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: K Budde, C Sommerer, T Becker, A Asderakis, F Pietruck, J M Grinyo, P Rigotti, J Dantal, J Ng, M J Barten, M Weber
• Journal: American journal of transplantation : official journal of the American Society of Transplantation and the American Society of Transplant Surgeons (Am J Transplant) Vol. 10 Issue 3 Pg. 571-81 (Mar 2010) ISSN: 1600-6143 [Electronic] United States
• PMID: 20121745 (Publication Type: Clinical Trial, Phase II, Journal Article, Multicenter Study, Randomized Controlled Trial, Research Support, Non-U.S. Gov't)

Chemical References

• Immunosuppressive Agents
• Protein Kinase Inhibitors
• Pyrroles
• Quinazolines
• sotrastaurin
• Protein Kinase C
• Tacrolimus

Topics

• Adult
• Aged
• Biopsy
• Female
• Glomerular Filtration Rate
• Humans
• Immunosuppressive Agents (therapeutic use)
• Kidney Transplantation (methods)
• Male
• Middle Aged
• Protein Kinase C (antagonists & inhibitors)
• Protein Kinase Inhibitors (pharmacology)
• Pyrroles (therapeutic use)
• Quinazolines (therapeutic use)
• Tacrolimus (therapeutic use)
• Treatment Outcome