Drugs that target protein kinases have become popular. The benefit of treatment with this class of therapeutics is clear: a high level of selectivity. The Food and Drug Administration has now approved several agents that inhibit cellular signaling of pathways activated by receptors of the platelet-derived growth factor, epidermal growth factor, vascular endothelial growth factor, hepatocyte growth factor pathway, and cytokines of the IL-2 family.1-5 These agents are given for the treatment of a wide range of diseases, that is, cancer, macular degeneration, auto immune diseases and for the prevention of allograft rejection after organ transplantation.
Allograft rejection is characterized by the production of a wide variety of cytokines including members of the IL-2, IL-12, IL-27 families, interferons, and growth factors. These soluble factors exert their biological functions through janus tyrosine kinases (Jaks) and signal transduction and activators of transcription (Stats), which enable direct communication from the transmembrane cytokine receptor to the nucleus to interact with regulatory elements for gene expression (Figure 1).6 In human cells, 4 different cytoplasmic tyrosine kinases have been identified: Jak1, Jak2, Jak3 and Tyk2, and 7 Stat proteins: Stat1, Stat2, Stat3, Stat4, Stat5a, Stat5b, and Stat6.7 The profound involvement of cytokines in allograft rejection makes the molecules that control their actions, members of the Jak-Stat pathway, ideal targets for pharmacological intervention. In vitro studies using human cells and cell lines have been performed with the small drug molecule named tofacitinib, an oral Janus kinase inhibitor (formerly known as tasocitinib and CP-690,550).3 These have demonstrated that this agent targets Jak1/Jak3-dependent Stat activation and can be used as a substitute for toxic calcineurin inhibitors (CNIs) in a murine model of heart transplantation and in cynomolgus monkeys receiving kidney transplants.3,8-10
For organ transplant patients in whom alloreactivity must be controlled by immunosuppressive medication, blockade of Jak3 signaling has a huge therapeutic potential as it inhibits allogeneic T, B, and natural killer (NK) cell–mediated antidonor responses in a nonredundant way. In this overview article, we will discuss the outcomes of clinical trials of tofacitinib in kidney transplantation, and put these data in a broader context to understand why these studies were relatively unsuccessful and had to be discontinued. In addition, we will discuss what we have learned from our mistakes, what immune monitoring has shown, and how a new trial in kidney transplantation could be planned because we believe this class of immunosuppressive drugs deserves a second chance using an improved trial design guided by immune monitoring.
Numerous studies have investigated the role of Jak3 in immune cell development and function, demonstrating that it is widely involved in the activation cascade and function of most immune cells.11 These studies demonstrate that the biology of Jak3 is not restricted to T, B, and NK cells and that Jak3 plays a functional role in the activation of all hematopoietic cells including cells of the myeloid lineage. Jak3 is expressed at low levels in resting monocytes and can be induced by lipopolysaccharide and in response to γc cytokines12 and during granulocytic differentiation Jak3 is phosphorylated as it is a response gene for granulocyte colony-stimulating factor.13,14 A mouse study by Ghoreschi et al15 reported that blocking Jak 3 phosphorylation also modulates the innate immune responses. The IL-2/IL-2receptor-triggered Jak1/Jak3/Stat5 signaling pattern in both conventional and regulatory T cells has been characterized16,17 and involvement of the Jak1/Jak3/Stat5 signaling pathway in B cell development has also been firmly established.18,19 Binding of IL-7 to its receptor activates this signaling pathway, which interacts with the regulatory elements of genes essential for B-cell development. Typical examples of the key role of Jak3 function in B cells are the reports showing that mutations in the Jak3 gene result in abnormal B-cell numbers and B-cell function.18,19 Recently, the role of Jak3 was further acknowledged by the work of Cattaneo et al19 who demonstrated abolished B-cell differentiation to plasmablasts in response to the CD40 ligand and IL-21.
