New medicinal compounds are proteins. These biopharmaceuticals can trigger immune responses causing side effects such as rash, fever, and fall in blood pressure. As long as these responses do not interfere with the effectiveness of the compound (e.g. via formation of anti-drug antibodies), or seriously hamper the patient’s well-being, the occurrence of these immune responses may be accepted by patients and pharmaceutical companies and regulatory bodies; the clinical development of the compound is not necessarily halted or terminated. For example, a monoclonal antibody like Herceptin, commonly used for the treatment of metastatic breast cancer, induces fever and inflammatory symptoms in 40-60% of all treated patients. As long as the benefit-risk balance for a drug is favorable, clinical use of the compound is defendable. However, it is remarkable from a scientific point-of-view that we administer compounds to humans when these inflammatory effects are poorly understood.
Some intravenously administered biopharmaceuticals reach a maximal plasma concentration at a time beyond the infusion duration. This phenomenon cannot be explained by conventional pharmacokinetic rules, and potential causes and consequences have only be speculated on so far.
These are examples of uncritical acceptance that certain drugs may behave ‘odd’. At CHDR we aim to optimally understand the behavior and effects of drugs, even if it concerns long-term marketed drugs. CHDR invests in the investigation of insufficiently understood drug behavior/effects. For example, we have recently demonstrated that therapeutic proteins non-specifically stick to the endothelium, which translates into delayed maximal plasma concentrations. Furthermore, we are relating inflammatory effects of biopharmaceuticals in vivo to drug responses observed in cell-based systems, aiming to develop in vitro methodology that better predicts drug effects in vivo. Importantly, a more extensive exploration of drug effects may exceed the level ‘nice to know’, as demonstrated by the first-in-human trial with anti-CD28 antibody TGN1412. All 6 healthy volunteers receiving this investigational compound experienced cytokine release syndrome, resulting in a potentially long-term disruption of the immune system. Evaluation of the TeGenero case by key opinion leaders led to the conclusion that the problems resulted from unforeseen biological drug action in humans, rather than from clinical misconduct. This case shows that drugs affecting previously unexplored pathophysiological pathways require careful exploration in tailored early phase clinical studies, with biomarkers that are fit-to-purpose.
CHDR advocates that recent evolutions in drug development require a more direct approach to monitor intended and unintended drug effects. For biopharmaceuticals and compounds with new mechanisms-of-action, biomarkers reflecting early/direct drug effects on cells or tissues should be selected. This will allow a more efficient, more rational, and safer translation between different stages in drug development: from animals to humans, from in vitro experiments on human cells to clinical studies, and from healthy volunteers to the targeted patient population. Such ‘translational biomarkers’ will play an increasingly important role in future drug development.
Research Director Translational Biomarkers