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Abstract: PO1886

GFB-887, a TRPC5 Inhibitor, Is Safe and Well Tolerated and Engages the TRPC5 Target, Leading to Reductions in Urinary Rac1 in Healthy Subjects

Session Information

Category: Glomerular Diseases

  • 1203 Glomerular Diseases: Clinical, Outcomes, and Trials

Authors

  • Walsh, Liron, Goldfinch Bio Inc, Cambridge, Massachusetts, United States
  • Lynam, Chris, Goldfinch Bio Inc, Cambridge, Massachusetts, United States
  • Johnson, Leslie, Goldfinch Bio Inc, Cambridge, Massachusetts, United States
  • Ge, Tingting, Goldfinch Bio Inc, Cambridge, Massachusetts, United States
  • Pan-Zhou, Xin-Ru, Goldfinch Bio Inc, Cambridge, Massachusetts, United States
  • Czerwiec, Frank S., Goldfinch Bio Inc, Cambridge, Massachusetts, United States
  • Dagon, Yossi, Goldfinch Bio Inc, Cambridge, Massachusetts, United States
  • Raghu, Hari, Goldfinch Bio Inc, Cambridge, Massachusetts, United States
  • Reilly, John F., Goldfinch Bio Inc, Cambridge, Massachusetts, United States
Background

Activation of the TRPC5-Rac1 pathway is a key driver of podocyte injury in focal segmental glomerulosclerosis (FSGS), minimal change disease (MCD), and diabetic nephropathy (DN). Inhibition of the TRPC5 ion channel may be a potential therapeutic target for these disorders. GFB-887 is a sub-type selective, small molecule TRPC5 ion channel inhibitor that has been shown in preclinical models to prevent podocyte damage mediated by Rac1 activation. This is a first-in-human study to evaluate the safety, tolerability, pharmacokinetics (PK) and pharmacodynamics (PD) of single ascending doses (SAD) of GFB-887 in healthy subjects.

Methods

This is a phase 1, double-blinded, randomized, placebo-controlled, study in healthy subjects. The objectives were to characterize safety, tolerability, PK profile, and effects on urinary Rac1 after single oral doses of GFB-887. Subjects were randomized to either GFB-887 or placebo (8:2) in 5, 20, 40, 80,160, 320, and 900 mg SAD cohorts. Each subject received a single dose, had 24-hour urine collection pre and post-dose, and followed for 28 days post-dose.

Results

70 healthy subjects (median age 43 years, 86% male, 56% Caucasians, 42% African Americans) were dosed with GFB-887. The most common adverse event (AE) was headache. All AEs were mild and non-serious. There were no clinically significant changes in ECGs, vital signs or laboratory results. Blood pressure was modestly and asymptomatically reduced at the highest doses. Cmax and AUC of GFB-887 increased with higher doses in a less than dose proportionally manner through 900mg. Urinary Rac1 was significantly reduced from baseline with increasing doses of GFB-887.

Conclusion

Single doses of GFB-887 were well tolerated with a favorable PK profile in healthy subjects. GFB-887 exhibits dose-dependent reduction in urinary Rac1, a regulator of podocyte cytoskeletal structure and motility, indicating that GFB-887 engages and inhibits the TRPC5-Rac1 pathway. The safety and efficacy of GFB-887 is currently being evaluated in patients with FSGS, MCD, and DN (NCT04387448).

Funding

  • Commercial Support