R Common to both approaches

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O High throughput screening O Informatics O Early toxicity studies

Fig. 4.22. Selection and Improvement Tools project know ahead of time what the target is (the optimal specifications), as well as what would be acceptable (minimal specifications). Firm stopping rules that are realistic, practical, and set up-front avoid endless searching in discovery so a team can move on to more productive projects.

Many groups have found it useful to work backwards through the development and approval process from proposed optimal and minimal package inserts, in an effort to better define the studies that may be needed to support early clinical trials and possible regulatory questions (Fig. 4.21). The major label claims involve five areas noted in the slide and drive at least the five noted aspects of development. As an example, consider the development of a new drug for a cancer indication. What cancers could be treated? How will the drug be used clinically (standalone or adjunctive therapy, first-line treatment or salvage treatment, etc.)? Are there patient subsets that may respond differently? Are there certain toxicities of existing drugs to avoid or not exacerbate? How will the drug be administered (oral, intravenous, subcutaneous, etc.), and for how long (a few minutes, days, months, years)? How large do phase III trials need to be and what is the approvable end point? Answers to these questions help define the phase II program, which in turn defines the phase I, toxicology and preclinical needs. Example package inserts are recommended to be reviewed for Lipitor® [24] and Epogen® [25].

In any development program, be it a small molecule or biologic, there is often a need to improve or optimize the activity of the lead compound (Fig. 4.22). For a small-molecule drug, what if the lead compound is active in animals but too toxic? For a biologic such as an antibody, what if the antibody binds the correct target and has function, but the affinity for that target is too low for therapeutic use (i.e., too much drug would be required)? In each case, tools are available to help further refine the properties of the compounds. Some examples for small molecules follow below:

Quantitative structure-activity relationships (QSAR), a process by which the functions of all structural elements of the compound are studied, quantified, and used to direct further modifications of the compound. Such studies are typically focused on attempting to identify the "pharmacophore," the most desirable chemical structure needed to safely achieve the desired efficacy.

Natural and artificial compound libraries, which can be screened in an effort to identify more preferred compounds. QSAR data may also be used to direct the preparation of new libraries, allowing iterative screening and selection.

Medicinal chemistry, involves chemical approaches to altering the safety, efficacy, and oral availability of compounds. Because biologics are larger molecules typically produced by recombinant techniques or monoclonal antibody products, they are less amenable to modifications that are commonly used for the small molecules. Instead, alternative techniques have been devised, and include a few as follows:

Display technologies, such as phage display [26], riboso-mal display [27], or bacterial display [28], allow for the production and screening of large numbers of protein variants or analogues with increased affinity or altered characteristics.

Protein manipulation techniques, such as truncation, gly-cosylation (more or less), peptide alteration, pegylation, or fusions, which alter the size, shape, or character of the protein, resulting in molecules that have very different physical properties (pharmacokinetics, toxicity, activity, etc.).

Humanization/de-immunization techniques, which seek to reduce the potential for generating an immune response in humans, lessens toxicity and increases activity. Most commonly, these techniques have been used to convert antibodies derived in mice into "humanized" antibodies that have the characteristics of human proteins [29].

Chimeric proteins are fusion proteins created by combining the genetic information for one protein with another. Like humanization techniques, chimeric proteins have been generated in an effort to reduce the potential for an immune response in humans, as well as to create molecules with altered pharma-cokinetics or biological characteristics. Importantly, chimeric proteins can also combine the biological functions of two (or more) proteins into a new, novel recombinant form.

Although the process of research and development typically follows a logical process, it has often been through serendipity that major new drugs have been developed (Fig. 4.23). This figure

r Many drugs are result of chance observations: 0 Alexander Fleming and Penicillin:

5> Searching for agents that could kill Staphylococci 5> Observed that bacteria on culture plates were lysed around contaminating airborne molds

> Concluded that something in the Penicillium mold was killing bacteria r "Rational" drug design often follows a tortuous path: O Viagra (PDE-5 inhibitor - 2003 US sales of $1.0 billion):

> Initially developed as anti-hypertensive drug, but specificity was low 5> Development was changed to focus on angina, but potency was low S> During clinical trials, patients commented on decreased erectile dysfunction r Once used to describe knowledge-based development decisions, "rational drug design" now focuses on underlying biology of disease, as an aid to appropriate target selection

Fig. 4.23. Serendipity vs. Rational Design

Source: Fleming's photo of bacteria and mold (http://www.pbs.org/wghb/aso/databank/entries/dm28pe.html)

shows Fleming's experiment with molds and penicillin production in a petri dish [30]. This serendipity follows from the fact that:

1. All the factors influencing the biology and the disease are not known.

2. Drugs often have unexpected in vitro or in vivo consequences.

Sometimes, these consequences can be too much toxicity (causing reevaluation or termination of the project), whereas other times they can be highly beneficial. Moreover, serendipitous consequences can occur anytime during the discovery and development process, as illustrated by the two examples here for penicillin and Viagra®. Viagra sales info is found in the Ref. 31.

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