Biologics in the Pipeline: Large Molecules With High Hopes or Bigger Risks?

550 • J Clin Pharmacol 2007;47:550-552 T more than ever, big pharmaceutical companies are venturing into the biotechnology arena with the hope that novel therapeutic biologics will fundamentally reshape the pharmaceutical landscape. Several companies are even projecting optimistically that, within the decade, therapeutic biologics will comprise a majority of their commercial portfolios. Therapeutic biologics derived from proteins are generally thought to be less prone to untoward effects than small molecular entities derived from chemical synthesis. Although this may often hold true for certain targeted biologics, this may not be the case for all biologics. The recent unexpected outcome of the first-in-human (FIH) study of TGN1412 clearly indicates the need for extra precaution whenever an investigational product is first evaluated in humans— but perhaps even more so during initial clinical investigation of monoclonal antibodies (mAbs) designed as agonists. In the TGN1412 FIH study, for example, this superagonist anti-CD28 mAb was rapidly administered intravenously (ie, the infusion lasted 3 to 6 minutes) to 6 healthy volunteers in short sequence (ie, 10 minutes apart). Even though the selected FIH dose was only 1/500th of the reported safe animal dose, all 6 volunteers experienced an acute, immunemediated cytokine storm that unfortunately led to multiorgan failure. The Medicines and Healthcare Products Regulatory Agency (MHRA), in conjunction with the German Regulatory Authorities, subsequently conducted a series of inquiries and inspections. Their final report recently concluded that the tragic events were not the result of any errors in TGN1412 manufacturing, formulation, dilution, or administration. An independent Expert Scientific Group (ESG) appointed by the Secretary of State for Health in the United Kingdom, however, determined that— although the animal safety and toxicology studies of TGN1412 adequately fulfilled the requisite regulatory requirements—the overall preclinical program did not adequately predict a safe FIH dose. The ESG then listed 22 specific recommendations for ensuring the safety of future FIH study participants. These recommendations particularly addressed methods of determining safe starting doses in humans as well as selecting appropriate observation time periods between sequential dose administrations in early phase I studies. The serious adverse events that occurred during the TGN1412 FIH study were, in hindsight, not altogether surprising considering the inherent properties of therapeutic biologics. That is, because therapeutic mAbs are purposefully engineered to show high affinities for specific human protein targets, these mAbs may show little or no binding to the homologous animal counterparts. By contrast, classic small-molecule drugs are often more likely to show similar potencies in animals and humans. Consequently, Hansen and Leslie recommended that future preclinical studies of antibodybased biologics “should also include comparative measurements of the binding affinities for both human antigen and primate antigen, to control for unforeseen variations in protein structure.” The TGN1412 incident will likely have an industrywide effect on future development strategies of novel biologic therapies. The more cautious stepwise approach that is commonly used to develop small molecular drugs, for example, might actually be safer and just as useful in the development of large molecular biologics. At the very least, stricter scrutiny of the transition from preclinical to FIH studies of therapeutic biologics is expected from institutional review boards, patient advocacy groups, and worldwide regulatory authorities alike. Biologics in the Pipeline: Large Molecules With High Hopes or Bigger Risks?