New Immunosuppressants in Kidney Transplantation
New Immunosuppressants in Kidney Transplantation
Phillip S. Weems, MD
University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin
Different classes of immunosuppressive drugs offer varied advantages and disadvantages for patients who have undergone kidney transplantation. At a symposium held during the 2012 American Transplant Congress, leaders in the field discussed the use of conventional and novel agents to suppress the immune system following transplant. The speakers provided an overview of past and current best practice and then focused on the results of clinical trials involving everolimus, belatacept, and tofacitinib. In addition, these experts described studies evaluating the safety and efficacy of immunosuppressive drugs in development.
Until recently, immunosuppression for renal transplant patients was limited mainly to corticosteroids, calcineurin inhibitors (cyclosporine, tacrolimus), azathioprine, and mycophenolate mofetil (MMF). Despite the excellent short- and mid-term outcomes achieved with these agents, side effects and toxicity represent an ongoing challenge which may ultimately hamper long-term graft and patient survival. The development of novel biologic agents with different mechanisms of action has pointed the transplant community toward new directions in immunosuppression.
At a symposium held during the 2012 American Transplant Congress, speakers discussed the advantages and disadvantages of using different classes of conventional and novel immunosuppressants. In addition, they reviewed the results of clinical studies comparing different immunosuppressants in patients who have undergone renal transplant. These experts also delved into the practice of switching immunosuppressive drug classes during prolonged therapy and peered into the future of medical suppression of the immune system.
The symposium was moderated by Martha Pavlakis, MD, Associate Professor of Medicine, Beth Israel Deaconess Medical Center, Boston, Massachusetts, and Rita Alloway, PharmD, Research Professor of Medicine, University of Cincinnati College of Medicine, Cincinnati, Ohio.
OVERVIEW OF IMMUNOSUPPRESSANTS
A number of different drug classes are used for immunosuppression following organ transplantation. Comparisons of these agents underscore their advantages and disadvantages in renal transplantation.
Calcineurin Inhibitors (CNIs)
An examination of kidney transplant outcomes from registry data shows a marked improvement in graft survival 1–4 years post transplantation that can be attributed to treatment with CNIs. However, the impact of long-term immunosuppression beyond 4 years has not been as obvious. In fact, current graft survival beyond 10 years after transplantation is somewhat worse than that noted during the 1970s. Some registry data suggest that patients maintained on CNIs for prolonged periods do worse than do those not using such drugs. Therefore, the development of new agents that offer a CNI-free regimen could positively impact graft survival and greatly benefit our patients.
The multihit hypothesis of graft loss/destruction relies on the theory that early in the life of a transplanted allograft, ischemia and acute/subclinical rejection are replaced by CNI toxicity, the harmful effects of underlying chronic disease, and chronic antibody-mediated rejection (AMR). CNIs effectively prevent acute and chronic rejection, but they carry the added detriment of long-term toxicity, which leads to interstitial fibrosis and arteriolar hyalinosis. Thus, as with many topics in this field, a short-term benefit is accompanied by a long-term price to pay.
Molecular Target of Rapamycin (mTOR) Inhibitors
The class of immunosuppressant drugs known as mTOR inhibitors—sirolimus and everolimus—comprises non-nephrotoxic agents that target downstream cytokine receptors. In addition to their immunosuppressive effects, mTOR inhibitors offer added antiproliferative mechanisms that may play a role in vascular remodeling. In cardiac transplantation, intravascular ultrasound data have shown that the coronary arteries of patients given sirolimus and cyclosporine have a thinner vascular intima and media, a wider mean lumen area, and lower plaque burden than the arteries of patients treated with azathioprine and cyclosporine.1
One of the Achilles’ heels of mTOR inhibitor therapy has been poor tolerability. In the ELITE-Symphony study,2 kidney transplant recipients received induction with standard-dose cyclosporine, MMF, and corticosteroids or daclizumab induction, MMF, and corticosteroids given with a low dose of cyclosporine, tacrolimus, or sirolimus. A higher withdrawal rate was noted among the low-dose sirolimus arm. Combined use of daclizumab, MMF, and corticosteroids plus low-dose tacrolimus was advantageous for renal function, allograft survival, and acute rejection rates when compared with regimens involving daclizumab induction plus either low-dose cyclosporine or low-dose sirolimus or standard-dose cyclosporine without induction. These results and others from studies involving sirolimus therapy indicated that de novo CNI elimination with mTOR inhibitor therapy may lead to poorer outcomes.
