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Novel Immunosuppressive Agents in Kidney Transplantation

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Novel Immunosuppressive Agents in Kidney Transplantation World Journal of W J T Transplantation Online Submissions: http://www.wjgnet.com/esps/ World J Transplant 2013 December 24; 3(4): 68-77 [email protected] ISSN 2220-3230 (online) doi:10.5500/wjt.v3.i4.68 © 2013 Baishideng Publishing Group Co., Limited. All rights reserved. REVIEW Novel immunosuppressive agents in kidney transplantation Karen L Hardinger, Daniel C Brennan Karen L Hardinger, Department of Pharmacy Practice and Ad- allograft rejection. Novel treatments for antibody medi- ministration, University of Missouri-Kansas City, Kansas City, ated rejection include bortezomib and eculizumab. Sev- MO 64108, United States eral investigational agents are no longer being pursed Daniel C Brennan, Department of Medicine, Washington Uni- in transplantation including the induction agents, versity School of Medicine in St. Louis, St. Louis, MO 63110, efalizumab and alefacept, and maintenance agents, so- United States trastaurin and tofacitinib. The purpose of this review is Author contributions: All authors have made substantial contri- butions to conception and design, acquisition of data, or analysis to consolidate the published evidence of the effective- and interpretation of data, drafting the article or revising it criti- ness and safety of investigational immunosuppressive cally for important intellectual content, and final approval of the agents in renal transplant recipients. version to be published. Correspondence to: Karen L Hardinger, PharmD, BCPS, © 2013 Baishideng Publishing Group Co., Limited. All rights Clinical Associate Professor of Pharmacy Practice, Depart- reserved. ment of Pharmacy Practice and Administration, University of Missouri-Kansas City, 2464 Charlotte Street, Rm 2241, Kansas Key words: Review; Immunosuppression; Investiga- City, MO 64108, United States. [email protected] tional agents; Renal/kidney transplant Telephone: +1-816-2769023 Fax: +1-816-2764751 Received: June 28, 2013 Revised: August 26, 2013 Accepted: October 16, 2013 Core tip: Many new agents are being studied that may Published online: December 24, 2013 improve outcomes after renal transplantation. Potential improvements to the calcineurin inhibitor class include a recently Food and Drug Administration approved, pro- longed release tacrolimus formulation and voclosporin, a cyclosporine analog. A novel, fully-human anti-CD40 Abstract monoclonal antibody, ASKP1240, is currently enrolling Excellent outcomes have been achieved in the field of patients in phase 2 trials with calcineurin minimization renal transplantation. A significant reduction in acute and avoidance regimens. Novel treatments for antibody rejection has been attained at many renal transplant mediated rejection include bortezomib and eculizumab. centers using contemporary immunosuppressive, con- sisting of an induction agent, a calcineurin inhibitor, an antiproliferative agent plus or minus a corticosteroid. Hardinger KL, Brennan DC. Novel immunosuppressive agents Despite improvements with these regimens, chronic in kidney transplantation. World J Transplant 2013; 3(4): 68-77 allograft injury and adverse events still persist. The Available from: URL: http://www.wjgnet.com/2220-3230/full/ perfect immunosuppressive regimen would limit or v3/i4/68.htm DOI: http://dx.doi.org/10.5500/wjt.v3.i4.68 eliminate calcineurin inhibitors and/or corticosteroid toxicity while providing enhanced allograft outcomes. Potential improvements to the calcineurin inhibitor class include a prolonged release tacrolimus formula- INTRODUCTION tion and voclosporin, a cyclosporine analog. Belatacept has shown promise as an agent to replace calcineurin Although significant advances in renal transplant immu- inhibitors. A novel, fully-human anti-CD40 monoclonal nosuppression have occurred in the past decades, a vital antibody, ASKP1240, is currently enrolling patients in need to improve long-term survival remains. Currently, phase 2 trials with calcineurin minimization and avoid- immunologic causes of early graft failure have become ance regimens. Another future goal of transplant im- rare, yet late graft loss has remained virtually unchanged. munosuppression is effective and safe treatment of One of the most common causes for graft loss is chronic WJT|www.wjgnet.com 68 December 24, 2013|Volume 3|Issue 4| Hardinger KL et al . Novel immunosuppressive agents Table 1 Summary of investigational and available agents Generic Brand FDA indication Company Alefacept1,2 Amevive Treatment of moderate-to-severe chronic plaque psoriasis in adults who are candidates for Astellas systemic therapy or phototherapy Alemtuzumab2 Campath Treatment of B-CLL Berlex Laboratories ASKP1240 Not FDA approved Astellas Azathioprine Imuran