19th Congress of the European Society for Organ Transplantation, 15-19 September 2019, Copenhagen, Denmark

27th Annual Meeting of the German Transplantation Society. Berlin. 7-10, 2018.

TTS 2018. 27th International Congress of The Transplantation Society. June 30-July 5 Madrid, Spain. Purpose To assess the potential of CFZ533 as primary immunosuppressant in a calcineurin(CNI)-free regimen in de novo kidney transplant (KTx) recipients. Method CFZ533 is a fully human, Fc-silenced, non-depleting, IgG1 mAb preventing CD40 pathway signaling and activation of CD40+ cell types. NCT02217410 is a 12-month multicenter randomized controlled Phase 2a clinical trial evaluating efficacy, safety, tolerability, and pharmacokinetics of CFZ533 (CFZ) in combination with mycophenolate mofetil (MMF) and corticosteroids (CS) compared with tacrolimus (TAC), MMF and CS in de novo KTx recipients. All patients received aIL-2 induction with basiliximab and corticosteroids as per center practice; a central, blinded pathologist reviewed all allograft biopsies. Results N=51 patients (pts) were transplanted and randomized (2:1) to either CFZ (N=33) or TAC (N=18). Twenty-five of 51 pts (49%) received a living donor allograft. After CD40 target saturation, CFZ was dosed IV every 4 weeks. CFZ was well tolerated with no infusion related nor thromboembolic events, and prospective Month 6 interim results demonstrated comparable efficacy on the composite endpoint of treated biopsy proven acute rejection, graft loss, or death (21.2 vs. 22.2%) and better renal function (55.8 vs. 45.5 mL/min) [Fig 1], less serious adverse events (SAE) (47.1 vs. 61.1%) and fewer infectious complications (50.0 vs. 77.8%) with no increase of opportunistic infections (viral overall: 26.5 vs. 50.0%; SAE CMV: 2.9 vs. 11.1%; BKV: 15.2 vs. 22.2%), and a lower rate of new-onset diabetes mellitus (14.7 vs. 38.9%) with CFZ vs. TAC, respectively. Conclusion CFZ533, a new anti-CD40 monoclonal antibody may have potential to become an effective CNI-free treatment for kidney Tx recipients improving transplant outcomes by preventing graft rejection without nephrotoxic (and other) CNI adverse effects. 12-month final study data will become available in Q1/2018 and will be presented at the 2018 TTS. JOURNAL/trans/04.02/00007890-201807001-00585/figure1-585/v/2018-08-28T120805Z/r/image-tiff CFZ533 Study Group investigators’ institutions received study honorarium. Copyright © 2018 Wolters Kluwer Health, Inc. All rights reserved.

American Transplant Congress, June 11-15, 2016, Boston, America.

American Transplant Congress, June 11-15, 2016, Boston, America.

American Transplant Congress, June 11-15, 2016, Boston, America.

26th International Congress of The Transplantation Society, August 18-23, 2016, Hong Kong.

American Transplant Congress 2015. May 2-6, Philadelphia, Pennsylvania, America.

Background and objective: Mycophenolic acid (MPA) is used as an immunosuppressive agent in renal transplant (tx) patients (pts). It limits lymphocyte proliferation by IMPDH inhibition. Two formulations are on the market: Mycophenolate-Mofetil (MMF) and Enteric Coated Mycophenolate Sodium (EC-MPS). Pantoprazole (PAN) is prescribed against gastrointestinal side effects. It leads to an increased gastric pH which may alter MPA exposure especially after MMF intake (Rupprecht et al., 2009). Setting and method: In this single-centre, open, randomized, 4 sequence, 4 treatment, crossover study an influence of PAN 40 mg o.m. on MPA exposure after MMF and EC-MPS intake were analysed in renal tx pts (>6 months posttx). Additionally the major metabolite MPAG and IMPDH activity were examined as well. Three dosing steps for MPA were allowed including standard dosing. MPA was administered with Ciclosporin +/- Glucocorticoids. PK/PD parameters were measured with a HPLC UV/Vis based method. PK parameters were dose normalized to equimolar doses of MPA including dose-normalized AUC (dAUC; ng*h/ml/mg), dCmax (ng/ml/mg), for IMPDH AEC (area under enzyme activity curve; mol/s per mol AMP*h) were calculated with Pharsight WinNonLin. Statistical analysis was performed by linear mixed effect model with MMF set up as reference treatment. Results: 20pts participated in the study; 12/20pts (60 %) received standard dosing. For statistical analysis full PK/PD profiles were eligible for 17/20pts (85 %). MMF + PAN intake led to lowest MPA exposure (37.32 +/- 18.24; p = 0.274) and exceeded lowest limit of 90 % CI (88.87; 74.25-106.38) for geometric mean ratio (GMR). For EC-MPS + PAN MPA exposure was highest (46.30 +/- 17.88; p = 0.231; GMR: 112.29 (90 % CI: 93.82-134.39)). Differences in dAUC in reference to MMF were for all treatment options not significant (EC-MPS: 43.42 +/- 19.37; p = 0.953; GMR: 100.55 (87.48-115.58)). For pts receiving standard dosing higher differences in dAUC were observed for MMF +/- PAN (43.7 +/- 16.2 vs. 35.6 +/- 15.0; p = 0.093). Similar results were obtained for dCmax except 90 % CI for GMR exceeded lower acceptance interval forGMR(14.69 +/- 6.78) vs. EC-MPS (16.06 +/- 10.24, p = 0.587; GMR: 89.95 %; 90 %CI: 65.03-124.43). PAN intake did not show any impact on MPAG AUC for MMF (p = 0.989) or IMPDH activity (AEC MMF +/- PAN: 859.36 +/- 241.29 vs. 816.60 +/- 217.41; p = 0.552). Conclusions: Bioavailability was decreased for MMF + PAN intake probably caused by insufficient dissolution of MMF at higher PH values. For ECMPS + PAN higher MPA exposure was examined. Gastric pH values>5 are observed in pts taking PAN 40 mg for at least two weeks which might lead to earlier dissolution of the tablet (Savarino et al., 1998). However, MPA dAUC remained within the therapeutic window (30-60 ng*h/ml) for all treatment options and had no significant impact on IMPDH activity (Shaw, L.M., et al., 2001). PAN + MPA administration in stable renal tx pts seems to be safe regardless of the administered formulation.