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

Abstract

†Members of the Study Scientific Committee who contributed to the design of the study.Sotrastaurin, a selective protein-kinase-C inhibitor, blocks early T-cell activation through a calcineurinindependent 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.

Overexpression of the autoimmunity-associated phosphatase PTPN22 promotes survival of antigen-stimulated CLL cells by selectively activating AKT

“…Induction of PTPN22 by bone marrow stromal cells could be efficiently blocked by ruboxistaurin and sotrastaurin, which are 2 oral PKC inhibitors that are currently undergoing phase 2 and phase 3 clinical testing for several nonmalignant diseases, including diabetic retinopathy, psoriasis, and prevention of renal allograft rejection. 47,48 Importantly, both compounds significantly enhanced the cytotoxic effect of soluble anti-IgM despite having no direct cytotoxic effect of their own. These data suggest that PKC inhibitors could selectively kill CLL cells in vivo by downregulating PTPN22, although it remains possible that the enhanced apoptosis induction observed with these agents may also involve additional mechanisms that are independent of PTPN22 expression.…”

Short-Chain Fatty Acid-Modified Hexosamine for Tissue-Engineering Osteoarthritic Cartilage

“…[29][30][31][32] Libraries of small molecules can be readily synthesized, which allows for evaluation of numerous small molecules with minor structural differences cocurrently. 28,33 In this work, we utilize a SCFA-modified hexosamine, 3,4,6-O-Bu 3 GlcNAc, as a small molecule drug candidate for reducing osteoarthritic changes that represents an emerging paradigm wherein monosaccharides present an attractive 3D scaffold for drug discovery efforts.…”

Immunosuppressive Drug Therapy

“…Phase II studies in de novo kidney transplant recipients randomized to sotrastaurin (n ¼ 81) showed a higher composite efficacy failure rate at 3 mo without CNI (Friman et al 2011). Biopsy-proven acute rejection occurred in 17 patients in the sotrastaurin arm.…”