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).

PYR-210 evaluated two doses of Pyridorin™ against placebo in 317 patients over a one year treatment period. Patients enrolled in the trial were type 2 diabetic patients with elevated serum creatinine (SCr) levels and significant proteinuria, and were on standard of care which included adequate blood pressure control and a stable regimen of ACEi/ARB therapy. Efficacy was evaluated based on a 12 month change in SCr from baseline.

Pyridorin™ was well tolerated and demonstrated a benign safety profile. Pyridorin™ did not produce a significant treatment effect in the entire patient population treated; however, in patients with less severe disease (i.e. baseline SCr values less than 1.9 mg/dL), Pyridorin™ produced a treatment effect greater than 50% relative to placebo that was statistically significant (P=0.046).

Patients treated with Pyridorin™ who were on previously established standard of care at screening, with a baseline SCr of up to 3 mg/dL, which includes patients with both mild and moderate levels of disease, showed a highly significant 57% treatment effect for the 300 mg arm (P = 0.009; n=64) and 45% for the 150 mg arm (P=0.045; n=62) relative to placebo.

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.