Goldfinch Bio Announces GFB-887 as Clinical Development Candidate and Presents Data Demonstrating Selective Inhibition of TRPC5 for the Treatment of Genetically-driven Kidney Disease
Goldfinch Bio, a biotechnology company focused on discovering and developing precision medicines for the treatment of genetically-driven kidney diseases, today announced GFB-887, its selective, small molecule inhibitor of transient receptor potential canonical 5 (TRPC5), as its development candidate. The clinical advancement of GFB-887 is supported by preclinical data presented by Goldfinch Bio at the American Society of Nephrology (ASN) Kidney Week 2018 Conference, demonstrating the potential of GFB-887 for the treatment of podocyte injury and proteinuria associated with focal segmental glomerulosclerosis (FSGS). Goldfinch expects to initiate clinical development of GFB-887 in the first half of 2019.
“We selected GFB-887 as our development candidate based on encouraging preclinical data in multiple models of kidney disease associated with proteinuria. This includes data reported at Kidney Week 2018 demonstrating its potent and selective activity against TRPC5, a calcium-permeable cation channel that drives a key pathway implicated in proteinuria, the hallmark of progressive kidney diseases such as FSGS,” said Anthony Johnson, M.D., President and Chief Executive Officer of Goldfinch Bio. “We plan to initiate clinical studies with GFB-887 in the first half of 2019 and look forward to advancing the development of this novel medicine to address the significant unmet needs of patients with proteinuric kidney diseases.”
In a poster titled ‘Small molecule inhibition of TRPC5 protects against podocyte injury and proteinuria in FSGS,’ Goldfinch Bio researchers described how the application of the Goldfinch Bio product engine, comprised of its biology platform and Kidney Genome Atlas, led to their identification of potent and selective novel small molecule inhibitors of TRPC5, including the development candidate, GFB-887, for the treatment of proteinuria in FSGS. In this poster Goldfinch Bio researchers demonstrated:
- TRPC5 nanomolar inhibitory activity, selectivity across other TRP channels and TRPC subtype specificity;
- prevention of the loss of stress fibers that are critical in maintaining kidney function, including protection against protamine sulfate induced loss of stress fibers and restoration of stress fibers in podocytes after knockdown of synaptopodin;
- suppression of pathogenic podocyte motility in a scratch assay; and
- amelioration of proteinuria in hypertension-induced FSGS in relevant preclinical models without altering blood pressure.
In addition to the data related to GFB-887, Goldfinch Bio presented data from its Kidney Genome Atlas demonstrating the identification of novel pathways and targets, such as TRPC5 and others, for the treatment of genetically-derived kidney diseases, including FSGS and diabetic kidney disease.
“The Goldfinch Kidney Genome Atlas, the most comprehensive patient registry in kidney disease, was established through collaborations with four major academic institutions. The Kidney Genome Atlas integrates genomic, transcriptomic, and proteomic data along with anonymized clinical data from thousands of patients and is the cornerstones of our product engine,” continued Dr. Johnson. “The data at Kidney Week demonstrate how the Kidney Genome Atlas enables the identification of new therapeutic targets by integrating genomic data with transcriptomes and high-quality clinical profiles to stratify patient subtypes most likely to respond to specific therapies.”
In a poster titled, “Kidney Genome Atlas: a whole-genome landscape of more than 2,000 kidney disease patients,” Goldfinch Bio researchers demonstrated the functionality of the KGA for advancing understanding of the molecular mechanisms of kidney diseases at a whole genome scale, with the ability to:
- enable the discovery of genetic variants associated with kidney disease and the integration of genomic and transcriptomic data to identify kidney disease-specific expression quantitative trait loci (eQTLs);
- establish relationships between genetic variants, histologic diagnoses, and quantitative clinical phenotypes of kidney function and disease progression;
- investigate and validate biological pathways derived from these analyses to stratify patients into subtypes most likely to respond to specific targeted therapies.
FSGS (focal segmental glomerulosclerosis) is a rare kidney disorder and histopathologic diagnosis characterized by severe scarring of the kidney's filtering units, or glomeruli, leading to proteinuria, an excess of essential proteins spilling into the urine. FSGS is associated with the injury and loss of podocytes, terminally differentiated cells of the kidney glomeruli essential for filtration and proper kidney function. Recent research into the genetics of kidney disease has identified over 30 genes associated with FSGS and implicates the podocyte as a central player in the pathogenesis of FSGS. There are currently no FDA approved treatments for FSGS.
TRPC5 is a calcium-permeable cation channel that has been implicated in the pathogenesis of FSGS by triggering a Rac1-TRPC5 disease pathway. Recent evidence has demonstrated that TRPC5 and Rac1, a critical regulator of cellular motility, form a vicious cycle that drives pathogenic remodeling of the actin cytoskeleton in podocytes. This causes podocyte loss and breach of the filtration barrier, which leads to proteinuria, the hallmark of progressive kidney diseases such as FSGS. Inhibition of TRPC5 offers a potential point of therapeutic intervention to halt progression of FSGS to kidney failure1.
About Goldfinch Bio
Goldfinch Bio is a biotechnology company that is singularly focused on discovering and developing precision therapies for patients with kidney diseases. Just as the goldfinch has long been a symbol of healing and renewal and was a prominent figure of the Renaissance, Goldfinch Bio is leading a new age of therapeutic discovery to transform the treatment paradigm for patients with kidney diseases. Goldfinch was launched in 2016 by Third Rock Ventures, and is headquartered in Cambridge, Mass. For more information, please visit www.goldfinchbio.com.
1. Y. Zhou et al., Science 358, 1332 (2017).
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