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Abstract
The primary goal of this meeting was to propose strategies for expediting the Phase 0 drug research process for valuable drug candidate identification by taking full advantage of innovative technologies and cost-effective decision-making procedures. A theme that recurred throughout the meeting was the identification, validation and full exploitation of specific integrated biomarkers, which serve as quantifiable indicators of normal biologic processes, pathophysiological states and responses to therapeutics. These are indispensable tools for generating reliable data from proof-of-mechanism, proof-of-principle and proof-of-concept investigations. Real-life biomarkers can also be obtained from modeling and simulating preclinical and early clinical findings. The successful migration of these and other pertinent data into predictive models of efficacy, toxicity and diseases is a sine qua non for translation medicine to become a discipline that realistically predicts clinical outcomes. Indeed, the discovery of novel, efficacious drug treatments for neurological and psychiatric diseases is intrinsically dependent on reliable translation medicine approaches. Novel microdosing technologies that enable Phase 0 pharmacokinetic profiling of drug candidates in humans improve the success rate of the drug development process. In addition, the clear identification of risk, the calculation of its probability, the assessment of its severity in relation to medical need and the availability of a management strategy can help to establish realistic safety goals. Performing in vitro and in vivo cardiac safety evaluation earlier in Phase 0 research can substantially reduce the number of drug candidates that eventually fail on the basis of unacceptable cardiac harm. Emerging ‘omics’ technologies allow the identification of species-specific toxicity and the reliable extrapolation of non-clinical observations to humans. Regulatory perspectives on the use of non-clinical information to gain approval for Phase I studies were given special consideration. In particular, key recommendations for preventing tragic events, such as those that resulted from a cytokine storm caused by the CD28 tumour antibody, TGN-1412, in healthy volunteers, were the subject of detailed scrutiny. Interestingly, the bispecific CD9/CD3 tumour antibody MT-103 produces target antigen-redirected lysis without causing notable adverse effects. In conclusion, this conference provided participants with state-of-the-art approaches for improving the present low predictive power of non-clinical information regarding clinical outcome.
Acknowledgements
The author assumes responsibility for any personal views expressed in this report and thanks warmly D de Alwis, D Fitzgerald, H Holzgrefe, S Kaddam, J Lampe, G Lappin, J Luthman, SO Mueller, H Parmar, M Perrone, I Pragst, T Reum, A Roach, F Rombout, R Small, A Wallnoeffer and A Wolf for critically reading the manuscript.