First-in-Man Intrathecal Application of Neurite Growth-Promoting Anti-Nogo-A Antibodies in Acute Spinal Cord Injury. (June 2018)

• Record Type: Journal Article
• Authors: Kucher, Klaus; Johns, Donald; Maier, Doris; Abel, Rainer; Badke, Andreas; Baron, Hagen; Thietje, Roland; Casha, Steven; Meindl, Renate; Gomez-Mancilla, Baltazar; Pfister, Christian; Rupp, Rüdiger; Weidner, Norbert; Mir, Anis; Schwab, Martin E.; Curt, Armin
• Is Part Of: Neurorehabilitation & neural repair. Volume 32:Number 6/7(2018)
• Page Start: 578
• Page End: 589
• Publication Date: 2018-06
• Subjects: spinal cord injuries -- regeneration -- neuronal plasticity -- clinical trial -- paraplegia -- tetraplegia; Nervous system -- Diseases -- Patients -- Rehabilitation -- Periodicals; Brain damage -- Patients -- Rehabilitation -- Periodicals; Spinal cord -- Wounds and injuries -- Patients -- Rehabilitation -- Periodicals; Nervous system -- Regeneration -- Periodicals; Neuroplasticity -- Periodicals; 616.804305
• DOI: 10.1177/1545968318776371
• Languages: English
• ISSNs: 1545-9683

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.