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Executive Summary

A Phase IV efficacy trial to evaluate the long-term effects of Genentech's Pulmozyme was recommended by FDA's Pulmonary-Allergy Drugs Advisory Committee during its review of the PLA for the cystic fibrosis therapy Aug. 9. The committee agreed that Pulmozyme (dornase alfa, rhDNase) would require a "rigorous follow-up" to determine the long-term efficacy of the recombinant drug, as well as to address certain safety issues. Committee Acting Chairman Richard Ahrens, MD, University of Iowa, remarked that "my long-term concern is that there are many therapies in cystic fibrosis which are sometimes very expensive and we are left, after using them for years, speculating over which one's really important." The committee voted seven-to-zero to recommend approval of DNase for the treatment of cystic fibrosis symptoms in patients five years of age and older, specifically in the reduction of respiratory tract infections and improvement of pulmonary function in patients with a forced vital capacity (FVC) 40% of predicted and above. About 30,000 people in the U.S. suffer from cystic fibrosis. Genentech estimates that 75% of those would be eligible for Pulmozyme therapy. At the meeting, Cystic Fibrosis Foundation Exec VP for Medical Affairs Robert Beall, PhD, noted that if approved, Pulmozyme would be the first new treatment for cystic fibrosis in three decades. Cystic fibrosis patients are currently treated with physical therapy, antibiotics and oral pancreatic enzymes. The "expectations out there are great" concerning the efficacy of Pulmozyme, committee member Lynn Taussig, MD, University of Arizona, noted. He cautioned however that "the concern I have is that people are going to think that this is the new cure-all drug for cystic fibrosis, which, I think we all agree right now, is not necessarily clearly the case." Taussig said that he would "like to see a caveat in the [package] insert that this is an adjunct therapy and does not replace any therapy and that all other therapies should be continued unless discontinued by physicians." Genentech kept its presentation to the advisory committee low- key. The company sent only a handful of representatives to the meeting; the lower turnout, both in the sponsor's section and in the audience, reduced the circus atmosphere present at previous high-profile biotech product evaluations. Genentech's ability to maintain that atmosphere is an example of the company's careful management of the PLA and its relations with FDA. FDA brought the Pulmozyme PLA (93-0251) before the committee after just four months of review. The agency has been proactive in the clinical development of Pulmozyme, meeting with Genentech numerous times and working closely with the company in the design of the protocol for the pivotal Phase III trial. "Throughout the development program, we regularly shared our clinical and manufacturing and preclinical plans with FDA," Genentech VP Regulatory Affairs David MacFarlane, PhD, said. "These plans were thoroughly reviewed by FDA and we received many excellent suggestions on how to optimize and improve our research and development program," he noted. FDA Commissioner Kessler, who was present throughout much of the committee meeting, emphasized that the application submitted in March was receiving an expedited review, not an accelerated review. "This is not a conditional approval," he said, noting that the primary endpoint of reduction in respiratory tract infections was a real clinical endpoint rather than a surrogate marker. FDA Office of Drug Evaluation I Director Robert Temple suggested that the approval of Pulmozyme could be followed by a "large simple trial...without a great deal of nonroutine measurements." A historical control would be acceptable to the committee "if that is the only thing that is practical," Acting Chairman Ahrens said. Endpoints for the Phase IV trial suggested by the committee included survival and declining forced expiratory volume (FEV[1]). Genentech Associate Director for Medical Affairs Henry Fuchs, MD, said the company plans to "gather as much data as possible after the approval of DNase on treated and untreated patients for the purposes of continually and prospectively characterizing the natural history of cystic fibrosis patients before and after the introduction of Pulmozyme." The firm has an ongoing study following over 4,000 patients who are not on DNase therapy. Efficacy data for Pulmozyme derive from a Phase III trial in 968 mildly to moderately sick cystic fibrosis patients. On average, patients had an FEV[1] 61% of predicted, FVC 78% of predicted, and a Taussig Score of 75%. All of the patients were 5 years of age or older with an FVC 40% of predicted or greater. The trial was conducted at 51 centers, representing 45% of the cystic fibrosis centers in the U.S. Patients in the study received 2.5 mg DNase once a day, 2.5 mg twice daily, or placebo for six months. The primary clinical endpoints of the trial were reduction in respiratory tract infections and improvement in pulmonary function, or FEV[1]. Secondary endpoints followed in the study included hospital stay, duration of parenteral antibiotic therapy and patient quality of life. Results from the trial show that DNase reduced the risk of respiratory tract infections by 28% when patients were treated with 2.5 mg once daily (q.d.) and by 37% when given the drug twice daily (b.i.d.). Treatment with DNase led to an increase in FEV[1] at the end of six months of 5.8% for the patients receiving the drug once a day and 5.6% in the b.i.d. group compared to no increase for the placebo-treated patients. There was an initial rapid improvement in pulmonary function in the first two weeks of therapy of 15%, which declined after one month to approximately 6% and remained stable out to six months. Patients were given the option to continue on or switch to 