FUJISAWA FK506 PHASE III TRIALS IN LIVER TRANSPLANTS UNDERWAY

FUJISAWA FK506 PHASE III TRIALS IN LIVER TRANSPLANTS UNDERWAY for primary and rescue indications as immunotherapy treatment in association with transplantation. The company disclosed the status of clinical trials in an Aug. 20 release following a flurry of publicity for the drug derived from reports presented at the XIII International Congress of the Transplantation Society in San Francisco, Aug. 19-24. At the medical meeting, 15 clinical studies and 30 lab studies on were presented involving the immunosuppressive. The University of Pittsburgh has been the primary development site for FK506 through Phase II in the U.S. The hospital says that it has treated "nearly 800" patients with the drug. In the most recent clinical results reported by the University of Pittsburgh, over 70% of 222 liver transplant patients who were failing on cyclosporine therapy improved when switched to FK506 treatment. University of Pittsburgh researcher John Fung, MD/PhD, reported the results of rescue treatment with FK506 over a 14-month period between February 1989 and April 1990. Patients were first treated with a combination of cyclosporine, high dose steroids, OKT3 and/or azathioprine. The patients experienced "uncontrollable rejection, kidney failure, and other serious complications," a University of Pittsburgh press release notes. Seventy-four percent of them were treated with OKT3 to avoid retransplantation. All patients in the study were then converted to FK506 and low-dose steroids. During the study, "22 of the patients died and 19 required retransplantation because of either progressive liver failure, blood clots in the main artery in the liver, or progressive hepatitis," the university release states. "The study also found that unlike cyclosporine, FK506 can reverse liver damage, such as bile duct loss, caused by chronic rejection," according to the release. "Of 37 patients with this complication, 21 have done well with FK506 and have functioning livers." Fung and his colleagues also found that 50% of the FK506 patients previously on cyclosporine no longer were on steroids or were receiving "significantly lower" doses. All patients experiencing steroid toxicity due to high doses of steroids had no further complications and were able to discontinue steroids after treatment with FK506, the university release says. The study was honored as one of the three best papers presented at the San Francisco conference. It will be published in Transplantation Proceedings. Among other FK506 clinical studies presented at the Transplantation Society conference, Andreas Tzakis, MD, University of Pittsburgh Medical Center, reported the results of a study of 42 children who underwent transplantations involving the liver, heart, and kidney. Tzakis and his colleagues found that "organs failing on cyclosporine could be salvaged by giving the patient FK506, preventing the need for another transplant," a university release states. Kidney dysfunction was observed in four of the 23 patients converted to FK506. Researchers again found that patients receiving FK506 did not need the high doses of steroids required with cyclosporine treatment. A study in 30 heart transplant patients, presented by University of Pittsburgh's John Armitage, MD, found that 26 of 30 patients initially given FK506 experienced "excellent cardiac function with few instances of rejection and infection" for a current survival rate of 87%. Armitage also found that FK506 "virtually eliminated" hypertension. FK506 was isolated from a soil fungus in 1984. The first clinical trial results with FK506, involving 40 organ transplant patients, were presented in Barcelona, Spain in October 1989 at a meeting of the European Society for Organ Transplantation. The preliminary data indicated that one-year patient survival with the drug might be as high as 80-90%, compared to cyclosporine's 70% patient survival rate. FK506 is the first Fujisawa product to enter Phase III U.S. clinical trials under the company's own development. The product is manufactured in Japan and exported to the U.S. In addition to the multicenter trials in the U.S., Fujisawa has begun a multicenter clinical trial in Japan with kidney transplant patients. A multicenter trial with liver transplant patients is scheduled to begin in Europe in the near future and further studies to investigate the potential role of FK506 in kidney and heart transplants are planned in the U.S. and Europe. Wyeth-Ayerst has a follow-up compound to FK506 under development, according to the reports from the Transplantation Society meeting. The 10 reports on rapamycin, a fungal macrolide metabolite structurally related to FK506, were the results of preclinical work. Three of the studies compared rapamycin to FK506. A Stanford study by Wu et al. concluded, for example, that "in rodent cardiac allograft models rapamycin is 50 times more potent and 8 times more effective than cyclosporine as well as more potent and effective than FK506." The study further stated that rapamycin "also induces antigen-specific unresponsiveness to allografts after a single post-transplant treatment." A Munich study by Meiser, Billingham and Morris reported that in Lewis or Brown Norway heart grafts transplanted into Lewis recipients, "rapamycin...is a potent inhibitor" of transplant coronary disease "while FK506 fails to prevent and may even cause accelerated transplant coronary disease." In an Observatory, South Africa study by Hildebrandt, Meiser et al., researchers found that both "FK-506 and Rapamycin prodrug proved to be powerful immunosupprressive agents, capable to prolong graft survival and to reverse acute rejection episodes" in Chacma baboons. According to the report, "FK-506 seemed to be more effective when given i.m. while Rapamycin showed better results when given i.v."