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Executive Summary

BOOTS MANOPLAX NDA FOR CONGESTIVE HEART FAILURE FILED on Sept. 28 based on clinical trial data involving over 3,000 patients worldwide. The NDA submission marks a turnaround in the drug's fortunes, which a little over a year ago were uncertain. In September 1989, Boots announced that it was considering the cancellation of further clinical studies based on a preliminary analysis of Phase III results that apparently showed an unexpectedly high rate of exercise tolerance improvement in the placebo groups. However, a re-analysis of the Manoplax (flosequinan) data a month later convinced the company to proceed with marketing registrations of the compound ("The Pink Sheet" Oct. 30, 1989, T&G-6). The results of what will likely be considered a pivotal efficacy trial, dubbed the REFLECT Study (Randomized Evaluation of Flosequinan on Exercise Tolerance), were presented for the first time at the American Heart Association's meeting Nov. 11-14 in Dallas. The 193-patient study found that 56% of patients taking Manoplax 100 mg once-a-day showed signs of "improved-well-being" after 12 weeks on the drug versus 34% of patients on the placebo. In addition, patients taking Manoplax showed significant improvement in exercise tolerance based on treadmill tests. The median improvement in the drug group was twice that of the placebo group -- 96 seconds versus 44.5 seconds. Worsening symptoms occured in 10% of the Manoplax group compared to 19% of the patients in the placebo group. The Class II-IV congestive heart failure patients enrolled in the study also received digoxin and diuretics. Milton Packer, MD, Mt. Sinai Hospital, noted in a presentation of the trial results that Manoplax "has been extraordinarily well tolerated." The most common side effect in the drug group was "a nitrate-like headache which disappeared after seven days of therapy." Packer indicated that a key advantage of Manoplax over current vasodilator therapies is the drug's continued effectiveness over a long period of time. "As opposed to nitrates, where repeated doses at brief intervals would result in the development of tolerance," Packer said, "when one gets repeated doses of flosequinan...tolerance does not develop." However, mortality results from the REFLECT study may raise some questions at FDA. During the three-month trial, seven patients died in the Manoplax group compared to only two patients in the control group. In addition, the drug may have inotropic effects. Packer noted that "large doses of this drug have been reported to exert positive inotropic effects in some clinical studies, but therapeutic doses of the drug do not increase contractility in isolated myocardium when evaluated in vitro." A study involving Ciba-Geigy's ACE inhibitor Lotensin (benazepril) in congestive heart failure patients also was presented at the AHA meeting. Researchers from the Northwestern University-based "Benazepril Heart Failure Study Group" presented their findings from a double-blind placebo-controlled trial designed to evaluate the effect of once-daily benazepril therapy on exercise tolerance and clinical status among patients suffering from congestive heart failure. The study, which examined the 12 week progress of 172 patients receiving either titrated doses of benazepril or comparable placebo therapy, demonstrated that after 12 weeks patients in the active control arm of the trial had increased exercise tolerance by over 95 seconds versus an improvement of only 37 seconds in the placebo control group. In addition, benazepril patients showed greater improvement "for fatigue, edema, rales, NYHA (New York Heart Association) class, and the patients global evaluation progress."

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