By Frances Bishopp
Hoffman-La Roche Inc. and Protein Design Labs Inc. have released additional positive data from two multinational Phase III trials evaluating Zenapax for the prevention of acute graft rejection in kidney transplant recipients. The trials demonstrated that six months after transplantation, patients treated with Zenapax had improvement in both mortality and graft survival compared to patients who did not receive Zenapax.
These new results are in addition to previously reported data (see BioWorld Today, Sept. 26, 1996, p. 3) of Phase III trials of Zenapax, a humanized monoclonal antibody, which has been under development with Swiss drug maker F. Hoffman-La Roche Holding Ltd. and the U.S. affiliate company since 1989. The Zenapax collaboration with Roche was the Mountain View, Calif., company's first deal since its founding approximately 11 years ago. Zenapax, developed by PDL founders Laurence Korn and Cary Queen, is the first product developed by PDL.
Last September's news sent PDL's stock (NASDAQ:PDLI) soaring 61 percent to $26. Tuesday's news pushed the stock up $2.375 to close at $39.
Fred Kurland, PDL's vice president and chief financial officer, told BioWorld Today, "This is the first time since cyclosporine that there has been a drug candidate that has had this kind of improvement worth noting in both patient survival and graft survival six months post-transplant," Kurland said.
"What it speaks to is the possibility that more patients can keep their transplanted kidney. Even if you make a pessimistic assumption, which I don't subscribe to, that there will not be any additional kidneys available for donation, there is still going to be an increase in the number of patients receiving transplants, because those who have received theirs already will get to keep them," Kurland said, "freeing up some more for additional patients. This has the possibility of increasing the number of people who can get successful kidney transplants."
Kurland said Roche intends to file for marketing clearance for Zenapax for this indication in the U.S., Canada and Europe in the first half of 1997.
This most recent pooled data from the two double-blind, controlled, randomized studies included a total of 535 evaluated patients, half (267) of whom received Zenapax. There was one death within six months of transplant among patients receiving Zenapax as compared with 10 deaths that occurred among patients who did not receive Zenapax.
Patient mortality at six months was 0.4 percent in Zenapax-treated patients and 3.7 percent in patients not receiving Zenapax. Graft loss at six months was 6 percent (16 grafts lost) in Zenapax-treated patients and 11.6 percent (31 grafts lost) in patients not receiving Zenapax.
In two previously reported Phase III trials of Zenapax conducted in a double-therapy trial, where all patients received an immunosuppressive regimen of cyclosporine and prednisone, acute rejection episodes were reduced by 40 percent in patients treated with Zenapax (47 percent incidence without Zenapax, 28 percent with Zenapax).
In the triple-therapy trial, in patients who received cyclosporine, prednisone and azathioprine, acute rejection episodes were reduced by 37 percent in patients treated with Zenapax (35 percent incidence without Zenapax, 22 percent with Zenapax). Certain secondary endpoints were also met and there was no increase in serious adverse events due to Zenapax.
Micheal Sheffery, an analyst with Mehta & Isaly, of New York, said the additional mortality data are good news for Protein Design Labs and Roche. "The results that were established in September of last year were very strong and I think that Roche indicated on the basis of that data, they were going to file. The data released today confirms the strength of the original results," Sheffery said.
PDL's successful Phase III results followed a late-stage clinical trial failure with Zenapax the previous year. The results showed that Zenapax is not able to prevent graft-vs.-host disease (GvHD), a cause of bone marrow transplant rejection.
Roche, of Basel, Switzerland, stood by PDL, saying at the time it had not lost confidence in PDL's technology or Zenapax. Kurland said PDL believed it did not work in graft-vs.-host disease because there are a number of avenues in the body where the disease is sustained and "blocking the IL-2 in bone marrow transplant is not sufficient to prevent GvHD. Zenapax, however, turned out to be very effective in preventing renal transplant rejection," Kurland said.
Zenapax binds to the alpha subunit, Kurland explained, of the high affinity Interleukin-2 receptor (IL-2 R). The high affinity IL-2 is expressed on activated T cells. Zenapax inhibits binding of IL-2 to the high affinity IL-2 receptor, thus preventing T-cell activity against allografts, he said.
PDL, as of the end of the calendar year, had $99.7 million in cash on hand.
PDL Studies Isotope In Leukemia Patients
In other PDL news, the company reported the effort to link a powerful alpha-particle emitting isotope to an antibody for the targeted treatment of cancer has led to the first clinical study of such a compound.
PDL developed the SMART M195 humanized monoclonal antibody used in the Phase I study. The isotope, Bismuth-213, is produced using an Actinium-225-Bismuth-213 tandem generator developed under the coordination of PharmActinium, of Dobbs Ferry, N.Y.
Patients with relapsed or refractory acute myeloid leukemia (AML) were treated using the lower of the planned dose levels of the SMART M195/Bismuth-213 compound. The data demonstrated the compound to be well-tolerated and localized rapidly and specifically to the cancer walls. Up to 24 AML patients will be treated in the open-label, dose escalation study, which seeks to determine the preliminary safety and activity of this radiotherapy. PDL and PharmActinium will use the results from this present study to plan further development of the SMART M195/Bismuth-213 compound.
"This is the first time an alpha particle has been used in a clinical trial setting," Kurland told BioWorld Today. "The whole idea is to link a radioisotope to an antibody, let the antibody seek out the cell you are trying to kill and the isotope kills it."
"The reason everyone is excited about antibodie, is because they are very specific and very selective," he said. "Alpha-emitting isotopes have relatively high energy, they are more dense than beta emitters and they have a shorter pass of energy emission. A single passage of an alpha particle through a cell nucleus is sufficient to kill the cell. This offers the potential for less damage to surrounding cells and targeted cell destruction in a more specific way," Kurland said.
PDL develops human and humanized monoclonal antibodies to prevent or treat a variety of autoimmune and inflammatory conditions and certain cancers and viral infections. The company currently has four potential products in human clinical trials. *