Kidney Week

Abstract: FR-OR69

Felzartamab Durably Reduces Disease-Relevant Biomarkers through Targeting of CD38+ Plasma Cells and Plasmablasts, the Upstream Drivers of IgAN

Session Information

• Innovative AKI Strategies and Drug Discoveries
  October 25, 2024 | Location: Room 7, Convention Center
  Abstract Time: 05:20 PM - 05:30 PM

Category: Pharmacology (PharmacoKinetics, -Dynamics, -Genomics)

• 2000 Pharmacology (PharmacoKinetics, -Dynamics, -Genomics)

Authors

• Barratt, Jonathan, University of Leicester, Leicester, United Kingdom

Jonathan Barratt, MBChB, PhD

• Shah, Millie, Human Immunology Biosciences Inc, South San Francisco, California, United States

Millie Shah, PhD

• Kivman, Lisa, Human Immunology Biosciences Inc, South San Francisco, California, United States

Lisa Kivman

• Kräft, Tabea, MorphoSys AG, Planegg, Bayern, Germany

Tabea Kräft, PhD

• Rauser, Julia, MorphoSys AG, Planegg, Bayern, Germany

Julia Rauser, PhD

• Boxhammer, Rainer, MorphoSys AG, Planegg, Bayern, Germany

Rainer Boxhammer

• Haertle, Stefan, MorphoSys AG, Planegg, Bayern, Germany

Stefan Haertle, PhD, DVM

• Schwartz, Brian M., Human Immunology Biosciences Inc, South San Francisco, California, United States

Brian M. Schwartz, MD

• Manser, Paul, Human Immunology Biosciences Inc, South San Francisco, California, United States

Paul Manser, PhD

• Chinn, Leslie, Human Immunology Biosciences Inc, South San Francisco, California, United States

Leslie Chinn

• Patel, Uptal D., Human Immunology Biosciences Inc, South San Francisco, California, United States

Uptal D. Patel, MD

• Flesher, Donna, Human Immunology Biosciences Inc, South San Francisco, California, United States

Donna Flesher, PhD

• Kiryluk, Krzysztof, Columbia University, New York, New York, United States

Krzysztof Kiryluk, MD

Background

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.

Conclusion

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.

Funding

• Commercial Support – Human Immunology Biosciences, Inc