Safety and Efficacy Study of Pyridorin in Patients With Nephropathy Due to Type 2 Diabetes

Diabetic kidney disease afflicts about 20% of all diabetics and is the major cause of end-stage renal disease (ESRD). There are an estimated 1.2 million diabetic overt nephropathy patients in the US, and approximately 5.1 million diabetic patients exhibiting signs of developing kidney disease. Hyperglycemia-induced microvascular disease is the fundamental cause of diabetic kidney disease. More specifically, hyperglycemia perturbs metabolic pathways, particularly in tissues that do not regulate intracellular glucose levels. This favors a broad range of pathogenic oxidative chemistries including the formation of advanced glycation end-products (AGEs), toxic carbonyls, and reactive oxygen species (ROS) that are considered to be the principal causative factors in the development of diabetic microvascular disease. Pyridorin™ has been shown to inhibit AGE formation and to scavenge ROS and toxic carbonyl compounds in extensive in vitro studies. The therapeutic potential of Pyridorin™ has been demonstrated in vivo by extensive preclinical studies that have been carried out in a number of independent laboratories by prominent investigators. In addition, Pyridorin™ has demonstrated a significant treatment effect in slowing the progression of diabetic nephropathy in two Phase 2 clinical trials. Thus, a solid scientific rationale and clinical evidence exists for the application of Pyridorin™ therapy to slow the progression of diabetic kidney disease. NephroGenex is initiating a new Phase 2b clinical trial (PYR-210) that is evaluating the safety and efficacy of Pyridorin™ in slowing the progression of overt nephropathy in patients with type 2 diabetes. This trial incorporates the latest discussion with the FDA regarding the use of an approvable surrogate marker that would be subsequently confirmed with hard clinical endpoints. In this double-blind, placebo-controlled study, eligible type 2 diabetic patients with overt nephropathy will be treated for one year with bid doses of either Pyridorin™ 150 mg, Pyridorin™ 300 mg, or placebo. The primary endpoint in the study is the change in serum creatinine (SCr) from baseline after 1 year of therapy. Secondary 1-year endpoints include the slope of SCr, the change in protein/creatinine ratio (PCR) derived from 24-hour urine collections, and the change from baseline and slope of serum cystatin C. The patient population studied will be type 2 diabetics with overt nephropathy defined as having a SCr between 1.3 and 3.3 mg/dl in females and between 1.5 and 3.5 mg/dl in males, accompanied by proteinuria in the macroalbuminuric range (PCR at least 1200 mg/g). In order to reduce confounding variables, careful control of blood pressure (BP) will be required. If not yet controlled, each patient's BP will brought to a level that the investigator believes is appropriate for the patient prior to randomization, and this will remain the target BP for that patient for the remainder of the study. Also, patients will be permitted to be on only one ACE inhibitor or angiotensin receptor blocker (ARB) and no other drugs that inhibit the renin-angiotensin-aldosterone axis throughout the study. A run-in period will be required in some patients to achieve the BP and ACEi/ARB requirements. This study will be conducted with the leadership of the Collaborative Study Group.