Novartis announced new two-year results from a Phase 3 study in liver transplantation that confirmed comparable efficacy to control and superior renal function results previously seen at 12 months; the trial evaluated the introduction of everolimus with reduced exposure tacrolimus (Prograf; Astellas) administered twice-daily starting one month after liver transplantation vs. standard-exposure tacrolimus. Everolimus is an immunosuppressant that binds to mammalian target of rapamycin (mTOR).

The results are from a multicenter, open-label, randomized, controlled study conducted in 719 de novo liver transplant patients. Four weeks following liver transplantation, patients treated with tacrolimus and corticosteroids (with or without mycophenolate mofetil [Cellcept; Roche]) were randomized to one of three groups: everolimus (C0 3–8ng/mL) in combination with reduced-exposure tacrolimus (C0 3–5ng/mL) (n=245), everolimus (C0 6–10ng/mL) followed by tacrolimus withdrawal at four months (n=231) or standard-exposure tacrolimus (C0 6–10ng/mL) only (control, n=243). All three study arms included twice-daily treatment. Additionally, all arms included corticosteroids for at least six months post-transplant. Enrollment into the tacrolimus withdrawal arm was prematurely halted due to a higher incidence of acute rejection episodes and adverse events leading to treatment discontinuation, clustered around the time of tacrolimus elimination at four months post randomization. The study protocol was amended at that time.

The original study protocol included two co-primary endpoints, which were composite efficacy failure 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. Both co-primary endpoints were met. In the original study protocol, composite efficacy failure was defined as graft loss, death or lost-to-follow-up. The amended endpoints assessed at 24 months included the composite efficacy failure rate (treated biopsy proven acute rejection [tBPAR], graft loss, or death) and its individual components, and change in renal function.

At 24 months, the incidence of composite efficacy failure (Kaplan-Meier estimates) was numerically lower with everolimus with reduced tacrolimus compared to the tacrolimus control group (10.3% vs. 12.5%; risk difference -2.2%; [97.5% CI: -8.8%, 4.4%]; P=0.452). The incidence of BPAR was significantly lower with everolimus with reduced tacrolimus compared to the tacrolimus control group (6.1% vs. 13.3%; risk difference: -7.2% [95% CI: -13.5%, -0.9%]; P=0.01). The incidence rates of graft loss, death, and tBPAR were comparable between the two groups. Superior renal function was maintained at Month 24 with everolimus with reduced tacrolimus compared with standard tacrolimus (mean difference in eGFR change: 6.7 mL/min/1.73m2 [97.5% CI: 1.9, 11.42]; P=0.0018) (ITT population). For on-treatment patients, the difference in eGFR at Month 24 was 11.5mL/min in favor of everolimus with reduced tacrolimus.  

Under the trade name Zortress, everolimus is approved for the prophylaxis of organ rejection in adult patients at low-moderate immunologic risk receiving a kidney transplant. Everolimus is also available from Novartis in different dosage strengths and for different uses in non-transplant patient populations under the brand name Afinitor. It is also used in drug-eluting stents.

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