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Executive Summary

Warner-Lambert's angiotensin converting enzyme inhibitor Accupril should be approved as a twice-daily treatment for congestive heart failure, FDA's Cardio-Renal Drugs Advisory Committee concluded Feb. 18. The committee unanimously voted that Accupril (quinapril) merits approval for the CHF indication on the basis of Warner- Lambert's clinical data from three separate trials demonstrating that the drug is superior to placebo in improving exercise tolerance. However, the committee voted 7-0 that the studies do not support a once-daily dose. Warner-Lambert presented a 32-patient, six-sequence, three-way crossover study comparing once-a-day Accupril to twice-daily Accupril and placebo. The rest of the company's efficacy data used twice-daily dosing. The crossover study showed a significant improvement in exercise tolerance for both dosing intervals of Accupril versus placebo, and "no difference" between once- and twice-daily dosing, Warner-Lambert's Andrew Uprichard, MD, told the committee. Accupril is currently approved for the treatment of hypertension in both once- and twice-daily regimens. The committee, however, was uncomfortable with the small sample size of the study. "If this is an effective dose, why not do a bigger study?," committee member Barry Massie, MD, San Francisco VA Hospital, asked. Committee member Salim Yusuf, McMaster University, said that he was persuaded that the once-daily dose "produces an effect that's different than placebo." However, he questioned "whether [the effect] is the same or smaller" than twice-daily dosing. Yusuf abstained from the vote on dosing schedule. FDA Office of Drug Evaluation I Director Robert Temple told the committee that "our experience as a general matter and with this drug in particular is that if a once-daily regimen is in [the label], it will be promoted heavily." The once-daily dose "is an important competitive matter," Temple added. "I'm very leery of trying to fence it in with modified labeling" if the committee believes it is not fully supported by the data. The committee was reminded that Merck's Vasotec (enalapril) CHF labeling states that the drug may be "given as a single dose or two divided doses." That statement is based on a 19-patient study showing equivalence of the two dosing schedules, whereas the CHF indication is based on the 2,500-patient SOLVD trial. Labeling notes that "the majority of patient experience in clinical studies has been with twice daily dosing." Following the committee vote, Temple said that "it seems fairly obvious that we need to revisit the once-a-day recommendation in enalapril labeling." The committee recommended an initial Accupril dose of 5 mg daily for most CHF patients, to be titrated up to a maximum of 40 mg per day. The committee agreed with Warner-Lambert's proposal to recommend a 2.5 mg starting dose for renally impaired patients. Warner-Lambert's three placebo-controlled efficacy trials for congestive heart failure involved nearly 500 patients, Uprichard indicated. Protocol 891-140 was a 225-patient multicenter trial conducted in Germany comparing three strengths of Accupril to placebo. The trial demonstrated that Accupril "provided a dose- related improvement in exercise capacity," Uprichard concluded. The 891-140 study showed a clear dose response between placebo, 10 mg quinapril and 20 mg quinapril, Uprichard said. "Here for the first time is actually a glimmer" of a dose response in a CHF product, Cardio-Renal Drug Products Division Director Raymond Lipicky commented. The committee agreed that labeling should encourage physicians to try to titrate to 20 mg unless patients were intolerant to the drug. Protocol 906-215 was the 32- patient crossover trial. Committee reviewer Jeffery Anderson, MD, cited 891-140 and 906-215 as the primary bases for his approval recommendation. The third trial, 906-276, was a placebo-controlled quinapril withdrawal study, in which all patients were given Accupril for a minimum of ten weeks and then randomized to receive either drug or placebo for 16 weeks. Measured in terms of exercise tolerance or number of dropouts due to a worsening of CHF, Accupril proved to be significantly superior to placebo in the 224-patient study, Uprichard concluded. Anderson, who characterized the trial as "supportive," said the 906-276 protocol "shows the effect of stopping Accupril therapy." The committee unanimously agreed that labeling should state that "there is no information on mortality" in studies of Accupril. Committee Chairman Craig Pratt, MD, Baylor College of Medicine, said that FDA should "judge each ACE on its own effects" and not refer to mortality benefits shown by other ACE inhibitors in Accupril labeling. Accupril labeling should also be "silent" on the issue of use in New York Heart Association Class IV CHF patients, the committee agreed. Only 35 of the 1,108 patients in Warner-Lambert's CHF database were Class IV. The committee unanimously voted that Class IV patients should not be specifically excluded from labeling. Labeling "can certainly emphasize that most of the patients were in Class II or III," Temple noted. Accupril was approved by FDA for treatment of hypertension in November 1991. That same month, Warner-Lambert filed the supplemental NDA for use in treating CHF. If Accupril is approved for CHF, it will join Vasotec and Bristol-Myers Squibb's Capoten in the CHF/ACE inhibitor market. Lisinopril (Merck's Prinivil and ICI's Zestril) was also recommended for approval for treating congestive heart failure on Feb. 18 (see following story). Accupril is fourth in terms of sales among ACE inhibitors (behind Vasotec, Capoten, and Prinivil/Zestril) and first among the "second generation" ACE inhibitors, Warner-Lambert said in a Feb. 18 press release. The drug had sales in excess of $100 mil. worldwide in 1992 and sales are expected "to exceed $250 mil. in just a few years," the firm added. Accupril is marketed in about 40 countries and is approved for treating CHF in most, Warner- Lambert said.

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