FELZARTAMAB DURABLY REDUCES DISEASE RELEVANT BIOMARKERS THROUGH TARGETING OF CD38+ PLASMA CELLS AND PLASMABLASTS, THE UPSTREAM DRIVERS OF IGA NEPHROPATHY (IGAN)

Introduction:

IgAN is driven by antibody secreting cell (ASC) production of galactose-deficient IgA1 (Gd-IgA1) and anti-Gd-IgA1 autoantibodies resulting in immune complex deposition-induced kidney damage. Felzartamab (felza) is a fully human anti-CD38 mAb that directly depletes CD38+ ASCs, the upstream cellular mediators of disease. In a placebo-controlled IgAN Ph2 trial (NCT05065970, IgNAZ), felza resulted in clinically meaningful prolonged UPCR reductions and eGFR stabilization. Here, we evaluate disease relevant biomarkers to understand molecular mechanisms of felza efficacy and durability in IgAN. 

Methods:

Whole-blood and serum from IgNAZ subjects were collected at baseline, on treatment, and during follow-up of a 2-year study. Samples were assessed for immune cells (flow cytometry), polyclonal immunoglobulins (turbidometry), and Gd-IgA1 (ECLIA). 

Results:

Felza induced rapid and durable depletion of Gd-IgA1 and total IgA. Patients who received 9 doses over a 5-month period maintained Gd-IgA1 reduction for at least 15 months after the first dose. Similar reductions in IgA were observed for 24 months after treatment start. IgG reduction was modest (< 20%) and rebounded to baseline by 12M. Circulating plasmablasts decreased on-treatment in felza arms versus placebo. Treatment did not impact early or memory B cell subsets or survival factors. Immunomodulation of other CD38+ cell types was observed.

Conclusions:

Felza targets and depletes the upstream cellular drivers of IgAN resulting in rapid reduction of major disease related biomarkers. Effects are maintained off-treatment while also preserving humoral immunity. These observations are consistent with other indications, supporting the disease modifying potential of felza in immune mediated diseases. 

This abstract was also submitted for ASN Kidney Week 2024 congress. 

I have potential conflict of interest to disclose.
I am an employee and shareholder of Human Immunology Biosciences, Inc, a Biogen company

I did not use generative AI and AI-assisted technologies in the writing process.