EVEROLIMUS IN KIDNEY TRANSPLANTATION
Based on a presentation by Philip O’Connell, MD, PhD, Clinical Professor of Medicine, Director of the Centre for Transplant and Renal Research, and Director of Transplant Medicine, Westmead Millennium Institute, New South Wales, and the University of Sydney, Australia
The first registration trials of everolimus compared the use of low (1.5 mg/d) or high (3 mg/d) doses of the drug plus standard doses of cyclosporine with the then-current standard of care, 2 mg/d of MMF plus standard-dose cyclosporine.3 Graft losses and rejection episodes were similar among patients receiving everolimus or MMF with cyclosporine, but those taking everolimus experienced a greater loss in overall graft function, as evidenced by a reduction in creatinine clearance. The investigators concluded that combining an mTOR inhibitor with a CNI may enhance the inherent nephrotoxicity of these drugs.
Later studies with the same two doses of everolimus and smaller doses of cyclosporine (~ 60% trough concentrations) revealed that everolimus was noninferior to cyclosporine in terms of efficacy, graft loss, survival, and rejection episodes, with equivalent graft function across all three study arms. 4 A subsequent meta-analysis confirmed this finding, showing that use of minimal cyclosporine doses with sirolimus or everolimus may lead to better overall graft function.5
Because high intracellular concentrations of CNIs can amplify the potential nephrotoxicity of everolimus, physicians planning to use the drug as de novo therapy with a CNI should use low doses of the CNI. Use of a CNI-free regimen without the addition of everolimus de novo is not recommended.
Switching from CNI Therapy to mTOR Inhibitor Therapy
If CNI therapy is beneficial in preventing early rejection, why not place patients on CNIs initially and then switch them to an mTOR inhibitor later? The ASCERTAIN study was one of the first to evaluate this question.6 This 24-month, open-label, multicenter study involved a fairly large number of patients who were randomized to one of three study arms. In the first arm, patients continued on CNI therapy; in the other two arms, patients also were given everolimus with reduced or discontinued CNI therapy. Patients in the everolimus arms were eligible for a switch any time from 6 months to 10 years post transplantation. The mean time for the switch to occur was at 5.6 years; therefore, the conclusions may not be applicable as an “early-switch” model. Overall, there was no difference in renal function (mean glomerular filtration rate [GFR] at 24 months from the time of switching therapy) or histology among the three study groups.
Switching early. What about early everolimus switching? In the European ZEUS study,7 patients were recruited prior to transplant, started on basiliximab induction, and placed on maintenance therapy using MMF, cyclosporine, and corticosteroids. At 4.5 months post transplantation, all patients were randomized either to continue the prior course of therapy or to add everolimus while gradually discontinuing use of the CNI. At 12 months, patients switched to the everolimus arm experienced an average increase of ~ 10 mL/min in GFR. However, at 36 months, this GFR increase was reduced to an average of about 4–5 mL/min.6 Therefore, the long-term benefits of everolimus therapy may not be quite as good as expected.
The benefits of early switching also were shown in different areas of the ZEUS trial.7 No differences in adverse events or serious infections were reported. However, when compared with patients in the cyclosporine group, those in the everolimus group showed higher rates of herpesvirus infection (6% vs 14%, respectively; P = 0.02), anemia (23% vs 27%; P = 0.51), thrombocytopenia (3% vs 17%; P = 0.01), and aphthous stomatitis (3% vs 17%; P < 0.0001).
Thus, an early switch from CNI therapy to the use of everolimus provides superior renal function with equivalent rejection rates; it seems that the earlier patients are switched to mTOR inhibitor therapy, the greater their chances of successful outcomes. Late switching to everolimus can be accomplished safely in selected patients with relatively good renal function (GFR > 40 mL/min; proteinuria < 500 mg/d). Although late switching from CNI therapy to treatment with everolimus has not been associated with improved renal function, it may benefit patients who develop intolerance to CNIs.
