There is increasing interest in pharmacodynamic biomarkers, defined as proteins in the blood that show response to a drug. The implementation of biomarkers into a drug development program very much depends on ‘context of use’ – How exactly is the biomarker going to be studied, and the data interpreted, to aid in drug development?
Three possible ‘contexts of use’ are:
- Mechanism of action of drug. A biomarker may show that a drug is hitting its intended target, and thus is working as you expect. This is more for a proof-of-principle, rather than testing for efficacy.
- Dose-finding. Dose finding (or dose optimization) is when different dosage levels of a drug are tested in a patient to identify the highest dose that is safe, and the lowest dose that is efficacious (shows clinical benefit). Finding this therapeutic window is a very important part of drug development, but is often under-emphasized. Biomarkers may provide subjective, reliable and rapid read outs for identification of the optimal dose.
- Surrogate outcome measure. This context of use is when the biomarker is felt to be a reliable predictor of later clinical changes. Dystrophin protein in muscle was used as a surrogate outcome measure in the recent Sarepta clinical trials leading to drug approval.
FED and the CDMRP program have been central in promoting biomarker research, and implementation of biomarkers in clinical drug development programs. FED has supported Yetrib Hathout and the CINRG network to define the natural history of blood biomarkers in DMD, compare these to the mdx mouse biomarkers, and define response to therapies.