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BOOTS' MANOPLAX RECOMMENDED FOR APPROVAL FOR HEART FAILURE PATIENTS INTOLERANT TO ACE INHIBITORS; MORTALITY DATA CAUSES COMMITTEE CONCERN

Executive Summary

Boots' Manoplax (flosequinan) was recommended for approval in the treatment of congestive heart failure patients who are intolerant to angiotensin converting-enzyme inhibitors by FDA's Cardiovascular & Renal Drugs Advisory Committee at its Oct. 24 meeting. In a four-to-two vote with one abstention, the committee agreed that flosequinan demonstrated sufficient efficacy to be used in the treatment of congestive heart failure patients who remain symptomatic following treatment with other therapies. However, the panel took the further step of restricting the use to only those patients who are intolerant to ACEs because of risk/benefit concerns about the arteriovenous vasodilator. The idea of the second-line indication was proposed by Milton Packer, MD, Mount Sinai Medical Center, who stepped down from his committee member post during the meeting to serve as a consultant for Boots. Packer, who was the principal investigator of the studies, suggested the restricted indication in anticipation of a committee vote against approval. In fact, the committee rejected the initial recommendation to approve flosequinan for the general indication of chronic heart failure by a four-to-three vote. Packer urged the committee "to consider the restricted use of this drug in patients who are intolerant of ACE inhibitors with the caveats that [the panel] would feel comfortable with as warnings in the labeling concerning mortality." Committee member Peter Kowey, MD, Lankenau Hospital, Pennsylvania, who voted against the first indication, said he voted for approval of the ACE intolerance indication only "with the proviso that the labeling contain very strong information about the fact that we don't know what this drug is going to do." The committee split three to three with one abstention on a recommendation that flosequinan be used to treat patients who are resistant to ACE inhibitors. The major concern of many panel members stemmed from a meta- analysis of mortality data presented by the company which showed that flosequinan-treated patients may have an increased risk of dying compared to patients on placebo. A secondary concern was that the results from four pivotal trials of flosequinan failed to provide unequivocal evidence of a significant benefit to patients from the therapy. "If one tries to develop a risk/benefit ratio, I think that we have some benefit [with flosequinan], although I am concerned that it is not well demonstrated," committee reviewer Edward Pritchett, MD, Duke University, remarked. He added that "the information is often weak with respect to dose relationship and efficacy, and we have some very major reservations about adverse events, particularly mortality." Mortality data on almost 3,000 patients from 11 trials submitted by Boots showed, upon metanalysis, that flosequinan therapy may be associated with a 1.46 relative risk, or a potential 46% increase in deaths. The incidence of deaths in the trial on an intent-to-treat basis was 5.4% in the flosequinan- treated patients compared to 3.3% for patients receiving placebo. The range of relative risk in the analysis was .8 to 2.6. Although the differences in mortality between flosequinan and placebo did not reach statistical significance, committee Chairman Craig Pratt, MD, Baylor College of Medicine, maintained that there is "a potential for an increase in mortality." He suggested that the mortality results, while insubstantial, could not be dismissed because of similar early findings in such trials as the Cardiac Arrhythmia Pilot Study (CAPS) that showed patients treated with encainide (Bristol-Myers Squibb's Enkaid) and flecainide (3M Pharmaceutical's Tambocor) may have relative risks of dying from .7 to 2.3. Encainide and flecainide were later found to increase mortality by 2.5-fold in the larger Cardiac Arrhythmia Suppression Trial (CAST). Pratt also noted that relative risk for flosequinan "is not that much different than" the Prospective Randomized Milrinone Survival Evaluation study, which found that milrinone (Sterling's Primacor) caused a 28% increase in mortality in patients with congestive heart disease. Of the flosequinan data, Salim Yusuf, National Heart, Lung, & Blood Institute Clinical Trials Branch, commented: "I don't think any one of us could walk away saying we are confident that there is no increase in mortality; in fact, if we wanted to play the game of odds, it is eight-to-two ...that there is an increase in mortality." While the committee agreed that the data pose serious concerns, they concluded that flosequinan's effect on mortality will not be definitively known until completion of the Prospective Randomized Flosequinan Longevity Evaluation (PROFILE) study begun this year. Results from the 3,500-patient trial are expected in 1995. "PROFILE may prove the point estimate from the meta-analysis to be wrong, in which case this may turn out to be a very important compound representing an alternative to ACE inhibitors," Pritchett commented. He voted against approval at this time. Acting as Boots' spokesman on the mortality and efficacy data, Packer offered several reasons why the flosequinan mortality experience is not likely to translate into a CAST or PROMISE situation. First, flosequinan is not a phosphodiesterase inhibitor like milrinone, but acts more like hydralazine, which, in combination with isosorbide dinitrate, has been