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The Many Shapes and Colors of Biomarkers

Posted on August 12th, 2016 by Jeffrey Paul, PhD in Pharma R&D

The future is biomarkers. This is an often-cited phrase you will have heard at drug development symposia and printed in articles. The line reminds me of the film, The Graduate, where Mr. McGuire tells young Benjamin that there is a “great future in in plastics.” Biomarkers are the plastics for personalized medicine, since they give information about the patient status and drug response. The many shapes and colors of biomarkers refers to the wide range of information biomarkers provide to clinicians and drug developers for decision-making. Let’s start with the definition of a biomarker that was agreed to by the joint 2015 joint NIH/FDA workshop on biomarkers (ref 1):

A defined characteristic that is measured as an indicator of normal biological processes, pathogenic processes, or responses to an exposure or intervention, including therapeutic interventions. Molecular, histologic, radiographic, or physiologic characteristics are types of biomarkers. A biomarker is not an assessment of how a patient feels, functions, or survives.

Notice, just about any biological measurement can be called a biomarker. The value of the biomarker, regardless of its assay or platform, is its ease to obtain and its predictive potential for correct decision-making.

Response or Pharmacodynamic (PD) biomarkers

This refers to biomarkers that track the direct pharmacologic response of the drug. If the response biomarker tracks well one can use a PD marker for dose response modeling, patient, enrichment strategies, and go-, no-go decision-making (ref 3). Several of my previous companies had a policy that no drug would be developed, unless it had a PD biomarker, reason being, that having a PD biomarker increases the probability of success. Overall, the most valuable biomarkers are those that track well with clinical outcome. Simple examples are hypoglycemic and anti-clotting drugs. The response biomarkers would be plasma glucose lowering and clotting time, respectively. These PD markers show drug activity and track well with clinical outcome. However for SSRI anti-depressants, serotonin uptake inhibition into blood platelets, as a biomarker, doesn’t predict clinical outcome. It turns out that PET brain imaging of the SSRI drug in the serotonin receptor does track well with therapeutic antidepressant outcome.

PD markers are typically developed by the company who is developing the drug, since they are experts in the drug’s biochemical or physiological actions. FDA urges drug companies to qualify new PD biomarkers since they can be misleading (i.e. false positives and negatives) and not be predictive of a patient’s health or outcome.

Safety biomarkers

A large number of drug development failures are due to unacceptable safety, making validated safety biomarkers highly desirable. The head of a pharma drug safety dept. once told me that he didn’t need biomarkers because as a toxicologist one can autopsy the animals and determine toxicity. He failed to acknowledge that by using safety biomarkers in humans it provides a way to monitor patient safety, other than just providing a large protective exposure buffer. An example of validated cardiac safety biomarkers is ECG QTc prolongation for fatal arrhythmias and serum troponin for myocardial damage. Recently, biomarkers for renal tubular damage in animals have been qualified by FDA.

Diagnostic biomarkers

Diagnostic markers give information about the nature of the patient’s disease and biology. Genetic tests are rapidly becoming useful, especially in oncology. As new research reveals the complexities and human variation of disease, diagnostic markers become important. Diagnostic testing can be in the form of imaging, blood tests, biopsy, or physiological measurements. Blood biochemical markers or simple tests at the physicians office are the most pragmatic for the patient. (ref 2).

Predisposition and Prognostic biomarkers

Predisposition refers to biomarkers (typically genetic) which identifies your risk to develop a disease. A well-known example is the BRAC gene for development of breast cancer, HBA1c for the blood glucose control of a diabetic patient and, APOE4 gene is a marker for high probability for late-onset Alzheimer’s Disease.

Companion diagnostic biomarkers

This is the holy grail of response/prognostic biomarkers – to be used as therapeutic decision-makers for a personalized or a targeted therapeutic. Companion diagnostic biomarkers are those that inform the clinician that the patient has a demonstrated positive response to the drug, or, is predicted to have a positive response—and therefore, will benefit.

In developing companion diagnostics, patient stratification and enrichment (ref 3) becomes key to its success. That is, can the trial be conducted in such a way to enroll patients who will respond to your drug, with high predictability, based on the biomarker. Thus, developers can use biomarkers in a way to increase the likelihood of a drug’s clinical success. An example of a companion diagnostic test and targeted therapy is the HER2 test and use of Herceptin (or similar) for breast cancer. Another example of an orphan drug is Ivacaftor for cystic fibrosis (ref 4). CF is an inherited disease where 4% of the patients have a specific genetic mutation for a chloride transport channel protein, for which Ivacaftor is very efficacious. A positive genetic blood test means that the drug is predicted to be efficacious.

So, in closing, when one is claiming to have biomarkers for the future- ask what kind they are and how they will be used for decision-making for the clinician, the patient, and the drug developer. Be critical of the biomarkers’ ability to guide correct decisions and predict patient outcomes. Not all biomarkers are created equally, some have more value than others.

References:

Ref 1: http://www.fda.gov/downloads/drugs/developmentapprovalprocess/drugdevelopmenttoolsqualificationprogram/ucm510443.pdf

Ref 2:
http://www.personalizedmedicinecoalition.org/Education/The_Basics

Ref 3:
http://www.fda.gov/drugs/newsevents/ucm295054.htm

Ref 4:
http://blogs.fda.gov/fdavoice/index.php/2012/01/how-science-and-strategic-collaboration-led-to-a-new-personalized-cystic-fibrosis-treatment-for-some-patients/

All opinions shared in this post are the author’s own.

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