The Need For Innovative Therapeutic Agents In The New Millennium

Current drug therapies are remarkably effective across a range of therapeutic areas. The use of H2-receptor antagonists, and more recently proton pump inhibitors, has

From: Farnesyltransferase Inhibitors in Cancer Therapy Edited by: S. M. Sebti and A. D. Hamilton © Humana Press Inc., Totowa, NJ

revolutionized the management of gastric ulcers. P-adrenergic receptor blockers and inhibitors of angiotensin-converting enzyme (ACE) have had a major impact in the area of cardiovascular disease. However, for many diseases cure or even good management cannot be achieved. The treatment of infectious diseases, often cited as a success story of drug development, remains suboptimal, as exemplified by the emergence of HIV/ AIDS and of drug-resistant strains. Moreover, in view of changing global demographics, the management of the chronic diseases associated with the aging population in developed countries represents a major unmet medical need. As examples we can cite cardiovascular disease, diabetes, inflammatory diseases (such as arthritis), asthma, neurological disorders, and cancer.

Let us look more closely at the case of cancer, as we shall do for illustrative purposes throughout this introductory chapter. The statistics are stark. More than 1 in 4 of the population will suffer from cancer in the developed world. In 1997, cancer caused 2.5 million, or 21%, of deaths in the developed world and a further 3.6 million in developing countries (1-3). The World Health Organization (WHO) predicts a rise in the annual worldwide incidence of cancer from 10 million new cases in 1997 to 20 million in 2020. Deaths from cancer will increase from 6 million to 10 million. For society this represents a major concern and cost. For the pharmaceutical industry, it represents a major market opportunity. For science it represents a major intellectual challenge.

Excellent results can be obtained with chemotherapy in a small group of cancers. For example, cures can be achieved in several childhood tumors and some adult malignancies, including testicular cancer, lymphoma, and leukemia. Incremental survival benefits are being achieved in certain adult tumors, for example by adjuvant treatment of breast and colon cancer (4). The incidence and morbidity rate for cancer in the United States has fallen over the period 1990-1995 (5). Useful palliation can be achieved in all patients. But we have a long way to go to achieve a significant gain in the curability of the major solid tumors, especially in their disseminated (metastatic or spread) stage, for which systemic drug therapy is the only realistic treatment choice.

The figures for 1999 show that a total of 92 cancer drugs had been approved by FDA for marketing in the United States (6). A recent WHO consultation process resulted in the categorization of 17 anticancers (plus two antiemetics) as justifying widespread availability and an additional 12 were seen as having some advantages in particular clinical settings. A further 13 drugs were viewed as not essential currently for the delivery of effective cancer care.

A great many of our current cancer drugs work by inhibiting DNA synthesis or the mechanics of cell replication. As a result of such nonspecific actions, biochemical selectivity is poor, side effects are frequently very severe, and drug resistance is the norm.

A very considerable amount of effort and research dollars are going into improving cancer treatment. For example, the Pharmaceutical Research and Manufacturers Association of America (PhRMA) reported that 316 cancer medicines were in development in 1997 and the research and development spending for the research-based pharmaceutical industry was estimated at almost $19 billion (7). In May 1999 it was reported that 1422 projects were in development, making cancer the leading developmental therapeutic area (8). This is perhaps not so surprising as the worldwide market for cancer drugs was $11.7 billion in 1997, about 4% of the worldwide pharmaceuticals market, and this figure is projected to hit $14.7 billion by the year 2000 (3). In view of the demographics and the scientific and recent technological advances (see later) the potential market is much greater.

Preclinical

6.5 years

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