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IMMUNEX' GM-CSF APPROVAL RECOMMENDED IN AUTOLOGOUS BONE MARROW TRANSPLANTS; CONDITIONAL APPROVAL FOR ENGRAFTMENT FAILURE SUGGESTED

Executive Summary

Immunex' Leukine (GM-CSF) was recommended for approval for the promotion of autologous bone marrow transplantation engraftment in patients with malignant lymphomas by FDA's Biological Response Modifiers Advisory Committee on Dec. 13. The committee unanimously recommended that FDA approve the granulocyte macrophage-colony stimulating factor for autologous transplants in patients with non-Hodgkin's lymphoma and acute lymphoblastic leukemia (ALL). Pediatric patients and patients with chemically purged marrows are included in the treatment populations. Up to 10,000 patients with malignant lymphoma in the U.S. could benefit from bone marrow transplants, according to an Immunex consultant. The panel also voted to include patients with Hodgkin's disease even though FDA had concluded that the studies showed "little or no benefit in Hodgkin's disease patients who had received many myelotoxins and radiation therapy." Committee Chairman Jerome Groopman, MD, New England Deaconess Hospital, said that the approval would extend to "patients with Hodgkin's disease, with certain caveats that will be put into the particular labeling indication, as well as a caveat [concerning] the lack of data, to date, in terms of chemically purged marrows." The committee conditioned the approval of a second indication for GM-CSF in the treatment of bone marrow engraftment failure on a re-analysis of data collected at one of the over 30 centers in the study. It is the second time that the committee has asked Immunex to re-analyze data for the treatment of engraftment failures indication ("The Pink Sheet" Aug. 6, p. 8). In the meantime, the company received a Treatment IND for the use in September ("The Pink Sheet" Oct. 1, T&G-6). Approximately 300-600 patients annually fail engraftment. Groopman said the approval was "contingent upon the FDA review of the hematological data and a re-examination of single center data at the [Fred] Hutchinson [Cancer] Center in terms of active treatment versus historical controls attempting to have a multivariate analysis." The committee agreed that Immunex would not have to come before the committee again before approval. Once approved, Immunex will co-market GM-CSF with Hoechst-Roussel Pharmaceuticals, which will market the product separately under the brandname Prokine. Immunex President Steven Gillis said in a press conference following the advisory committee meeting that the two companies' supply agreement calls for a 50-50 split "up to a point and that point has been drawn in the sand. Beyond this point, anything that Immunex makes is Immunex'. Their supply is capped." The company is building a second plant to produce more GM-CSF. That plant, which the company hopes to complete in 1992 and have approved by 1993-94, is not covered by the agreement with Hoechst. Immunex' PLA for the promotion of bone marrow transplant engraftment included data on 128 patients from three pivotal studies conducted at the Fred Hutchinson Cancer Center in Seattle, the University of Nebraska at Omaha, and the Dana-Farber Cancer Center in Boston. Although the studies were conducted in different disease populations, they all followed the same protocol of GM-CSF given within four hours of bone marrow infusion at a dose of 250 mcg/m dose per day as a two-hour I.V. infusion continued over 21 days. When compared to placebo, Leukine significantly reduced the median time to an absolute neutrophil count of over 1,000 in two of the three centers -- from 28 days to 20 at Hutchinson and from 43 days to 29 at Dana-Farber, which had all non-Hodgkin's patients. GM-CSF also significantly increased the proportion of patients at day 21 with neutrophil counts over 1,000. At Hutchinson, 60% of patients showed neutrophil counts over 1,000 at day 21 compared to 19% for placebo-treated patients. GM-CSF also signicantly decreased the number of days in the hospital for patients in two of the three centers. The median time to discharge was reduced from 34 days to 28 at Hutchinson and from 27 days to 23 at Dana-Farber. There were no statistical differences between drug and placebo in the reduction of the number of days of fever and febrile neutropenia, although there was a trend in favor of GM-CSF. The number of patient infections, however, was cut by half in the GM-CSF group at Hutchinson and the duration of infections was significantly reduced. The requirement of antimicrobial treatment was significantly reduced by GM-CSF at Dana-Farber, from 27 to 23 days. Hutchinson also showed a reduction in the need for antimicrobial therapy, from 28 to 25 days, although the reduction was not considered significant. In addition, GM-CSF patients did not experience significantly more adverse events than placebo patients. One-year survival, however, was not significantly different between GM-CSF patients and placebo treated patients. As suggested by the committee recommendation, GM-CSF seemed to work best in the 104 patients (out of a total of 128 patients) with non-Hodgkin's lymphoma and ALL. Data from all three centers showed that in these groups absolute neutrophil counts of 500 were achieved in 18 days in the GM-CSF group versus 24 days with placebo, and counts over 1,000 were achieved by 24 days for GM-CSF treated patients compared to 32 days for placebo. The average number of days of hospitalization in the non-Hodgkin's lymphoma and ALL patients was decreased from 31 to 25, days of infection were reduced from 4 days to one, and days on antibacterials were reduced from 25 days to 21. The decreased hospital stays and the reduction in antimicrobial use in the GM-CSF study group is expected to be the subject of a recently completed cost-benefit study conducted by the Battelle Institute. The study results will be presented at the May meeting of the American Society for Clinical Oncology. The committee also agreed that absolute neutrophil count increases may serve as a surrogate endpoint of efficacy in future Immunex GM-CSF studies. That recommendation should help the review of GM-CSF in autologous transplants for breast cancer. GM-CSF is in Phase III studies for that use.

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