Protein Design Labs Inc.'s Zenapax, a humanized monoclonalantibody under development with Swiss drug maker Roche HoldingLtd., has demonstrated it can significantly reduce kidney transplantrejection episodes, which affect nearly half of all those receivingdonor organs.
The success of the two Phase III studies, reported Wednesday, is afirst for Protein Design Labs, of Mountain View, Calif., followingtwo late-stage clinical trial failures in the last year. One setbackinvolved Zenapax, which in July 1995 was not able to prevent graft-vs.-host disease (GvHD), a cause of bone marrow transplantrejection.
Roche, of Basel, Switzerland, stood by Protein Design Labs after lastyear's disappointment, saying it had not lost confidence in itspartner's technology or Zenapax.
"This vindicates those folks working on the drug," said DarienWilson, spokeswoman for Roche's U.S. subsidiary, Hoffmann-LaRoche Inc., of Nutley, N.J.
Wall Street investors agreed, sending Protein Design Labs' stock(NASDAQ:PDLI) soaring 61 percent to $26, a $9.875 increase on2.3 million shares traded.
The market gain represented a rally from the beating the stock tooklast month when Protein Design Labs revealed another monoclonalantibody, Protovir, failed in a Phase II/III trial for treatment ofcytomegalovirus retinitis. Protovir was not developed with the sametechnology used to make Zenapax. (See BioWorld Today, Aug. 16,1996, p. 1.)
Kidney transplants account for the majority of solid organ transplantsin the U.S. and the rest of the world. More than 55,000 patientsreceive donor organs each year worldwide and 36,000 get kidneytransplants. Another 45,000 patients are awaiting donor organs.
In the U.S., 12,000 of the 19,000 solid organ transplants performedannually involve kidneys.
"Between 30 percent and 50 percent of transplant patients haverejection episodes," Wilson observed.
Regulatory Filings Expected In First Half Of 1997
Armed with data from the two Phase III trials in Europe and the U.S.,Roche expects to file for approval of Zenapax in the U.S., Canadaand Europe in the first half of 1997.
The studies involved a total of 535 patients and they were dividedinto two groups, one receiving the typical anti-rejection therapy andthe other receiving the conventional treatment plus Zenapax.
In Europe, 275 patients were enrolled. All received cyclosporine andprednisone and 141 also received Zenapax. In the group taking themonoclonal antibody, rejection episodes were reduced by 40 percent.
In the U.S., 260 patients participated and all received a three-drugtherapy of cyclosporine, prednisone and azathioprine, which is notmarketed in Europe. In the group of 126 who also received Zenapax,rejection episodes were reduced by 37 percent.
In both trials, investigators said the patients experienced no adverseevents, a finding that confirmed data from the study in bone marrowpatients. Although Zenapax did not show efficacy in preventingGvHD in that 1995 trial, the drug demonstrated it had overcome akey problem in using antibodies derived from mice; that is,generation of human anti-mouse antibody (HAMA) response inwhich a patient's immune system destroys the monoclonal antibodiesand their effectiveness as long-term treatments.
Zenapax (daclixmab) is made with Protein Design Labs' patentedSMART antibody technology. The monoclonal antibody targets theinterleukin-2 receptor on activated T cells, blocking it and preventingtheir proliferation and assault on the donor organ.
Human monoclonal antibodies can be developed for infectiousdiseases. But when targeting cancer and autoimmune diseases,mouse-derived antibodies are most often used. HAMA has been amajor stumbling block with murine monoclonal antibodies.
To date the FDA has approved only two monoclonal antibodies, oncetagged magic bullets for disease, as drugs. One, Orthoclone OKT3, isused for kidney transplant rejection and is made by Johnson &Johnson, of New Brunswick, N.J. The other, ReoPro, was developedby Centocor Inc., of Malvern, Pa., as a platelet inhibitor to preventblood clots.
In Protein Design Labs' monoclonal antibodies, human amino acidsare substituted for mouse amino acids, creating an antibody that is asclose to human as possible.
Roche markets another drug, CellCept (mycophenolate mofetil), forkidney transplant rejection. If Zenapax were approved it would beused with CellCept as well as the conventional therapy. Roche isconducting a study to assess the safety and activity of combiningCellCept and Zenapax.
Roche also expects to conduct clinical trials of Zenapax in kidneytransplants for children and in trials for two other diseases _psoriasis and uveitis. n
-- Charles Craig
(c) 1997 American Health Consultants. All rights reserved.