Alefacept combined with tacrolimus, mycophenolate mofetil and steroids in de novo kidney transplantation: a randomized controlled trial.

Memory T cells play a central role in mediating allograft rejection and are a rational target for immunosuppressive therapy. Alefacept is a recombinant LFA3/IgG1 fusion protein that reduces the number of memory T cells in both psoriatic lesions and the peripheral circulation of psoriasis patients. This study evaluated the efficacy and safety of alefacept compared with placebo when combined with tacrolimus, mycophenolate mofetil and corticosteroids in de novo renal transplant recipients. Between December 2007 and March 2009 patients were randomized in a double-blind fashion to receive alefacept (n = 105) or placebo (n = 107) for 3 months and were then followed for a further 3 months. The primary efficacy endpoint was the incidence of biopsy-confirmed acute T cell mediated rejection (Banff grade ≥ 1) through Month 6. Memory T cell counts were significantly reduced in the alefacept group from Week 3 to study end compared with placebo. However, there was no significant difference between the alefacept and placebo groups for the primary efficacy endpoint (alefacept, 11.0% vs. placebo, 7.0%, p = 0.3). Patient and graft survival as well as renal function was similar between treatment groups. Safety and tolerability were generally similar between the treatment arms. Malignancy was higher in the alefacept treatment arm.

Safety, tolerability, pharmacokinetics, pharmacodynamics and efficacy of the monoclonal antibody ASK8007 blocking osteopontin in patients with rheumatoid arthritis: a randomised, placebo controlled, proof-of-concept study.

OBJECTIVES: Osteopontin is an extracellular matrix protein with diverse immunomodulatory functions. The authors assessed the safety, tolerability, pharmacokinetics, pharmacodynamics and initial efficacy of the humanised monoclonal antibody ASK8007, which blocks osteopontin. METHODS: In this double-blind, multicentre, combined first-in-man, single-dose escalation (phase I, part A) and proof-of-concept, multiple-dose (phase IIA, part B) study, rheumatoid arthritis (RA) patients with active disease were randomly assigned to receive ASK8007 or placebo intravenously. Safety monitoring, pharmacokinetic and pharmacodynamic analyses and clinical assessments were performed throughout the study. The expression of phenotypic cell markers was evaluated in synovial tissue biopsy samples obtained at baseline and 43 days after initiation of treatment (part B) by immunohistochemistry and digital image analysis. Two co-primary efficacy endpoints were the change from baseline in the disease activity score evaluated in 28 joints (DAS28) and the change from baseline in the number of CD68 synovial sublining macrophages, both assessed on day 43 (part B). RESULTS: ASK8007 was overall safe and well tolerated up to the highest studied dose (20 mg/kg). Quantifiable concentrations of ASK8007 were detected in synovial fluid. No differences were observed for changes from baseline in DAS28 and CD68 sublining macrophages between ASK8007 and placebo-treated patients. Within the ASK8007 treatment group, there were also no apparent clinical responses or changes in sublining macrophages. In addition, ASK8007 treatment did not change other assessed biomarkers. CONCLUSIONS: Osteopontin blockade is well tolerated and not related to safety concerns. These results consistently show that osteopontin blockade is unlikely to induce robust clinical improvement in RA patients.