The Stages of Drug Development and the Human Genome Project: Drug Discovery


Journal of Practical Psychiatry and Behavioral Health, November 2000, 341-344

This series of columns will be devoted to how drugs are developed and how that will likely change as a result of the human genome project. Drug development has become a highly refined process over the last 100 years with well-defined sequential phases (Table 1). Each phase sets the stage for the next phase and a drug may be "killed" at any of these phases for causes such as toxicity, poor tolerability; and/or lack of efficacy. The overarching goal of this sequential approach to drug development is to reduce the uncertainty about the drug's effect (good and bad).

Regular readers of this column will recognize the following equation:

   (Equation 1)
Effect =  affinity for  x     drug      x biological
         site of action   concentration    variance

In previous columns, this equation has been used to explain the effects of a single drug1 or a combination of drugs2 in a patient. However, this equation is also fundamental to understanding the drug development process. The first variable in this equation is the principal focus of the drug discovery and preclinical stages of the drug development process. Drug concentration is the principal focus of Phases I and II. In the past, biological variance in humans has generally not been an issue until the drug entered phase III. At that time, studies were done to assess the pharmacodynamics (first variable in equation 1) and the pharmacokinetics (second variable) in special populations, such as patients with significant liver and renal impairment or the young or old. Such studies were necessarily limited in scope and focused on obvious differences among patients caused by disease or associated with aging. As will become clear in this series of columns, the study of how human biological variance modifies the expression of a drug's effect will occur earlier in the drug development process and will be both more extensive and more specific as a result of the human genome project.

For convenience, Table 2 lists definitions for some terms and concepts that will be used in this column and that are fundamental to modern drug development. Subsequent columns will provide additional definitions as terms and concepts are used that may be new to some readers.

Drug discovery

This column focuses on the first stage of drug development: drug discovery. As the name implies, the goal of this stage is to find (i.e., synthesize) a new molecule or new chemical entity, NCE, (Table 2) with the potential to be a clinically useful drug (i.e., produce a clinically useful effect).

The first step in this stage is deciding what therapeutic areas are likely to be worth the investment required for new drug development in the United States. This decision is not made lightly, because it is fundamental to the viability of the pharmaceutical company making it.

Enormous sums of money are at stake.3,4 First, there is the cost of developing the drug. It takes an estimated 500 million dollars to successfully bring a new drug to the market in the United States. Second, successful drugs are critical to the ability of a company to remain financially solvent. A blockbuster drug can generate over a billion dollars a year in revenue. An unsuccessful drug may not recoup its costs. Even worse is a drug that is found to have significant liability problems after it has been marketed. Such a drug can seriously compromise the viability of even a large and successful company.

Detecting such liability problems is one of the goals of the sequential phases of drug development (Table 1). Recall that the goal of drug development is to reduce uncertainty about the effects (good or bad) of the drug. Depending on the severity of the problems posed by the adverse effects of a drug, the company may decide to "kill" the drug's development rather than invest more money. In such a situation, the company will often switch to a backup NCE, which is generally a structural analog of the first drug. Alternatively, they may abandon that line of discovery or even the entire therapeutic area.

A number of considerations go into the decision to invest in a given therapeutic area. The size of the market is important because it helps to determine how much revenue the drug may generate. The likelihood of competition in the area is also important. An ideal situation is when all of the existing drugs have either gone off patent or soon will go off patent. Under these circumstances, there will be generic competition, but the new drug will not be counter-detailed by a competitor. Consider the difference between when fluoxetine and risperidone entered their respective markets versus nefazodone or quetiapine. It is also helpful if the existing drugs in a therapeutic area have significant limitations in terms of safety; tolerability, and/or efficacy. Good leads about a novel and potentially promising mechanism of action can also be critical to this decision process, as I will explain below. Based on an analysis of all these considerations, a company may decide to pursue a drug discovery program in a specific area (e.g., antidepressants, antipsychotics, antibiotics, antihypertensives).
After the company has decided to work in a therapeutic area, the critical question is what should the new drug do and/or not do (i.e., the first variable in equation 1). To answer this question, it is necessary to know something about a mechanism profile that is either likely to produce an advantage over existing treatments or represents a completely new approach to a disease process.5-7

Table 1. Stages of drug development
1. Drug Discovery
    A. Serendipity
    B. Chemistry
    C. Biology

