Class DTarget Maintains Physiological Functions in Normal and Disease States

This class of targets encompasses the largest group of molecular targets exploited so far by modern drugs. Many members of this class have yielded highly beneficial therapies. This class consists of molecular targets that are known to have important physiological functions, which cannot be differentiated within a disease context; that is to say the target is not different in its expression levels (gene, protein) or signaling pathway in the normal and disease states. A priori, such targets harbor the greatest risk for mechanism-based adverse effects, as there is no apparent reason to expect that modulation of the target in the disease state will spare the normal physiological function of the target.

Examples of such targets include the coagulation factor inhibitors (e.g., FIX, FXa and thrombin), which are critical to maintain a physiological level of homeostasis; hence, inhibition of these targets carries inherent bleeding liabilities. Likewise, all current anti-arrhythmic drugs (e.g., amiodarone, lidocaine, dofetilide), while effective in treating life-threatening arrhythmias, all carry significant liability for mechanism-based pro-arrhythmic effects and the potential for sudden death. The biomarker challenges for this class are defining the fine balance needed between efficacy in the disease context and expected safety limitations. Biomarkers that define the acceptable therapeutic index are key to the successful utility of drugs that modulate such targets. However, targets in this class do not necessarily exhibit narrow safety margin for clinically meaningful adverse effects. Significant examples are the L-type Ca2+ channel blockers. The L-type Ca2t channel is an essential conduit of Ca2+ needed for 'beat by beat' Ca2+ fluxes that secure precise rhythm and contractility of the heart, skeletal muscle, neuronal excitability and hormone and neurotransmitter release. Yet, L-type Ca2+ channel blockers are important and sufficiendy safe drugs that are used to treat hypertension, angina and cardiac arrhythmias with undisputable medical benefits. However, inherent to the L-type Ca2+ channel blockers in this class of targets are mechanism-based adverse effects associated with rhythm disturbances, hypotension, edema and other liabilities.

Probably the best example for system specificity of physiological targets that provide major medical benefits with a high safety margin is the Renin-Angiotensin-Aldosterone (RAAS) system. The RAAS is an important blood pressure, blood volume and blood flow regulatory system, yet its manipulation by several different pharmacological agents (rennin inhibitors, angiotensin I converting enzyme inhibitors, angiotensin II receptors antagonists) has yielded highly beneficial drugs that reduce risk of morbidity and mortality from hypertension, heart failure and renal failure, despite the fact that the system does not demonstrate significant operational selectivity between normal and disease states (especially hypertension). However, mechanism-based hypotension and electrolyte disturbances can limit the therapeutic benefit of these drugs and elicit significant adverse effects when the RAAS is excessively inhibited.16 The biomarker challenge for these targets is to define the relative or preferential role of the target in its various physiological activities, where minor manipulation in one organ might provide sufficient therapeutic potential while providing a low likelihood for adverse effects that result from more substantial inhibition of the same target in other organs.

Conclusion

The analysis and classification offered in this chapter regarding biomarkers in drug discovery and development aim to highlight the need to carefully study and analyze the significance of the target selected for therapeutic intervention as the first cross road for success or failure in the development of effective and safe drugs.17 The analysis and utility of biomarkers along the process of drug discovery and development has become an integral part of the "learn and confirm" paradigm of drug discovery and development in leading pharmaceutical organizations such as Wyeth research. Such analyses are useful to guide the "learn phase" in search for biomarkers that can better assess the benefits and risks associated with manipulation of the molecular target.

The scope of this paper does not allow for a detailed review of the "learn and confirm" paradigm, for which the readers are directed to recent references.18'19 Various technological and strategic activities are needed to establish the biomarker strategies for the various targets described. The need to address these issues via biomarkers research, validation and implementation commencing at the very early stages of the drug discovery and development process is emphasized. In the pharmaceutical setting, it means commencing efforts to identify biomarkers for all 5 categories listed above. Such efforts could commence even before a tractable compound (biological) is in hand, a time where target validation is a clear focus of the program. As compound becomes available, compound—target interaction, pharmacodynamic (efficacy and safety) biomarkers and strategies for patient selection and adaptive design needs must be explored. At the onset of the "first in human" studies, all strategies, plans and biomarkers research should be well worked out (as much as possible). We believe that fundamental changes in the structure, function and interfaces of Pharmaceutical R&D is urgendy needed to provide for a key role of translational medicine and biomarkers research towards more successful discovery and development of innovative medicines.

References

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2. Trusheim R, Ernst R, Berndt ER et al. Stratified medicine: strategic and economic implications of combining drugs and clinical biomarkers. Nature Reviews Drug Discovery 2007; 6:287-293.

3. Feuerstein GZ, Rutkowski JL, Walsh FS et al. The role of translational medicine and biomarkers research in drug discovery and development. American Drug Discovery 2007; 2:23-28.

4. US Food and Drug Administration (FDA) report. Challenge and opportunity on the critical path to new medical products, http:www.fda.gov/oc/initiatives/criticalpath/whitepaper.pdf (2004).

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9. Dorph-Petersen KA, Pierri JN, Perel JM et al. The influence of chronic exposure to antipsychotic medications on brain size before and after tissue fixation: a comparison of haloperidol and olanzapine in macaque monkeys. Neuropsychopharmacology 2005; 30(9):1649-61.

10. Berry DA. Bayesian Clinical Trials. Nature Drug Discovery Reviews 2006; 5:27-36.

11. Gallo P, Chuang-Stein C, Dragalin V et al. Adaptive design in Clinical Drug Development- an executive summary of the PhRMA working group. Journal of Biopharmaceutical Statistics 2006; 16:275-283,

12. Krams M, Lees KR, Hacke W et al. Acute Stroke Therapy by Inhibition of Neutrophils (ASTIN). Stroke 2003; 34:2543-2548.

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15. Chien KR. Herceptin and the heart—a molecular modifier of cardiac failure. N Engl J Med 2006; 354:789-790.

16. Hershey J, Steiner B, Fischli W et al. Renin Inhibitors: An antihypertensive strategy on the verge of reality. Drug Development Today 2005; 2:181-185.

17. Simmons D. What makes a good anti-inflammatory drug target? Drug Discovery and Development 2006; 5/6:210-219.

18. Gombar C, Loh, E. Learn and Confirm. Drug Discovery and Development 2007; 10, 22-27.

19- Sheiner LB. Learning versus confirming in clinical drug development. Clin Pharm Ther 2007; 61: 275-291.

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