More than 20 leading transplant centers in the U.S., Canada and Europe, including Emory University, participated in a Phase II study comparing LEA29Y, also known as BMS-224818, to a similar regimen containing standard therapy with cyclosporine.
Study results showed that six months following kidney transplant, LEA29Y was as effective as standard therapy with cyclosporine in preventing acute rejection. However, LEA29Y-treated patients demonstrated significant improvement in kidney function, blood pressure and total cholesterol levels compared to patients receiving cyclosporine.
"Data from this trial suggests that LEA29Y may have one of the most promising safety and effectiveness profiles of any new immunosuppressive agent tested in the 20 years since the introduction of cyclosporine," said Christian Larsen, MD, DPhil, director of the Emory Transplant Center and a co-investigator.
"Currently available anti-rejection drugs like cyclosporine are non-selective and associated with significant side effects, including kidney toxicity, high blood pressure, and elevated cholesterol," said Flavio Vincenti, MD, of the University of California San Francisco, a study investigator who presented the findings today. "These side effects can contribute to the loss of the transplanted organ over time and negatively impact the patient's quality of life. However, LEA29Y has a unique and more selective way of working that may minimize or avoid many of these problems." A total of 221 kidney transplant patients participated in the study and received either LEA29Y (148 patients) or cyclosporine (73 patients) as part of their maintenance treatment regimen. All patients were also treated with mycophenolate mofetil, corticosteroids and basiliximab -- standard immunosuppressive treatments used to help prevent rejection and maintain transplanted organ function.
The study's primary endpoint was 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.
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 who received LEA29Y had lower blood pressure levels compared to those on cyclosporine. In addition, the patients who received LEA29Y had less post-transplant hypertension, less use of anti-hypertensive medication and significantly lower cholesterol levels than those who received standard cyclosporine therapy.
"Cardiovascular disease is the leading cause of death in patients with a kidney transplant," said Dr. Vincenti. "That is why it is critical to find anti-rejection therapies that may help to minimize cardiovascular risk in this patient population."
Dr. Larsen and Emory colleague Thomas Pearson, MD, DPhil, have been studying a particular immune pathway for more than ten years in collaboration with Bristol-Myers Squibb Company and conducting pre-clinical research in non-human primates at Emory University's Yerkes National Primate Research Center. This pre-clinical course of investigation, using rhesus macaque monkeys, was crucial not only to the current clinical trial but to other planned studies.
"The data from the primate studies as well as the current clinical trial have formed the basis of a new study to be conducted by Emory and the Immune Tolerance Network at UCSF that avoids both cyclosporine and steroids by using LEA29Y," Dr. Larsen said.
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 damage and cause rejection of the transplanted organ. Immunosuppressive drugs greatly decrease the risks of rejection, helping protect the transplanted organ and preserving its function. LEA29Y is an injectable protein therapeutic that is designed to suppress the body's immune response to a transplanted organ in a selective way.
"Two signals are required for T-cells to become fully activated and initiate an immune response against a transplanted organ," said Dr. Larsen. "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 in Phase II development by Bristol-Myers Squibb Company. Dr. Larsen and Dr. Pearson have served as consultants to Bristol-Myers Squibb Company and have received research funding support from the company as well as from the National Institutes of Health.