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Abstract: INFO26

Precision Medicine Proof of Concept for TNF Inhibition in FSGS and Treatment Resistant Minimal Change Disease

Session Information

Category: Glomerular Diseases

  • No subcategory defined

Authors

  • Trachtman, Howard, NYU Langone Health, New York, New York, United States
  • Mariani, Laura H., University of Michigan, Ann Arbor, Michigan, United States
  • Ju, Wenjun, University of Michigan, Ann Arbor, Michigan, United States
  • Eddy, Sean, University of Michigan, Ann Arbor, Michigan, United States
  • Sedor, John R., Cleveland Clinic, Cleveland, Ohio, United States
  • Massengill, Susan F., Levine Children's Hospital, Charlotte, North Carolina, United States
  • Desmond, Hailey, University of Michigan, Ann Arbor, Michigan, United States
  • Kurtz, Vivian, University of Michigan, Ann Arbor, Michigan, United States
  • Kretzler, Matthias, University of Michigan, Ann Arbor, Michigan, United States
  • Gipson, Debbie S., University of Michigan, Ann Arbor, Michigan, United States
Description

The TNF precision medicine study is a proof-of-concept, open-label trial addressing the potential for targeted treatment of focal segmental glomerulosclerosis (FSGS) or treatment-resistant minimal change disease (TR-MCD). The underlying premise is that FSGS and MCD are heterogeneous disorders with multiple mechanisms of glomerular injury that can be elucidated by molecular phenotyping. Hierarchical clustering of kidney tissue transcriptional profiles from NEPTUNE subjects with FSGS and MCD identified a cluster with poorer GFR and proteinuria outcomes, with evidence for TNF pathway activation.

Our previous study (Mariani et al. Bioarchives doi10.1101/427880) shows that a subset of FSGS and TR-MCD patients with up-regulation of TNF pathway can be identified through assay of urine MCP1/Cr and TIMP1/Cr levels by ELISA. This profiling serves as a non-invasive biomarker of intra-renal TNF pathway activation. This study tests the hypothesis that TNF inhibition with adalimumab in patients with activated intra-renal TNF pathway will result in reduction in urinary MCP1 and/or TIMP1.

8 patients will be treated for 8 weeks with adalimumab, adminstered biweekly for 5 total doses. The primary outcome is the change in target engagement biomarker levels from baseline to week 10. Secondary outcomes include safety labs, adverse events and change in eGFR and proteinuria from baseline to week 10. Eligibility criteria: increased urinary excretion of biomarkers of TNF activation, eGFR>45, urine protein:creatinine ≥1.5 g/g, age 6-70, stable immunosuppression and ACEi/ARB therapies for 30 days before enrollment. Additional criteria at clinicaltrials.gov/NCT04009668.

This investigator-initiated trial is a partnership between NEPTUNE and Kidney Research Network and sponsored by the University of Michigan, New York University, Cleveland Clinic and Levine Children’s Hospital.

Funding

  • University of Michigan, New York University, Cleveland Clinic, and Levine Children’s Hospital/Atrium Health.