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Abstract: SA-PO893

Analysis of the NefIgArd Part A Study Confirms Nefecon Modulates Proteins Involved in the Intestinal Immune Network for IgA Production

Session Information

Category: Glomerular Diseases

  • 1402 Glomerular Diseases: Clinical, Outcomes, and Trials

Authors

  • Thomas, Roisin Clare, University of Leicester, Leicester, United Kingdom
  • Nawaz, Nadia, University of Leicester, Leicester, United Kingdom
  • Molyneux, Karen, University of Leicester, Leicester, United Kingdom
  • Barratt, Jonathan, University of Leicester, Leicester, United Kingdom
Background

Nefecon, the targeted release formulation of budesonide, is delivered to the gut-associated lymphoid tissue (GALT) of the terminal ileum, a major site of immunoglobulin A (IgA) production. Results from the Phase 2b NEFIGAN and Phase 3 NefIgArd trials demonstrated that treatment with 16 mg/day Nefecon significantly reduces proteinuria and loss of estimated glomerular filtration rate compared with placebo. A number of serum biomarkers have been measured in the 2 trials and many of those identified to be modulated by Nefecon in the Phase 2b study have now been validated in Part A of the NefIgArd study. The aim of this study was to determine biological pathways modulated by Nefecon treatment using the data currently available from the Part A biomarker analysis program.

Methods

NefIgArd is a Phase 3 double-blind, randomized, controlled clinical trial designed to determine the efficacy of Nefecon in patients with immunoglobulin A nephropathy (IgAN) at high risk of progressive kidney disease despite optimized supportive care. The trial comprised 9 months of treatment with placebo or Nefecon 16 mg/day, and a 3-month (Part A) or 15-month (Part B) off-drug observational follow-up period. An interactome analysis was performed incorporating all serum proteins significantly modulated by treatment with Nefecon 16 mg/day in Part A of the NefIgArd study using the STRING protein-protein interactions database, which contains known and predicted protein interactions, to determine which biological processes and pathways are modulated by Nefecon treatment.

Results

Consistent with the Phase 2b findings, functional analysis demonstrated that serum biomarkers significantly modulated by Nefecon treatment in Part A of the NefIgArd trial are enriched for proteins involved in the KEGG (Kyoto Encyclopedia of Genes and Genomes) pathway database for intestinal immune network for IgA production, and biological processes involved in B cell activation control, indicating the mechanism of action of Nefecon is, at least in part, driven by an effect within the GALT.

Conclusion

These findings support a disease modifying effect of Nefecon at the ileal mucosal surface and a direct effect on the ileal GALT, further strengthening the link between the gut and the kidneys in IgAN.

Funding

  • Commercial Support – Calliditas