Emerging Safety Biomarkers
“Safety-related problems continue to be one of the major causes of drug attrition in preclinical and clinical development,” said Rakesh Dixit, senior director and global head of toxicology at MedImmune (www.medimmune.com). “The search for biomarkers that can be objectively linked to adverse effects and target organ toxicities, and can then be translated from preclinical to clinical development, is becoming an urgent matter for academics, federal agencies, and pharmaceutical companies alike.”
One of the key points, said Dixit, is that the safety of the compound and drug in question is absolutely crucial. “In the preclinical stages, you can look and see what effect a compound has in animals, but when you attempt to examine the effects in man, it is harder to do because of the limited noninvasive tests.”
One of the primary challenges in using biomarkers to examine safety is that the tools available to reveal that information are already 20–30 years old. “With regard to validating safety, there is really nothing out there that is cutting-edge in regards to detecting low-level adverse responses noninvasively,” stated Dixit.
However, there are newer and noninvasive ways to look at biomarkers, such as analyzing whole blood, plasma, urine, and limited human biopsy samples (e.g., skin, muscle, buccal mucosal cells), which are “probably the best line of analysis in humans right now,” reported Dixit. “The next line would be to do a genetic profile, and that’s easier to do, too. But if you’re doing a clinical trial, repeat muscle biopsies, for example, are harder to get.”
Dixit also discussed the difference in definition between safety biomarkers and toxicity biomarkers. “Some people use these terms interchangeably, but there are subtle differences,” explained Dixit. “The key thing to keep in mind is that toxicology is about how high you can push the dose before things go wrong. Safety is how low you can go in dose response before subtle, low-grade toxicities may appear.
“Safety biomarkers have a higher bar to reach than efficacy biomarkers. It’s harder to evaluate. But, the best way to validate is to conduct exploratory safety biomarker analyses and see what you experience in the clinic along with conventional biomarkers. However, the burden of proof is high, and the key challenge facing newer biomarkers is obtaining that proof,” Dixit said.