Original Report: Patient-Oriented, Translational Research

Effects of Pyridoxamine in Combined Phase 2 Studies of Patients with Type 1 and Type 2 Diabetes and Overt Nephropathy
Mark E. Williams^a, W. Kline Bolton^b, Raja G. Khalifah^c, Thorsten P. Degenhardt^c, Robert J. Schotzinger^c, Janet B. McGill<sup>d

a</sup>Joslin Diabetes Center, Boston, Mass.,
^bUniversity of Virginia, Charlottesville, Va.,
^cBioStratum Inc., Durham, N.C., and
^dWashington University, St. Louis, Mo., USA

Address of Corresponding Author

Am J Nephrol 2007;27:605-614 (DOI: 10.1159/000108104)

  Key Words

• Diabetic nephropathy
• Pyridoxamine
• Serum creatinine
• Urinary transforming growth factor-beta 1
• Advanced glycation end products
• Phase 2 clinical studies, pyridoxamine

  Abstract

Background/Aims: Treatments of diabetic nephropathy (DN) delay the onset of end-stage renal disease. We report the results of safety/tolerability studies in patients with overt nephropathy and type 1/type 2 diabetes treated with pyridoxamine, a broad inhibitor of advanced glycation. Methods: The two 24-week studies were multicenter Phase 2 trials in patients under standard-of-care. In PYR-206, patients were randomized 1:1 and had baseline serum creatinine (bSCr) 2.0 mg/dl. In PYR-205/207, randomization was 2:1 and bSCr was 2.0 for PYR-205 and 2.0 but 3.5 mg/dl for PYR-207. Treated patients (122 active, 90 placebo) received 50 mg pyridoxamine twice daily in PYR-206; PYR-205/207 patients were escalated to 250 mg twice daily. Results: Adverse events were balanced between the groups (p = NS). Slight imbalances, mainly in the PYR-205/207 groups, were noted in deaths (from diverse causes, p = NS) and serious adverse events (p = 0.05) that were attributed to pre-existing conditions. In a merged data set, pyridoxamine significantly reduced the change from baseline in serum creatinine (p < 0.03). In patients similar to the RENAAL/IDNT studies (bSCr 1.3 mg/dl, type 2 diabetes), a treatment effect was observed on the rise in serum creatinine (p = 0.007). No differences in urinary albumin excretion were seen. Urinary TGF-1 also tended to decrease with pyridoxamine (p = 0.049) as did the CML and CEL AGEs. Conclusion: These data provide a foundation for further evaluation of this AGE inhibitor in DN.

Copyright © 2007 S. Karger AG, Basel

  Author Contacts

Mark E. Williams, MD, FACP, FASN
Harvard Medical School, Joslin Diabetes Center
1 Joslin Place
Boston, MA 02215 (USA)
Tel. +1 617 732 2477, Fax +1 617 732 2467, E-Mail mark.williams@joslin.harvard.edu

  Article Information

Conflicts of Interest: Drs. Khalifah, Schotzinger, and Degenhardt were employed during the study by BioStratum Inc., the study drug sponsor. Drs. Williams and Bolton have been consultants for BioStratum.

Received: April 23, 2007
Accepted: July 26, 2007
Published online: September 6, 2007
Number of Print Pages : 10
Number of Figures : 4, Number of Tables : 4, Number of References : 40