12-month safety and efficacy of everolimus with reduced exposure cyclosporine in de novo renal transplant recipients

Abstract

Summary The proliferation signal inhibitor everolimus (Certican), has demonstrated efficacy with full‐dose cyclosporine (CsA) (Neoral®). Two multicenter randomized controlled studies were performed to compare 12‐month efficacy and safety of everolimus 1.5 and 3.0 mg/day with reduced‐dose CsA. Study 1 enrolled 237 de novo renal allograft recipients, randomizing 222 nonblack patients to either everolimus 1.5 or 3.0 mg/day, with the Neoral® dose guided by C2 (monitoring of CsA concentration 2 h after dosing). Study 2 had a similar protocol, with basiliximab included, enrolling 256 recipients and randomizing 243 nonblack patients. In Study 1, there was a lower incidence of acute rejection in nonblack patients on 3 mg/day (16.4%) compared with 1.5 mg/day (25.9%), P = 0.08. In Study 2, the inclusion of basiliximab lowered the overall incidence of acute rejection; 14.3% of nonblack patients (3 mg/day) and 13.6% of nonblack patients (1.5 mg/day) had acute rejection by 12 months (P =0.891). Renal function was preserved throughout the study, with no differences observed between groups within studies. Everolimus was well tolerated with no significant differences between doses. Everolimus, in combination with reduced‐dose Neoral®, demonstrated efficacy and was well tolerated. Basiliximab allows for utilization of lower doses of everolimus with reduced dosing of Neoral®.

Immunosuppressive therapy for kidney transplantation in adults: a systematic review and economic model

“…361 The model, however, applied costs to the TAC arm at a quoted BNF recommended dose of 0.25 mg/kg/day for a group of individuals of 70 kg mean weight, thus resulting in a mean daily dose of 17.5 mg, which is considerably higher than the actual drug use that corresponds to the efficacy outcomes used by the model. The dose behind the TAC drug acquisition costs used in the Novartis submission is also larger than the mean daily doses for immediate-release TAC reported by Tedesco-Silva et al, 349 which Astellas adopted in its submission, and which are consistent with the report of Dean et al…”

“…349 The company also cites the results of an indirect comparative analysis conducted by Bristol-Myers Squibb, which showed 'no significant difference' between BEL and TAC for mortality, graft loss or GFR at 12 and 36 months (All Wales Medicines Strategy Group 2012) 350 and higher ARR and lower incidence of NODAT for BEL than for TAC.…”

Everolimus Plus Reduced‐Exposure CsA versus Mycophenolic Acid Plus Standard‐Exposure CsA in Renal‐Transplant Recipients

“…, and is highly effective in preventing acute rejection in renaltransplant recipients (6)(7)(8)(9). Although, in initial trials, everolimus plus standard-exposure CsA (ST-CsA) demonstrated equivalent efficacy to MMF plus ST-CsA in de novo renal-transplant recipients, renal function was reduced in everolimus-treated patients (6,9,10).…”

The use of everolimus in renal-transplant patients

“…37 Less data are available about everolimus, but in the A2306 and A2307 studies, conducted in de novo renal-transplant recipients, proteinuria (determined by a spot urine protein/creatinine ratio) was detected in 5% of patients. 38 The onset of abundant urinary protein excretion is of importance because proteinuria is a marker for the risk of progressive decline in renal function 39 and is an important predictor of renal dysfunction following conversion from a CNI-to a PSI-based regimen. 40 However, the mechanisms of PSI-induced proteinuria continues to be debated.…”