Patient selection. A tricky question remains—which patients would benefit most from switching to mTOR inhibitor therapy, and when should they be switched? When evaluating a switch to an mTOR inhibitor from a CNI, all effects of the mTOR inhibitor must be considered. For example, sirolimus therapy is strongly associated with the development of new-onset diabetes after transplant.8
Transplant patients have a higher incidence of new onset of both skin and solid organ cancers than do age-matched cohorts. Results of the A2309 study revealed a reduced, although not statistically significant, incidence of neoplasms after 12 months of everolimus therapy.4 According to the results of other studies, a change in therapy from a CNI to an mTOR inhibitor is associated with a significantly lower malignancy rate at 2 years. 10 For solid organ cancers, good data suggest that mTOR inhibitor therapy is associated with fewer de novo malignancies, compared with CNI therapy.10 In nonmelanoma skin cancers, the use of CNIs was associated with a statistically reduced incidence of squamous cell carcinoma and a numerically, but not statistically, significant reduction in that of basal cell carcinoma.11
In summary, patients using a CNI who have a history of solid organ or skin malignancies, particularly nonmelanoma skin cancers, would benefit significantly from a switch to an mTOR inhibitor such as everolimus. In addition, such a switch also may benefit patients at high risk of cytomegalovirus (CMV) disease. CNI therapy is associated with abnormal lipid profiles, so a change to treatment with an mTOR inhibitor may reduce the risk of development of cardiovascular disease. Patients who are intolerant to CNI therapy or who suffer from its nephrotoxic side effects would benefit from such a switch.
On the other hand, patients who would not benefit from a switch from a CNI to an mTOR inhibitor include those at high immunologic risk, because mTOR inhibitors are less immunosuppressive than are CNIs. Finally, renal transplant patients with poor graft function, proteinuria, or lung disease and those at risk for new-onset diabetes would not benefit from a switch to mTOR inhibitor therapy.
Based on a presentation by Robert S. Gaston, MD, Outgoing President of the American Society of Transplantation and Endowed Professor of Transplant Medicine and Medical Director of the Kidney and Pancreas Transplant Program, The University of Alabama at Birmingham
Belatacept is a monoclonal antibody fusion protein designed to act as a selective costimulation blocker. It binds to CD80/86 on antigen-presenting cells (APCs), blocking CD28-mediated costimulation of T cells. Costimulation blockade inhibits cell division, cytokine production, anergy, and apoptosis.
When compared with CNI-based therapy, belatacept use is associated with significant advantages that seem to translate into better long-term allograft survival, including preservation of the GFR and a favorable metabolic profile. In addition, patients taking belatacept have fewer “late” rejections and experience an impact on de novo donor-specific antibody (DSA) formation.
BENEFIT and BENEFIT-EXT Studies
In both the BENEFIT study12 (using standard-criteria donor allografts) and the BENEFIT-EXT study13 (using extended-criteria donor allografts), patients received basiliximab induction and a corticosteroid taper; MMF and cyclosporine were given as maintenance immunosuppressants. The patients then were randomized into one of two study arms. Both the more-intensive and the less-intensive arms received 10 mg/kg of belatacept for the first month. Between months 1 and 6, the more-intensive therapy arm was maintained on 10 mg/kg of belatacept, whereas the less-intensive therapy arm was given 5 mg/kg of the drug. At month 6, patients in both arms were maintained on 5 mg/kg of belatacept given every 28 days.
The BENEFIT12 and BENEFIT-EXT13 studies had a composite endpoint of time to a calculated GFR < 30 mL/min/1.73 m2, graft loss, or death. Both studies revealed a significant increase in mean GFR when compared with a cyclosporine control group. If the data were pooled, a survival advantage among patients maintained on belatacept, as compared with those using cyclosporine, would be noted. In fact, the GFR data were strikingly similar to those of nontransplanted, nephrectomized patients having one kidney. The less-intensive BENEFIT group also experienced advantageous reductions in both systolic and diastolic blood pressure and favorable decreases in lipid and triglyceride profiles when compared with patients given cyclosporine.
Over time, we have learned that antibody-mediated renal injury compromises long-term graft survival. The DeKAF study14 evaluated patients who underwent late biopsies 7 ± 5 years post transplantation; 69% of patients diagnosed with CNI toxicity evidenced C4d deposition and/or DSA formation on biopsy. Patients with neither C4d deposition nor DSA formation experienced excellent long-term graft survival, but those with evidence of antibody-mediated injury did poorly. DSA formation and the development of a humoral immune response to the donor clearly are important for long-term graft survival, and patients maintained on belatacept seem to be less predisposed to DSA formation.