Experience With Jak3 Inhibitors in Kidney Transplant Patients
Tofacitinib is licensed by the Food and Drug Administration as a disease-modifying treatment for rheumatoid arthritis, and has been assessed in a placebo-controlled randomized trial for the management of moderate-to-severe psoriasis.20 Clinical trials are also exploring the use of tofacitinib in psoriatic arthritis,21 inflammatory bowel disease (Crohn disease and ulcerative colitis),22 ankylosing spondylitis.23 In kidney transplantation, 3 randomized trials have been undertaken in progressively larger populations, between 2005 and 2012.
The first study was performed in 28 stable kidney transplant recipients, evaluating the pharmacokinetics, pharmacodynamics, safety and tolerability of 3 dose levels of tofacitinib (5, 15 and 30 mg, twice a day [BID]).3 It was a double-blind study comprising 28 days of treatment with a subsequent 28-day follow up period. Patients between 1.1 and 11.7 years after transplantation were included but there was no mention of baseline renal function or any exclusion criteria. Patients were randomized (3:1) to tofacitinib or placebo in 4 sequential dose escalation cohorts. Compared with first dose, measures of drug exposure (Cmax, area under the curve [AUC]0–12, C12) remained at steady state after 28 days for the 5- and 15-mg doses but not for 30-mg BID. Higher mean dose-normalized AUC0–12 values were observed after 5 mg BID (15%) and 15 mg BID (54%), groups in that all but 1 patient was receiving CNI therapy, compared with the 30 mg BID group in that all patients were CNI-free. The lack of dose linearity suggests that coadministration with CNIs may moderately increase tofacitinib exposure. Importantly, although good correlations were observed between early time points (1, 2, and 4 hours) after drug administration and AUC0–12, the correlation with trough concentrations was poor, limiting its utility for therapeutic drug monitoring.
There were no deaths, malignancies, systemic opportunistic infections or acute rejection episodes during the study. No consistent changes were observed in vital signs, including electrocardiogram evaluations. Infections and gastrointestinal disorders were the most frequent adverse events reported. A dose-dependent reversible reduction in hemoglobin and reticulocyte counts was observed primarily after the administration of 15 mg BID and 30 mg BID. No significant changes in CD3, CD4, and CD8 lymphocytes were observed, but a mean 50% decrease in absolute NK cell counts (CD16 and CD56) were observed after the administration of 15 or 30 mg BID. A mean 130% increase in absolute CD19+ B lymphocytes was observed after the administration of 30 mg BID.3
Subsequently, a randomized 2-stage 6-month study comparing the efficacy of tofacitinib with tacrolimus in de novo kidney allograft recipients receiving IL-2 receptor antagonist induction, mycophenolate mofetil and corticosteroids was undertaken.24 In stage 1 (pilot trial), 61 patients were randomized to receive tofacitinib 15 mg BID (n = 20) or 30 mg BID (n = 20), or tacrolimus (n = 21). Patients completing 6 months of treatment were enrolled in an extension study to month 12 and doses of tofacitinib were reduced to 10 mg BID and 15 mg BID, respectively. The numbers of biopsy proven acute rejection (BPAR) at 6 months were 1, 4 and 1, respectively with no further episodes by month 12. At 12 months' mean estimated glomerular filtration rates (GFRs) were 83.6, 77.6 and 73.3 mL/min, respectively. Patients receiving tofacitinib presented higher incidences of serious adverse events and clinically significant infections including cytomegalovirus (CMV) disease, herpes zoster, and BK viremia and nephropathy (Table 1). Due to a high incidence of BK virus nephropathy only in patients receiving tofacitinib 30 mg BID, mycophenolate mofetil was discontinued in this group. In addition, patients receiving to facitinib showed modest lipid elevations and a trend toward more frequent anemia and neutropenia during the first 6 months. Again, NK cells were reduced by 77% or less in tofacitinib-treated patients. Altogether these data indicated that tofacitinib at 15 mg BID showed an efficacy/safety profile that was comparable to the tacrolimus control group, except for a higher rate of viral infection. Stage 2, anticipating enrollment of an additional 195 patients, was not implemented due to signs of overimmunosuppression in the 30-mg BID dose group.24
Based on the results of this pilot study, a phase 2b prospective study was conducted, enrolling 331 low-to-moderate risk de novo kidney transplant patients.25 Patients were randomized to receive tofacitinib 15 mg BID from months 1 to 6, reduced to 10 mg BID (more intensive [MI] regimen, n = 110), or 15 mg BID from months 1 to 3, reduced to 10 mg BID (less intensive (LI) regimen, n = 111) or cyclosporine (CsA) (n = 110). All patients received basiliximab induction, mycophenolic acid (MPA) and corticosteroids (Table 1). There were no differences in the incidences of first clinical BPAR at 6 or 12 months (Table 1). African American patients receiving tofacitinib showed a higher incidence of acute rejection compared to CsA (30.2%, 29.5%, and 8.3%). Patients receiving the LI regimen showed only vascular rejection (>IIA) and 2 of these patients eventually lost their graft. More patients in the CsA group were diagnosed with antibody mediated rejection (1.9%, 0.9%, and 4.6%).
