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Abstract: SA-PO654

Treatment With Nefecon Reduces Circulating Levels of Galactose-Deficient IgA1 in Patients With IgA Nephropathy in the NefIgArd Clinical Trial

Session Information

Category: Glomerular Diseases

  • 1302 Glomerular Diseases: Immunology and Inflammation

Authors

  • Molyneux, Karen, University of Leicester, Leicester, Leicestershire, United Kingdom
  • Nawaz, Nadia, University of Leicester, Leicester, Leicestershire, United Kingdom
  • Taylor, Scott, University of Leicester, Leicester, Leicestershire, United Kingdom
  • Barratt, Jonathan, University of Leicester, Leicester, Leicestershire, United Kingdom
Background

IgA nephropathy (IgAN) is characterized by mesangial accumulation of IgA1-containing immune complexes (IgA1 ICs), which generate a pro-inflammatory and pro-fibrotic glomerular microenvironment, breakdown of the glomerular filtration barrier and progressive tubulointerstitial inflammation and scarring. IgA1 IC formation in the circulation is mainly driven by increased levels of polymeric galactose-deficient IgA1 (Gd-IgA1), thought to be derived from mucosally primed B cells, mostly residing in the gut associated lymphoid tissue (GALT). The therapeutic effect of selectively targeting the GALT was first investigated in the NEFIGAN study (NCT01738035) and results have now been confirmed in the larger NefIgArd clinical trial (NCT03643965).

Methods

NefIgArd is a randomized, double-blind, placebo-controlled Phase 3 trial, comprising PART A (9-month treatment and 3-month follow-up period) and PART B (12 month no-treatment follow-up period). Serum samples were collected at screening (placebo n=81; 16 mg Nefecon n=81), Month 3 (placebo n=81; 16 mg Nefecon n=81), Month 6 (placebo n=81; 16 mg Nefecon n=79), and Month 9 (i.e. end of treatment: placebo n=79; 16 mg Nefecon n=81). Gd-IgA1 levels were measured with an ELISA using the Gd-IgA1 specific antibody, KM55 (IBL, Japan). Between-group comparisons at each time point were undertaken using unpaired t-tests (significance level = 0.05).

Results

16 mg Nefecon treatment significantly reduced levels of circulating Gd-IgA1. Mean Gd-IgA1 levels fell by 21.4% (p<0.0005) at Month 3, 23.5% (p<0.0017) at Month 6 and 34% (p<0.0001) at Month 9 vs placebo.

Conclusion

To date, two large independent studies have shown that targeting the GALT with Nefecon results in a significant reduction in both proteinuria and a critical pathogenic biomarker in IgAN. Gd-IgA1-containing immune complexes have been shown to activate mesangial cells, promote glomerular scarring, and high levels are associated with more severe glomerular injury in kidney biopsies and worse kidney survival in clinical studies. This significant reduction in Gd-IgA1, combined with the proteinuria reduction reported in the NefIgArd trial, are consistent with Nefecon having a direct disease-modifying effect in IgAN.

Funding

  • Commercial Support