Pharmacogenomics Strategies Hypothesis Based Approaches

Certain target- or disease-related genes may be obvious candidates for Pgx investigation. Replacement therapies have clear diagnostic paradigms and are not generally considered for Pgx analysis. Most Pgx studies focus on protein therapies that augment or interfere with existing pathways within a heterogeneous disease setting. For example, oncology agents may be directed against pathways that are upregulated in only a subset of tumors. Likewise, elevation of a specific cytokine may identify a population of autoimmune patients who would benefit from targeted blockade of that factor. Candidates for Pgx analysis might include both the therapeutic target and genes that are mechanistically related to that target.

The drug target must be considered in relation to the heterogeneity of the disease population, as most diseases are polygenic in nature and few therapies are effective in all treated patients. As the size of the indication is usually considered quite early in development, it makes sense to anticipate patient selection strategies and estimate the fraction of the disease population likely to benefit from a targeted approach. For novel pathways, this may require additional epidemiological or clinical association research. We suggest to

■ develop a list of candidate markers on the basis of the medical hypothesis for a given target;

■ integrate selected markers into early studies, as justified by preclinical data, epidemiology, and the results of exploratory biomarker analyses;

■ accrue data over multiple studies to judge the utility of such candidate markers; and

■ prioritize confirmed markers for further development, including assay validation.

The value of using a candidate marker approach is that mechanistic hypotheses may be tested. This can simplify statistical analysis and may lend credibility to data generated early in development when patient numbers are especially limited. There is a risk, however, that the candidate marker will be falsely associated with a patient response end point. This can occur for a variety of reasons, including assay failure, population skewing, and an inappropriate threshold for significance. The risk of false association may be amplified by a sense that mechanisms are well understood and that a positive result is "confirmatory." Initial Pgx studies must always be considered exploratory, and their results must be interpreted with caution. Associations must be confirmed using independent population(s) of appropriate size and qualified, fit-for-purpose assays. Statistical approaches to development of Pgx classifiers are discussed in section "Statistical Considerations."

A rich literature is developing on Pgx candidate markers that associate with responses to many different classes of protein drug (3,15). Candidate genes may include upstream factors that poise the patient for differential sensitivity to treatment, the target itself, if variably expressed in the disease, or the presence of polymorphisms in downstream pathways that influence the magnitude of PD responses. Mechanisms involved with protein drug clearance and altered PK have been examined less widely (see sect. "Effect of Patient Variability on Exposure").

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