A critical appraisal of the NXY-059 neuroprotection studies for acute stroke: a need for more rigorous testing of neuroprotective agents in animal models of stroke.

Neuroprotection represents a failed strategy to improve outcome after acute ischemic stroke (AIS). However, most neuroprotective drugs have been inadequately studied in animal stroke models, which led to the creation of the STAIR guidelines on preclinical and clinical testing of therapeutics for AIS. NXY-059, a free radical spin trap agent, was felt by many to have followed these criteria and it was recently shown to improve outcome in AIS patients in the SAINT I trial. However, the repeat, SAINT II trial was a neutral study, the results of which cast doubt on neuroprotection as a viable strategy for AIS. A critical analysis of the NXY-059 preclinical data, however, reveals several shortcomings that have not been addressed in the literature. This report contends that the preclinical evaluation of NXY-059 lacked strenuous testing and was not shown to reproducibly lead to robust protection in extended time windows in clinically relevant stroke models, at several different academic research laboratories. The clinical trials of NXY-059 were inadequately designed, in part, because of inappropriate treatment windows and inclusion of diverse stroke patients. Future neuroprotective agents need more rigorous testing in animal models of focal cerebral ischemia and appropriate evaluation in clinical studies that better match the preclinical data.