title: Sotrastaurin, a novel small molecule inhibiting protein-kinase C: randomized phase II study in renal transplant recipients.
abstract: 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.
authors.affiliation: Transplant Institute, Sahlgrenska University Hospital, Göteborg, Sweden. styrbjorn.friman@surgery.gu.se
authors.forename: S
authors.initials: S
authors.lastname: Friman
authors.forename: W
authors.initials: W
authors.lastname: Arns
authors.forename: B
authors.initials: B
authors.lastname: Nashan
authors.forename: F
authors.initials: F
authors.lastname: Vincenti
authors.forename: B
authors.initials: B
authors.lastname: Banas
authors.forename: K
authors.initials: K
authors.lastname: Budde
authors.forename: D
authors.initials: D
authors.lastname: Cibrik
authors.forename: L
authors.initials: L
authors.lastname: Chan
authors.forename: J
authors.initials: J
authors.lastname: Klempnauer
authors.forename: S
authors.initials: S
authors.lastname: Mulgaonkar
authors.forename: M
authors.initials: M
authors.lastname: Nicholson
authors.forename: J
authors.initials: J
authors.lastname: Wahlberg
authors.forename: K-M
authors.initials: KM
authors.lastname: Wissing
authors.forename: K
authors.initials: K
authors.lastname: Abrams
authors.forename: S
authors.initials: S
authors.lastname: Witte
authors.forename: E S
authors.initials: ES
authors.lastname: Woodle
mesh_terms: D000328:Adult; D065095:Calcineurin Inhibitors; D005260:Female; D006801:Humans; D016030:Kidney Transplantation / Q000502:physiology*; D008297:Male; D009173:Mycophenolic Acid / Q000627:therapeutic use; D011493:Protein Kinase C / Q000037:antagonists & inhibitors*; D011758:Pyrroles / Q000627:therapeutic use*; D011799:Quinazolines / Q000627:therapeutic use*; D016559:Tacrolimus / Q000627:therapeutic use
chemical_list: D065095:Calcineurin Inhibitors; D011758:Pyrroles; D011799:Quinazolines; C543528:sotrastaurin; D011493:Protein Kinase C; D009173:Mycophenolic Acid; D016559:Tacrolimus