The FDA's Pulmonary Allergy Drugs Advisory Committee onMonday unanimously recommended for approval GenentechInc.'s recombinant DNase for treating cystic fibrosis.
Voting 7-0, the committee urged that the drug, Pulmozyme, beapproved for use in cystic fibrosis (CF) patients in stablecondition over 5 years of age whose lung function is greaterthan 40 percent (as measured by FVC, or forced vital capacity).
"The evidence suggests that in general, patients will get a smallimprovement in lung function and a decrease in the number ofpulmonary exacerbations, which will probably not be uniformfrom patient to patient," the committee said. Ever cautious, thepanel emphasized that Pulmozyme is not a cure. "We have tobe honest. It's important to emphasize that other therapies (fortreating CF) have to be continued."
Although the committee didn't find it difficult to decide thatthe drug works, it did spend a great deal of time discussing thedrug's appropriate dosage (once or twice a day). In the end itdecided to recommend that a once-daily regimen be followedfor the defined patient population, with suggestions for twice-daily schedules for patients outside the defined parameters tobe included in the clinical pharmacology section of the packageinsert. The committee was uncertain as to whether patientsover the age of 20 might do better on a twice-a-day dose.
Also a point of intense discussion among the panelists was thechoice of inhaler to be used by patients taking the drug, whichis delivered as an aerosol. A number of different disposable orreusable inhalers apparently are available. To avoid potentialproblems with effective doses as well as cross-contamination(when more than one member of a family uses the sameinhaler, for instance), the committee suggested that only theinhalers used in the Genentech study be recommended.
The overall positive recommendation was based on Genentech'spivotal, placebo-controlled double-blind Phase III clinical trialin 968 patients. Patients received 2.5 milligrams of Pulmozymeor placebo once or twice daily for 24 weeks. The trial wasdesigned to measure improvement in pulmonary function andreduction in the rate of respiratory infections in mild-to-moderate CF patients.
Secondary clinical end points included improvement in FVC,quality of life, cumulative days on antibiotics and cumulativemorbidity due to CF.
The trial results demonstrated that twice-daily use of the drugreduced the use of antibiotics to treat all respiratory infectionsby 31.8 percent as compared with placebo, but once-a-day usewas almost as good (31 percent). The results were similar forthe drug's effects on lung function (as measured by forcedexpiratory volume, or FEV1). There, FEV1 improved by 5.6percent when the drug was used twice daily, and by 5.8percent when used once a day.
Genentech had concluded that there doesn't seem to be anyadded benefit in using the drug twice a day. And after muchdiscussion, the committee members recommended once-dailyadministration. For one thing -- ever important in the currentcost-sensitive environment -- "we have a fiduciaryresponsibility to the patients that we don't recommendsomething when it isn't warranted," said David Kessler,commissioner of the FDA, who attended the meeting.
Questions remain, however, especially as to Pulmozyme's long-term effects on the morbidity and mortality of CF patients. Thecommittee also felt that it will be important to characterize thedrug's safety and efficacy in patients younger than 5 years ofage and those with an FVC of less than 40 percent. Also neededare studies with higher doses and increased frequency ofadministration, as well as more insight into the drug'smechanism of action in vivo, the committee said. Long-termsafety and efficacy issues are being addressed by ongoingstudies.
Genentech of South San Francisco, Calif., still has to deal withsome manufacturing issues as part of the licensing process forPulmozyme, a point that was brought up by the committee.David MacFarlane, Genentech's vice president of regulatoryaffairs, explained that not only is the manufacturing process forthe product complex and time-consuming, but also thatGenentech has just finished validating its new manufacturingfacility for Pulmozyme.
"We're just beginning to produce product for commercial use,"MacFarlane told the committee. "It takes time to do that. Wecan't say when an adequate amount of product will beavailable to support product launch and then keep the pipelinefull," he added. "Additional time may be needed."
-- Jennifer Van Brunt Senior Editor
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