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ABBOTT’s BIAXIN (CLARITHROMYCIN) FOR MYCOBACTERIUM AVIUM COMPLEX

Executive Summary

ABBOTT's BIAXIN (CLARITHROMYCIN) FOR MYCOBACTERIUM AVIUM COMPLEX in an AIDS Clinical Trial Group study (ACTG 157) of 108 people showed the antibiotic to be "highly active as monotherapy for suppressing disseminated MAC bacteremia over 12 weeks," Richard Chaisson, MD, Johns Hopkins University, told the American Society for Microbiology's Interscience Conference on Antimicrobial Agents and Chemotherapy in Anaheim Oct. 13. A quality of life survey in 68 of the 108 trial participants found "significant improvements in overall health, pain, social functioning, level of energy, quality of life, and severity of symptoms," Chaisson said. These results "were highly consistent with the microbiological results," he noted. The study 157 found median decreases in bacteremia, measured by blood culture, of 2.6 to 2.8 logs. Patients receiving 2,000 mg clarithromycin b.i.d. became culture negative significantly faster than those receiving either twice-daily doses or 1,000 mg or 500 mg. However, Chaisson emphasized that "eventually the majority of patients in all treatment groups became culture-negative on at least one occasion." MAC resistance to clarithromycin, defined as an increase in minimum inhibitory concentration of greater than four micrograms per ml, appeared in 47% of all patients within 12 weeks, Chaisson reported. The earliest appearance of resistance appeared within eight weeks, with the mean time to resistance being 104 days. There was no relationship between time to resistance and dosage level. "The development of resistance to clarithromycin monotherapy is not unexpected as drug-resistant mutants of MAC occur frequently in vitro," he commented. Resistance, however, was associated with a reemergence of MAC symptoms indicating that "a combination therapy with other drugs active against MAC will be necessary to prevent the emergence of resistance," Chaisson said. "Nevertheless," Chaisson maintained that clarithromycin "represents a major therapeutic advance in the treatment of MAC infection that will become an important addition to the repertoire of agents used to manage advanced HIV disease." Abbott Macrolide Venture Group Head Carl Craft, MD, told an ICAAC session on AIDS-related MAC that clarithromycin produced an 81% "bacteriologic success rate" after four weeks at a dosage of 1,000 mg b.i.d. in clinical trials. The company said Oct. 15 that it plans to file a supplemental NDA for Biaxin's use in treating MAC "very soon." Craft reported on interim results from an open-label trial that involved 159 patients randomized to 500 mg b.i.d. or 1,000 mg b.i.d. of clarithromycin. Defining "bacteriologic success" against MAC as a "one log or greater decrease" in colony-forming units of the bacteria, Craft said that the data show a 68% bacteriologic success rate at four weeks for patients receiving clarithromycin 500 mg b.i.d., which represented a statistically significant reduction in efficacy from the 1,000 mg group. While initial success rates were greater for the 1,000 mg patients, "the 500 mg group caught up" to them after six to eight more weeks. By the patients' next evaluation at approximately 10-12 weeks, Craft said the success rates between the two clarithromycin dosage levels were "comparable" at 79% for the 500 mg group and 77% for the 1,000 mg patients. However, the difference in the percentage of patients whose blood cultures were negative was statistically significant at 10 to 12 weeks -- 37% for the 500 mg group and 60% for the 1,000 mg group. From these differences, Craft concluded that the 1,000 mg dose "showed higher eradication rates, earlier time to first eradication, and longer duration of eradication" than the 500 mg dose. Median survival time of all patients in the trial was 318 days, versus an "historical control of between 160 days to 230 [days] for these patients." A parallel study (ACTG 577A) of people with AIDS-Related Complex who either had participated previously in a clarithromycin trial or had "pre-treated themselves" with Biaxin obtained abroad, had a mean survival rate of 471 days- 399 at 500 mg b.i.d. and 854 days at 1,000 mg b.i.d. Increased survival time was an unmet endpoint in the clinical trials for Adria's Mycobutin (rifabutin) NDA for the prophylaxis of MAC in people with AIDS. FDA's Antiviral Drugs Advisory Committee recommended rifabutin for approval Sept. 24 even though the drug showed only trends towards a survival benefit ("The Pink Sheet" Sept. 28, p. 3). Craft reported that "a clinical improvement was seen in the majority of patients in both [dosage] groups, with greater than 72% success for both." Clinical improvement involved assessment of signs and symptoms of MAC, such as fever, night sweats and weight loss.

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