Current Trends In Drug Development

With the emergence of new technologies— including genomics, proteomics, molecular biology, combinatorial chemistry, computer-assisted drug design, robotics, and high-throughput screening—our ability to generate new molecular entities that are high-affinity ligands or receptors has greatly increased. However, success in developing these new entities through preclinical and clinical testing has not improved significantly. It is estimated that less than 40% of NMEs produced by drug discovery groups in pharmaceutical companies are candidates for preclinical testing [4]. Only about 10% of them actually make it through clinical trials and are approved for marketing [5].

There is intense economic pressure on the pharmaceutical industry by those who pay for its products to make the development of drugs more efficient and thereby reduce or at least contain costs. Industry executives ignore this clamor at their own peril. A widely embraced strategy to improve productivity is to integrate drug discovery and development by bringing company researchers from basic, preclini-

Merck assembled

AIDS research Team

1987

3-D structure of HIV-protease was elucidated to be used in rational drug

Over 3,000 NMEs were screened and L-735524, indinavir was identified as the one with the most acceptable pharmacokinetic profile.

In less than 3 years the three phases of clinical trials were completed with more than 4000 patients enrolled.

3-D structure of HIV-protease was elucidated to be used in rational drug

Over 3,000 NMEs were screened and L-735524, indinavir was identified as the one with the most acceptable pharmacokinetic profile.

In less than 3 years the three phases of clinical trials were completed with more than 4000 patients enrolled.

Merck assembled

AIDS research Team

1987

A renin class of protease Scale-up of FDA approved Crixivan in a inhibitor was shown to be toxic in a dog study; allowing the scientist to learn what to avoid in NME structures early in development.

indinavir from 12 mg to 600 g for human testing within 6 months record 42 days after Merck's NDA submission.

Identification, characterization, and cloning of HIV protease

A renin class of protease Scale-up of FDA approved Crixivan in a inhibitor was shown to be toxic in a dog study; allowing the scientist to learn what to avoid in NME structures early in development.

indinavir from 12 mg to 600 g for human testing within 6 months record 42 days after Merck's NDA submission.

Figure 2.2. Timeline of fast-track development of an HIV protease inhibitor, indinavir (Crixivan) by Merck through a project research team approach. Adapted from Merck's account on Crixivan development.

cal, and clinical sciences together to work very early in the development of a drug candidate or even during discovery efforts as a project team. In the ideal, the project team, relying on the collective wisdom of the group, and, when needed, calling upon academic experts, is charged with anticipating problems that may be encountered in the preclinical and clinical testing of a drug candidate. The team is expected to develop a drug product with an acceptable pharmacokinetic profile, a low potential for drug-drug interactions, clear-cut efficacy, and a comfortable safety margin. The team, by identifying the target population, must strive to exclude from clinical trials patients who are unlikely to derive a benefit from the new drug and eliminate those likely to respond to its effects adversely.

Already, the project team approach has recorded successes (Figure 2.2). A project team at Merck, using advanced physical, chemical, and molecular biotechnologies coupled with rational drug design to predict the most promising lead compounds as part of the drug discovery process, significantly accelerated the development of the antiretroviral protease inhibitor indinavir (Crixivan), once the most widely used protease inhibitor for the treatment of HIV infection and still a very important drug. With continuous feedback from the project team, Merck scientists sequenced HIV protease, demonstrated its vital role in viral replication, cloned and purified the enzyme, and produced sufficient quantities to identify the protein's three-dimensional structure, all in about two years [6]. Similar efforts in the past had taken 8-10 years.

Based on the crystal structure of HIV protease, ideas about what an inhibitor should look like emerged. With the availability of a quantity of HIV protease sufficient for enzyme assays, the construction and evaluation of HIV-protease inhibitor candidates began. In all, about 3000 candidates were screened, in the search for those with acceptable pharmaceutical properties that also demonstrated potent antiviral activity. These efforts led to the discovery of indinavir in 1992 [7]. By anticipating problems and issues early in the development process, through the project team approach, Merck completed clinical testing of Crixivan in about 3 years (1993-1996) [8]. In the face of an extraordinary demand for new drugs by HIV-infected patients and their advocates, the FDA approved Crixi-van in a record time of 42 days after Merck had filed the NDA.

Clearly, from this example, we can see the benefits of the multidisciplinary project-team approach. The team effort integrates pharmaceutical technology and biotechnology to identify and isolate biologic targets of sufficient purity and in sufficient quantity for in vitro drug screening. Experts in advanced physical and chemical sciences can help develop high-affinity ligands, and introduce strategic considerations early in the development process, and can help pharmaceutical companies to increase the efficiency of drug development in many therapeutic areas.

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