GENENTECH’s ACTIMMUNE (INTERFERON GAMMA) RECOMMENDED FOR APPROVAL IN TREATING CHRONIC GRANULOMATOUS DISEASE; LONG-TERM PHASE IV STUDIES SUGGESTED

Genentech's Actimmune interferon gamma should be approved for the treatment of chronic granulomatous disease (CGD), FDA's Biological Response Modifiers Advisory Committee unanimously recommended at its inaugural meeting July 30.

The advisory committee agreed with FDA's view that gamma interferon "clearly seems to have an effect on the prevention of serious infections in CGD patients." However, in questions to the committee, FDA expressed its concern with Genentech's study results, which were based on an average treatment time of nine months, and the likelihood that interferon gamma, if approved, would be used as a lifetime treatment. Noting that most CGD patients are children or adolescents, FDA pointed out that the product's effect on patients' normal growth and development, pubescence, and childbearing potential are unknown.

The committee suggested that any long-term safety questions could be addressed in Phase IV post-marketing studies.

CGD is a rare, inherited disorder that affects infants and young children, and is characterized by the inability of a patient's white blood cells to fight certain bacteria and fungi. Approximately 80% of those diagnosed with CGD develop unusually frequent or severe infections before the second year of life that in some cases can retard development or lead to death. FDA granted orphan status to Genentech for its interferon gamma in September 1988; the company filed a PLA for Actimmune in December 1989.

Genentech's initially proposed a Phase IV study involving follow-up evaluations at six-month intervals for up to 50 patients over three years. At the committee meeting, Genentech proposed increasing the study population to 100 patients and conducting the study for up to three years in the adults and through adolescence in younger patients. The proposed evaluations would include: patient history and physical, complete blood count, chemistry panel and urinalysis, endocrine and development evaluation, and an assay for interferon gamma antibody.

Addressing panel concerns that the proposed study might not provide adequate information on growth, development and immunologic function in a prepubescent population, Genentech Clinical Research Director Howard Jaffe, MD, said that the company "will certainly survey the population available and try to insure that more than half of that group are prepubetal." Jaffe noted that the drug has shown no evidence of immunogenicity in tests of over 800 patients, 54 of whom came from the Phase III study.

FDA consultant Rebecca Buckley, MD, a pediatric immunologist at Duke University, suggested that Phase IV studies follow a parallel group that is not undergoing interferon gamma treatment. Buckley said that the well-being of CGD patients is more dependent on the use of prophylactic antibiotics and the care of knowledgeable physicians than on interferon gamma treatment. Buckley questioned whether "this drug is going to be imperative therapy because there are many patients who do very well without it."

Genentech's placebo-controlled, double-blind study included 135 patients and was conducted at 13 institutions in four countries. Of the 128 patients eligible for analysis, 63 received the drug three times a week for a year, while the remainder received a placebo. With an average of nine months of patient experience, 77% of interferon gamma patients and 30% of placebo patients were free of serious infections after one year.

The company also compared the total number of serious infections among the two patient groups. In the interferon gamma group, 14 patients developed a serious infection, including six patients who had two episodes of serious infection, for a total of 20 serious infections. Thirty of the 65 placebo patients developed serious infections, including 26 with two bouts of serious infection, for a total of 56 serious infections in the placebo population. The placebo group had nearly three times the number of serious infections as the interferon gamma group.

The mean hospital stay for placebo patients needing treatment was 48 days in the Genentech study, compared to 32 days in the interferon gamma group.

Nonetheless, the committee expressed concern that the potentially high cost of gamma interferon treatment may substantially exceed hospitalization expenses. Genentech said it has not yet determined what the cost of interferon gamma treatment will be. The recommended dosage is 50 micrograms per square meter taken intravenously or intramuscularly three times a week. As with Activase and Protropin give-away programs, Genentech said it is "prepared to make sure that the drug is available to all patients regardless of their economic background." Genentech's interferon gamma is also in clinical studies for the treatment of small-cell lung cancer, malignant melanoma, and trauma-related infections.