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: 5.68). 03/2010; 10(3):571-81. DOI: 10.1111/j.1600-6143.2009.02980.x
Source: PubMed


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.

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Available from: Markus J Barten, Nov 11, 2014
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    • "Particularly, the efficacy and specificity of sotrastaurin (formerly named AEB071), a low molecular mass synthetic compound that potently inhibits all PKC isoforms is currently being studied in kidney transplant patients (Table 1). The phase II trial of sotrastaurin showed little benefit to renal graft function with an excess of acute rejection episodes, gastrointestinal disorders and serious infections when used as maintenance therapy in combination with mycophenolate mofetil and steroids [5,6]. "
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