More aggressive companies are looking to discover biomarkers that will help predict patients' response for an entire class
of drugs. "The emergence of class-specific biomarkers is inevitable over the next five years," Dracopoli says. A current example
comes from BMS' work on its new drug ixabepilone (BMS 247550). Because ixabepilone and Taxol (paclitaxel) both affect polymerization
of tubulin, preventing cellular division, it is likely they share some markers for drug response.
This hypothesis was tested, beginning with human cell lines and animal testing, and showed that gene changes from IC50 response
in a human cell line predictive model had similarities with a response profile in animals. By the time the compound progressed
to an early Phase II trial, the goal was to prospectively test whether these markers that had been identified (or some subset)
could be used in human patients to predict drug response of the tumor.
Some similarity in gene changes was evident in the Phase II neoadjuvant trial, showing that biomarkers are a very useful tool
in critical path research. This predictive profile will be tested in subsequent clinical studies.
By using biomarkers this way in Phase II and III trials, BMS is enabling an offense strategy, with implications for other,
competitive compounds in the same class. In addition, class-specific rather than drug-specific biomarkers may be more cost
effective at the physician/patient level—an important consideration in promoting the widespread use of personalized treatment.
Imaging Sometimes the key to understanding a disease or therapy is a matter of understanding not just what biomarkers to measure,
but where they are localized—for example, discovering where specific receptors are occupied or not. In those cases, biomarkers
enhance functional imaging. "Looking at the biological activity within an anatomical context (for example, receptor occupancy)
can be much more important than looking at solely the anatomy," says Lilly's Edmonds.
In a Novartis investigation using a PET tracer to assess drug activity and mechanism of action (via displacement) for "a nervous
system target in a psychiatric disease that is by definition not well defined," researchers found a high concordance between
tracer distribution and location of specific receptors. This outcome confirmed the drug activity and mechanism and supported
assessment of receptor distribution in humans to support clinical development of the drug candidate.
Biomarkers in Clinical Trials
After two years, Vonderscher says, biomarkers "have reached full integration across R&D" at Novartis, and the company has
early biomarker plans in place for each compound. But that doesn't mean that 100 percent—or even close to 100 percent—of Novartis
trials include innovative biomarkers. That will not happen until programs launched two years ago progress to Phase IV. Meanwhile,
the company is putting diagnostic partnerships in place, with an eye toward developing companion tests for drug candidates.
Another area where the company has made great progress is in using biomarkers in Phase IV trials, especially in oncology,
CNS, and cardiovascular. The opportunity in these trials is to study the disease, gain samples for additional testing, and
define subsets of patients (for patient stratification based on risk or efficacy).
Novartis routinely develops safety biomarkers for new compounds early in research. By knowing the target and looking at which
organs are affected, researchers can more easily identify a compound's impact on the wrong organs.
"We look within a given pathway, both upstream and downstream of the target, to look for any indication of toxicity," Vonderscher
says. "Consequently, and as a 'positive' by-product, we have several examples in the pipeline where a drug that failed in
early safety testing was identified to hit another target that could be interesting for another disease," Vonderscher says.
For example, a CNS drug was dropped because it induced apoptosis of gastric secreting cells in the stomach. In the old paradigm
the compound would simply have been "killed" because it affected the wrong organ. Under the new paradigm it can be explored
as a potential treatment in some stomach diseases. "From a 'failed' compound with a clear phenotypic read-out, we can find
a new pathway/target important for another disease," Vonderscher says.