Cyclosporine as Therapy for Traumatic Brain Injury

Abstract

Drug development in traumatic brain injury (TBI) has been impeded by the complexity and heterogeneity of the disease pathology, as well as limited understanding of the secondary injury cascade that follows the initial trauma. As a result, patients with TBI have an unmet need for effective pharmacological therapies. One promising drug candidate is cyclosporine, a polypeptide traditionally used to achieve immunosuppression in transplant recipients. Cyclosporine inhibits mitochondrial permeability transition, thereby reducing secondary brain injury, and has shown neuroprotective effects in multiple preclinical models of TBI. Moreover, the cyclosporine formulation NeuroSTAT^® displayed positive effects on injury biomarker levels in patients with severe TBI enrolled in the Phase Ib/IIa Copenhagen Head Injury Ciclosporin trial (NCT01825044). Future research on neuroprotective compounds such as cyclosporine should take advantage of recent advances in fluid-based biomarkers and neuroimaging to select patients with similar disease pathologies for clinical trials. This would increase statistical power and allow for more accurate assessment of long-term outcomes.

Keywords: Biomarkers; Brain injuries, Traumatic; Clinical trials as topic; Cyclosporine; Diffuse axonal injury; Drug evaluation, Preclinical.

Fig. 1

Translational efficacy outcomes of NeuroSTAT in a piglet study with controlled cortical impact injury. Neuroimaging on day 5 post-injury depicting A magnetic resonance imaging anatomical images representative of the median injury in the NeuroSTAT-treated group and B in the placebo group. C Volume of injury measured by manual tracing on each slice of area of increased signal abnormality on FLAIR imaging by board-certified neuroradiologist blinded to treatment group. D Fractional anisotropy in peri-contusional tissue using diffusion tensor imaging. E Neurofilament light (NF-L) in serum day 1–5 post-injury. Data are presented as mean and SEM. *p<0.05. Adapted from [29, 30] with permission from the publisher

Fig. 2

Pharmacodynamic signal of NeuroSTAT in the Copenhagen Head Injury Ciclosporin Phase Ib/IIa clinical trial. Temporal profile of brain injury biomarker neurofilament light (NF-L) in cerebrospinal fluid (CSF). A Individual levels of NF-L in CSF samples drawn at predose, during the continuous NeuroSTAT infusion, and after treatment had ended. Dashed vertical lines indicate the start and stop of infusion. CSF, cerebrospinal fluid. B Slopes of NF-L change during NeuroSTAT infusion and during follow-up after infusion stop. Data are presented as mean and SEM. *p<0.05. Adapted from [28] with permission from the publisher