Clinical trial shows drug may offer a new option to prevent rejection of transplanted kidneys

Results of a preliminary study suggest that a treatment called LEA29Y works as well as the standard therapy, cyclosporine, to prevent acute kidney transplant rejection, with less potential for long-term harm to the organ and the patient, and better functioning of the transplanted kidney.

LEA29Y is a new type of drug called a co-stimulatory blocker, which prevents the immune system from attacking the transplanted kidney in a more selective manner than traditional anti-rejection drugs. It blocks one of the two signals needed to activate T-cells, once they recognize the transplanted organ as foreign, but leaves the T-cells intact to fight off infections.

More than 20 transplant centers in the U.S., Canada and Europe, including UCSF Medical Center, participated in the phase II clinical trial comparing LEA29Y, also known as BMS-224818, to a similar anti-rejection regimen containing cyclosporine.

“With further clinical study, this may represent a new option to help prevent acute rejection of transplanted kidneys,” said Flavio Vincenti, MD, a principal investigator of the trial, who will present the findings on Monday, May 17, 2004, at the American Transplant Congress in Boston. Vincenti is professor of medicine and surgery at the University of California, San Francisco and UCSF Medical Center.

Results of the study show that six months following kidney transplant, LEA29Y was as effective as cyclosporine in preventing acute kidney rejection. However, LEA29Y-treated patients had better kidney function, blood pressure, and total cholesterol levels at six months compared to cyclosporine-treated patients.

“Currently available anti-rejection drugs like cyclosporine are not as selective as this new agent in blocking the immune system,” Vincenti said. “These older drugs prevent rejection very well, but they are associated with toxic side effects, including a reduction in kidney function and elevations in blood pressure and cholesterol. This can lead to the loss of the transplanted organ over time and negatively impact the patient’s quality of life.”

A total of 221 kidney transplant patients participated in the study. Of those, 148 received LEA29Y and 73 took cyclosporine as part of their maintenance treatment regimen. All patients also were treated with mycophenolate mofetil, corticosteroids and basiliximab—standard immunosuppressive treatments used to help prevent rejection and maintain transplanted organ function.

The study compared the incidence of biopsy-proven acute kidney rejection at six months.  The rates of acute rejection were similar in both patient groups: 19 percent of LEA29Y patients had acute rejection compared to 18 percent of patients receiving cyclosporine. The difference was not statistically significant.

Acute rejection episodes usually are reversible. In this study, only three percent of the LEA29Y patients and four percent of those receiving standard therapy lost their transplanted kidneys within six months of transplant.

At the American Transplant Congress, Vincenti will present the six-month safety and efficacy data. Additional data from the same study regarding kidney function, blood pressure and cholesterol level will be presented at the Congress by B. Nashan of the Klinik fur Viszeral und Transplantation Chirurgie in Germany.

The function of the transplanted kidney observed in patients who received LEA29Y was better than the function in those receiving cyclosporine.  The glomerular filtration rate (GFR)—a measure of the kidney’s ability to filter waste—was significantly better at six months in LEA29Y patients compared to cyclosporine patients.  Patients treated with LEA29Y also had significantly lower levels of total cholesterol than patients treated with cyclosporine.  In addition, trends toward lower blood pressure and less use of anti-hypertensive medication were observed in LEA29Y treated patients. The rates of discontinuation from the study and of adverse events (including infection and malignancies) were similar for the two patient groups.

“Cardiovascular disease is the leading cause of death in patients with kidney transplants,” Vincenti said.  “That is why it is critical to find anti-rejection therapies that may help to minimize cardiovascular risk in this patient population.”

LEA29Y is an injectable protein therapeutic that is designed to suppress the body’s immune response to a transplanted organ. When a kidney is transplanted from one person into another, the recipient’s immune system triggers a hostile response against the new organ, setting off a chain of events that can cause rejection of the transplanted organ. Immunosuppressive drugs greatly decrease the risks of rejection, helping protect the transplanted organ and preserve its function.

Two signals are required for T-cells to become fully activated and initiate an immune response against a transplanted organ. LEA29Y works by preventing the second, or co-stimulatory, signal from occurring, thereby blocking the activation of T-cells and the subsequent immune response that can ultimately lead to rejection of the transplanted organ.

LEA29Y is based on research into the molecular basis of immune tolerance. Its precursor, CTLA4Ig, was first shown to induce transplant tolerance in research by immunologist Jeffrey Bluestone, PhD, UCSF professor of medicine and director of the UCSF Diabetes Center. Bluestone is director of the UCSF-based Immune Tolerance Network, an NIH-funded international network of more than 80 researchers coordinating clinical testing of new therapies to induce immune tolerance.

Christian Larsen, MD, of Emory University, another of the clinical trial’s primary investigators, has also studied LEA29Y in animal models. “This study is part of the ongoing research being conducted to investigate whether a selective co-stimulation modulator, such as LEA29Y, can reduce the risk of rejection of transplanted organs by interrupting the co-stimulatory signal required for full T-cell activation,” Larsen said.

The next step, Vincenti said, will be a new clinical trial to be conducted through the Immune Tolerance Network that will avoid both cyclosporine and steroids by using LEA29Y.

LEA29Y was discovered by Bristol-Myers Squibb Company and is in phase II development. This study was funded solely by Bristol-Myers Squibb Company.