WHOLE BLOOD RNASEQ PROFILING IDENTIFIED FUNCTIONALLY ENRICHED GENE EXPRESSION PATTERNS IN FELZARTAMAB-TREATED PATIENTS WITH IGA NEPHROPATHY: DATA FROM THE PHASE 2 IGNAZ STUDY

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Abstract Title *

WHOLE BLOOD RNASEQ PROFILING IDENTIFIED FUNCTIONALLY ENRICHED GENE EXPRESSION PATTERNS IN FELZARTAMAB-TREATED PATIENTS WITH IGA NEPHROPATHY: DATA FROM THE PHASE 2 IGNAZ STUDY

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Co-author 1

Millie Shah millie.shah@biogen.com Biogen Clinical Development South San Francisco, CA United States -

Co-author 2

Yirui Chen yirui.chen@biogen.com Biogen Genomic Technology & Integrative Analytics South San Francisco, CA United States -

Co-author 3

Tess Delfino tess.delfino@biogen.com Biogen Clinical Development South San Francisco, CA United States -

Co-author 4

Lisa Kivman lisakivman@gmail.com Biogen Clinical Development South San Francisco, CA United States -

Co-author 5

Tabea Kraft t.kraeft@gmx.net MorphoSys GmbH, a Novartis company Clinical Biomarkers Planegg Germany -

Co-author 6

Leslie W. Chinn leslie.chinn@gmail.com Biogen Clinical Pharmacology & Pharmacometrics South San Francisco, CA United States -

Co-author 7

Brian M. Schwartz brian.schwartz@biogen.com Biogen Clinical Development South San Francisco, CA United States -

Co-author 8

Nicholas S. Jones nick.jones@biogen.com Biogen Clinical Development South San Francisco, CA United States -

Co-author 9

Valeria Beckett valeria.beckett@biogen.com Biogen Clinical Development South San Francisco, CA United States -

Co-author 10

Uptal D. Patel uptal.patel@biogen.com Biogen Clinical Development South San Francisco, CA United States -

Co-author 11

Donna Flesher donna.flesher@biogen.com Biogen Clinical Development South San Francisco, CA United States *

Co-author 12

Jonathan Barratt jb81@leicester.ac.uk University of Leicester Department of Cardiovascular Sciences Leicester United Kingdom -

Co-author 13

Krzysztof Kiryluk kk473@cumc.columbia.edu Columbia University Division of Nephrology, Department of Medicine New York, NY United States -

Co-author 14

Co-author 15

Introduction

Felzartamab, a fully human anti-CD38 monoclonal antibody targeting CD38+ plasmablasts and plasma cells, reduced proteinuria and stabilized eGFR in patients with IgA nephropathy (IgAN) in the Phase 2 IGNAZ study (NCT05065970). We used whole blood RNAseq profiling to examine gene expression patterns in felzartamab-treated patients with IgAN.

Methods

In Part 1 of IGNAZ, 48 patients with IgAN were randomized 1:1:1:1 to placebo or intravenous felzartamab (2, 5, or 9 doses). In Part 2, 6 Japanese patients received the open-label 9-dose regimen. Whole blood was collected in PAXgene® Blood RNA Tubes over time and bulk RNA sequencing was performed (Illumina NovaSeq X). Differential expression, gene clustering, functional enrichment, gene set variation, and cellular deconvolution analyses were performed to identify changes following felzartamab treatment.

Results

Overall, 792 genes were differentially expressed in felzartamab-treated patients (9-dose arms) compared to placebo. Two significantly downregulated genes, JCHAIN and IGHA1, have been previously identified as part of a plasma cell gene signature and are relevant to the pathogenesis of IgAN. Differentially expressed genes clustered into distinct groups displaying treatment-associated reductions over time. Gene clusters were functionally enriched for gene programs related to CD38+ cellular subsets. Treatment-associated reduction in these clusters were consistent with the mechanism of action of felzartamab and corresponding clinical observations of circulating immunoglobulins, B lineage subsets, and lymphocyte subsets. Additionally, cluster gene set variation analysis showed dose regimen–dependent trends over time.

Conclusion

Felzartamab treatment-related gene expression changes detected by whole blood RNAseq are functionally enriched for CD38+ cell types, including immunoglobulin and IgA-related genes, supporting targeting and reduction of plasma cells in IgAN. These results validate the use of this dataset for further analyses to understand the mechanism of action of felzartamab and to further characterize felzartamab treatment response in patients with IgAN.

This abstract was also submitted for ASN Kidney Week 2025 congress.

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