Advantages and Disadvantages
The relationship between immunosuppression and histology is considerable.15–17 Histologic findings of peritubular capillaritis 3 months after renal transplantation have been shown to predict the development of chronic AMR at 12 months. Further, biopsy-proven AMR and low tacrolimus exposure at 3 months are associated with high AMR chronicity at 12 months. Both of these phenomena may result in graft fibrosis and significant impairment of long-term graft survival. In these studies, nonadherence to the immunosuppressant regimen has been associated with greater C4d deposition, graft fibrosis, and subsequent atrophy. One benefit of belatacept, therefore, may be that the drug is given once monthly as an infusion, potentially fostering adherence, but it can also be a disadvantage because of the logistical difficulties in scheduling monthly office visits.18
Treatment with belatacept may have its disadvantages. Within the first 12 months, patients using belatacept show a higher incidence of acute rejection, compared with other immunosuppressants.19–21 Patients maintained on belatacept have a higher incidence of post-transplant lymphoproliferative disorder (PTLD) and progressive multifocal leukoencephalopathy.12,13 Finally, the cost of belatacept as compared with that of other agents also must be justified, and the regulatory environment/burden associated with use of the drug in the United States must be navigated.18
Evidence of acute rejection from the BENEFIT study12 showed that neither the more-intensive nor less-intensive belatacept treatment groups achieved a threshold of noninferiority when compared with the cyclosporine control group. In the BENEFIT-EXT study,13 this 20% noninferiority threshold was reached, and it nearly matched the low rate of acute rejection seen with cyclosporine. The types of graft rejections encountered were in no way innocuous, but patients who did not suffer graft rejection while on belatacept therapy seemed to do better long term. This finding is unlike that seen with the use of many immunosuppressants in transplantation, suggesting that another mechanism may be involved.
In terms of risk of post-transplant infection, there seems to be little difference between the rates of infection with CMV, BK polyomavirus, or herpes virus between belatacept-treated patients and those receiving other immunosuppressants; however, the rate of tuberculosis (TB) is higher with belatacept. 12,13 Although the rate of TB infection is inherently low in the United States, the increased risk of TB infection on belatacept must be considered in areas where TB is endemic.
PTLD rates, although more frequent with use of belatacept, are not that different from those noted with the use of new immunosuppressants. Reported PTLD cases have ranged from those limited to the allograft to disseminated disease that involves the central nervous system. Secondary analyses have shown that more PTLD cases occur among Epstein-Barr virus (EBV)-naïve patients who received an organ from an EBV-positive patient.12,13 In patients who have had EBV infections, PTLD rates are similar to those to which we have become accustomed. Thus, the US Food and Drug Administration has reflexively labeled belatacept to be used only in transplant recipients who are EBV seropositive at the time of surgery.
Beyond any obvious advantages/disadvantages to the use of belatacept are other issues that ultimately will decide where the drug fits into the mix of available drugs for post-transplant immunosuppression. Clinical investigators must determine how belatacept therapy compares with the current standard of care (tacrolimus and MMF). In addition, use of the drug in alternative protocols (eg, with mTOR inhibitors, CNIs, or steroid-free maintenance therapy) must be assessed. Lastly, the effects and long-term outcomes of conversion to belatacept from other maintenance immunosuppressive protocols must be considered.
Ongoing clinical trials are investigating some of these issues. Immunosuppression with belatacept-based, steroid-sparing regimens in de novo kidney transplant recipients recently was evaluated by Ferguson and others.19 All patients received rabbit antithymocyte globulin induction therapy and then were randomized into one of three treatment arms: the first one received belatacept and MMF, the second one received belatacept and sirolimus, and a third (control) arm received tacrolimus and MMF. In the belatacept/MMF arm, the rate of acute rejection was 12% at 12 months, compared with only 3% in the tacrolimus/MMF arm. Patients in the belatacept/sirolimus arm, however, did reasonably well, with only a 4% rate of acute rejection at month 12. In both belatacept-containing arms, a significant increase in GFR was observed when compared with the tacrolimus/MMF arm.19
Grinyó and others22 reported that when transplant recipients were switched from cyclosporine or tacrolimus to belatacept, the GFR showed significant improvement 1 and 2 years after the switch. When compared with cyclosporine, the conversion to belatacept resulted in the same mean change in GFR as seen in early phase II and phase III trials of belatacept. The consequence of conversion, however, was a higher rate of acute rejection. Further trials to evaluate the feasibility and safety of conversion from CNI to belatacept therapy are ongoing and planned.
In conclusion, belatacept is a novel immunosuppressant that may change current paradigms. Distinct advantages and disadvantages are associated with its use. Its acceptance as an alternative maintenance immunosuppressant is limited by uncertainties about various issues. The ultimate impact of the drug will be determined by the results of further studies.
