Sotrastaurin, a novel small molecule inhibiting protein kinase C: first clinical results in renal-transplant recipients.

Department of Nephrology, Charité University, Berlin, Germany.
American Journal of Transplantation (Impact Factor: 6.19). 03/2010; 10(3):571-81. DOI: 10.1111/j.1600-6143.2009.02980.x
Source: PubMed

ABSTRACT Sotrastaurin, a novel protein-kinase-C inhibitor, blocks early T-cell activation. In this 12-month, Phase II study, de novo renal-transplant patients were randomized to sotrastaurin (200 mg b.i.d.) + standard-exposure tacrolimus (SET) or reduced-exposure tacrolimus (RET) (SET: n = 76; RET: n = 66), or control (SET + mycophenolic acid [MPA, 720 mg b.i.d.]; n = 74). In both sotrastaurin groups, patients were converted from tacrolimus to MPA after Month 3, achieving calcineurin inhibitor-free immunosuppression. The primary endpoint was composite efficacy failure (treated biopsy-proven acute rejection, graft loss, death or loss to follow-up). The key secondary endpoint was glomerular filtration rate (GFR). Composite efficacy failure rates were: 4.1%, 5.4% and 1.5% at Month 3 (preconversion) and 7.8%, 44.8% and 34.1% at study end in the control, sotrastaurin + SET and sotrastaurin + RET groups, respectively; these results led to premature study discontinuation. Median GFR at Month 6 was: 57.0, 53.0 and 60.0 mL/min/1.73 m(2), respectively. Study-drug discontinuations due to adverse events occurred in 16.2%, 18.4% and 12.1%, respectively. Leukopenia and neutropenia occurred more frequently preconversion in control versus sotrastaurin groups: 13.7%, 5.6%, and 4.6%; and 11.1%, 4.3% and 3.1%, respectively. The initial sotrastaurin + tacrolimus regimen was efficacious and well tolerated but the postconversion sotrastaurin + MPA regimen showed inadequate efficacy. Longer-term evaluation of sotrastaurin + tacrolimus is warranted.

  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Significant advances have been made in post-kidney transplantation immunosuppression. The introduction of calcineurin inhibitors (CNIs) has led to a reduction in acute rejection and improved 1-year outcomes. However, long-term allograft survival has not improved. This may in part be due to the chronic nephrotoxicity of CNIs and negative effects on the cardiovascular and metabolic risk profile via worsening hypertension, diabetes, and dyslipidemia. New drug development now focuses on maintaining low rejection rates but maximizing long-term allograft survival and modulating the cardio-metabolic side effects seen with CNIs. Two small molecules are currently undergoing Phase 2 investigation. CP-690550 (tasocitinib) is a JAK 3 inhibitor, and AEB-071 (sotrastaurin) is a protein kinase C inhibitor. Two biologic agents are also undergoing development. Belatacept is a humanized antibody that blocks the T-cell co-stimulation pathway and has had promising results in both Phase 2 and 3 investigation. Alefacept is a humanized antibody that inhibits T-cell adhesion and is currently undergoing Phase 2 investigation. This article will review the mechanisms of these drugs and outline the available trial data results.
    Dialysis & Transplantation. 01/2011; 40(1).
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: The last several decades have seen a substantial decrease in the prevalence of acute allograft rejection fallowing kidney transplantation, while similiar improvements in long-term graft function have not been realized. The immunosuppressive drugs lack specificity and are still associated with a large number of acute and chronic adverse events, most of hem related to increasing cardiovascular risk factors and to the development of progressive scarring of the graft, leading to interstitial fibrosis and tubular atrophy. Therefore primary focus of new immunosuppressive drug development has expanded to include ease of use, improved side effect profiles, and reduced nephrotoxicity in addition to goal of improved short-term outcomes. A number of novel drugs are currently under investigation in Phase I, II, or III clinical trials primarily to replace the nephrotoxic but highly effective calcineurin inhibitors. Eculizimab, belatecept, alefacept, efaluzimab, voclosporine, sotrastaurin, tasocitinib and bortezomib are some of the novel molecules which are currently under investigation. This article reviews the mechanisms of action and preliminary results of the Phase I-III clinical trials involving these novel immunosuppressive agents.
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Although current immunosuppression is highly effective in avoiding acute rejection, it is associated with nephrotoxicity, cardiovascular morbidity, infection, and cancer. Thus, new drugs dealing with new mechanisms, as well as minimizing comorbidities, are warranted in renal transplantation. Few novel drugs are currently under investigation in Phase I, II, or III clinical trials. Belatacept is a humanized antibody that inhibits T-cell co-stimulation and has shown encouraging results in Phase II and III trials. Moreover, two new small molecules are under clinical development: AEB071 or sotrastaurin (a protein kinase C inhibitor) and CP-690550 or tasocitinib (a Janus kinase inhibitor). Refinement in selecting the best combinations for the new and current immunosuppressive agents is probably the main challenge for the next few years.
    Kidney International Supplements. 08/2011; 1(2):47-51.

Full-text (2 Sources)

Available from
Nov 11, 2014