By Lisa Seachrist

Washington Editor

GAITHERSBURG, Md. — An FDA advisory panel Friday unanimously recommended the first humanized monoclonal antibody for approval for the prevention of acute graft rejection in kidney transplant recipients.

Should the FDA take the advice of its Biological Response Modifiers Advisory Committee, Mountain View-based Protein Design Labs Inc.'s humanized monoclonal antibody, Zenapax, would be the first humanized monoclonal antibody approved for any indication.

"It's quite clear that Zenapax is effective in transplants of cadaveric kidneys," said panel member Manikkam Suthanthiran, a transplant surgeon with the New York Hospital-Cornell Medical Center. "I think the facts presented can be generalized to the entire renal transplant community."

The panel's recommendation smoothes the path to approval for Zenapax, which began with a rocky start when a Phase III trial for the prevention of graft-vs.-host disease in bone marrow transplants failed. Despite the setback, Protein Design Labs (PDL) and its collaborative partner Hoffman-La Roche Ltd., of Basel, Switzerland, proceeded undeterred for use of the drug in renal transplantation.

"We are very pleased with the data that Roche brought to the committee," Jon Saxe, president of PDL, told BioWorld Today. "We are very happy with the recommendation."

"This was the first compound and it was our dream when we founded this company," said Laurence Jay Korn, PDL CEO. "It's an important day for us, and we are pleased with the support that we have received from Hoffman-La Roche."

Trading in PDL's stock (NASDAQ:PDLI), halted for much of Friday, resumed in the afternoon and the company's shares closed up $0.25 to $46.375.

Delaying rejection is the most important factor in decreasing graft failure and death among renal transplant patients. Zenapax targets the alpha chain of the interleukin-2 receptor and neutralizes the main player in organ rejection: the activated T cell. The drug is given in a series of five infusions over a six-month period.

Data From European, North American Trials

The companies presented data comparing the incidence of biopsy-proven acute graft rejection with the addition of Zenapax or placebo to double and triple immunosuppressive therapy. The double immunotherapy study was conducted in Europe and tested the drug in combination with cyclosporine and corticosteroids. The North American study tested the drug in combination with cyclosporine, corticosteroids and azathioprine. Each study consisted of more than 250 patients.

Patients receiving Zenapax in the double therapy trial experienced 40 percent fewer acute rejection episodes compared to patients receiving placebo. In the triple therapy study, patients taking Zenapax had 37 percent fewer incidences of acute rejection episodes compared to the placebo arm.

Combining the two studies, one patient in the Zenapax arms and seven in the placebo arms died in the one-year follow-up.

"The promise of monoclonal antibodies has largely been unrealized," said Robert Kirkman, a transplant surgeon at Brigham and Women's Hospital, in Boston, Mass., and professor at Harvard University Medical School who has participated in the preclinical and clinical development of the drug. "The data you have seen presented here today has changed that. It proves that treatment with Zenapax results in fewer transplant rejection episodes."

Kirkman emphasized that delaying rejection episodes decreases the need for second kidney transplants, which in effect would increase the limited supply of organs.

The primary fear in using immunosuppressive drugs after transplantation is that the drug will lead to a generalized immunosuppression, which puts the recipient at risk for immune-based cancers and infectious diseases.

Zenapax proved to have few adverse events. The tremors, hypertension and renal insufficiency which appeared more often in Zenapax-treated patients are also primary side effects of treatment with cyclosporine.

The major concern for monoclonal antibodies is that patients will develop allergic responses to the drugs. Fifteen percent of those treated with Zenapax developed antibodies against the drug, but those antibodies didn't result in an increased risk of graft rejection or death, nor did they result in allergic reactions when finishing the treatment series of Zenapax.

Long-Term Use Of Drug Questioned

The panel was extremely concerned, however, that long-term treatment with Zenapax or a subsequent treatment as a result of a second transplant could trigger allergic response and recommended that the company study the long-term treatment.

In addition, the panel was concerned about third-party reimbursements for transplant medications. Most transplant medications that have proven to be useful for kidney transplants end up being useful in all solid organ transplants. However, if the Zenapax label contained an indication specific for kidney transplantation alone, health insurance would refuse to reimburse a liver transplant patient for the use of the medicine.

"I can't believe that Zenapax won't be used in all solid organ transplants, and I can't believe it won't be effective," said panel member Hugh Auchincloss, associate professor of surgery at Harvard Medical School. "I would propose voting on whether we would not expand our recommendation to include transplantation of all solid organs."

The committee took the unusual step of voting on an indication that had no data supporting it and deadlocked 6-6.

Because all trial data came from adults, the committee had questions on whether or not Zenapax would prove safe for use in children. The companies have undertaken a clinical study in 60 children, but it is not yet fully enrolled.

"I am concerned that Zenapax may have a permanent effect on a child's ability to mount appropriate immune responses," said panel member Lawrence Hunsicker, medical director for the transplant section of the University of Iowa Hospitals and Clinics, in Iowa City.

"Don't exclude the children from this label," said panel member Abbey Meyers, president and executive director of the National Organization for Rare Disorders. "No one will get reimbursed."

The committee voted 9-3 to expand its recommendation for approval to include all kidney transplants, whether in adults or children.*

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