Rho Inhibitor VX-210 in Acute Traumatic Subaxial Cervical Spinal Cord Injury: Design of the SPinal Cord Injury Rho INhibition InvestiGation (SPRING) Clinical Trial

Abstract

Traumatic spinal cord injury (SCI) is associated with a lifetime of disability stemming from loss of motor, sensory, and autonomic functions; these losses, along with increased comorbid sequelae, negatively impact health outcomes and quality of life. Early decompression surgery post-SCI can enhance patient outcomes, but does not directly facilitate neural repair and regeneration. Currently, there are no U.S. Food and Drug Administration–approved pharmacological therapies to augment motor function and functional recovery in individuals with traumatic SCI. After an SCI, the enzyme, Rho, is activated by growth-inhibitory factors and regulates events that culminate in collapse of the neuronal growth cone, failure of axonal regeneration, and, ultimately, failure of motor and functional recovery. Inhibition of Rho activation is a potential treatment for injuries such as traumatic SCI. VX-210, an investigational agent, inhibits Rho. When administered extradurally after decompression (corpectomy or laminectomy) and stabilization surgery in a phase 1/2a study, VX-210 was well tolerated. Here, we describe the design of the SPRING trial, a multicenter, phase 2b/3, randomized, double-blind, placebo-controlled clinical trial to evaluate the efficacy and safety of VX-210 (NCT02669849). A subset of patients with acute traumatic cervical SCI is currently being enrolled in the United States and Canada. Medical, neurological, and functional changes are evaluated at 6 weeks and at 3, 6, and 12 months after VX-210 administration. Efficacy will be assessed by the primary outcome measure, change in upper extremity motor score at 6 months post-treatment, and by secondary outcomes that include question-based and task-based evaluations of functional recovery.

Advances in the Signaling Pathways Downstream of Glial-Scar Axon Growth Inhibitors

“…Because of the promising results of phase I/IIa clinical trial, VX-210 was moved to a phase IIb/III SPRING (SCI Rho inhibition investigation) trial for acute traumatic cervical SCI (NCT02669849). The major goal of this randomized, double-blind, placebo-controlled trial was to evaluate its safety and efficacy in promoting functional recovery by Rho inhibition (Fehlings et al, 2018 ). However, this trial was terminated by Vertex probably because of lack of efficacy after an interim analysis.…”

The Higher Sensitivity of GABAergic Compared to Glutamatergic Neurons to Growth-Promoting C3bot Treatment Is Mediated by Vimentin

“…This has been investigated in different animal models (Dubreuil et al, 2003 ; Boato et al, 2010 ; Loske et al, 2012 ). Moreover, systematic reviews and meta-analyses (Watzlawick et al, 2014 ), as well as clinical trials in humans, have subsequently confirmed these findings (McKerracher and Anderson, 2013 ; Fehlings et al, 2018 ).…”

Neuroprotektion und Regeneration im Zentralnervensystem

“…Ihnen gemeinsam ist, dass ihr am detailliertesten untersuchter Wirkmechanismus nach zellulärer Internalisierung auf einer enzymatischen Inaktivierung von kleinen GTP-bindenden Proteinen der Rho-Familie (A, B und C) beruht [16]. Da, wie vorab erwähnt, insbesondere die Aktivierung von RhoA in der überwiegenden Mehrzahl der untersuchten Modellsysteme zur neuronalen Regeneration hemmend auf das Auswachsen von Axonen wirkt, stellt eine Hemmung der Hemmung ein attraktives Ziel zur Förderung des neuronalen (Wieder-)Auswachsens dar, was bereits Eingang in klinische Studien im Zusammenhang mit der Querschnittslähmung gefunden hat [17].…”