At month 12, iohexol-measured GFRs were higher for MI and LI versus CsA and fewer patients in the MI or LI groups developed chronic allograft lesions (Table 1). Drug discontinuations, serious infections, CMV disease, anemia, neutropenia, and posttransplant lymphoproliferative disease (PTLD) occurred more frequently in the MI and LI groups compared with CsA. A lower frequency of posttransplant diabetes mellitus or impaired glucose fasting glucose was observed in patients receiving tofacitinib compared to CsA (24.2%, 17.8%, and 38%).25 It was also noted that in patients receiving tofacitinib, MPA exposure was 37.4% higher compared with patients receiving CsA.25
When patients were analyzed according to tofacitinib plasma concentrations, those below the median level of the whole group showed a similar incidence of serious infection or CMV disease compared to CsA. Univariate analysis showed that tofacitinib exposure, as measured by C0 and C2, donor and recipient age, and use of CMV prophylaxis were associated with occurrence of serious infection.26 Using multiple regression analysis, only tofacitinib C2 concentrations were independently associated with serious infection (C0 was not entered into the multiple regression analysis). Interestingly, MPA C0 concentrations were not associated with serious infections. Serious infections occurred more frequently in patients with tofacitinib exposure above median (AME, 53.0%) than below median exposure (BME, 28.4%) or in those given cyclosporine (25.5%). PTLD only occurred in the AME subgroup. In terms of efficacy, no differences were observed in the incidence of first BPAR at 6 and 12 months comparing BME and CsA groups, but patients in the AME group tended to show lower rates compared to the BME and CsA groups. Among black patients, first BPAR was observed more frequently in the BME group compared to the AME and CsA groups (0%, 30.6%, and 8.3%), respectively. Measured GFR was higher in both the AME and BME groups versus CsA (61.2 and 67.9 vs 53.9 mL/min) at month 12. Fewer patients developed interstitial fibrosis and tubular atrophy at month 12 in the AME (20.5%) and BME (27.8%) groups versus CsA (48.3%). These data suggest that monitoring of plasma concentrations of tofacitinib may preserve the overall benefits including low rates of acute rejection, improved renal function, and a lower incidence of interstitial fibrosis and tubular atrophy with similar rates of serious infection and no PTLD.26
Pharmacokinetics, Pharmacodynamics, and Drug-Drug Interactions
In healthy individuals, pharmacokinetic characterization revealed that about 74% of the oral dose of tofacitinib is rapidly absorbed reaching peak plasma concentrations after 0.5 to 1 hour.27 After intravenous administration, tofacitinib shows moderate tissue distribution, with a volume of distribution of 87 L. In plasma, about 70% is parent drug, and the protein binding is about 40%. Clearance mechanisms appear to be 70% through hepatic metabolism and 30% renal excretion of the parent drug. The metabolism of tofacitinib is mediated by CYP3A4 with a minor contribution from CYP2C19. Thus, inhibitors and inducers of CYP3A4 are likely to alter the disposition of tofacitinib. Steady-state pharmacokinetics in healthy subjects are predictable from single-dose data, with no evidence of accumulation. The elimination half-life (t½) is about 3 hours.28
Due to interindividual variability, it is difficult to determine the optimal therapeutic regimen for each patient. Individual variations in drug sensitivity can be determined by pharmacodynamic monitoring, which focuses on measuring the biological effects of a drug. For tofacitinib monitoring, the phosphorylation of Stat5 can be used as a measure guiding dosing.29 IL-2–induced pStat5, the key substrate of Jak3, was reduced in the presence of serum collected from 8 patients receiving 30 mg BID of tofacitinib for 29 days, an effect observed in both CD4 and CD8 T cells. This effect was associated with the plasma concentration of tofacitinib and with reduced expression of several Stat5 target genes, including FoxP3, granzyme B, FAS ligand, and IFN-γ. IL-2–induced pStat5 predominated in regulatory CD4 T cells (71%) compared with effector T cells (42%). Ex-vivo addition of tofacitinib blocked the IL-2 induced pStat5, while the pStat5 of regulatory T cells was barely inhibited. In addition, tofacitinib preserved the suppressive activity of these patient-derived regulatory T cells.17
