FDA Panel Recommends Approval of 3TC with AZT to Treat AIDS

Date: November 7, 1995
Source: Food and Drug Administration (FDA)

The Food and Drug Administration's Anti-Viral Drugs Advisory Committee yesterday recommended that the agency grant accelerated approval for the drug lamivudine, or 3TC, for use in combination with AZT (zidovudine) in treating AIDS and HIV infection. The following may be useful in answering questions:

Both AZT and 3TC are members of the nucleoside analogue class of drug compounds, and both inhibit the replication of HIV, the virus that causes AIDS. AZT was approved by the agency in 1987. It was the first drug approved for the treatment of HIV infection. 3TC and AZT are manufactured by Glaxo-Wellcome Inc. of Research Triangle Park, N.C. The registered trade name for 3TC is Epivir; for AZT, Retrovir.

The committee based its recommendation on data form four controlled, randomized clinical trials evaluating laboratory measures of infection in adults. Data were also presented form ongoing open-label protocols for children and adults.

In the four controlled trials, 974 HIV-infected subjects were randomized to receive either combined therapy with 3TC and AZT, 3TC as a single therapy, AZT as a single therapy, or combined therapy with AZT with ddc (Roche's anti-AIDS nucleoside analogue, which received accelerated approval in 1992). Patients included those with and without prior AZT therapy.

The primary marker of drug affect was changes in CD4 cell counts (a reflection of immune system strength). Secondary measures included assessments of the amount of HIV in patients' blood. Duration of the trials was 24 weeks. Baseline CD4 cell counts of patients at time of enrollment ranged form 100 to 500. (Values greater than 800 are normal for healthy individuals.) Doses of 3TC were 150 milligrams or 300 milligrams twice a day.

In patients who had no prior AZT therapy, the 3TC/AZT combination treatment was associated with an average increase in CD4 counts of about 50 above baseline. In patients previously on AZT therapy, the 3TC/AZT combination was associated with CD4 increases of about 30 above baseline. Duration of this effect is not fully determined, although generally it lasted for at least 24 weeks.

Adverse events observed in patients on the AZT/3TC regimen were similar to those associated with other nucleoside analogue AIDS drugs. They included nausea, diarrhea, anemia, neutropenia, pancreatitis (especially in children who had received prior nucleoside analogue therapy) and neuropathy. Some of the more severe adverse reactions required withdrawal from therapy.

3TC has been studied in humans since April 1991. Since October 1993, the drug has been available to patients outside of controlled clinical trials under an open-label protocol. More than 35,000 patients have received the drug under this expanded access program. Approval of the 3TC/AZT application would be granted as an accelerated approval, a regulatory mechanism under which the agency may grant early marketing status for a product based on laboratory markers used to measure drug activity, rather than on clinical endpoints. Only products treating serious diseases and providing meaningful therapeutic benefit over existing treatments can qualify for an accelerated approval.

To grant accelerated approval, the agency must conclude that responses of markers in trials are probable predictors of clinical benefit. In the case of the 3TC/AZT marketing application, laboratory markers are the CD4 cell counts and assessments of amount of HIV in patients' blood.

Manufacturers of products granted accelerated approval must demonstrate within a reasonable period of time that the product provides true clinical benefit--such as delay in death or reduction in opportunistic infections--or the agency may withdraw accelerated approval. Trials deigned to demonstrate clinical benefits of the 3TC-AZT treatment regimen are currently ongoing in adult and pediatric patients.

Information on ongoing clinical trials testing drugs for HIV infections may be obtained from the National Institute of Health's AIDS Clinical Trial Information Service at 1-800- TRIALS-A.