Based on a presentation by Stephan Busque, MD, MSc, FRCSC, Professor of Surgery and Director of the Adult Kidney and Pancreas Transplant Program, Stanford University School of Medicine, Palo Alto, California
Janus kinase (JAK), a family of intracellular, nonreceptor tyrosine kinases, is named after the two-faced Roman god of gates and doors, beginnings and endings. Currently, there are four known Janus kinases—JAK1, JAK2, JAK3, and TYK2. JAK3 is restricted to the immune system and is involved in signal transduction of cytokines via signal transducers and activators of transcription. Scientists became interested in JAK3 as a target for immunosuppression when a mutation in the γ protein of the receptor was associated with a form of severe combined immunodeficiency disease (SCID).23
Tofacitinib, a JAK3 inhibitor originally known as CP-690,550, initially was believed to be highly selective to JAK324; however, it also is effective in the signaling of JAK1 and, to a much lesser extent, of JAK2. New findings of a beneficial synergistic and additive effect from blocking both JAK1 and JAK3 have led investigators to believe that this broader form of JAK inhibition may be advantageous.
Several phase II trials are evaluating tofacitinib therapy in the immunosuppressive management of renal transplantation, rheumatoid arthritis, psoriasis, inflammatory bowel disease, and dry eye syndrome. With regard to kidney transplantation, the drug was developed and tested as an alternative to CNI-based therapy. After a phase I study involving 28 patients,25,26 two phase II trials (IIa and IIb) have been completed. 27,28
The phase IIa study was carried out in a population of renal transplant recipients at low immunologic risk, the majority receiving a living-donor kidney. 27 Less-intensive (15 mg twice daily) and more-intensive (30 mg twice daily) regimens of tofacitinib were compared with tacrolimus. All study patients received induction with an interleukin-2 receptor blocker (basiliximab or daclizumab). Maintenance therapy included MMF and a steroid taper to 5–10 mg/d of prednisone by week 12.
Tofacitinib was noninferior to tacrolimus in regard to the percentage of patients with biopsy-proven acute rejection. However, early in the study, it became apparent that tofacitinib was associated with a higher rate of infectious complications, when compared with tacrolimus. In particular, four patients on tofacitinib 30 mg twice daily developed polyomavirus-associated nephropathy; this led to amendment of the initial protocol to eliminate the use of MMF in this arm and reduce the aggregate level of immunosuppression.
These early results demonstrate that clinical JAK3 inhibition is effective in preventing acute rejection of kidney allografts in CNI-free regimens. Use of tofacitinib at 30 mg twice daily plus MMF may be associated with overimmunosuppression, resulting in a higher incidence of transplant-associated infections, in particular, CMV and BK polyomavirus infections, as well as PTLD. Renal function was excellent through month 6 and was similar among all three treatment arms. Trends toward increased neutropenia and anemia and mild increases in serum lipid levels were noted in the tofacitinib treatment arms.
In the phase IIb study, the same two doses of tofacitinib were compared with cyclosporine in 331 renal transplant recipients, with ~ 60% of the organs coming from deceased donors.28 Induction and maintenance therapies were similar to the regimens used in the phase IIa study. In these low- to moderate-risk patients, tofacitinib was equivalent to cyclosporine in preventing acute rejection at 6 months; was associated with improved renal function, as measured by GFR at month 12 (P < 0.01); and led to significantly fewer (P < 0.05) patients developing chronic allograft nephropathy at month 12 (24% for 15 mg of tofacitinib twice daily; 25% for 30 mg twice daily) compared with cyclosporine (48%). However, serious infections, anemia, neutropenia, and PTLD occurred more frequently in the tofacitinib arms of the study than in the cyclosporine arm.
Based on these early data, further evaluation of tofacitinib in patients who have received renal transplants appears to be warranted.
IMMUNOSUPPRESSIVE AGENTS IN PHASE I/II CLINICAL TRIALS
Based on a presentation by Diane M. Cibrik, MD, MS, Clinical Associate Professor of Internal Medicine, Division of Nephrology, University of Michigan Medical School, Ann Arbor
New potential therapeutic agents for kidney transplantation have emerged in three categories: ischemic-reperfusion injury (IRI), induction therapy, and maintenance immunosuppression.
The two-hit insult hypothesis of tissue injury is fundamental to the understanding of diannexin’s mechanism. The ischemic insult from hypoxia that occurs during organ procurement results in an overall proinflammatory state. Reperfusion is essential to halt ongoing ischemic damage, but it also results in additional graft injury. Also involved are necrotic and apoptotic pathways, including recruitment of inflammatory mediators, Toll-like receptors (TLR2/TLR4), reactive oxidative species, cellular infiltration, complement, and the coagulation system.
In the first insult of the IRI cascade, hypoxia results in increased inducible nitric oxide synthase, impaired oxidative metabolism, and depletion of adenosine triphosphate (ATP). In addition, increases in anaerobic glycolysis, inhibition of the sodium/potassium ATPase pump, and decreased expression of cytoprotective genes occur. All of these insults collectively result in tissue injury and ultimately harm transplanted allografts.