It is possible that drug-drug interactions between tofacitinib and MPA may have contributed to the relatively high incidence of infections and malignancies observed in clinical studies. Therefore, the pharmacokinetics of MPA were evaluated in patients receiving tofacitinib or tacrolimus. Plasma MPA concentrations were obtained from 17 adult patients who received either 15 mg or 30 mg tofacitinib BID (8 patients) or tacrolimus (9 patients) after kidney transplantation. All patients also received concomitant mycophenolate mofetil, prednisone, and basiliximab induction. The median mycophenolate mofetil dose was 1000 mg BID. Based on individual estimates, oral clearance from the population pharmacokinetic model, mean steady-state area under the concentration-time curve values for a mycophenolate mofetil dose of 1000 mg BID were 63 mg/h per liter (22%) and 59 mg/h per liter (36%) for the tofacitinib and tacrolimus groups, respectively, that is, tofacitinib does not influence systemic MPA exposure.30
It is well recognized that pharmacokinetic and pharmacodynamic characteristics are influenced by other drugs, such as antibiotics and cardiovascular drugs, factors related to the underlying disease, and age of the recipient. These factors, combined with a highly complex immune system that is specific to each patient, makes it extremely difficult to predict the efficacy and safety of immunosuppressive drugs, such as tofacitinib. Ideally, the effects of Jak3 blockade should be studied on graft-infiltrating cells attacking the transplant by single-cell analysis. Apart from the limited availability of tissue, this is technically challenging and currently cannot be used for diagnostic purposes. The ultimate goal would be to have a set of pharmacodynamic and immunological parameters to establish an immunological and safety risk profile. This would be a valuable pharmacodynamic tool kit for clinicians to help with transplantation-related risk assessment and tailoring of immunosuppressive medication, for example, in vulnerable groups of patients such as the frail and older adults because aging and immune senescence have an impact on treatment and outcomes.31
JAK 3 Inhibitors
Initial studies suggested that tofacitinib was a selective inhibitor of JAK3 kinase.8 Subsequent studies showed that tofacitinib also inhibits JAK1, JAK2 and Tyk2 kinases at nanomolar concentrations.32 This finding may account for the occurrence of adverse events observed in clinical studies beyond those which would be anticipated based on selective inhibition of γc/Jak3-dependent cytokines. Selective JAK3 inhibitors could improve the safety profile of tofacitinib. Several compounds were tested but none showed sufficient selectivity in in vitro kinase and cellular assays.33 Nevertheless, a series of elegant studies has indicated that Jak1 has a dominant role over Jak3 in γc-dependent signal transduction. This suggests that selective pharmacological inhibition of the catalytic activity of Jak3 is not enough to achieve efficient immunosuppression, as demonstrated in severe combined immunodeficiency patients with Jak3 mutations.41 These observations show that Jak1 activation by the IL-2 family of cytokines, or other Jak1-dependent cytokines like IL-6, can compensate for the impaired Jak3 responsiveness that results in the activation of immune competent cells. Cytokines also have the ability to activate multiple signaling pathways which contribute to cellular functions. These “backup” elements of the immune system make it impossible for immunosuppressive drugs to provide complete suppression of immune competent cells.
