Promising Treatment for High Risk Kidney Recipients in First Year Post-Transplant

Newswise — High risk kidney transplant patients may have a new treatment option according to data presented at the American Society of Nephrology Annual Meeting. Data from a 12-month, open-label study indicate that sirolimus-based therapy in combination with either tacrolimus (TAC) or cyclosporine (CsA) is efficacious in high immunologic risk renal allograft recipients when initiated as an early-use regimen during the first year post-transplant.

High immunologic risk patients are defined as black and/or repeat transplant recipients, and/or subjects with high panel reactive antibodies (PRA >80%). High immunologic risk patients are at the greatest risk for acute organ rejection, which is organ rejection that occurs in the first year post-transplant.

A. O. Gaber, M.D., who initiated this research while at the University of Tennessee in Memphis, TN, together with a distinguished group of researchers from other leading transplant programs in the U.S., found that sirolimus-based therapy, used in the first year post-transplant in combination with a calcineurin inhibitor (CNI) such as TAC and corticosteroids after antibody induction, provided low biopsy confirmed acute rejection (BCAR) rates and excellent renal function in high immunologic risk recipients.

"Acute rejection in the first year post-transplant is one of the most significant risk factors in determining the success of a new organ and a kidney recipient's survival in the longer term," said A. Osama Gaber, M.D., now director of transplantation at The Methodist Hospital, Houston, Texas. "Our team of investigators was able to determine that sirolimus, in combination with TAC or CsA, can be an effective and safe therapy when initiated immediately post-transplant in patients already at the highest risk for organ rejection."

Study ResultsThe study demonstrated that sirolimus-based therapy whether combined with TAC or CsA provided similar efficacy, similar patient and graft survivals, low BCAR rates, and excellent renal function in high immunologic risk patients in the first year post-transplant.

In the intent to treat population, renal function, as calculated using Nankivell glomerular filtration rate (GFR), was not superior in the sirolimus and TAC arm (54.5mL.min) versus the sirolimus and CsA arm (52.6 mL/min; 95% confidence interval (CI) -3.58, 7.80, p=0.466). However, in the on-therapy population, GFR was significantly higher in the sirolimus and TAC group at most time points as indicated in the table below, which suggests better renal function in that group.

Mean Calculated Nankivell GFR (mL/min): Evaluable Patients On TherapyVisit Sirolimus + TAC Sirolimus + CsA p-Value(a)Month 1 60.4 (198) (b) 55.8 (193) 0.011Month 3 65.6 (169) 60.6 (178) 0.004Month 6 63.3 (151) 59.2 (159) 0.010Month 9 63.8 (138) 58.6 (138) 0.010Month 12 63.2 (123) 59.6 (128) 0.069(a) ANOVA with treatment, site, and race stratum as covariates(b) # observations used to calculate the mean

"It is promising to see these types of GFR rates in such high risk patients using a combination regimen that includes early use of a non-nephrotoxic agent like sirolimus. Beyond acute rejection, preserving kidney function is among the top priorities for managing kidney recipient cases," said Charles Van Buren, M.D., Professor of Surgery, Assistant Director, Division of Immunology and Organ Transplantation, Department of Surgery at the University of Texas Medical School at Houston and key study investigator.

Study DesignThe study was a 12-month, prospective, randomized, open-label study of 448 high-risk renal allograft recipients. Patients were randomly assigned (1:1) to sirolimus and tacrolimus (TAC) or sirolimus and cyclosporine (CsA). All subjects received corticosteroids and 382 (85.3%) received antibody induction. Eligible subjects included high immunologic risk patients: Black and/or repeat transplant recipients, and/or subjects with high panel reactive antibodies (PRA >80%). Efficacy endpoints for the trial included: graft loss, efficacy failure, renal function, graft loss or death at 6 months, GFR at 6 months and incidence of BCAR at 6 and 12 months. Safety endpoints included: new-onset diabetes mellitus, lipid profile, incidence of wound-related complications, tremor, hirsutism and gingival hyperplasia, and urine protein-creatinine ratios.

"Managing the nephrotoxic effect of CNIs is one of the challenges facing physicians in kidney transplant cases. We know that sirolimus works by a novel mechanism of action that differs from CNIs and is non-toxic to the kidneys. Data showing efficacy and safety with an early-use regimen that includes a non-nephrotoxic agent is an exciting development for physicians and patients, who are not only trying to prevent acute rejection but also maintain long term graft function and health," said Barry Kahan, M.D., Division Director, Professor of Surgery and Director, The Organ Transplantation Center at the University of Texas Medical School at Houston and key study investigator.

