Sotrastaurin, a Novel Small Molecule Inhibiting Protein‐Kinase C: Randomized Phase II Study in Renal Transplant Recipients

• Published in: American journal of transplantation Vol. 11; no. 7; pp. 1444 - 1455
• Main Authors: Friman, S., Arns, W., Nashan, B., Vincenti, F., Banas, B., Budde, K., Cibrik, D., Chan, L., Klempnauer, J., Mulgaonkar, S., Nicholson, M., Wahlberg, J., Wissing, K.‐M., Abrams, K., Witte, S., Woodle, E. S.
• Format: Journal Article
• Language: English
• Published: Malden, USA Blackwell Publishing Inc 01-07-2011; Wiley
• Subjects: Adult; Allotransplantation; Antibiotics. Antiinfectious agents. Antiparasitic agents; Antiviral agents; Biological and medical sciences; calcineurin inhibitor toxicity; Calcineurin Inhibitors; drug development; efficacy; Female; Fundamental and applied biological sciences. Psychology; Fundamental immunology; Humans; immunosuppression; Kidney Transplantation - physiology; Male; Medical sciences; MEDICIN; MEDICINE; mycophenolic acid; Mycophenolic Acid - therapeutic use; Pharmacology. Drug treatments; Protein Kinase C - antagonists & inhibitors; Pyrroles - therapeutic use; Quinazolines - therapeutic use; renal function; safety; Surgery (general aspects). Transplantations, organ and tissue grafts. Graft diseases; T-cell activation; tacrolimus; Tacrolimus - therapeutic use; Tissue, organ and graft immunology; Protein kinase C; Mycophenolic acid; Renal function; Calcineurin inhibitor; Toxicity; Transplantation; Homotransplantation; Kidney; Randomization; Surgery; safety; Phase II trial; Allotransplantation; Graft; Antiviral; Complication; Clinical trial; Sotrastaurin; Protein synthesis inhibitor; calcineurin inhibitor toxicity; Kidney disease; Urinary system disease; Small; Enzyme; Transferases; Treatment efficiency; tacrolimus; IMP dehydrogenase; Enzyme inhibitor; drug development; Lactone; Clinical research; Macrolide; efficacy; T-cell activation; Immunomodulator; Antibiotic; Immunosuppression; Treatment; Urinary system; Oxidoreductases; Mycophenolate mofetil; Antibacterial agent
• ISSN: 1600-6135; 1600-6143; 1600-6143
• DOI: 10.1111/j.1600-6143.2011.03538.x

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 m2, 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.
A calcineurin inhibitor‐free regimen including sotrastaurin, a novel small molecule inhibiting protein‐kinase C, is shown to be associated with insufficient efficacy, but better renal function, in patients on study drug compared with the control regimen. See editorial by Meier‐Kriesche and Kaplan on page 1355.