Future Investigation in Kidney Transplantation
Studies conducted thus far in kidney transplant recipients and in patients with autoimmune diseases have confirmed that Jak3 inhibition is a good target for immunosuppression and that tofacitinib is a potent inhibitor of Jak3.20,28,34 Tofacitinib, in combination with mycophenolate, is efficacious for the prevention of acute rejection after kidney transplantation.24,25 Various questions, however, remained unexplored.
First, combination of tofacitinib with mycophenolate has been associated with higher incidence of viral infections and perhaps viral-associated malignancies. Whether this safety profile is due to the drug combination or tofacitinib alone is not known. Mycophenolate has been associated with a higher incidence of viral infection.35 Tofacitinib possibly shares the same characteristic.36 Although no rigorous studies have been done so far, the consistent and reproducible reduction in NK cells under tofacitinib may be associated with this observation. On the other hand, the effect of tofacitinib on NK, T, and B cells may reduce the incidence of chronic antibody mediated rejection.37 Also, 1 experimental study in mice demonstrated that JAK3/Stat6 stimulates bone marrow-derived fibroblast activation in renal fibrosis. Treatment with tofacitinib significantly reduced myofibroblast transformation, matrix protein expression, interstitial fibrosis development, and apoptosis.38 Follow-up of patients in both phase 2 trials may also provide important information on the long-term efficacy/safety profile of tofacitinib.
Second, the pharmacokinetics of tofacitinib based on serum concentration, together with pharmacodynamic monitoring, provide tools for the optimization of this compound in individual transplant patients. It is unfortunate that due to the adverse event profile under a fixed dosing regimen, tofacitinib clinical development for transplantation was prematurely terminated. Tofacitinib has a narrow therapeutic index, with a 5- to 6-fold intersubject variability in drug exposure among patients receiving the same dose, and efficacy/safety appear to be associated with plasma concentration rather than with oral dose.26 The relatively short half-life may hamper trough plasma concentration monitoring, suggesting that an earlier time point (C2) may be preferable. Also, because tofacitinib is metabolized by CYP3A4 and CYP2C19, there is potential for drug-to-drug interaction with drugs commonly used to treat comorbidities. As for sirolimus,39 everolimus,40 and belatacept,41 the chosen higher-dose groups tested in clinical trials were not associated with increased efficacy but did incur increased toxicity. Therefore, concentration-controlled studies are needed to evaluate the efficacy/safety profile of tofacitinib, and it could be anticipated that therapeutic drug monitoring—possibly with reduced exposure over time posttransplant—may improve outcomes and reduce serious infections and PTLD.
Third, as has been observed previously in CNI-free immunosuppressive regimens using mammalian target of rapamycin (mTOR) inhibitors,42 the combination of tofacitinib with mycophenolate has been challenging due to overlapping toxicities, primarily infections and bone marrow toxicities. Whether a combination with an mTOR inhibitor or belatacept would result in a better efficacy/safety profile is not known.
Proposed Study Designs
Considering the rational for use to tofacitinab and the studies performed to date, the next trial would compare tofacitinib, using concentration-controlled dosing based on C2 monitoring versus tacrolimus. All patients would receive induction with basiliximab, and maintenance therapy with mycophenolate and steroids. Two target tofacitinib concentration ranges would be tested, with minimal overlap between them, to further explore concentration-effect relationships. Prophylaxis for viral infections would be mandatory for at least 6 months. Serial measurements of viral replication, including Ebstein-Barr Virus and polyomavirus viremia, would also assist dose adjustments as indicators of over immunosuppression. After determination of the therapeutic concentrations of tofacitinib, early conversion trials could be explored, whereby patients receiving tacrolimus would be converted to tofacitinib at 3 to 6 months after transplantation, a period when the risk of acute rejection and viral infections is lower.
Another possible study design would combine tofacitinib and an mTOR inhibitor. This approach offers 2 advantages. First, it has been demonstrated that patients receiving mTOR inhibitors have a lower incidence of viral infections. Second, based on in vitro and ex vivo studies, this combination could enhance the number and function of regulatory T cells. However, the trial would require therapeutic drug monitoring of 2 drugs and the concerns associated with de novo use of mTOR inhibitors regarding wound healing and recovery of renal function would have to be taken into account.
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