Use of Biomarkers in Drug Discovery

Drug discovery and development is traditionally divided into a number of phases such as discovery, preclinical and clinical development, regulatory, marketing, and postmarketing, although the exact terminology varies from company to company. In modern drug discovery and development, biomarkers play a critical and rapidly growing role in the early phases (see Chapter 2), although the way a biomarker is used varies in each phase (Figure 11.32).

In the discovery phase, biomarkers are used to identify and validate new drug targets. This involves the development of in vitro assays and animal models in which the biomarker can be evaluated for its involvement in a particular cancer type and its value as a drug target. These experiments determine whether early lead agents (whether small molecules, or macromolecules such as antibodies) hit the right target and are potentially capable of successfully modulating the disease pathway. This helps to select the best lead compounds to take forward into development.

In the preclinical development phase, other biomarkers provide information on safety ((.(e.g., based on DNA sequencing, immunohistochemistry, mass spectrometry, etc.) may inform the development of Companion Diagnostic Kits that will be used both in clinical trials and after regulatory approval to identify patients suitable for treatment with the agent.

In the final stages of the drug development process in the clinic, biomarkers help to improve the statistical power of clinical trials, even with lower numbers of patients enrolled, through the use of so-called “adaptive designs” (see Section 11.6.7). The biomarkers identified from the earlier phases can be used to select patients for the trials whose tumors are

TABLE 11.5

Drugs Metabolized by CYP2D6 and CYP2C19 which were evaluated by the AmpliChip™ Device (Taken from the Original DNAVision website)

Genes

Mutations

Substrate Examples

CYP2D6

*2, *3, *4, *5, *6. *7. *8, *9, *10, *11 *14, *14. *15, *17, *19, *20, *25, *26, *29, *30, *31, *35, *36. *40, *41. 1XN. 2XN.4XN. I0XN. I7XN, 35XN.41XN

Beta-blockers

Carvedilol

Metoprolol

Propafenone

Timolol

Antidepressants

Amitriptyline

Clomipramine

Desipramine

Imipramine

Paroxetine

Venlafaxine

Antipsycliotics

Haloperidol

Risperidone

Thioridazine

Others

Codeine

Dextromethorphan

Flecainide

Mexiletine

Ondansetron

Tamoxifen

Tramadol

CYP2C19

*2, *3

Proton pump inhibitors

Omeprazole

Lansoprazole

Pantoprazole

Anti-epileptics

Diazepam

Phenobarbitone

Phenytoin

Others

Amitriptyline

Clomipramine

Cyclophosphamide

Progesterone

expressing the biomarker and so are most likely to respond. The biomarkers are also used throughout the trials to help monitor efficacy and detect adverse events. Increasingly, regulatory bodies such as the FDA, MHRA, and EMA request biomarker data before they approve a new anticancer therapy, and biomarkers continue to be studied postmarketing so that the pharmaceutical companies can continue to monitor the relationship between the expression of the biomarker and disease progression. Several new anticancer therapies including those based on small molecules, antibodies or cells have emerged, and some of the most important examples to date are outlined in Table 11.6.

With some new therapies developed against a specific biomarker, regulatory approval is only granted on the proviso that patients are tested for the presence of the relevant biomarker prior to prescribing. For example, with trastuzumab (Herceptin™), a laboratory test (e.g., the Hercept™ test), must be carried out on biopsy material from the patient’s breast tumor to establish that tumor cells are expressing the HER2 antigen (i.e., they are HER2-positive) before trastuzumab can be prescribed. So far, only a limited number of biomarkers have become mandatory (or even recommended) for prescription or prognosis; however, the use of biomarkers for this purpose will inevitably grow in the near future, and will feed into marketing strategies.

There is a paradox that the growing emphasis on patient selection through biomarkers may potentially reduce global sales for pharmaceutical companies by targeting a smaller population of patients compared to the previous one-size-fits-all

Use of biomarkers in early and late-stage drug development

FIGURE 11.32 Use of biomarkers in early and late-stage drug development.

TABLE 11.6

Examples of Cancer Therapies Discovered and Developed Based on Specific Biomarkers

Biomarker

Drug Type

Drug Discovered Based on Biomarker

BCR-ABL

Small Molecule

Imatinib (Gleevec™)

BRAF V600E

Small Molecule

Vemurafenib (Zelboraf™)

EML4-ALK

Small Molecule

Crizotinib (Zalkori™)

HER2

Antibody

Trastuzumab (Herceptin™)

EGFR

Antibody

Cetuximab (Erbitux™)

VEGF

Antibody

Bevacizumab (Avastin™)

CD30

Antibody-Drug Conjugate

Brentuximab Vedotin (Adcetris™)

CD22

Antibody-Drug Conjugate

Inotuzumab ozogamicin (Besponsa™)

CD33

Antibody-Drug Conjugate

Gemtuzumab ozogamicin (Mylotarg™)

“block-buster” approach to drug marketing. However, the counterargument is that despite the potentially lower sales volume, a higher unit cost can be justified for such therapies due to the higher cost of research and development, and, most importantly, patients are likely to receive a greater benefit. Another financial factor is that the anticipated decrease in serious side effects should reduce the cost of litigation against pharmaceutical companies and health care organizations such as the NHS.

 
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