2. Preclinical Testing
    A. In vitro
        1. Pharmacodynamics (e.g., receptor binding profile)
        2. Pharmacokinetics (e.g., human cytochrome P450 enzymes)
    B. Isolated organs
    C. Animals -- acute versus sub-acute versus chronic
        1. Toxicology -- single and multiple dosing
        2. Animal models
        3. Reproductive functioning
        4. Teratogenicity
        5. Carcinogenicity
        6. Pharmacokinetics in animals

3. Phase I Studies
    A. Normal Volunteer
        • Goals are safety, tolerability and pharmacokinetics
        • The first studies involve single dose exposure while subsequent studies involve
           multiple dose exposure
    B. Mildly Symptomatic Volunteers ("bridging studies")
        • Goals are safety, tolerability, pharmacokinetics and preliminary evidence of efficacy
        • The first studies involve single dose exposure while subsequent studies involve
           multiple dose exposure

4. Phase II Studies
    A. Establish efficacy
    B. Determine optimal dose for Phase III studies
    C. The design of these studies can be quite varied, ranging from open-label to double-blind
         and from uncontrolled to controlled (usually placebo only). They are usually smaller
         in scale than phase III studies in terms of number of subjects and sites. In fact, they
         may involve only a single site. These studies generally involve only short-term
         exposure (e.g., 6 weeks) until there is sufficient evidence of efficacy to justify
         longer-term exposure.

         The earliest studies in this stage are proofs of concept.

5. Phase III Studies
    A. Together with the phase II studies, accumulate sufficient evidence to merit FDA
         approval (i.e., minimum of two pivotal studies)
    B. Obtain supportive data for long-term maintenance efficacy (e.g., 1 year)
    C. Increase the extent of the human exposure database in terms of numbers of patients
         and patient years. These studies are double-blind, large-scale, multicenter, placebo
         and active controlled, short- and long-term
         (e.g., 6 weeks followed by 1 year extension protocols).

6. Phase IV Studies
    Goal: These are postmarking studies and can have quite varied designs.
        The purpose is usually to support the marketing campaign.
        • These studies are generally done in the same target population as the original studies
           that established the indication.
        • If the study is done with the goal of submitting for a new indication, then it is usually
           considered a phase II or III study even though the drug is already marketed.

Better profile

The first scenario (i.e., seeking a better mechanism profile) was the situation facing drug developers in the 1970s working on antidepressants. Both tricyclic antidepressants (TCAs) and monoamine oxidase inhibitors (MAOIs) had serious limitations, and they were also going off patent. The market was sizable but not as big as it could be because the TCAs and MAOIs were not "user friendly" and hence physicians were leery about prescribing them.

As discussed in the series of columns on antidepressants I have recently completed,8-15 the TCAs and MAOIs served as blueprints for the development of newer antidepressants. The goal was to develop drugs that had the same actions believed to mediate the antidepressant action of the TCAs and MAOIs, while avoiding the problems associated with these classes of medications. Thus, the approach was to develop NCEs that had specific effects, principally agonistic, on either serotonin or norepinephrine, while avoiding effects on histamine and acetylcholine receptors as well as fast sodium channels.

In this situation, the approach involves identifying a target that is likely to be useful as well as targets to be avoided and then, through iterative steps, refining the structure of the molecule so that it affects the desired but not the undesired targets at low concentrations (i.e., developing and refining structure-activity relationships). Thus, the bulk of the initial effort in the drug discovery stage is focused on the first variable in equation 1.

Two developments in the 1970s made this rational approach to drug discovery possible for the first time in psychiatry. The first was the development of hypotheses about which mechanisms of action mediated the desired and undesired effects of TCAs and MAOIs, as well as of other psychiatric medications. The ability to use the pharmacology of chance discovery drugs to refine structure-activity relationships is the pivotal value of such drugs. They serve as probes into the pathophysiology and potentially even the pathoetiology of the disease being treated. In psychiatry, the earliest drugs, which were all chance discoveries, provided the first tools that allowed researchers to begin relating brain mechanisms to psychiatric illnesses. Studies of their pharmacology resulted in the dopamine theory of schizophrenia and the biogenic amine theories of affective illnesses.16

The second development was the ability to isolate these mechanisms of action and study them in vitro. Using these in vitro tools, structure-activity relationships (SARs) could be established to guide the synthesis of NCEs that had the desired mechanism of action profile.

Drug discovery and the human genome project

The process just described has been quite useful in terms of improving on existing therapies (e.g., the development of newer antidepressants that have replaced the TCAs as the treatment of choice for clinical depression, at least in the United States).17 Nevertheless, this approach does not lead to the development of novel treatments, but rather refines existing treatments. This is because it uses the pharmacology of existing drugs to develop derivative treatments.

