Article

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.

Langue : ANGLAIS