For over a decade the University of Texas Medical School at Houston Organ Transplant program has performed basic research studies and pioneering patient trials using the promising immunosuppressant sirolimus. The clinical transplant programs, based at Memorial Hermann-Texas Medical Center and Saint Luke's Episcopal Hospital, have used this novel drug as a mainstay of their renal and pancreas transplant programs for over eight years, gaining one of the largest patient experiences in the world. The recently completed multicenter clinical trial of sirolimus in high risk patients following renal transplantation confirms the prior University of Texas Houston experience: that a sirolimus based treatment protocol can achieve high rates of success in this difficult to treat patient population. Further clinical studies will answer the ultimate question: whether sirolimus therapy is better for maintaining the health and well-being of patients who have received the gift of a transplanted organ.

Clinical results from the 12-month open label study were presented in a poster session on Friday, November 17, 2006 at the American Society of Nephrology Annual Meeting in San Diego. Poster session: Transplantation Pharmacokinetics, Pharmacodynamics and Related Issues. Poster title: A Comparison of Sirolimus and Tacrolimus Versus Sirolimus and Cyclosporine in High-Risk Renal Allograft Recipients: 12-Month Results from an Open-Label, Randomized Trial. Poster board number: F-PO1089.

A second poster detailing delayed graft function (DGF) outcomes from the same trial was also presented in a poster session on Thursday, November 16, 2006. Poster session: Allograft Dysfunction: Chronic Allograft Nephropathy and Recurrent Disease. Poster title: Impact of Delayed Graft Function in High-Risk Renal Allograft Patients Receiving Sirolimus and Tacrolimus vs. Sirolimus and Cyclosporine. Poster board number: TH-PO055.

About sirolimusSirolimus, marketed by Wyeth Pharmaceuticals as Rapamune®, is in a novel class of immunosuppressant agents called mammalian target of rapamycin (mTOR) inhibitors, a key regulatory enzyme involved in cell growth and survival. Sirolimus works by arresting T cell development early in the cell cycle, resulting in inhibition of lymphocyte proliferation. Sirolimus inhibits the mTOR pathway and avoids the calcineurin pathway. It is indicated for the prophylaxis of organ rejection in patients aged 13 years or older receiving renal transplants. For more information please visit http://www.rapamune.com.

About The Methodist Hospital at Houston The Methodist Hospital is one of the nation's largest private, non-profit general hospitals. Dedicated to providing the highest level of patient care, Methodist has a 90 year legacy of medical breakthroughs, such as the world's first multiple-organ transplant in the 1960s, gene therapy for prostate cancer and the first islet cell transplants in Texas. The Methodist Hospital is home to famed heart pioneer Dr. Michael E. DeBakey.

Methodist is primarily affiliated with Weill Medical College of Cornell University and NewYork Presbyterian Hospital, two of the nation's leading centers for patient care, medical education and research. Methodist also is affiliated with the University of Houston. Its international physician referral network" with information centers in Guatemala City, Istanbul and Mexico City and affiliations with hospitals and physician groups spanning four continents" has extended the Methodist reach into the world community as well. U.S. News&World Report names Methodist among the country's top hospitals in seven specialties. The Methodist Hospital System—comprised of the Texas Medical Center location and three community hospitals—was named in 2006 as one of FORTUNE's "100 Best Companies to Work For." Methodist is consistently ranked as most preferred by National Research Corporation's annual public opinion survey and was recognized by Hospitals and Health Networks as one of "Health Care's 100 most Wired." Hundreds of Methodist physicians are recognized as "America's Best Doctors."

Methodist is home to The Methodist Hospital Research Institute, which is dedicated to accelerating the process of translating the best basic research into new treatments for diseases.

The Methodist Hospital System also includes three community hospitals—Methodist Sugar Land Hospital, Methodist Willowbrook Hospital and San Jacinto Methodist in Baytown. Methodist is committed to providing the finest spiritual care coupled with healing skill, compassion and respect for human dignity.

Research was initiated while Dr. Gaber was at the Methodist University Transplant Institute in Memphis, TN (amend as appropriate). Dr. Gaber was named the director of transplantation at The Methodist Hospital at the Texas Medical Center in June, 2006.