Introduction

1. Everolimus plus Reduced-Exposure CsA is as Efficacious as Mycophenolic Acid plus Standard-Exposure CsA Reference: Silva Jr HT, Cibrik D, Johnston T, et al. Everolimus plus reduced-exposure CsA versus mycophenolic acid plus standard-exposure CsA in renal-transplant recipients. Am J Transplant. 2010;10(6):1401–1413.

2. Introduction • In recent years, there has been a signifi cant improvement in short-term outcomes following renal transplantation, thanks to breakthroughs made in the immunosuppressive therapy. • However, long-term graft survival has not shown the same improvement. • Chronic graft dysfunction is the direct result of nephrotoxicity of calcineurin inhibitors (CNIs). • In such a scenario, it is critical to optimize the renal function in order to maintain long-term graft function. • For this to be accomplished, there is a need for new immunosuppressive strategies that ensure early CNI minimization or elimination and thus reduce CNI-related adverse events (AEs) without increasing rejection rates.

3. Everolimus, which is a mammalian target of rapamycin (mTOR) inhibitor/proliferation-signal inhibitor, is highly effective in preventing rejection in renal transplant patients. • The molecule has also demonstrated potent immunosuppressive and antiproliferative effects. • In the initial trials with the drug, renal function was reduced in patients although everolimus plus standard-exposure Cyclosporine A (ST-CsA) demonstrated equivalent efficacy to mycophenolate mofetil (MMF) plus ST-CsA in de novo renal transplant recipients. • However, these results were not evident in phase II trials, where everolimus maintained good efficacy and renal function while allowing CNI minimization. • Following these results, a variety of everolimus and CsAdosing regimens have been tested with an aim to minimize rejection and also reduce the risk of CNI nephrotoxicity by CNI minimization.

4. Silva Jr et al. undertook the A2309 study to assess the effi cacy and safety of two regimens of everolimus plus reduced-exposure CsA (RD-CsA) compared with mycophenolic acid (MPA) plus ST-CsA in de novo renal transplant recipients. • They report results at the half-way point in the 24-month study.

5. Materials and Methods • The trial was a phase IIIb, 24-month, multicenter, openlabel trial involving 833 patients who were randomized to receive one of the following regimens within 24 h after transplantation. • Everolimus 1.5 mg (0.75 mg po BID targeted to 3–8 ng/mL)+RD-CsA (n=277). • Everolimus 3.0 mg (1.50 mg po BID targeted to 6–12 ng/mL)+RD-CsA (n=279). • Mycophenolic acid 1.44 g (720 mg po BID)+ST-CsA (n=277). • Cyclosporine A doses were reduced overtime with >50% of patients having CsA trough levels within the target range from day 14 onward in everolimus groups. Overall, 595 (71.4%) patients remained on study medication at month 12, at which results are reported.

6. Results • Mean everolimus trough levels were within target ranges at all time points during the 12 months. • About 76–85% of patients in the 1.5 mg group were within the target range vs. 60–69% in the 3.0 mg group from month 1 onwards (see Fig. 1). • Compared with the MPA group, the percentage reductions in mean CsA trough levels at months 1, 6 and 12 were 31%, 46% and 60%, respectively, for the everolimus 1.5 mg and 29%, 51% and 64%, respectively, for the 3.0 mg groups.

8. Efficacy • Composite efficacy failure rates at month 12 were 25.3%, 21.9% and 24.2% in the everolimus 1.5 mg, 3.0 mg and MPA groups, respectively. Both everolimus groups were statistically noninferior to MPA in this regard. • The combined incidence of death, graft loss and loss to follow-up at month 12 was 11.6%, 11.1% and 9.4% in the everolimus 1.5 mg, 3.0 mg and MPA groups, respectively. • Overall 53, 42 and 54 treated biopsy-proven acute rejections (BPARs) were reported in the everolimus 1.5 mg, 3.0 mg and MPA groups. • Rates of antibody-treated rejection were similar between groups at 3.6%, 4.3% and 5.4% for the everolimus 1.5 mg, 3.0 mg and the MPA, respectively. • Around 4.3% of patients in the everolimus 1.5 mg, 4.7% in the 3.0 mg and 3.2% in the MPA groups suffered graft loss at month 12.

9. Safety Renal Function • Mean estimated glomerularfiltration rate (eGFR) was 54.6, 51.3 and 52.2 mL/min/1.73 m2 in the everolimus 1.5 mg, 3.0 mg and MPA groups, respectively at month 12 indicating that renal function in both everolimus groups was statistically noninferior to MPA. • Significantly higher eGFR values were reported at months 1, 6, 7 and 9 in the everolimus 1.5 mg vs. MPA groups (see Fig. 2). • About 20% of patients in the everolimus 1.5 mg group experienced an increase in GFR to 60 mL/min/1.73 m2 by month 12 vs. only 15% and 12% in the 3.0 mg and MPA groups, respectively.

10. Safety Adverse Events • About 98.9%, 99.3% and 98.9% of patients in the everolimus 1.5 mg, 3.0 mg and MPA groups, respectively experienced AEs. A similar pattern was seen in the incidence of serious AEs with 56.6%, 60.4% and 53.8% of patients in the everolimus 1.5 mg, 3.0 mg and MPA groups, respectively experienced an serious AE. • Posttransplant diabetes mellitus was reported in 5.1%, 7.9% and 7.0% in the 1.5 mg, 3.0 mg and MPA groups, respectively, whereas infections and infestations were reported as AEs in 61.7%, 64.0% and 67.8% of patients in the everolimus 1.5 mg, 3.0 mg and MPA groups, respectively. • Neoplasms were infrequent in all groups with an average incidence of 3.3%, 2.9% and 5.9% of patients in the everolimus 1.5 mg, 3.0 mg and MPA groups, respectively. • The incidence of BK viruria and BK viremia was higher in the MPA group (3.3 and 1.8%) as compared with the everolimus groups (everolimus 1.5 mg: 0.7 and 1.1%; and 3.0 mg: 0.4 and 0.7%).

11. Congenital cytomegalovirus (CMV) infection was observed in a higher proportion of patients in the MPA (5.9%) vs. everolimus groups (0.7% and 0.0% in the everolimus 1.5 mg and 3.0 mg groups, respectively). • Mean urinary protein: creatinine ratios at month 12 were comparable in the everolimus 1.5 mg and MPA groups, but higher in the everolimus 3.0 mg group. • Adverse wound-healing events were reported in 35.0%, 38.8% and 25.6% of patients in the everolimus 1.5 mg, 3.0 mg and MPA groups, respectively. • There were seven, nine and six deaths in the everolimus 1.5 mg, 3.0 mg and MPA groups, respectively.

12. Discussion • The A2309 study demonstrated that outcomes with everolimus are comparable with MPA in renal transplant recipients. • Efficacy and safety outcomes with everolimus treatment were maintained with CsA minimization of approximately 50% and 60% vs. the MPA group by months 6 and 12, respectively. • Previous attempts to lower CNI nephrotoxicity by reducing or eliminating CNIs from immunosuppressive regimens have resulted in an acute increase in graft rejection rates. • This was not seen in the present study, in which everolimus with RD-CsA was as effective as MPA plus STCsA in preventing BPAR; patients in the 3.0 mg everolimus group had the lowest BPAR rates. • The safety and efficacyprofi le of everolimus was similar to that seen in previous studies. • Some AEs like hematological disorders, woundhealing events, hyperlipidemia and proteinuria were more prevalent in everolimus groups as compared to the MPA group. • But the incidence of infections, particularly BK virus and CMV were lower in everolimus groups than the MPA group.