When organs are reperfused in the second insult, leukocytes are recruited into the graft with activation of chemokines and inflammatory cytokines. Increased oxygenation at the cellular level leads to the generation of reactive oxygen species, thereby damaging cellular components and injuring tissues.
Diannexin is a recombinant homodimer of the endogenous human annexin V protein. Annexin V functions as a coagulation inhibitor by competing with phosphatidylserine (PS) binding sites for prothrombin. The binding of diannexin to exteriorized PS on the surface of endothelial cells/platelets blocks the leukocyte/platelet attachment and subsequent activation of the inflammatory cascade. Secretory phospholipase A2 activity is inhibited, and factor XII activation is prevented. The combined effects of blocking the IRI cascade at its beginning lead to less inflammation, thrombosis, and vasoconstriction.
The first phase IIa study of diannexin analyzed its impact on outcomes in marginal kidney donors.29 This study included extended-criteria donors, donors after cardiac death, and standard-criteria donors with cold ischemic times > 24–36 hours. Delayed graft function occurred in 33% of patients given 400 μg/kg of diannexin and 56% of patients given placebo. In addition to these immediate effects, statistically significant, long-term improvement in GFR was observed at 12 months in patients given 400 μg/kg of diannexin.
An IRI agent known as QPI-1002 (I5NP) is a synthetic, double-stranded, small-interfering RNA, 19 base-pair oligonucleotide against p53 messenger RNA (mRNA). The tumor suppressor protein p53 can activate proteins involved in DNA repair, induce growth arrest during the cell cycle, and initiate apoptosis. The antisense strand of QPI-1002 is incorporated into the RNA-induced silencing complex. In the presence of QPI-1002, this complex destroys p53 mRNA, thereby decreasing production of p53. This mechanism allows proximal tubule cells the necessary time to repair cellular damage and avoid apoptosis.
There are no data on the use of QPI 1002 in human transplantation. However, animal autotransplantation data30 pointed to significant decreases in serum creatinine levels at 24 hours when the drug was given 15 minutes before organ removal and eventual reperfusion.
ASKP1240 is a fully human monoclonal antibody directed against CD40. It inhibits both humoral and cellular immune responses by blocking the CD40/CD40 ligand complex between T cells, B cells, APCs, and endothelial cells. Exposure to the drug also inhibits proliferation of CD40 ligand-induced B cells and mature dendritic cell cytokines in vitro. Other studies have pointed to prolonged allograft survival (kidney, liver, islets) in nonhuman primates given ASKP1240.31 More recently, a phase IIa, single-dose study in de novo renal transplant recipients has been completed; a phase IIb study currently is in development.
TOL101, a murine monoclonal immunoglobulin M antibody against the αβ subunit of the T-cell receptor of CD3+ T cells, has not been shown to be active against the γδ T-cell receptor. TOL101 downregulates the αβ T-cell receptor to induce minimal T-cell proliferation and proinflammatory cytokine release in vitro. In addition, by not inhibiting the γδ T-cell receptor, TOL101 preserves the tolerogenic and protective effects of γδ T cells. 32 This is noteworthy, because the human αβ T-cell receptor protein sequence is conserved only in higher primates; in vivo animal models of pharmacologic activity/outcomes have not been performed. TOL101 is currently in phase I/II development.
Sotrastaurin is a novel, small-molecular-weight molecule that inhibits protein kinase C (PKC)-dependent T-cell activation. Sotrastaurin selectively blocks a CNI-independent pathway downstream from both signals 1 and 2. The drug is hepatically metabolized.
In the A2207 study,33 investigators compared the use of sotrastaurin plus MMF with the use of tacrolimus/MMF (control group). Patients given the study drug showed significantly poorer graft survival. The composite efficacy failure that led to the early termination of the study was driven by the high rate of biopsy-proven acute rejection (26%) in the sotrastaurin group. The company developing sotrastaurin recently decided to forego further investigation of it based upon efficacy and other concerns.
This extended-release form of tacrolimus is given once daily. It uses the MeltDose drug delivery technology to improve bioavailability, providing improved systemic absorption and reduced peak/trough fluctuation and food-effect variability.
Polvino and others34 revealed a consistent maximum plasma concentration of LCP-Tacro when compared with a baseline tacrolimus control group. Data on the area under the curve reflected minimal variability in drug concentration over 24 hours in liver transplant patients.35
- Keogh A, Richardson M, Ruygrok P, et al. Sirolimus in de novo heart transplant recipients reduces acute rejection and prevents coronary artery disease at 2 years: a randomized clinical trial. Circulation. 2004;110:2694–2700.
