Sotrastaurin, a Novel Small Molecule Inhibiting Protein-Kinase C: Randomized Phase II Study in Renal Transplant Recipients
2011 (English)In: American Journal of Transplantation, ISSN 1600-6135, E-ISSN 1600-6143, Vol. 11, no 7, 1444-1455 p.Article in journal (Refereed) Published
Sotrastaurin, a selective protein-kinase-C inhibitor, blocks early T-cell activation through a calcineurin-independent mechanism. In this study, de novo renal transplant recipients with immediate graft function were randomized 1: 2 to tacrolimus (control, n = 44) or sotrastaurin (300 mg b.i.d.; n = 81). All patients received basiliximab, mycophenolic acid (MPA) and steroids. The primary endpoint was the composite of treated biopsy-proven acute rejection (BPAR), graft loss, death or lost to follow-up at month 3. The main safety assessment was estimated glomerular filtration rate (eGFR); modification of diet in renal disease (MDRD) at month 3. Composite efficacy failure at month 3 was higher for the sotrastaurin versus control regimen (25.7% vs. 4.5%, p = 0.001), driven by higher BPAR rates (23.6% vs. 4.5%, p = 0.003), which led to early study termination. Median (+/- standard deviation [SD]) eGFR was higher for sotrastaurin versus control at all timepoints from day 7 (month 3: 59.0 +/- 22.3 vs. 49.5 +/- 17.7 mL/min/1.73 m(2), p = 0.006). The most common adverse events were gastrointestinal disorders (control: 63.6%; sotrastaurin: 88.9%) which led to study-medication discontinuation in two sotrastaurin patients. This study demonstrated a lower degree of efficacy but better renal function with the calcineurin-inhibitor-free regimen of sotrastaurin+MPA versus the tacrolimus-based control. Ongoing studies are evaluating alternative sotrastaurin regimens.
Place, publisher, year, edition, pages
2011. Vol. 11, no 7, 1444-1455 p.
Allotransplantation, calcineurin inhibitor toxicity, drug development, efficacy, immunosuppression, mycophenolic acid, renal function, safety, tacrolimus, T-cell activation
Medical and Health Sciences
IdentifiersURN: urn:nbn:se:uu:diva-156263DOI: 10.1111/j.1600-6143.2011.03538.xISI: 000292264000016OAI: oai:DiVA.org:uu-156263DiVA: diva2:431236