FK778, a novel compound with multiple modes of action - a breakthrough in transplant immunosuppression?

VENICE (Italy) September 24 (PROTEXT/PRNewswire) - Firstclinical data presented today at the 11th Congress of theEuropean Society for Organ Transplantation in Venice suggestFK778, a novel compound with multiple mechanisms of action, isefficacious, well tolerated and safe in kidney transplantpatients, potentially offering a breakthrough inimmunosuppressive therapy.

FK778 is the first of a new class of low molecular weightimmunosuppressants, the malononitrilamides, currently underdevelopment for organ transplantation. In animal models, FK778has been shown to block both cellular (T cell) and humoral(antibody) immune responses, potentially allowing FK778 toprevent not only acute rejection but also chronic allograftdysfunction - notoriously difficult to treat and one ofthe main reasons for late graft loss.

Final results of the Phase II study (1)(n=149 adult renaltransplant recipients) revealed that after 4 months treatmentFK778 was efficacious and well tolerated when used in combinationwith the calcineurin inhibitor Prograf(r) (tacrolimus) andcorticosteroids. Presenting the results on behalf of the studygroup, Professor Yves Vanrenterghem (Department of Nephrology,Universitaire Ziekenhuizen, Leuven, Belgium) revealed that FK778treated patients showed lower acute rejection rates, especiallywhen patients were under higher drug exposure early on aftertransplantation.

Unlike currently available immunosuppressants, FK778 exertsits immunosuppressive activity at the molecular level via thesuppression of de-novo pyrimidine biosynthesis, inhibiting theaction of dihydroorotate dehydrogenase, an enzyme critical in theprocess, and consequently inhibiting cell proliferation.

In addition to its immunosuppressive properties, FK778 hasalso been shown in in-vitro and animal studies to exhibitantiviral activity, inhibiting the virion assembly process ofcytomegalovirus (CMV) and polyoma virus. This is important inimmunocompromised transplant patients because CMV infection is acommon complication after transplantation and for patientsaffected it is a risk factor for chronic allograft dysfunction.For polyoma virus the effect of FK778 is even more important,because the infection often causes subsequent graft failure.

Clinical development of FK778 will continue. Recently a largescale, pan-European, multicentre dose finding Phase IIb study hasstarted.Notes to Editors

Acute rejection is mediated by T cells (cellular acuterejection) and by B-cell-derived antibodies (vascular acuterejection), and tends to occur within days to the first fewmonths after organ transplantation.

The mechanism behind chronic allograft dysfunction, whichoccurs months to years after transplantation, has not been fullyelucidated, but both cellular and humoral immune responses play arole. Important risk factors for chronic allograft dysfunctioninclude episodes of unresolved acute rejection and an array ofnon-immunological factors, including CMV infection.

Fujisawa GmbH is a subsidiary of Fujisawa Pharmaceutical Co.,Ltd., based in Osaka, Japan. Fujisawa Pharmaceutical Co., Ltd. isamong the world's top 30 pharmaceutical companies and employsover 8000 people in Japan, Europe, North America and Asia. Sinceits launch of Prograf(r) in Japan in 1993, the first in theworld, Fujisawa has become one of the world's leading transplantand immunosuppression companies.Fujisawa plans to maintain its commitment to transplantation, andis dedicated both to improving the results of solid-organtransplantation and to ensuring the health and quality of life ofpatients. Prograf(r) is currently available in nearly 70countries and forms the centrepiece of Fujisawa's continuinggrowth. Additional information on Fujisawa GmbH can be found onthe Company's Web site at www.fujisawaeurope.com.Reference1. Vanrenterghem Y, van Hooff J, Wlodarczyk Z, Klinger M,Squifflet J and the European FK778-Kidney-Transplant-Study-Group.A multicentre, randomised, double-blind study to evaluate thesafety, tolerability, efficacy and pharmacokinetics ofmalononitrilamide FK778 in combination with tacrolimus andsteroid therapy in renal transplantation. Presented at the 11thCongress of the European Society for Organ Transplantation, 20-24September 2003, Venice, Italy. Abstract 102.Contact:Marité OdeFujisawa GmbH, Munich, GermanyT: +49 89 45442249F: +49 89 434129media@fujisawa.de Subscribers please note that material bearing the slug"PROTEXT" is not part of CTK's news service and is not to bepublished under the "CTK" slug. Protext is a commercial serviceproviding distribution of press releases from clients, who areidentified in the text of Protext reports and who bear fullresponsibility for their contents. PROTEXT