- Ekberg H, Tedesco-Silva H, Demirbas A, et al. Reduced exposure to calcineurin inhibitors in renal transplantation: ELITE-Symphony Study. N Engl J Med. 2007;357:2562–2575.
- Lorber MI, Mulgaonkar S, Butt KM, et al. Everolimus versus mycophenolate mofetil in the prevention of rejection in de novo renal transplant recipients: a 3-year randomized, multicenter, phase III study. Transplantation. 2005;80:244–252.
- Tedesco Silva H, Cibrik D, Johnston T, et al. Everolimus plus reduced-exposure CsA versus mycophenolic acid plus standard-exposure CsA in renal-transplant recipients. A2309 Study. Am J Transplant. 2010;10:1401–1413.
- Webster AC, Lee VW, Chapman JR, Craig JC. Target of rapamycin inhibitors (sirolimus and everolimus) for primary immunosuppression of kidney transplant recipients: a systematic review and meta-analysis of randomized trials. Transplantation. 2006;81:1234–1248.
- Holdaas H, Rostaing L, Serón D, et al. Conversion of long-term kidney transplant recipients from calcineurin inhibitor therapy to everolimus: a randomized, multicenter, 24-month study. ASCERTAIN Investigators. Transplantation. 2011;92:410–418.
- Budde K, Becker T, Arns W, et al. Everolimus-based, calcineurin-inhibitor-free regimen of de-novo kidney transplants: an open-label, randomized, controlled trial. ZEUS Study Investigators. Lancet. 2011;377:837–847.
- Johnston O, Rose CL, Webster AC, Gill JS. Sirolimus is associated with new-onset diabetes in kidney transplant recipients. J Am Soc Nephrol. 2008;19:1411–1418.
- Schena FP, Pascoe MD, Alberu J, et al. Conversion from calcineurin inhibitors to sirolimus maintenance therapy in renal allograft recipients: 24-month efficacy and safety results from the CONVERT Trial. Sirolimus CONVERT Trial Study Group. Transplantation. 2009;87:233–242.
- Kauffman HM, Cherikh WS, Cheng Y, Hanto DW, Kahan BD. Maintenance immunosuppression with target-of-rapamycin inhibitors is associated with a reduced incidence of de novo malignancies. Transplantation. 2005;80:883–889.
- Campbell SB, Walker R, Tai SS, Jiang Q, Russ GR. Randomized controlled trial of sirolimus for renal transplant recipients at high risk for nonmelanoma skin cancer. Am J Transplant. 2012;12:1146–1156.
- Vincenti F, Larsen CP, Alberu J, et al. Three-year outcomes from BENEFIT, a randomized, active-controlled, parallel group study in adult kidney transplant recipients. Am J Transplant. 2012;12:210–217.
- Pestana JO, Grinyo JM, Vanrenterghem Y, et al. Three-year outcomes from BENEFIT-EXT: a phase III study of belatacept versus cyclosporine in recipients of extended criteria donor kidneys. Am J Transplant. 2012;12:630–639.
- Mannon RB, Matas AJ, Grande J, et al. Inflammation in areas of tubular atrophy in kidney allograft biopsies: a potent predictor of allograft failure. DeKAF Investigators. Am J Transplant. 2010;10:2066–2073.
- Lerut E, Naesens M, Kuypers DR, Vanrenterghem Y, Van Damme B. Subclinical peritubular capillaritis at 3 months is associated with chronic rejection at 1 year. Transplantation 2007;83:1416–1422.
- Naesens M, Lerut E, Damme BV, Vanrenterghem Y, Kuypers DR. Tacrolimus exposure and evolution of renal allograft histology in the first year after transplantation. Am J Transplant. 2007;7:2114–2123.
- Lerut E, Kuypers DR, Verbeken E, et al. Acute rejection in non-compliant renal allograft recipients: a distinct morphology. Clin Transplant. 2007;21:344–351.
- Gabardi S, Halloran PF, Friedwald J. Managing risk in developing immunosuppressive agents: the new regulatory environment. Am J Transplant. 2011;11:1803–1809.
- Ferguson R, Grinyó J, Vincenti F, et al. Immunosuppression with belatacept-based, corticosteroid-avoiding regimens in de novo kidney transplant recipients. Am J Transplant. 2011;11:66–76.