2.5 mg b.i.d. for another six months in an open-label trial. Several committee members and consultants commented on their perception of the modest effect of DNase on pulmonary function. "While I have been impressed by the reproducibility of the FEV[1] results in various studies," committee member Taussig said, "I am also impressed by the small size of the magnitude of the change." Committee consultant Susan Pingleton, MD, University of Kansas Medical Center, concurred: "My concern is not the statistical significance of those numbers, which I think you have demonstrated quite nicely, but the clinical importance that [I] view as a rather minor decrease in airways obstruction." FDA's Temple said that not only was the agency concerned about the modest effect of the drug on pulmonary function but also about a possible downward trend in efficacy. "Why should this basically local effect go away substantially after two to three weeks and diminish to something that is quite modest," Temple asked. "It was modest to begin with; at 6% it gets more modest and in the extension goes down to 4%." He added that in the open-label trials there was "a conspicuous uptick in the infection rate." Genentech's Fuchs maintained that Pulmozyme's effect on pulmonary function remains stable after about a month of therapy. "There is no slope to that line." He contended that the "up and then down in pulmonary appears to be an [artifact of] the population; we don't in fact see that in individual patients." The number of days of hospitalization was statistically significantly reduced by DNase therapy. Patients receiving once- daily DNase stayed an average 6.2 days in the hospital compared to 7.6 days for placebo-treated patients. DNase also reduced the number of days patients required parenteral antibiotics from 11.2 days for the placebo-treated group to 8.5 days for patients receiving DNase once daily. Patients responding to a questionnaire also reported greater well-being, less dyspnea (shortness of breath), and fewer symptoms associated with cystic fibrosis. Side effects associated with DNase therapy included: voice alteration (hoarseness) in 12% of patients treated once daily with DNase compared to 7% for placebo; pharyngitis in 36% of the patients receiving DNase once daily compared to 32% of placebo- treated patients; and rash in 10% of the DNase-treated patients compared to 7% for placebo. Antibodies to DNase formed in 3% of patients receiving a single daily dose and in 5% of the patients who were treated b.i.d. The committee suggested that Genentech further explore the side effects of Pulmozyme therapy through follow-up patient monitoring, possibly in the long-term trial, especially with regard to voice alteration and pharyngitis. Pingleton added that "there should be more information obtained...about the clinical significance of a positive [anti-DNase] antibody test." Some committee members were also concerned about a "theoretical" possibility that DNase's effect on the enzyme elastase in the lung could lead to impairment in lung function. Taussig said Genentech should "move aggressively ahead" on studies in patients under the age of five years, calling them an "incredibly important group." If the goal is to "prevent the incidence of infections, then [physicians are] going to want to treat early on in the course of the disease to prevent progression," he reasoned. The committee agreed that Pulmozyme should be administered in the once daily dosing regimen of 2.5 mg/2.5 ml with one of three marketed nebulizers used in the DNase clinical trials -- Marquest's Acorn II, Hudson's T-Updraft II or Pari's LC. The advisory committee disagreed, however, on whether clinical trial results from the three nebulizers could be extrapolated to allow for the use of other nebulizers with similar in vitro performance, as proposed by Genentech. FDA Pulmonary Group Medical Officer Michael Sevka, MD, told the committee: "We do not feel that in vitro characterization alone is sufficient for establishing clinical equivalency of different nebulizer systems." Data pertinent to dosing in older patients should be presented in the clinical pharmacology section, the committee agreed. However, some members objected to placing any reference to the possible superiority of b.i.d. dosing in that patient group. The committee voted 5-3 on the issue in favor of including the data in the dosage section. Taussig contended that the advisory body and agency had a "fiduciary responsibility" to patients not to recommend a higher dose when the data were not certain. In patients 21 years and older, once-daily dosing was not statistically significantly better than placebo in the reduction of respiratory tract infections. However, the conclusiveness of subpopulation analyses was questioned because of the smaller number of patients involved. While Genentech seems to have the clinical approval of Pulmozyme assured, some manufacturing issues remain. "There are some issues we are addressing that could impact when DNase is actually approved," Genentech's MacFarlane said. MacFarlane reported that Genentech completed its DNase manufacturing facility in December and has finished validation and scale-up but is "only [now] beginning to produce product that will be available for commercial use." MacFarlane said the company wants "to make sure that we are going to have enough material to launch, and that takes some time to produce that amount of product." Genentech is working "as quickly as possible," he said but does not know "how long it will take to develop that amount of product and when it will be available." Pulmozyme will be available in plastic single-use ampules of 2.5 mg/2.5 ml of liquid. The company proposes to market the drug in foil packages of six ampules. Five of the foil packages will be placed in a box of 30, which is one month's medication, MacFarlane said.

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