The Discovery Process

Before we begin our discussion, let's first review terms particularly relevant to discovery and early development. These include the six terms shown in Figure 4.1

Target: A protein, enzyme, receptor, signaling or other molecule that may play a role in a particular disease process. It is the target molecule or process upon which the discovery and therapeutic strategy will be focused. Hit: A test protein, peptide, or compound that appears to act on the target. Depending upon the target and the biological or chemical system, thousands of hits may be evaluated, looking for the most active compounds to test further. Lead: Among numerous hits or variants, the protein, peptide, or compound showing the highest degree of activity. It is the lead compounds that will be further examined in greater detail.

Candidate: A protein, peptide, or compound that has most or all of the properties of the desired therapeutic (a development candidate). Incorporated into the thinking here is not only the level of activity that a lead has, but also how easy is it to formulate and manufacture, how safe is it, and does it meet the in vitro and in vivo requirements and medical needs. Candidates usually enter into clinical trials to establish safety and then efficacy. IND: Investigational New Drug application, filed for the initial testing of each new drug in humans. This is the actual document filed with the FDA or other regulatory body requesting their approval to begin clinical testing in humans. It contains a summary of the compound to be tested, especially all the animal pharmacology and toxicology data, the rationale for testing in a particular indication in humans, a detailed description of the clinical protocol itself, as well as the methods used to manufacture and test the compound. Product: A marketed therapeutic drug or biological, approved for use by regulatory bodies.

With these terms in mind, let's take a look how new drug candidates are identified and moved toward clinical testing. In its simplest form, drug development can be viewed as a stepwise r Target - A protein, enzyme, receptor, signaling or other molecule that may play a role in particular disease proces r Hit - A test protein, peptide or compound that appears to act on targets r Lead - Among numerous hits or variants, the protein, peptide or compound showing highest degree of activity r Candidate - A protein, peptide or compound that has most or all of properties of desired therapeutic (a development candidate)

r IND - Investigational New Drug application, filed for initial testing of each new drug in humans r Product - A marketed therapeutic Fig. 4.1. Important Terms - General process involving a series of sequential discovery and development decisions that are based on the target and the potential product (12 such steps in two phases are shown in Figure 4.2). This process is commonly separated into two sections, discovery and early development (often referred to as non-clinical or preclinical development, as it relates to studies needed prior to clinical testing), because they involve different approaches, skills, and facilities. A definition for both terms is provided on figure 4.2.

The first part of the drug development process is called discovery. Discovery is driven by unmet medical needs and financial opportunity and focuses on understanding the disease process and the identification of disease targets and potential therapeutic compounds. This stage of the process is perhaps the most variable and least successful of all aspects of drug development. These difficulties are due in part to the fact that discovery research is highly dependent upon a detailed knowledge of the disease in question and because it involves the isolation, production, and testing of compounds that may not have existed previously. Thus, if the disease biology is only poorly understood, it is difficult to know what an appropriate target for intervention might be. Similarly, even if the disease biology is quite clear and a suitable target can be readily identified, it is not uncommon that many thousands of compounds may have to be synthesized, purified, and screened in an effort to find initial "hits" that can be further developed.

Once a target has been identified, methods to influence that target are then considered. Typically, this involves the design or identification of compounds that either stimulate or inhibit the actions of the target, initially in vitro (in the test tube, a "hit") and then in vivo (in animals, a "lead"). Preliminary studies are also conducted to evaluate the in vivo properties of the leads as possible therapeutic candidates (pharmacokinetics, pharmacodynamics, efficacy, toxicity, etc.), and those compounds that have acceptable activity and safety profiles may be passed along to development as "candidates".

At the early development stage, a new group of scientists gets involved who have expertise in translating what has been accomplished at the laboratory scale into methods and systems that will ensure the reliable and reproducible manufacture, also called process engineering, and testing of the product. Thus, it is at this stage that robust methods for purifying, formulating, manufacturing, and testing (e.g., analysis, stability) the product candidate will be developed. As an example, groups studying antibodies will initially work with material derived from tissue culture systems or small fermen-tors (<10 L), but during process development systems may be scaled up to 30 L, 150 L or 500 L fermentors, depending upon the initial development and clinical needs. Subsequently, for large-scale manufacturing and product sales, multiple 15,000 L fermentors may be utilized. A more detailed description of the steps involved in development is presented elsewhere in this volume. Here we will focus only on those tasks that have relevance to the filing of an IND.

Fig. 4.2. Drug Discovery & Non-Clinical Development r Target identification - Process by which potential targets are investigated, screened and prioritized: c. Involves a detailed knowledge of the disease process, such as up-regulation of certain proteins in cancer cells r Target validation - Process by which role a target plays in a disease is characterized and established: c Involves a combination of invitro and in vivo functional studies c Common tools are cellular-based assays, antisense, RNAi and knockout mice r Lead identification - Process by which potential therapeutics are screened and prioritized:

c. Utilizes knowledge of the specific target to identify/design an appropriate agonist / antagonist r Lead optimization and validation - Process by which actions of products on diseases are characterized and confirmed: c Compound is tested in animal models of target disease c Improvements ar edesigned and evaluated

Not all aspects must be completed to move candidates into clinical trials

Fig. 4.3. Important Steps in Discovery

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