Abstract
INTRODUCTION: Inflammatory cell recruitment, which is potentially mediated by the monocyte chemoattractant protein 1/C-C chemokine receptor type 2 (CCR2) system and by C-C chemokine receptor type 5 (CCR5) activity, may play a role in the development and progression of diabetic nephropathy. PF-04634817 is a dual chemokine CCR2/5 receptor antagonist that is being developed for the treatment of diabetic nephropathy. METHODS: We evaluated the efficacy of PF-04634817 compared with matching placebo for reduction of albuminuria after 12 weeks of treatment in subjects with type 2 diabetes who received standard of care (SOC; angiotensin-converting enzyme inhibitor or angiotensin receptor blocker therapy), in a randomized, double-blind, placebo-controlled, parallel-group phase 2 study. RESULTS: A total of 226 subjects who received SOC with baseline estimated glomerular filtration rates between 20 and 75 ml/min per 1.73 m(2) and a baseline urinary albumin-to-creatinine ratio (UACR) of ≥300 mg/g were randomly assigned 3:1 to receive PF-04634817 (150 or 200 mg orally, once daily) or placebo. The primary analysis was Bayesian, with an informative prior for placebo response (equivalent to including an additional 80 subjects in the placebo arm). We observed a placebo-adjusted reduction in UACR of 8.2% (ratio 0.918; 95% credible interval: 0.75-1.09) at week 12 in the PF-04634817 arm. PF-04634817 appeared to be safe and well-tolerated. CONCLUSION: Despite the good safety profile shown by PF-04634817, clinical development for this indication was discontinued in light of the modest efficacy observed.