The role of everolimus in liver transplantation

Figures & data

Table 1 Summary of randomized controlled trials of everolimus in liver transplantation

References	Study design	Study population	Treatment groups	Key results
				Efficacy	Renal function	Safety
De Simone et al,^Citation76 Saliba et al^Citation77 (H2304)	24-month prospective, randomized, multicenter, open-label study	De novo liver transplant recipients	EVR + reduced TAC (N=245): EVR C0 3–8 ng/mL and TAC C0 3–5 ng/mL TAC control (N=243): TAC C0 8–12 ng/mL until month 4 and C0 6–10 ng/mL thereafter TAC-withdrawal (N=231): EVR C0 6–12 ng/mL with CNI elimination at month 4	Comparable composite efficacy failure rate at month 12* and month 24 between EVR + reduced TAC and TAC control	Superior renal function assessed by eGFR in EVR + reduced TAC group compared with TAC control	Higher incidence of hyperlipidemia, neutropenia, peripheral, edema, stomatitis/mouth ulceration, and thrombocytopenia in the EVR group
Fischer et al^Citation79 (PROTECT)	12-month prospective, randomized, multicenter, open-label study	De novo liver transplant recipients	EVR (N=101): EVR C0 5–12 ng/mL (C0 8–12 ng/mL with CsA) Control (N=102): CNI-based regimen	Similar incidence of graft loss and rejection episodes	No significant difference in mean calculated GFR (Cockcroft-Gault) at 11 months postrandomization* Significant improvement in GFR using Modification of Diet in Renal Disease in favor of EVR at month 11	Higher incidence of infections, leukopenia, hyperlipidemia, anemia, and arterial hypertension in the EVR group
Masetti et al^Citation78	12-month, prospective, randomized, single-center, open-label study	De novo liver transplant recipients	Early CNI withdrawal followed by EVR monotherapy (N=52): C0 6–10 ng/mL until day 30, 8–12 ng/mL until the end of month 6 and 6–10 ng/mL thereafter Standard CsA (N=26): C0 225±25 ng/mL until day 30, then 200±25 ng/mL until the end of month 6 and 150±25 ng/mL thereafter	Similar incidence of acute rejection	Significant improvement in renal function (eGFR, Modification of Diet in Renal Disease 4) at Month 12 in the EVR group versus CsA group*	Higher incidence of incisional hernia, elevated serum cholesterol, high-density lipoprotein and low-density lipoprotein, and inferior limbs edema in the EVR group
De Simone et al^Citation74	6-month prospective, randomized, multicenter, open-label study (with additional 6-month follow-up)	Maintenance liver transplant recipients	EVR with CNI reduction or elimination (N=72): EVR (C0 3–8 ng/mL) plus CNI (C0 3–5 ng/mL) or EVR (C0 6–12 ng/mL) with CNI elimination CNI (N=73): standard exposure TAC or CsA	Low incidence of efficacy failure events in both the groups	Similar mean change in creatinine clearance (Cockcroft-Gault) from baseline to month 6*	Higher incidence of hyperlipidemia, mouth ulceration, increased hepatitis C virus viral titer, dry skin, eczema, and rash in the EVR group
Levy et al^Citation80 (B158 study)	12-month randomized, double-blind, placebo-controlled study (with 24-month open-label extension)	De novo liver transplant recipients	EVR 1 mg/day + CsA (N=28) EVR 2 mg/day + CsA (N=30) EVR 4 mg/day + CsA (N=31) Placebo + CsA (N=30)	Similar incidence of composite efficacy failure between groups and lower rate of treated acute rejections in the EVR group versus placebo	Stable serum creatinine and creatinine clearance from month 1 onward	Higher incidence of anemia, tachycardia, constipation, edema, elevated blood creatinine, and agitation in the EVR group. More frequent EVR-related adverse events with higher doses

Notes:

* Indicates primary endpoint. Composite efficacy failure = treated biopsy-proven acute rejection, graft loss, or death.

Abbreviations: EVR, everolimus; TAC, tacrolimus; C0, trough level; CNI, calcineurin inhibitor; eGFR, estimated glomerular filtration rate; PROTECT, Prevention of Transplant Atherosclerosis With Everolimus and Anti-cytomegalovirus Therapy; CsA, cyclosporine.