- Vincenti F, Grinyó JM, Charpentier B, et al. Primary outcomes from a randomized, phase III study of belatacept vs cyclosporine in kidney transplant recipients (BENEFIT study). Presented at the 2009 American Transplant Congress; May 30–June 3, 2009; Boston, Massachusetts. Am J Transplant. 2009;9(suppl 2):191. Abstract 4.
- Durrbach A, Larsen C, Medina-Pestana D, et al. Primary outcomes from a randomized, phase III study of belatacept vs cyclosporine in ECD kidney transplants (BENEFIT-EXT study). Presented at the 2009 American Transplant Congress; May 30–June 3, 2009; Boston, Massachusetts. Am J Transplant. 2009;9(suppl 2):199. Abstract 27.
- Grinyó J, Mainan G, del Carmen Rial M, et al. Renal function at 2 years in kidney transplant recipients switched from cyclosporine or tacrolimus to belatacept: results from the long-term extension of a phase II study. Presented at the 2011 American Transplant Congress; April 30–May 4, 2011; Philadelphia, Pennsylvania. Am J Transplant. 2011;11:99. Abstract 226.
- Pesu M, Candotti F, Husa M, Hofmann SR, Notarangelo LD, O’Shea JJ. Jak3, severe combined immunodeficiency, and a new class of immunosuppressive drugs. Immunol Rev. 2005;203:127–142.
- Flanagan ME, Blumenkopf TA, Brissette WH, et al. Discovery of CP-690,550: a potent and selective Janus kinase inhibitor for the treatment of autoimmune diseases and organ transplant rejection. J Med Chem. 2010;53:8469–8484.
- van Gurp E, Weimar W, Gaston R, et al. Phase 1 dose-escalation study of CP-690 550 in stable renal allograft recipients: preliminary findings of safety, tolerability, effects on lymphocyte subsets and pharmacokinetics. Am J Transplant. 2008;8:1711 –1718.
- van Gurp EA, Schoordijk-Verschoor W, Klepper M, et al. The effect of the JAK inhibitor CP-690,550 on peripheral immune parameters in stable kidney allograft patients. Transplantation. 2009;87:79 –86.
- Busque S, Leventhal J, Brennan D, et al. CP-690,550, a JAK3 inhibitor, in de novo kidney transplant recipients: 6-month results of a phase 2 trial. Am J Transplant. 2007;7:304. Abstract 601.
- Vincenti F, Tedesco Silva H, Busque S, et al. Randomized phase 2b trial of tofacitinib (CP-690,550) in de novo kidney transplant patients: efficacy, renal function and safety at 1 year. Am J Transplant. 2012 June 8. Epub ahead of print.
- Cooper M, Kapur S, Stratta R, et al. Diannexin, a novel ischemia/reperfusion therapeutic agent, reduces delayed graft function (DGF) in renal transplant recipients from marginal donors. Am J Transplant. 2010;10(suppl 4):83. Abstract 145.
- Imamura R, Isaka Y, Sandoval RM, et al. Intravital two-photon microscopy assessment of renal protection efficacy of siRNA for p53 in experimental rat kidney transplantation models. Cell Transplant. 2010;19:1659–1670.
- Pearson TC, Trambley J, Odom K, et al. Anti-CD40 therapy extends renal allograft survival in rhesus macaques. Transplantation. 2002;74:933–940.
- Getts D, Mulgaonkar S, Melton L, et al. TOL101—anti-αβTCR monoclonal antibody immune monitoring during initial phase 2 renal transplant trials. Presented at the 2012 American Transplant Congress; June 2–6, 2012; Boston, Massachusetts. Abstract 192.
- Friman S, Arns W, Nashan B, et al. Sotrastaurin, a novel small molecule inhibiting protein-kinase C: randomized phase II study in renal transplant recipients. Am J Transplant. 2011;11:1444–1455.
- Polvino WJ, Melkus TC, Nigro V. Reduction in tacrolimus Cmax by conversion from twice-daily tacrolimus capsules (Prograf) to once-daily extended release MeltDose tacrolimus tablets (LCP-Tacro): phase II randomized trial in stable kidney transplant patients. Presented at the 2012 American Transplant Congress; June 2–6, 2012; Boston, Massachusetts. Abstract 1295.
- Feng S, Chapman WC, DuBay D. A phase 2 randomized study of the pharmacokinetics, safety and efficacy of LCP-Tacro tablets once-a-day vs Prograf capsules twice-a-day in de novo liver transplants. Presented at the 2012 American Transplant Congress; June 2–6, 2012; Boston, Massachusetts. Abstract 709.
Dr. Weems is Clinical Instructor of Surgery, Division of Abdominal Transplantation, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin.