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Sotrastaurin, a Novel Small Molecule Inhibiting Protein Kinase C: First Clinical Results in Renal‐Transplant Recipients
Author(s) -
Budde K.,
Sommerer C.,
Becker T.,
Asderakis A.,
Pietruck F.,
Grinyo J. M.,
Rigotti P.,
Dantal J.,
Ng J.,
Barten M. J.,
Weber M.
Publication year - 2010
Publication title -
american journal of transplantation
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.89
H-Index - 188
eISSN - 1600-6143
pISSN - 1600-6135
DOI - 10.1111/j.1600-6143.2009.02980.x
Subject(s) - medicine , renal transplant , small molecule , kinase , urology , pharmacology , transplantation , biochemistry , chemistry
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.