Figure 1 Incidence of biopsy-proven acute rejection at month 12 in comparative trials of everolimus.

Note: *The CNI was cyclosporine in the study by Masetti et al⁷⁸ and tacrolimus in the H2304 study.
Abbreviations: EVR, everolimus; CNI, calcineurin inhibitor; BPAR, biopsy-proven acute rejections; NR, not reported; NS, not significant.

Figure 2 Mean estimated glomerular filtration rate with everolimus + reduced tacrolimus versus tacrolimus control in the H2304 study.

Note: Copyright © 2012 The American Society of Transplantation and the American Society of Transplant Surgeons. De Simone P, Nevens F, De Carlis L, et al; H2304 Study Group. Everolimus with reduced tacrolimus improves renal function in de novo liver transplant recipients: a randomized controlled trial. Am J Transplant. 2012;12(11):3008–3020.⁷⁶ Copyright © 2013 The American Society of Transplantation and the American Society of Transplant Surgeons. Saliba F, De Simone P, Nevens F, et al; H2304 Study Group. Renal function at two years in liver transplant patients receiving everolimus: results of a randomized, multicenter study. Am J Transplant. 2013;13(7):1734–1745.⁷⁷
Abbreviations: EVR, everolimus; TAC, tacrolimus; eGFR, estimated glomerular filtration rate.

Figure 3 Key adverse events with everolimus + reduced tacrolimus versus tacrolimus control in the H2304 study.

Note: Copyright © 2013 The American Society of Transplantation and the American Society of Transplant Surgeons. Saliba F, De Simone P, Nevens F, et al; H2304 Study Group. Renal function at two years in liver transplant patients receiving everolimus: results of a randomized, multicenter study. Am J Transplant. 2013;13(7):1734–1745.⁷⁷
Abbreviations: AE, adverse event; CI, confidence interval; CMV, cytomegalovirus; CV, cardiovascular; EVR, everolimus; GI, gastrointestinal; HCC, hepatocellular carcinoma; ILD, interstitial lung disease; NODM, new-onset diabetes mellitus; TAC, tacrolimus.

