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Abstract: TH-PO422

Identification of Noninvasive Surrogates as Predictors of Response to FT011 in Kidney Disease

Session Information

Category: Glomerular Diseases

  • 1301 Glomerular Diseases: Fibrosis and Extracellular Matrix

Authors

  • Eddy, Sean, University of Michigan, Ann Arbor, Michigan, United States
  • Kompa, Andrew, University of Melbourne, Fitzroy, Victoria, Australia
  • Hartman, John R., University of Michigan, Ann Arbor, Michigan, United States
  • Eichinger, Felix H., University of Michigan, Ann Arbor, Michigan, United States
  • Godfrey, Brad A., University of Michigan, Ann Arbor, Michigan, United States
  • Ju, Wenjun, University of Michigan, Ann Arbor, Michigan, United States
  • Edgley, Amanda J., University of Melbourne, Fitzroy, Victoria, Australia
  • Langham, Robyn G., University of Melbourne, Fitzroy, Victoria, Australia
  • Mariani, Laura H., University of Michigan, Ann Arbor, Michigan, United States
  • Kelly, Darren J., University of Melbourne, Fitzroy, Victoria, Australia
  • Kretzler, Matthias, University of Michigan, Ann Arbor, Michigan, United States
Background

Interstitial fibrosis is not only a common endpoint of injury in most kidney diseases, it is also a strong predictor of disease progression. With the development of a novel agent FT011, that has demonstrated anti-fibrotic efficacy in preclinical models, and an excellent safety profile in Phase I studies, a pharmacotranscriptomic analysis of the effects in rats was undertaken. Comparative analysis with human kidney RNAseq profiles was then performed to identify potential predictive clinical and biomarker profiles of patients from the NEPTUNE cohort most likely to respond to FT011 treatment.

Methods

RNAseq profiles were generated from kidneys harvested at 12 weeks in Sprague Dawley rats who had undergone Sham (n=9), subtotal nephrectomy (STNx, n=8), or STNX+FT011 treatment (n=8). Differentially expressed gene (DEG) profiles were generated, and enrichment analysis performed. Ortholog mapping was performed using Ensembl to map animal profiles onto human kidney RNAseq profiles from the NEPTUNE cohort (n=388). Urine biomarker profiles were generated NEPTUNE biobanked urine.

Results

At week 12 STNx+FT-011 attenuated proteinuria and plasma creatinine compared to STNx (p<0.05). DEG profiles for STNx vs Sham (9373, q<0.01) and STNx+FT011 vs STNx (4996, q<0.1) comparisons were performed. 4546 DEGs were shared and direction of expression was reversed by FT011 in 99.9% of these genes. The top 500 DEGs were carried forward as an FT011 response signature. Top enriched pathways and upstream regulators of the signature were fibrosis pathways and TGFb-1 (p<0.001). The signature was then mapped onto human expression profiles. The signature was elevated in kidney biopsy profiles of patients with FSGS and MN, was negatively correlated with eGFR (p<0.001), and positively correlated with UPCR (p<0.01). Non-invasive urine biomarkers also showed strong correlation with the signature (p<0.001).

Conclusion

FT011 treatment reduced a fibrosis-associated transcriptional profile in the STNx rat model. The signature was highly significant in human kidney disease profiles, associated with more advanced disease, and strongly correlated with non-invasive biomarkers, offering a promise of identifying patients with an intrarenal profile best responsive to FT011 in clinical trials.

Funding

  • NIDDK Support