Efficacy and Safety of a Tofacitinib-based Immunosuppressive Regimen After Kidney Transplantation: Results From a Long-term Extension Trial

Abstract

BackgroundTofacitinib is an oral Janus kinase inhibitor. This open-label, long-term extension (LTE) study (NCT00658359) evaluated long-term tofacitinib treatment in stable kidney transplant recipients (n = 178) posttransplant.MethodsPatients who completed 12 months of cyclosporine (CsA) or tofacitinib treatment in the phase IIb parent study (NCT00483756) were enrolled into this LTE study, evaluating long-term tofacitinib treatment over months 12 to 72 posttransplant. Patients were analyzed by tofacitinib less-intensive (LI) or more-intensive (MI) regimens received in the parent study. For both groups, tofacitinib dose was reduced from 10 to 5 mg twice daily by 6 months into the LTE. Patients were followed up through month 72 posttransplant, with a focus on month 36 results.ResultsTofacitinib demonstrated similar 36-month patient and graft survival rates to CsA. Biopsy-proven acute rejection rates at month 36 were 11.2% for CsA, versus 10.0% and 7.4% (both P > 0.05) for tofacitinib LI and MI, respectively. Least squares mean estimated glomerular filtration rates were 9 to 15 mL/min per 1.73 m2 higher for tofacitinib versus CsA at month 36. The proportions of patients with grade 2/3 interstitial fibrosis and tubular atrophy in month 36 protocol biopsies were 20.0% for LI and 18.2% for MI (both P > 0.05) versus 33.3% for CsA. Kaplan-Meier cumulative serious infection rates at month 36 were numerically higher for tofacitinib LI (43.9%; P = 0.45) and significantly higher for MI (55.9%; P < 0.05) versus CsA (37.1%).ConclusionsLong-term tofacitinib continued to be effective in preventing renal allograft acute rejection and preserving renal function. However, long-term tofacitinib and mycophenolic acid product combination was associated with persistent serious infection risk.

A short course of Tofacitinib sustains the immunoregulatory effect of CTLA4-Ig in presence of inflammatory cytokines and promotes long-term survival of murine cardiac allografts

“…As standalone immunosuppressant Tofa demonstrated great inhibitory capacity, 28,29 but safety concerns deriving from its long-term administration paused its further clinical investigation in transplantation. [67][68][69] We propose a different utilization of Tofa: short-term administration intervals that parallel the infusion of CTLA4-Ig. This regimen would be more cost-effective than the combination of CTLA4-Ig with biologics like complement inhibitors 23,70 or blocking antibodies, 22,41 while preserving similar efficacy.…”

“…In addition, the reported rapid normalization of blood parameters after treatment termination, 71 and the quick reversibility of inhibition of DC phenotype we reported, indicate that Tofa allows great flexibility in patient management. [67][68][69] With further elucidation of the mechanisms underlying the synergism between Tofa and CTLA4-Ig and with optimization of the administration protocol, e.g. by implementing a localized delivery of Tofa (a strategy we are currently exploring), 72 we believe there is great potential for designing safer and highly effective strategies for management of transplant recipients.…”

Translating JAKs to Jakinibs

“…In some patients with inherited autoinflammatory disease, the doses required to control symptoms were high, and treatment was associated with BK viremia (83). A third consideration is that in some settings multiple immunosuppressive drugs are used, thus increasing the incidence of infection (84). In transplant trials, tofacitinb was found effective compared with cyclosporin A; however, these patients were also treated with mycophenolate and steroids.…”

“…In transplant trials, tofacitinb was found effective compared with cyclosporin A; however, these patients were also treated with mycophenolate and steroids. Perhaps unsurprisingly, there was a higher incidence of infections and some patients developed posttransplant Epstein-Barr virus-related lymphoproliferative disease (84).…”

Multiphase Assembly of Small Molecule Microcrystalline Peptide Hydrogel Allows Immunomodulatory Combination Therapy for Long‐Term Heart Transplant Survival

“…[ 26 ] Tofacitinib has shown promising antirejection efficacy in nonhuman primate transplant models and in humans receiving kidney transplantation. [ 27–29 ] Unpublished data from our lab suggest that a combination therapy of tofacitinib delivered via repeated oral gavages synergizes with CTLA4‐Ig to enhance the survival of mice receiving heterotopic heart transplants. Although promising, systemic and prolonged administration of tofacitinib can be problematic.…”