American Journal of Transplantation 2015; 15: 1137–1138 Wiley Periodicals Inc.
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Copyright 2015 The American Society of Transplantation and the American Society of Transplant Surgeons doi: 10.1111/ajt.13179
Editorial
Sotrastaurin in Liver Transplantation: Has It Had a Fair Trial? J. F. Trotter1,* and G. Levy2 1
Baylor University Medical Center, Dallas, TX University of Toronto Transplant Institute, Multi Organ Transplant Program, University Health Network, Toronto, Ontario, Canada Corresponding author: James F. Trotter, [email protected] 2
Received 02 December 2014, revised 10 December 2014 and accepted for publication 11 December 2014
Although calcineurin-inhibitors (CNI) are highly effective immunosuppressive agents, their use is associated with chronic renal failure, diabetes and cancer (1). Strategies to reduce CNI toxicity including dose reduction, therapeutic drug monitoring and combinations with antiproliferative agents have had only variable success (2). Despite the need for new, less toxic immunosuppressants, drug development in liver transplantation has been very limited. No new immunosuppressants have been approved for liver transplantation in nearly 20 years, since mycophenolate mofetil in 1996. The only exception is the recent approval of the mTORi (mammalian target of rapamycin inhibitor) everolimus, although sirolimus had been used extensively off-label in liver transplantation for the past 15 years. Therefore, the publication of a registration trial evaluating a new class of immunosuppressive drug in liver transplantation offers the potential for important and longneeded improvement in anti-rejection therapy. In this issue, Pascher et al. report the results of a phase II study in de novo liver transplant patients evaluating the efficacy and safety of sotrastaurin-based regimens and assessing whether this drug would lead to improved renal function compared to a mycophenolate mofetil-tacrolimus based control group (3). Sotrastaurin (AEB071) represents a new class of immunosuppressant, an oral protein kinase C inhibitor of PKCF, PKCa, and PKCb which have been shown to be important in activation of T and B cells (4). In rodents and non human primates, sotrastaurin prevents allograft rejection. Equally important, sotrastaurin has none of the vexing adverse effects of CNI’s such as renal failure, diabetes or hypertension. Therefore, this agent offers the potential for a major advancement in immunosuppressive management for liver transplant recipients.
Unfortunately, more sotrastaurin-treated patients experienced serious adverse events versus the control group and the study was prematurely stopped at 6 months. Despite these concerns, there are several important characteristics about this study which likely confounded any conclusions about sotrastaurin’s efficacy. There were numerous exclusion criteria, principally the exclusion of HCV-infected recipients, which limited enrollment. Important exclusion criteria included: (approximate % of US liver recipients) multiple organ transplant (7%), HCV (50%), MELD score >35 (5%), acute liver failure (5%), living donor liver transplantation (5%) and retransplantation (6%). The low enrollment rate is demonstrated by entry of only 204 patients from 36 centers over 2 years (
C
Copyright 2015 The American Society of Transplantation and the American Society of Transplant Surgeons doi: 10.1111/ajt.13179
Editorial
Sotrastaurin in Liver Transplantation: Has It Had a Fair Trial? J. F. Trotter1,* and G. Levy2 1
Baylor University Medical Center, Dallas, TX University of Toronto Transplant Institute, Multi Organ Transplant Program, University Health Network, Toronto, Ontario, Canada Corresponding author: James F. Trotter, [email protected] 2
Received 02 December 2014, revised 10 December 2014 and accepted for publication 11 December 2014
Although calcineurin-inhibitors (CNI) are highly effective immunosuppressive agents, their use is associated with chronic renal failure, diabetes and cancer (1). Strategies to reduce CNI toxicity including dose reduction, therapeutic drug monitoring and combinations with antiproliferative agents have had only variable success (2). Despite the need for new, less toxic immunosuppressants, drug development in liver transplantation has been very limited. No new immunosuppressants have been approved for liver transplantation in nearly 20 years, since mycophenolate mofetil in 1996. The only exception is the recent approval of the mTORi (mammalian target of rapamycin inhibitor) everolimus, although sirolimus had been used extensively off-label in liver transplantation for the past 15 years. Therefore, the publication of a registration trial evaluating a new class of immunosuppressive drug in liver transplantation offers the potential for important and longneeded improvement in anti-rejection therapy. In this issue, Pascher et al. report the results of a phase II study in de novo liver transplant patients evaluating the efficacy and safety of sotrastaurin-based regimens and assessing whether this drug would lead to improved renal function compared to a mycophenolate mofetil-tacrolimus based control group (3). Sotrastaurin (AEB071) represents a new class of immunosuppressant, an oral protein kinase C inhibitor of PKCF, PKCa, and PKCb which have been shown to be important in activation of T and B cells (4). In rodents and non human primates, sotrastaurin prevents allograft rejection. Equally important, sotrastaurin has none of the vexing adverse effects of CNI’s such as renal failure, diabetes or hypertension. Therefore, this agent offers the potential for a major advancement in immunosuppressive management for liver transplant recipients.
Unfortunately, more sotrastaurin-treated patients experienced serious adverse events versus the control group and the study was prematurely stopped at 6 months. Despite these concerns, there are several important characteristics about this study which likely confounded any conclusions about sotrastaurin’s efficacy. There were numerous exclusion criteria, principally the exclusion of HCV-infected recipients, which limited enrollment. Important exclusion criteria included: (approximate % of US liver recipients) multiple organ transplant (7%), HCV (50%), MELD score >35 (5%), acute liver failure (5%), living donor liver transplantation (5%) and retransplantation (6%). The low enrollment rate is demonstrated by entry of only 204 patients from 36 centers over 2 years (
