Rationale for Pyridorin™ Therapy

Extensive evidence now exists for the role of advanced glycation end products (AGEs) and their harmful chemical intermediates and breakdown products, such as reactive oxygen species (ROS) and toxic aldehydes and related compounds (carbonyls and dicarbonyls), in the development of diabetic complications, including neuropathy, retinopathy and kidney disease. There is also a broad foundation of evidence that Pyridorin™ possesses activity against these oxidative chemistries. Thus, a solid scientific rationale exists for the use of Pyridorin™ therapy to slow the progression of diabetic kidney disease.

Safety and Efficacy

In previous clinical trials, Pyridorin™ was generally safe and well tolerated. However, as a drug candidate filed under an Investigational New Drug (IND) application, Pyridorin™ should only be taken under the supervision of a physician during an FDA-approved clinical trial.

In earlier Pyridorin™ clinical trials that tested its ability to slow the progression of overt nephropathy, the increase from baseline in serum creatinine, a well-accepted marker for kidney filtration, was decreased at week 26 by 48% when all Phase 2 patients receiving Pyridorin™ for 6 months were compared to those receiving placebo (p = 0.03). In the subset of type 2 patients who were receiving standard-of-care therapy for diabetic nephropathy and who also had elevated serum creatinine levels at baseline (>1.3 mg/dL), the increase from baseline in serum creatinine was reduced by 73% in patients receiving Pyridorin™ when compared to those receiving placebo (p = 0.003).

Confirmation of the improvement of the glomerular filtration rate (GFR) was observed by examining the level of serum cystatin C, an endogenous marker of glomerular filtration that overcomes some of the limitations of creatinine particularly in earlier stages of disease. Pyridorin™ treatment reduced the rate of increase in serum cystatin C (slope and change from baseline). Additional indicators of benefit in patients receiving Pyridorin™ was a slowed rate of decline in creatinine clearance, a measure of kidney filtration.

Positive effects were seen on important biomarkers, such as the level of urinary TGFβ1 when compared to patients receiving placebo. TGFβ1 is a cytokine that has been causally implicated in kidney disease. Furthermore, plasma AGE levels (both carboxymethyllysine and carboxyethyllysine) were reduced by Pyridorin™ treatment, while they continued to increase in the placebo arm.