Adjunctive therapy in prevention of rejection of kidney transplants; management of active Generic manufac- rheumatoid arthritis turers Basiliximab Simulect Prevention of acute rejection in kidney transplantation Novartis Belatacept Nulojix Prevention of acute rejection in renal transplant recipients Bristol-Myers- Squibb Bortezomib Velcade Treatment of multiple myeloma; treatment of relapsed or refractory mantle cell lymphoma Millenium Pharma- ceuticals Cyclosporine Neoral Prevention of acute rejection in renal transplant recipients Novartis Eculizumab Soliris Treatment of PNH to reduce hemolysis and aHUS Alexion Pharma- ceuticals Efalizumab1,2 Raptiva Management of moderate to severe chronic plaque psoriasis in adults Genentech Everolimus Afinitor, Zortress Treatment of advanced renal cell cancer (Afinitor®); treatment of subependymal giant cell Novartis astrocytom associated with tuberous sclerosis (Afinitor®); treatment of advanced, metastatic or unresectable pancreatic neuroendocrine tumors (Afinitor®); prophylaxis of organ rejection in patients at low-moderate immunologic risk receiving renal transplants (Zortress®) Mycophenolate Cellcept Prophylaxis of organ rejection concomitantly with cyclosporine and corticosteroids in patients Genentech Mofetil receiving allogeneic renal cardiac, or hepatic transplants Mycophenolate Myfortic Prophylaxis of organ rejection concomitantly with cyclosporine and corticosteroids in patients Novartis Sodium receiving allogeneic renal transplantation Horse or Rabbit Atgam or Thy- Treatment of corticosteroid resistant rejection in kidney transplantation Pfizer/Sanofi anti-thymocyte moglobulin Globulin Rituximab Rituxan Treatment of CD20-positive non-Hodgkin’s lymphomas ; Treatment of moderately- to severe- Genentech ly-active rheumatoid arthritis in adult patients with inadequate response to one or more TNF antagonists; Treatment of Wegener’s granulomatosis; Treatment of microscopic polyangiitis Sirolimus Rapamune Prevention of acute rejection in renal transplant recipients Pfizer Sotrastaurin, Not FDA approved Novartis AEB-0711 Tacrolimus Prograf Prevention of acute rejection in renal transplant recipients Astellas Tacrolimus Pro- Astragraf XL Preventing organ rejection in kidney transplant recipients, as combination therapy with myco- Astellas longed Release phenolate mofetil and corticosteroids, with or without tasiliximab induction Tolfacitinib1 Xeljanz Treatment of moderate to severe rheumatoid arthritis Pfizer Voclosporin Not FDA approved Isotechnika Pharma 1No longer being investigated for transplantation; 2Withdrawn from United States Market. FDA: Food and Drug Administration; B-CLL: B-cell chronic lymphocytic leukemia; PNH: Paroxysmal nocturnal hemoglobinuria; aHUS: Atypical hemolytic uremic syndrome. allograft nephropathy. Additionally, significant drug basiliximab induction for low-risk patients and an anti- improvements in transplantation have come with the thymocyte globulin for high-risk patients in conjunction expense of side effects. Many of these adverse events, with maintenance immunosuppression including tacro- including new onset diabetes after transplant, dyslipid- limus and mycophenolate[1]. Potential improvements to emia, and hypertension, may contribute to cardiovascular the calcineurin inhibitor class include a prolonged release related deaths after transplantation. The ideal immuno- tacrolimus formulation and voclosporin, a cyclosporine suppressive regimen would improve long-term outcomes analog (Table 2). A novel, anti CD-40 molecule has com- while minimizing exposure to drug toxicity and infection. pleted phase 1 studies. Induction agents are typically antibodies (anti-thy- Another area for improvement is treatment of hu- mocyte globulins) or interleukin 2 receptor antagonists moral rejection. Historically, treatment has been diffi- (basiliximab). Another induction agent, alemtuzumab has cult and not well studied. Humoral rejection is typically been removed from the United States market, but is still treated with intravenous immunoglobulin, rituximab and available through a special manufacturer program. The plasmapheresis. Investigational treatments for antibody five drug classes that currently comprise maintenance mediated rejection that will be discussed include bortezo- regimens may include calcineurin inhibitors (cyclospo- mib and eculizumab. rine and tacrolimus), mTOR inhibitors (sirolimus and In the past years, several clinical trials have been everolimus), antiproliferative agents (azathioprine and unsuccessful and therefore many agents are no longer mycophenolic acid), costimulation blockers (belatacept) being pursued for transplantation. These agents include and corticosteroids (Table 1). KDIGO Clinical Practice two inductions agents, efalizumab and alefacept, and two Guidelines suggest that first-line agents should include
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