Everolimus Plus CsA Improves Renal Function in Kidney Transplant Recipients

Jim Kling

May 14, 2010

May 14, 2010 (San Diego, California) — Everolimus (Zortress, Novartis) can be combined with reduced-dose cyclosporine A (CsA) to improve renal function without an effect on efficacy or safety in kidney transplant recipients, according to the results of a study presented here at the American Transplant Congress 2010.

The 24-month randomized trial had 2 everolimus treatment groups (3 to 8 ng/mL and 6 to 12 ng/mL), with each group receiving minimal doses of CsA. Patients in the control group received 1.44 g/day of enteric-coated mycophenolate sodium (MPA) and standard CsA dosing. All patients received basiliximab induction therapy and steroids.

In all groups, donor and recipient characteristics were comparable. At 12 months, the researchers determined efficacy (defined as the composite end point of biopsy-proven acute rejection, graft loss, death, and loss to follow-up) and safety (renal function estimated using the Modification of Diet in Renal Disease formula) between the treatment groups and the control group.

Both everolimus groups received about a 60% reduction in CsA exposure (mean CsA dose, 55 ng/mL with lower-dose everolimus and 49 ng/mL with higher-dose everolimus); the mean CsA dose in the MPA group was 137 ng/mL.

Both everolimus groups were statistically noninferior to the MPA control group for the composite efficacy end point and for renal function at 12 months.

Everolimus patients had a better glomerular filtration rate (GFR), measured by the Cockcroft-Gault formula and the least square means method for repeated measures. At 12 months, with lower-dose everolimus, mean GFR was 56.3 mL/min per 1.73 m2 (standard deviation [SD], 20.1) and median GFR was 55.3 mL/min per 1.73 m2. With higher-dose everolimus, mean GFR was 55.0 mL/min per 1.73 m2 (SD, 19.8) and median GFR was 53.8 mL/min per 1.73 m2. In the MPA group, mean GFR was 54.4 mL/min per 1.73 m2 (SD, 26.4) and median GFR was 50.8 mL/min per 1.73 m2.

Previous studies have shown that everolimus combined with standard CsA doses results in heightened renal dysfunction, so the current study was designed to decrease CsA exposure in the hope of achieving a better outcome, according to Diane Cibrik, MD, associate professor at the University of Michigan in Ann Arbor, who presented the results.

"If you target everolimus between 3 and 8 ng/mL with reduced cyclosporine A exposure of 60%, you can achieve good efficacy and renal function — at least at month 12," Dr. Cibrik told Medscape Transplantation.

There were some concerns about wound-healing adverse effects. "I think people are going to be a little hesitant to use [everolimus] posttransplant based on these side effects, especially because the patients in the trial were likely [carefully] selected. Once you get in the real world, you have a lot of patients who are overweight, or have a high [body mass index], or diabetes, that are going to be even higher risk for these complications. We'll need a full publication before we can use this protocol," Greg Knoll, MD, MSc, medical director of kidney transplantation at the Ottawa Hospital, in Ontario, who moderated the session, told Medscape Transplantation.

The study should help physicians gain a better understanding of everolimus. "With a medicine that's newly released in the United States, it helps us to understand the appropriate dose level that we should try to achieve. It showed there was sustained renal function improvement, despite a higher rate of acute rejection, which is sort of paradoxical, but it's reassuring that we can supplement renal function despite a slightly higher risk of acute rejection," Todd Pesavento, MD, medical director of kidney and pancreas transplantation at the Ohio State University Medical Center in Columbus, told Medscape Transplantation.

The study was funded by Novartis Pharmaceuticals. Dr. Cibrik reports being a scientific advisor for Novartis. Dr. Knoll reports being a scientific advisor for Novartis Canada. Dr. Pesavento has disclosed no relevant financial relationships.

American Transplant Congress (ATC) 2010: Abstract 378. Presented May 4, 2010.


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