Drug Development: An Overview
By Marshall J. Glesby, MD, PhD

Among the most important challenges facing HIV researchers is the development of new safe and effective drugs for treating HIV infection. Although there have been remarkable therapeutic advances in the past few years, we are clearly in need of additional antiretrovirals which are active against drug-resistant HIV strains, easier to take, and free of major side effects. Developing such drugs is obviously not a simple task. In addition to being costly and laborious, the drug development process is highly dependent on basic scientific discoveries. Fortunately, in the past few years there have been important scientific advances in the understanding of how HIV infects cells and multiplies in the human body. These types of discoveries should lead to the development of new classes of antiretroviral drugs.

The Development Process
Advances in basic science can lead to therapeutic advances through a process known as rational drug discovery. Rather than randomly screening thousands of chemicals for activities against the disease in the test tube, which has been done for HIV as well as for cancer drugs, scientists start with a known chemical structure and use computers to design drugs which may be able to bind to the structure. For example, knowing the chemical structure of HIV's protease enzyme has led to the synthesis of protease inhibitors which bind to and inhibit the function of the enzyme which is critical for HIV replication. Considerable efforts go into modifying the initially conceived parent drug molecule in order to come up with a final drug which has maximal activity against the virus and minimal toxicity.

Extensive testing of a new drug must be undertaken prior to use in humans. These preclinical tests include thorough safety studies in laboratory animals. If the preclinical testing is satisfactory, initial clinical trials, called Phase I studies, are undertaken in humans. Phase I studies involve a small number of subjects who may be healthy volunteers and focus on the pharmacokinetics of the dru-g-that is, measures of things like the levels of the drug in the bloodstream after a single dose or multiple doses. Phase II studies involve more patients (typically several hundred) and give insight into common toxicities of the drug as well as an initial look at how active the drug is (efficacy). Phase III studies are even larger and yield more definitive safety and efficacy data. Sometimes the different phases are combined (e.g. a Phase II/III trial) to speed up the development process. The data from two Phase III studies are usually submitted to the Food and Drug Administration (FDA) as the key or pivotal studies to demonstrate the safety and efficacy of a new drug.

The average time from discovery of a new drug to its approval for use in people is about 15 years. Fortunately, this timeline has been accelerated somewhat for HIV drugs so that today's basic scientific discoveries may translate into therapeutic advances in a shorter time frame. Nonetheless, for every 5,000 drugs undergoing preclinical testing, only about five will likely make it into clinical trials, and only one of these five will actually get approved by the FDA. Partly because of this relative inefficiency, the estimated cost of bringing a new drug to market is $500 million.

Drug development is of particular interest to us at ACRIA because it is an important intersection between the two prongs of our mission-clinical research and treatment education. As a research organization that typically conducts Phase II and III trials , we have extensive experience with investigational drugs before they are approved by the FDA. We are able to incorporate this experience into our treatment education efforts, which has enabled us to become a leading provider of information on new and emerging therapies for HIV infection and its complications to residents of New York City and beyond.

This issue of ACRIA Update focuses on drugs in the pipeline for treating HIV infection and related clinical problems. Tim Horn, a regular contributing writer, has concisely summarized the current state of antiretroviral drugs in early clinical development. To help us understand the targets of these and other potential antiretroviral drugs, David Pieribone, ACRIA's Director of Treatment Education, has sketched out HIV's life cycle in the centerfold of the periodical.

We initially planned to include information on drugs in the pipeline for opportunistic infections (OIs), but the dramatically decreased incidence of OIs in the developed world as a result of more effective antiretroviral therapy seems to have squelched such drug development. Instead, we are fortunate to have an article by Dr. Mark Sulkowski of Johns Hopkins on a clinical problem of increasing significance for many persons living with HIV infection - hepatitis C virus (HCV) co-infection. The principles of rational drug design are actively being applied to HCV drug development, a field in which there have been impressive basic scientific advances in recent years. Finally, Tim Horn has reviewed the epidemiology, current treatment, and drugs in the pipeline for two of the HIV-related cancers which have not disappeared - Kaposi's sarcoma and non-Hodgkin's lymphoma.