Lessons Learnt from Past Clinical Trials of Neuroprotective Agents

The brief history of neuroprotective drug discovery and development over the past 20-25 years outlined above could be fairly characterized as a series of often high-profile and expensive failures. Although these have largely dampened the enthusiasm of the pharmaceutical industry for this therapeutic area, much has been learned that could, and should, serve as a roadmap for future efforts aimed at pharmacological neuroprotection and improved neurological recovery after stroke, TBI, and SCI. Postmortem analyses of mistakes made in stroke15,16 and TBI19 drug development have been published, and a careful reading of these reveals a host of shortcomings in past preclinical testing of candidate neuroprotective agents and in clinical trial design and conduct that need to be addressed in the future. A summary of these issues is given in Table 2.

Firstly, the discovery of the first generation of neuroprotective agents, which included glutamate receptor antagonists, calcium channel blockers, and antioxidants, occurred prior to the elucidation of an adequate understanding of the intricacies of the targeted secondary injury mechanisms. In each case, knowledge of the time course and interrelationships of these events and their therapeutic windows for effective treatment intervention was lacking. In the case of reactive oxygen mechanisms, knowledge of the key ROS species and their sources and cellular targets was inadequate to guide the design of optimum antioxidant neuroprotective new compound entities. Secondly, the preclinical efficacy testing of new compound entities was, in some cases, woefully inadequate, and even naive. In contrast, it is now realized that several issues need to be addressed in preclinical evaluations in order to guide the design of clinical trials. These include:

1. the demonstration of the time course of the target pathophysiological mechanism in relevant animal models - this is needed to determine when treatment needs to begin and for how long it must be maintained

2. rigorous dose-response analysis with regard to effects on the target mechanism, and ability to reduce posttraumatic neurodegeneration and improve behavioral recovery

3. correlation of neuroprotective action with plasma and CNS tissue pharmacokinetics

4. correlation of plasma and CNS pharmacokinetics with a plasma or CNS biomarker (e.g., LP products)

5. comparison of single versus multiple dose regimens in order to establish the optimum treatment regimen (i.v. bolus plus infusion make the most sense)

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