Table 2. Key terms in drug development
New chemical entity (NCE): a molecule that is the product of drug discovery focused on a specific therapeutic area.

Investigational new drug (IND): the NCE has been submitted to the Food and Drug Administration (FDA) and approved to enter human testing

New drug application (NDA): the manufacturer's application to the FDA to approve the IND for marketing. The NDA is the result of all the drug development work on the IND as well as the quality control work on its mass production.

Agonist: NCE that has the same effect on the receptor as the endogenous neurotransmitter.

Antagonist: NCE that occupies the receptor but does not activate it and thus blocks the action of the endogenous neurotransmitter.

Inverse agonist: NCE that has an effect on the receptor that is the opposite of that of the endogenous neurotransmitter.

Structure-activity relationship (SAR): the structure that the NCE must have to affect a specific regulatory protein in a specific way (e.g., being an agonist, an antagonist, or inverse agonist at a specific receptor).

High throughput screening: the process of using automated assays that can screen the effects of large numbers of molecules against a large number of clinically important human proteins. The results of such screening are used to refine the SARs which the chemists in drug discovery use to synthesize NCEs in the hope that these molecules will become INDs for which a successful NDA can eventually be filed so that a new drug or medicine can be marketed.

Thus, the new treatments have the same mechanisms as the old. The advantage of the agents developed using this approach comes not from having a novel but rather a refined mechanism of action.

In contrast, the human genome has the potential to enable researchers to define truly novel mechanisms of action.5, 18 This is because regulatory as opposed to structural proteins (e.g., receptors, enzymes) are the sites of action of most drugs, and regulatory proteins are the products of genes. The human genome contains an estimated 100,000 genes. That in turn translates into an estimated 100,000 structural and regulatory proteins.

While the entire human genome has now been sequenced in several individuals, the project is far from complete. The best estimate is that only 10% of the genes that code for human proteins have been identified. One of the next phases of the project will be to go through the sequenced human genome with the aim of identifying the remaining approximately 90,000 genes and then identifying their structural or regulatory protein products. Each of the regulatory proteins could represent a clinically useful target for drug action and a possible novel mechanism of action. At the same time, another goal will be to identify biologically important mutations in these genes that may either represent disease mechanisms or influence drug action either pharmacodynamically or pharmacokinetically To restate this second goal in terms of equation 1, the goal will be to understand how genetically determined biological variance (variable 3) affects the site of action (variable 1) or the mechanisms responsible for determining drug concentration achieved on a given dose (variable 2)
After a new human gene has been identified, several steps can be taken. First, the amino acid sequence of the protein can be deduced from the nucleotide sequence. The three-dimensional configuration of the protein can then be deduced. That configuration in turn defines the SAR needed to affect the target.

Three different types of drugs can potentially be developed for a regulatory protein such as a receptor. The drug may be a) an agonist, b) an antagonist, or c) an inverse agonist. An agonist has the same effect on the receptor as the endogenous neurotransmitter. An antagonist occupies the receptor but does not activate it, thus blocking the endogenous neurotransmitter from affecting the target. An inverse agonist has an effect on the receptor that is the opposite of the endogenous neurotransmitter's effect. Parenthetically, binding affinity does not tell whether the drug is an agonist, antagonist, or inverse agonist.

Once the gene coding for a regulatory protein has been identified, it can be isolated and transfected into either a single cell organism or cell line. These transfected cells will express the regulatory protein of interest and can therefore be used to refine the SAR to produce a NCE that stereoselectively affects that target. Currently, using high throughput screening, every major pharmaceutical company has the capacity to develop novel drugs to affect desired targets while avoiding undesired targets, such as CYP enzymes.19,20 This can be done even before the usual function subsumed by the regulatory protein (e.g., a receptor) has been identified.

Estimates are that every major company can use high throughput methods to screen libraries of 0.5 to 1.0 million compounds against most known human proteins likely to be clinically useful targets for drug development. Such screening is done to develop the SAR that conveys the desired pharmacodynamic profile.19 Using this SAR, the chemist can synthesize an NCE for preclinical testing, which is the next step in drug development. Once NCEs are synthesized, the issue becomes whether they are sufficiently safe, well tolerated and efficacious to become clinically useful drugs. At this point, they are passed from the scientists in drug discovery to those in preclinical pharmacology. The next column will expand on this discussion of how the human genome project is likely to change the discovery phase of drug development in psychiatry.


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