shown to improve survival. Secondly, Packer said, "the greater number of deaths in patients treated with flosequinan compared to placebo is entirely related to a greater number of deaths related to progressive heart disease," not to sudden death as in the PROMISE trial. Thirdly, the difference between flosequinan and placebo in the meta- analysis "is primarily related to a difference of five deaths in one study," Packer maintained. In the meta-analysis of intent-to- treat data, four studies showed more deaths in the flosequinan group, compared to two studies that showed greater mortality in placebo-treated patients and five studies that showed equal survival in both treatment groups. In addition to questions about mortality data, several committee members expressed some dissatisfaction with the efficacy data, although most agreed that there were strong trends in favor of efficacy of flosequinan. Four controlled exercise-tolerance trials were presented by Packer. The first pivotal study (BPI 919) enrolled 190 CHF patients who continued to be symptomatic following prior therapy with digoxin, diuretics and/or ACE inhibitors. Changes were measured in terms of the patients' maximal exercise capacity. Flosequinan-treated patients showed a statistically significant increase in treadmill test time of 96 seconds compared to a 44- second improvement with placebo. In the study, patients' maximal oxygen consumption also improved. There was also a nonstatistically significant trend toward improvement in patients symptoms. Patients received concomitant digoxin and diuretics. Another large study of 298 patients (BPI 925) showed that flosequinan 100 mg/day significantly improved exercise tolerance by 96 seconds compared to 51 seconds for placebo. Patients receiving a dose of 50-75 mg/b.i.d. did not show a significant improvement in exercise tolerance over placebo. Patients also improved in maximal oxygen consumption but only showed a trend in symptom improvement. A third study in 135 patients with doses of flosequinan from 75 mg to 125 mg showed no statistically significant improvement in any of the endpoints, although there was a trend in favor of flosequinan. The most convincing study in terms of results presented by Packer was a 20-patient trial, in which flosequinan-treated patients improved an average of 248 seconds in the exercise- tolerance test, while the exercise capacity of placebo-treated patients declined by 81 seconds. Significant improvements were also noted in maximal oxygen comsumption, N.Y. Heart Association score and symptoms such as dyspnea and fatigue. The major side effect in the trials was an increase in headaches. In one trial, flosequinan produced a 31% incidence of non-lifethreatening arrhythmias compared to 6% for placebo. Many committee members considered the first trial (BPI 919) to be inconclusive because of what they considered to be a retrospective statistical analysis performed by the company. The committee agreed with the FDA statistical reviewer that the company, when faced with abnormally-distributed data from BPI 919, may have used a statistical test that favored flosequinan in the outcome. Regarding the study, committee reviewer Pritchett commented, "I am very concerned about [it] because of the way the data was handled." Boots' preliminary analysis of this trial in September 1989 almost discouraged the manufacturer from continuing with the development of Manoplax; however, a month later the company decided to continue with its registration plans based on an "encouraging" reanalysis of the data ("The Pink Sheet" Oct. 30, 1989, T&G-6). A majority of committee members considered the second trial (BPI 925) to be the most clear cut. However, NHLBI's Yusuf pointed out that data from the study had not yet been reviewed by the agency. FDA Cardio-Renal Drug Products Division Director Raymond Lipicky, MD, said that if the agency's review of the data from that study reveals discrepancies, the issue will be brought before the committee. The consistently significant results of the 20-patient trial impressed most members of the committee, but several members questioned the validity of the findings considering the study's small size. "As clever as it is, it is not large enough for me to consider accurate," Pritchett commented. Lipicky argued that a trial does not have to be large to be considered adequate. Other committee members found the results of the small trial to be quite compelling. Overall, many committee members felt that all of the flosequinan trials went "in the right direction," although the improvements in exercise tolerance might not be considered large clinical improvements. Packer maintained that "the magnitude of the benefit [in the flosequinan trials] in terms of exercise tolerance and symptoms is superimposable on ACE inhibitors." Lipicky pointed out that captopril (Bristol-Myers Squibb's Capoten) was approved based on an 8% increase in exercise tolerance. Flosequinan improved treadmill tests by 5%-10% overall. If approved, Manoplax will be copromoted by Warner-Lambert. Boots signed a cross-promotion agreement with Warner-Lambert to copromote the cholesterol-regulating drug Lopid in July ("The Pink Sheet" July 29, T&G-2). There are close to 3 mil. people in the U.S. who suffer from congestive heart failure, of which 40,000 die annually and there are 400,000 new cases each year. Researchers estimate that about 20% of CHF patients, the most seriously ill, are being treated with ACE inhibitors to improve symptoms of the disease.
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