germany

    11 University of Zurich, Zurich, Switzerland

    12 Balgrist University Hospital, Zurich, Switzerland

Corresponding Author: Klaus Kucher, Novartis Institutes for BioMedical Research, Novartis Pharma AG, CH-4002 Basel, Switzerland. Email: [email protected]

* Current affiliation: AxonGuidance, MA, USA

† Equal contribution senior authors.

Neurorehabilitation and Neural Repair 32(7):p 578-589, June-July 2018. | 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.

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