Table 2 Summary of key ongoing trials of everolimus in liver transplantation

Study	Estimated enrollment	Study population	Study design	Treatment groups	Key endpoints
NCT01888432	470	Living-donor liver transplant recipients (male or female, 18–70 years)	24-month, open-label, multicenter, randomized, controlled trial (Phase III)	EVR + reduced TAC: EVR (C0 3–8 ng/mL) plus reduced TAC (C0 3–5 ng/mL) with or without corticosteroids Standard TAC: 8–12 ng/mL until month 4 and decreased by 6–10 ng/mL until end of the study	Composite efficacy failure of tBPAR, graft loss, or death at month 12 posttransplantation* Change in eGFR at month 12 AEs and SAEs including infections
NCT01551212 (HEPHAISTOS)	330	De novo liver transplant recipients (age, 18–65 years)	12-month, open-label, multicenter, randomized, controlled study (phase 3)	EVR: EVR as add-on to tacrolimus TAC: TAC monotherapy	eGFR (Modification of Diet in Renal Disease 4 formula) at month 12* Composite of tBPAR, graft loss, or death Incidence of HCV and HCV-related fibrosis
NCT01150097	266	Liver transplant recipients who completed the core H2304 study with assigned treatment (age, 20–72 years)	Extension study to the open-label, multicenter, randomized, controlled study (phase 3)	EVR + reduced TAC: EVR C0 3–8 ng/mL and TAC C0 3–5 ng/mL EVR: EVR C0 6–12 ng/mL TAC: TAC C0 6–10 ng/mL	Renal function by eGFR, efficacy failure defined as tBPAR, graft loss, or death, and rate of progression of HCV-related allograft fibrosis at month 36 and 48 posttransplantation* Incidence of AEs, SAEs, hypertension, neurotoxicity, and NODM
NCT01625377 (SIMCER)	184	De novo liver transplant recipients (age, ≥18 years)	Open-label, multicenter, randomized, controlled study (phase 3)	EVR: EVR (6–10 ng/mL) with MPA 1440 mg/day with TAC withdrawal ± steroids TAC: TAC 6–10 ng/mL with MPA 1,440 mg/day ± steroids	Change in eGFR (abbreviated Modification of Diet in Renal Disease formula) at month 6* Treatment failure (BPAR, graft loss, and death) at month 6 Incidence of AEs and SAEs at months 3 and 6
NCT01423708 (EPOCAL)	117	De novo liver transplant recipients (age, 18–70 years)	Prospective, open-label, randomized controlled study (phase 2)	EVR: EVR (6–12 ng/mL) with gradual reduction of TAC (<5 ng/mL) and possible discontinuation of TAC Control: TAC (6–12 ng/mL) + steroids	BPAR at month 3* Graft survival at month 3* Patient survival at month 3* EVR monotherapy after day 30* Renal function at month 24 Incidence of AEs
NCT01807767	100	Liver transplant recipients with Model for End-Stage Liver Disease score ≥25 (age, 18–70 years)	Prospective, open-label, randomized controlled study	EVR: EVR (6–12 ng/mL) with MPA 360–720 mg bid and TAC (TAC discontinued within 8 weeks of EVR initiation) CNI: MPA 360–720 mg bid and TAC (5–12 ng/mL)	Proven acute rejection at month 12* Composite efficacy endpoint (BPAR, graft loss, and death)*
NCT01598987	75	Pediatric liver transplant recipients (male or female, 1 month–17 years)	24-month, open-label, single-group, prospective, multicenter trial (phase 3)	EVR-based regimen: conversion at baseline from immunosuppressive regimen (CsA or TAC ± MPA and corticosteroids) to EVR with reduced dose of CsA or TAC	Change in eGFR at month 12* Composite efficacy failure rate of tBPAR, graft loss, or death at month 12 Incidence of AEs and SAEs at months 12 and 24
NCT01023542 (BUILT_01)	45	Liver transplant recipients with Model for End-Stage Liver Disease score ≥25 (age, ≥18 years)	Prospective, open-label, randomized controlled study (phase 2)	Delayed CNI: basiliximab 20 mg with MMF (2×1 g intravenously/day), CsA (day 5 after LTx; 100–150 ng/mL), and steroids (1 mg/kg/day from day 0) eliminated by month 6 after LTx “Bottom”-up-CNI: basiliximab 20 mg with MMF (2 × 1 g intravenous/day), steroids (1 mg/kg/day from day 0) eliminated by month 6 after LTx and CsA (within 30 days of LTx; 100–150 ng/mL) “Bottom”-up-EVR: basiliximab 20 mg with MMF (2 × 1 g intravenous/day), steroids (1 mg/kg/day from day 0) eliminated by month 6 after LTx and EVR (within 30 days of LTx; C0 6–10 ng/mL)	eGFR (abbreviated Modification of Diet in Renal Disease formula) at month 12*
NCT01707849	40	Liver transplant recipients, RNA-HCV positive within 12 months previous to the transplant (age, ≥18 years)	Unicenter, prospective, randomized, pilot study (phase 3)	EVR: EVR 1 mg twice daily (2–4 ng/mL) + TAC (8–10 ng/mL) MMF: MMF 1 g twice daily + TAC (8–10 ng/mL)	Liver fibrosis progression (≥2 under Ishak score) 12-months posttransplant* To identify viral and recipient factors associated with liver fibrosis progression
NCT00890253	29	De novo liver transplant recipients	Prospective, open-label, single-group, two-stage study (phase 2)	CNI-free immunosuppression: basiliximab, enteric-coated mycophenolate sodium, and everolimus	Steroid-resistant rejection at day 30* Steroid-resistant rejection at 1 year Liver function at 1 year Calculated GFR at 1 year
NCT01936519	24	Liver transplant recipients (age, 18–70 years)	Randomized prospective trial	EVR: Conversion to EVR combined with MPA and complete discontinuation of CNI at 3 months posttransplant CNI: CNI with MPA	Renal function at month 24* Patient and graft survival at 6, 12, and 24 months

Note:

* Indicates primary outcome.

Abbreviations: EVR, everolimus; TAC, tacrolimus; C0, trough level; tBPAR, treated biopsy-proven acute rejection; HCV, hepatitis C virus; eGFR, estimated glomerular filtration rate; AE, adverse event; SAE, serious adverse event; NODM, new-onset diabetes mellitus; MPA, mycophenolic acid; CNI, calcineurin inhibitor; CsA, cyclosporine; MMF, mycophenolate mofetil; LTx, liver transplantation.

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