Biomarker is an umbrella term that extends across the entire spectrum of drug development, encompassing a variety of pharmacogenomic, proteomic, metabolic, pharmacological, and toxicological markers that contribute information on a drugs target, pathway, mechanism, safety, or effect on disease progression.
Dr. Littman classified biomarkers into three types: target, mechanism, and outcome. “Target biomarkers demonstrate drug interaction with targets, such as receptor occupancy using a positron emission tomography ligand,“ he explained.
“Mechanism biomarkers demonstrate physiological, biochemical, genomic, or behavioral changes downstream of the drug target, such as glucose reduction for a diabetes drug,“ Dr. Littman added.
Finally, outcome biomarkers act as substitutes for clinical efficacy or safety and are independent of drug mechanism. “Quantifying viral load for antiviral drugs, is an example of this.“
Another class of biomarkers is toxicity biomarkers that report on the toxicology of a drug in a specific model system. “Investing in exploratory toxicology, earlier in the drug discovery process is particularly important for unprecedented targets, that is, targets where there is no drug already available as a precedent for your approach,“ said Dr. Rolfe.
For Dr. Littman, a thorough understanding of a drugs mechanism is a critical tool, early in the development pipeline, and biomarkers play an important role in decision-making at this stage. “As opposed to past practices, we no longer take mystery mechanisms into human testing.“ One of the specific benefits of establishing a robust mechanism is in defining the therapeutic index—essentially, a comparison of the amount that causes the therapeutic effect to the amount that causes toxic effects.
“Most drugs will have toxicity associated with very high doses, so you have to understand the mechanism of action to optimize dose selection for efficacy and minimize off-target toxicity or target-related toxicity,“ Dr. Littman explained.
“This is much easier to do if you can construct a pharmacokinetic model and select doses that optimize the desired therapeutic index,“ he added. “We have reported on a novel immunosuppressant that targets JAK3 but also has some unwanted JAK2 activity. By using biomarkers of JAK3 and JAK2 activity we can select doses that optimize JAK3 inhibition and minimize JAK2 mediated toxicity.“