title: Sotrastaurin, a novel small molecule inhibiting protein kinase C: first clinical results in renal-transplant recipients.
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.
authors.affiliation: Department of Nephrology, Charité University, Berlin, Germany. klemens.budde@charite.de
authors.forename: K
authors.initials: K
authors.lastname: Budde
authors.forename: C
authors.initials: C
authors.lastname: Sommerer
authors.forename: T
authors.initials: T
authors.lastname: Becker
authors.forename: A
authors.initials: A
authors.lastname: Asderakis
authors.forename: F
authors.initials: F
authors.lastname: Pietruck
authors.forename: J M
authors.initials: JM
authors.lastname: Grinyo
authors.forename: P
authors.initials: P
authors.lastname: Rigotti
authors.forename: J
authors.initials: J
authors.lastname: Dantal
authors.forename: J
authors.initials: J
authors.lastname: Ng
authors.forename: M J
authors.initials: MJ
authors.lastname: Barten
authors.forename: M
authors.initials: M
authors.lastname: Weber
mesh_terms: D000328:Adult; D000368:Aged; D001706:Biopsy; D005260:Female; D005919:Glomerular Filtration Rate; D006801:Humans; D007166:Immunosuppressive Agents / Q000627:therapeutic use*; D016030:Kidney Transplantation / Q000379:methods*; D008297:Male; D008875:Middle Aged; D011493:Protein Kinase C / Q000037:antagonists & inhibitors*; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D011758:Pyrroles / Q000627:therapeutic use*; D011799:Quinazolines / Q000627:therapeutic use*; D016559:Tacrolimus / Q000627:therapeutic use; D016896:Treatment Outcome
chemical_list: D007166:Immunosuppressive Agents; D047428:Protein Kinase Inhibitors; D011758:Pyrroles; D011799:Quinazolines; C543528:sotrastaurin; D011493:Protein Kinase C; D016559:Tacrolimus