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Executive Summary

Bristol-Myers Squibb's Videx (didanosine or ddI) is now approved for use in "adult patients with advanced HIV infection who have received prolonged prior AZT (zidovudine) therapy," new labeling states. FDA approved Bristol-Myers Squibb's supplemental NDA for the new indication on Sept. 28. On the basis of preliminary data, ddI (didanosine) had been approved on Oct. 9, 1991 for use in people with advanced HIV infection who are intolerant to AZT (Burroughs Wellcome's Retrovir) or have demonstrated significant clinical or immunologic deterioration during AZT therapy ("The Pink Sheet" Oct. 14, 1991, p. 15). The Videx labeling change is based on the results of AIDS Clinical Trials Group study 116B/117, the results of which were published by Kahn et al. in the Aug. 28 issue of The New England Journal of Medicine. The randomized, double-blind 913-patient study found that people with HIV who had been receiving AZT for 16 weeks or more and were switched to ddI at the recommended dose of 500 mg per day had significantly fewer new AIDS-defining events and deaths than patients who continued AZT therapy or were switched to 750 mg per day of ddI. Of 298 subjects assigned to 500 mg of ddI, 94 died or had a new non-recurring AIDS-defining event. Of the 311 subjects receiving 750 mg of ddI, and 304 people infected with HIV assigned to continue on AZT, 115 and 125, respectively, died or had a new non-recurring AIDS-defining event. Kahn et al. concluded of ACTG 116B/117 that "the results of this trial suggest that the role of didanosine should not be limited to persons who do not tolerate zidovudine therapy or in whom such therapy has failed; rather, they support the expanded use of didanosine in the defined study population." Bristol-Myers Squibb said it submitted the supplemental NDA incorporating the ACTG 116B/117 data on June 1. An Oct. 1 FDA "Talk Paper" points out that "the study [ACTG 116B/117] provided no information on the optimal time at which patients should be switched from AZT to ddI." The revised Videx labeling contains a description of the trial. "Physicians can then interpret the information in the context of the individual patient," FDA said In an editorial accompanying the Aug. 28 NEJM article, Jerome Groopman, MD, New England Deaconess Hospital, and Jean-Michel Molina, MD, of France, noted that "low-dose didanosine [500 mg] had a toxicity profile that was more favorable than that of zidovudine." In ACTG 116B/117, rates of leukopenia were 14%, 22% and 26% for 750 mg ddI, 500 mg ddI and AZT, respectively. Rates of severe anemia were 3%, 3% and 7%, respectively, for the three regimens. Pancreatitis and elevated serum amylase levels, however, were significantly more common in high-dose ddI patients than in those people taking AZT. Peripheral neuropathy occurred in 14% of AZT and 750 mg ddI patients and 13% of 500 mg ddI patients -- not a statistically significant difference. Groopman and Molina also pointed out that, based on ACTG 116B/117, "survival is not increased" by ddI usage in patients with AIDS. For patients with AIDS-Related Complex (ARC) or asymptomatic HIV infection, there was a statistically significant effect on mortality in favor of both dosages of ddI. For those people who entered the study with AIDS, however, there were no differences in mortality between the treatment groups. Despite a lack of mortality benefit in people with AIDS, Groopman and Molina said the trial suggests "a change to didanosine may improve the quality of life by delaying the progression to AIDS." While the approval of the Videx labeling supplement expands the antiretroviral agent's indication, ddI is still a second-line therapy behind AZT. Another trial, ACTG study 116A, which compares AZT and ddI head to head as first-line therapies, is expected to be completed later this autumn. Other studies of ddI combined with AZT are also being conducted, BMS said. Preliminary data from ACTG 116B/117 were presented to FDA's Antiviral Drugs Advisory Committee at an April 20, 1992 meeting. The committee felt that the findings confirmed the October 1991 approval of ddI but was divided on how labeling might be expanded to reflect the ACTG 116B/117 results ("The Pink Sheet" April 27, p. 18). For the Phase I/II studies upon which FDA based its initial approval of Videx, CD4 cell counts and p24 antigenemia served as surrogate efficacy markers of expected clinical benefit. Had the ACTG 116B/117 results not confirmed the predictive nature of CD4 counts, FDA could have required Bristol-Myers Squibb to conduct an accelerated withdrawal of Videx from the market.

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