1. Safety and Efficacy of GFB-887, a TRPC5 Channel Inhibitor, in Patients With Focal Segmental Glomerulosclerosis, Treatment-Resistant Minimal Change Disease, or Diabetic Nephropathy
- Author
-
Howard Trachtman, James R Woodworth, Frank S. Czerwiec, Krishna Padmanabhan, Leslie Johnson, Hiddo J.L. Heerspink, Youssef M K Farag, Debbie S. Gipson, Caitlin Cornwall, Xin-Ru Pan-Zhou, Liron Walsh, John F. Reilly, Katherine R. Tuttle, Gregory A Gaich, Real World Studies in PharmacoEpidemiology, -Genetics, -Economics and -Therapy (PEGET), and Groningen Kidney Center (GKC)
- Subjects
medicine.medical_specialty ,Proteinuria ,business.industry ,precision medicine ,Urology ,medicine.disease ,Placebo ,Interim analysis ,TRPC5 ,Diabetic nephropathy ,FSGS ,Focal segmental glomerulosclerosis ,Tolerability ,Nephrology ,Clinical Research ,Medicine ,biomarker ,Minimal change disease ,medicine.symptom ,proteinuria ,business ,Rac1 ,Kidney disease - Abstract
Introduction A critical unmet need exists for precision therapies for chronic kidney disease. GFB-887 is a podocyte-targeting, small molecule inhibitor of transient receptor potential canonical-5 (TRPC5) designed specifically to treat patients with glomerular kidney diseases characterized by an overactivation of the TRPC5-Rac1 pathway. In a first-in-human study, GFB-887 was found to be safe and well tolerated, had a pharmacokinetic (PK) profile allowing once-daily dosing, and dose dependently decreased urinary Rac1 in healthy adults. Methods TRACTION-2 is a phase 2a, double-blind, placebo-controlled, multiple−ascending dose study of GFB-887 in patients with focal segmental glomerulosclerosis (FSGS), treatment-resistant minimal change disease (TR-MCD), or diabetic nephropathy (DN) (NCT04387448). Adult patients on stable renin−angiotensin system blockade and/or immunosuppression with persistent proteinuria will be randomized and dosed in 3 ascending dose levels to GFB-887 or placebo for 12 weeks. Cohorts may be expanded or biomarker-enriched depending upon results of an adaptive interim analysis. Results The primary objective is to evaluate the effect of increasing doses of GFB-887 on proteinuria. Safety and tolerability, quality of life, pharmacokinetic/pharmacodynamic profiles, and the potential association of urinary Rac1 with efficacy will also be evaluated. The projected sample size has 80% power to detect a treatment difference in proteinuria of 54% (FSGS/TR-MCD) or 44% (DN) compared to placebo. Conclusion TRACTION-2 will explore whether targeted blockade of the TRPC5-Rac1 pathway with GFB-887 is an efficacious and safe treatment strategy for patients with FSGS, TR-MCD, and DN and the potential value of urinary Rac1 as a predictive biomarker of treatment response., Graphical abstract
- Published
- 2021