A Phase 3 study published in the American Journal of Transplantation found that patients who started treatment with RAD001 (everolimus) with reduced tacrolimus one month after liver transplant experienced non-inferior efficacy at month 12 compared to patients treated with standard tacrolimus. Significant differences in renal function were observed as early as one month after the introduction of RAD001, and were maintained throughout the study period. RAD001 is being investigated for the prevention of organ rejection in adult patients receiving a liver transplant.
Significant unmet medical needs remain in liver transplantation. Calcineurin inhibitors (CNI), such as tacrolimus, are part of the standard-of-care treatment regimen for immunosuppression in liver transplantation, but they can contribute to complications, including impaired renal function.
“In this study, patients treated with RAD001 plus reduced tacrolimus showed superior differences in renal function, compared to the tacrolimus control group, as early as one month after the introduction of RAD001, with no apparent decline over the one-year study period,” said John Fung, MD, PhD, director, Transplantation Center, Cleveland Clinic Foundation, Cleveland, Ohio. “Despite early and reduced tacrolimus exposure, we did not see any compromise in the control of rejection, and that is very encouraging.”
This study includes two sets of endpoints. The original study protocol included two co-primary endpoints, which were composite efficacy failure (defined as graft loss, death or lost-to-follow-up) and renal function measured by estimated glomerular filtration rate (eGFR) based on the four-variable Modification of Diet in Renal Disease (MDRD4) equation at 12 months after liver transplantation. The study protocol was amended when enrollment into the RAD001 with tacrolimus withdrawal arm was prematurely halted due to a higher incidence of treated biopsy-proven acute rejection (tBPAR) episodes and adverse events leading to treatment discontinuation (45 events), clustered around the time of tacrolimus elimination (at four months post randomization). When the protocol was amended, composite efficacy failure, defined as tBPAR, graft loss or death, became the primary efficacy endpoint and renal function became the key secondary endpoint.
These published results are from the amended protocol and show that the study met the primary endpoint, which was the composite efficacy failure rate of treated biopsy-proven acute rejection (tBPAR), graft loss or death. The composite efficacy failure rate in the RAD001 plus reduced-exposure tacrolimus group was lower compared to the control group at month 12. The results showed non-inferiority (against the non-inferiority margin of 12%) for the RAD001 plus reduced-exposure tacrolimus group as compared to the tacrolimus control group. In addition, the study met the key secondary endpoint, demonstrating non-inferiority in change in renal function. Testing was done for superiority, measured by significant changes in renal function, one month after starting RAD001 plus reduced tacrolimus, with sustained improvement to month 12, compared to standard-exposure tacrolimus.
“Novartis shaped the landscape of transplant medicines more than 25 years ago, and we continue to study innovative treatment approaches that reflect the evolving needs of transplant patients today,” said Usman Azam, MD, Head of U.S. Medical & Chief Scientific Officer, Novartis Pharmaceuticals Corporation. “This Phase 3 study with RAD001 underscores our ongoing commitment, as results suggest a promising immunosuppressive strategy for patients who have had a liver transplant and are susceptible to the effects of immunosuppressive agents, including damage to the kidneys.”
Antigen-activated T cells play a key role in transplant rejection by recognizing foreign substances and multiplying in an attempt to protect the body. RAD001 acts as an immunosuppressant by binding to a protein called mammalian target of rapamycin (mTOR) and preventing the proliferation of these antigen-activated T cells. Immunosuppressants of the mTOR inhibitor class, including RAD001, act synergistically with CNIs, offering an opportunity to potentially lower CNI exposure.
The U.S. Food and Drug Administration (FDA) has accepted the filing for RAD001 for the prevention of organ rejection in adult liver transplant patients, and a decision is expected by Q4 2012.
Date: August 13, 2012
Source: Novartis Pharmaceuticals Corporation
Filed Under: Drug Discovery
