Previous Clinical Studies


Early Studies Show Clinical Benefit for Target Patient Population

Pyridorin well tolerated, with adverse event rates similar to placebo

Following several preclinical and Phase 1 studies, four placebo-controlled PYRIDORIN® (pyridoxamine dihydrochloride) Phase 2 trials provided the guidance to support the design of the Phase 3 PIONEER program. This included PYR-206, PYR-205/207, and PYR-210. All four studies suggested a clinical benefit in diabetic nephropathy for patients with mild-to-moderate levels of disease and those with advanced disease who had previously established a stable regimen of standard of care.

In multiple Phase 1 and 2 clinical studies, Pyridorin was well tolerated, with adverse event (AE) rates similar to those seen in subjects receiving placebo. The only AEs observed that showed an increase over placebo, observed at the highest dose of 300 mg BID, were small increases in diarrhea and constipation.

PYR-206

PYR-206 was a Phase 2, multi-center, placebo-controlled, randomized, double-blind study, which evaluated the safety and tolerability of 50 mg of Pyridorin for 24 weeks in patients with Type 1 or Type 2 diabetes (65 received Pyridorin, 63 placebo). Although the study was designed as a safety and tolerability study, post-hoc analyses were performed on various efficacy parameters, including SCr, urinary creatinine clearance, and TGF- β1.

Treatment with Pyridorin reduced the change in SCr concentration for all patients from baseline by 27%. While the treatment did not achieve statistical significance for the Intent to Treat (ITT) patient population, which included all patients that received at least one dose of study drug, this effect was statistically significant for a subgroup of patients with Type 2 diabetes and a starting baseline SCr > 1.3 mg/dL, which exhibited a higher level of disease progression. Urinary TGF-b1 was increased in the placebo arm by 43% and decreased in the Pyridorin arm by 25%.

PYR-206 — Serum Creatinine Change from Baseline Analysis

(1) Mean ± SD in mg/dL
(2) Unadjusted mean within group change from baseline in mg/dL
(3) Difference relative to placebo in unadjusted mean change from baseline where a negative value indicates a lesser change from baseline in Pyridorin patients ( i.e. reno-protection)
** Statistically significant, p<0.01

PYR-205/207

PYR-205 and PYR-207 were identical in design, with the exception of the patient entrance criteria. PYR-205 required SCr < 2.0 mg/dL versus PYR-207 > 2.0 mg/dL but < 3.5 mg/dL. The data from these two studies were merged and analyzed as a single trial, as pre-specified in the Statistical Analysis Plan. They were Phase 2, international, multi-center, randomized, double-blind, placebo-controlled, escalating dose studies to evaluate the safety, tolerability, and biologic activity of Pyridorin given orally to patients with Type 1 or 2 diabetes. Dosing was 50mg BID for two weeks, followed by 100 mg BID for two weeks followed by 250 mg BID for 20 weeks, or placebo.

PYR-205/207 — Serum Creatinine Change from Baseline Analysis

(1) Mean ± SD in mg/dL
(2) Unadjusted mean within group change from baseline in mg/dL
(3) Difference relative to placebo in unadjusted mean change from baseline, where a negative value indicates a lesser change from baseline in Pyridorin patients ( i.e. , reno-protection)
(4) Determined using repeated measures mixed model analysis with baseline SCr as a fixed covariate and treatment effect being the difference relative to placebo in change from baseline measured in mg/dL
* Statistically significant, p<0.05

Pyridorin reduced the change from baseline SCr in either a statistically significant fashion or trending toward a significant p-value near 0.05 in all prospectively defined patient subgroups. The beneficial effect of Pyridorin was seen to an equal degree across all patient groups with an approximate 70% reduction relative to placebo in increases of baseline SCr. Urinary TGF-b1 was increased in the placebo arm by 55% and decreased in the Pyridorin arm by 15%.

PYR-210

PYR-210 was a randomized, double-blind, placebo-controlled study of Pyridorin at doses of 150 mg and 300 mg, both twice daily, versus placebo for 12 months. Patients selected for the PYR-210 study had Type 2 diabetes, macroalbuminuria and impaired renal function. Baseline SCr values of up to 3.7 mg/dL were included in the study in order to evaluate Pyridorin safety in more advanced disease.

Because other treatments are known to affect baseline SCr values, a pre-specified analysis was planned of patients on established standard of care (SOC) at screening versus patients that were not on a stable course of SOC treatment when screened. Patients not on a stable course of SOC at screening required a ‘run-in’ period to establish SOC prior to being randomized.

Patients in the study who were on established, or stable SOC regimens at screening exhibited a highly dose-dependent treatment effect (57% for the 300 mg dose, p=0.009; and 45% for the 150 mg dose, p=0.041) in the FDA approvable renal patient population of baseline SCr between 1.3 and 3.0 mg/dL. Urinary TGF-b1 was increased in the placebo arm by 60% and decreased in the Pyridorin arm by 2%.

Patients not on SOC at screening and requiring a run-in period, exhibited higher initial blood pressure readings, more frequent medication changes, and drops in blood pressure during treatment, confounding SCr measurements and leading the overall study results to be negative. However, this observation was key in the design of the Phase 3 PIONEER program where patients must be on an establish and stable regimen of SOC for 6 months prior to randomization.

Change in Serum Creatinine (mg/dl) From Baseline to Endpoint in Various Subgroups from PYR-210

(1) A separate analysis of this group was pre-specified in the statistical analysis plan.
(2) The patient population used in the RENAAL clinical trial of Losartan is considered to be the established population used for pivotal trials in diabetic nephropathy.
*Statistically significant, p<0.05
**Statistically significant, p<0.01