Fast-tracking the first AIDS drug

FDA Consumer, Oct, 1987 by Brad Stone

Fast-Tracking the First AIDS Drug

The drug zidovudine, brand name Retrovir (formerly called azidothymidine or AZT), was originally developed in 1964 as a potential cancer treatment, but it showed little promise for this use. Years later, a fresh look at the compound's anti-viral properties led to its becoming the first drug approved to treat AIDS--acquired immune deficiency syndrome.

Close cooperation between FDA and the drug's sponsors, Burroughs Wellcome Co. of Research Triangle Park, N.C., and the National Cancer Institute, helped to expedite the testing and review of zidovudine. FDA approved the drug to treat certain patients with AIDS on March 20, 1987--within just four months of receiving a new drug application from Burroughs Wellcome.

FDA press officer Brad Stone interviewed Dr. Ellen Cooper, group leader (anti-virals) of FDA's Division of Anti-Infective Drug Products, and Dr. James Bilstad, deputy director (medical affairs) of FDA's Office of Biologics Research and Review, to trace the development and approval of this important new drug.

FDA CONSUMER: Zidovudine is categorized as an anti-viral drug. What is an anti-viral drug, and how does it work in treating AIDS?

COOPER: An anti-viral drug interferes with viral replication. Zidovudine works in part by inhibiting reverse transcriptase, an enzyme necessary for the replication of HIV [human immunodeficiency virus], the retrovirus that causes AIDS. In addition, the virus is "tricked' into incorporating zidovudine into its DNA replication chain. This action effectively aborts the virus's ability to replicate itself.

FDA CONSUMER: How does zidovudine trick the virus?

COOPER: Zidovudine's chemical structure is in some ways very similar to thymidine --one of the key nucleosides, or links, that make up the DNA genetic chain that reproduces the AIDS virus. Evidently, the AIDS virus mistakes zidovudine for real thymidine and incorporates the drug as a link on the DNA chain. While zidovudine is similar enough to thymidine to link onto one end of the chain, it lacks features that would allow other nucleosides to link on and complete the chain. In this sense, zidovudine can be seen as a deliberately defective link that preempts the virus's reproductive chain.

FDA CONSUMER: How did zidovudine receive FDA approval so quickly?

BILSTAD: Because of the urgent need for effective AIDS therapies, experimental treatments for this disease receive top priority for review. NDAs [new drug applications] for drugs for diseases for which there is a satisfactory existing therapy sometimes have to wait in line for review. This is not the case with AIDS drugs--Commissioner [Frank E.] Young has determined that they are to get immediate review, and we are striving to meet that goal.

COOPER: In addition, the new drug application for zidovudine was based largely on a placebo-controlled study with which FDA staff had been quite familiar from the beginning. FDA and Burroughs Wellcome had cooperated closely from the time clinical trials began in April 1985. This cooperation was mutually beneficial as it kept both parties abreast of the other's problems, advances and needs. Since many of the details of the study were already known to FDA reviewers, it took less time to review the results than might otherwise have been the case.

FDA CONSUMER: Didn't FDA do some of the preliminary research on zidovudine as a treatment for AIDS?

COOPER: Yes. Well before Burroughs Wellcome first applied for permission to begin clinical [human] testing, the company asked Dr. Gerald Quinnan's lab at FDA's Division of Virology to test the drug in vitro [in the test tube] against the AIDS virus, because earlier animal studies conducted by the company had indicated zidovudine's high level of activity against the virus. Dr. Samuel Broder's lab at the National Cancer Institute and Dr. Dani Bolognese's lab at Duke University [in Durham, N.C.] did additional testing.

FDA CONSUMER: Is this type of extensive cooperation and ongoing consultation between FDA and AIDS researchers unusual, or is it the norm for AIDS drugs?

BILSTAD: Definitely the norm. FDA is eager to work whenever possible with any companies or research or academic institutions pursuing promising treatments for this disease. We encourage all companies working on AIDS therapies to communicate with us even before they apply for clinical testing, because this cooperation can be of tremendous value in expediting the review and approval processes.

COOPER: The urgency of the AIDS situation really requires close cooperation, and there has been a strong emphasis within the agency on working to streamline the process by eliminating any gaps in communication.

FDA CONSUMER: What patients benefit from zidovudine, and how?

COOPER: The AIDS patients who were shown to benefit from zidovudine in the placebo-controlled trial [which provided the definitive data on the drug's efficacy] had recovered from a recently diagnosed episode of Pneumocystis carinii pneumonia [the most common opportunistic infection in AIDS patients in the United States] and lacked any signs of other opportunistic infections or of Kaposi's sarcoma [a malignancy that produces lesions on the skin and other areas of the body].