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BRISTOL’s DEOXYSPERGUALIN PHASE I STUDIES SUGGEST "IMPROVEMENT"

Executive Summary

BRISTOL's DEOXYSPERGUALIN PHASE I STUDIES SUGGEST "IMPROVEMENT" in preventing HAMA (human anti-mouse antibody) responses in patients receiving monoclonal antibodies, Susan Kelly, MD, a representative from Bristol-Myers Squibb's Clinical Cancer Research group, said during a July 1 session of the Conference on Drug Research in Immunologic and Infectious Diseases. Company and academic researchers presented data from preclinical and clinical tests of deoxyspergualin (DSG), claiming that preliminary results demonstrate the compound's potential efficacy and safety as an immunosuppressive agent. A Phase I study of 25 patients receiving anti-tumor monoclonal antibodies was initiated in the summer of 1991 at the M.D. Anderson Cancer Center, Kelly said. Preclinical data has suggested that DSG could block an antibody response to MAbs without interfering with the ability of the monoclonal "to reach its presumed target," Kelly explained. Also, DSG does not "seem to interfere in the IL-2 receptor expression." The Phase I study is testing the ability of three doses of DSG to "inhibit the HAMA response," Kelly explained, adding that safety issues and evidence of an anti-tumor response prompted by the monoclonal also would be investigated. Among eight patients receiving the lowest dose who were evaluable, "a HAMA response was totally prevented in six" patients, Kelly said, noting that "this is clearly a suggestion of an improvement over the historical experience" of patients. She also stressed that "safety of DSG combined" with the monoclonal "does not seem to be an issue." These results, Kelly continued, "appropriately set the stage for some additional clinical studies to assess the ability of the drug to block this type of immunogenicity of these very potentially clinically important proteins." DSG initially was studied as an anti-cancer drug. After Phase II trials conducted by NCI indicated that DSG was "not promising" as an anti-tumor drug, researchers "shifted focus onto the more promising aspects of this drug as an immunosuppressant," Kelly said. Bristol-Myers Squibb licensed DSG in 1988 from Nippon, which has maintained development rights for the drug in Japan. BMS filed an IND for DSG in April 1991, Kelly said. Early clinical trials underway in the U.S., Japan and Europe address DSG's immunosuppressive activity in complications involving organ transplants as well as in multiple sclerosis, systemic lupus and nephrosis. Behringwerke has been testing the drug in Europe. Several trials are focusing on DSG's ability to prevent graft rejections in such procedures as transplants of renal glands, pancreatic islets and bone marrow. While Kelly emphasized the preliminary nature of the data, collected from studies designed as dose escalation trials, she by Ehringwerke of DSG in also stressed the low toxicity of DSG. A Phase I study conducted by Behringwerke of DSG in patients with renal graft rejection showed that toxicities were dose related and included "mild degrees of bone marrow suppression, nausea, vomiting...diarrhea, fluctuations in blood pressure, but nothing that was very dramatic," Kelly said. * In another presentation, Frank Thomas, MD, University of North Carolina Medical Center, claimed that DSG "offers by far the best potential at present for solving the oppressive problems of organ donor shortage, which have plagued human transplantation since its inception." Presenting results from comparative preclinical trials of immunosuppressive agents including DSG, cyclosporin (Sandoz' Sandimmune) and FK-506 (Fujisawa's Prograf) in mouse and rat models subjected to discordant xenografting, Thomas explained that researchers "have now achieved some very striking prolongations of the same xenograft model using...a DSG-based immunosuppressive therapy, and we are getting survivals in the range of 60 days consistently and now even higher." Cyclosporin, the "gold standard of suppression...showed absolutely no prolongation of graft survival," Thomas said. FK-506 "produced only a pitiful prolongation of the xenograft survival beyond control," he added. Thomas explained that DSG is effective because of its potency as an agent that blocks "the critical anti-donor, xenogeneic humeral antibody response, which is responsible for the early destruction" of the transplants and grafts. He also cited the therapeutic potential of DSG in the area of islet transplantations for patients with Type 1 diabetes and emphasized the clean safety profile of the drug.

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