Early De-risking Strategy for Novel Biotherapeutics

Nonclinical to clinical correlations of biotherapeutics generally support the utility of nonclinical studies for predicting adverse clinical responses, if the fidelity of the pharmacodynamics of human biotherapeutics is maintained in nonclinical models. However, toxicities associated with immunomodulation—opportunistic infections, cytokine release syndrome, and other indirect outcomes of immunomodulation—are less likely to be predicted by routine nonclinical studies. Predicting adverse reactions to biotherapeutics is further complicated by the rapidly expanding array of modalities. Predicting adverse reactions to biotherapeutics is further complicated by the rapidly expanding array of modalities. In this chapter, we discuss safety considerations for establishing the safety profiles for various modalities of biotherapeutics in early nonclinical development and provide examples of adverse events, with special emphasis on immunotoxicity. Special approaches to predicting immunotoxicity due to on-target and off-target toxicities to ensure the well-being of healthy volunteers as well as patients are also discussed. Novel and scientifically appropriate additional nonclinical studies are necessary to make informed drug development decisions in addition to information gathered from routine nonclinical studies.