Phase 1b/2a Study Assessing the Safety and Efficacy of Felzartamab in Anti-Phospholipase A2 Receptor Autoantibody-Positive Primary Membranous Nephropathy

Abstract

Introduction: Primary membranous nephropathy (PMN) is most often caused by autoantibodies to phospholipase A2 receptor (PLA2R). M-PLACE (NCT04145440) is an open-label, phase 1b/2a study that assessed the safety and efficacy of the fully human anti-CD38 monoclonal antibody felzartamab in high-risk anti-PLA2R+ PMN.

Methods: Patients with newly diagnosed or relapsed PMN (cohort 1 [C1]; n = 18) or PMN refractory to immunosuppressive therapy (IST) (cohort 2 [C2]; n = 13) received 9 infusions of felzartamab 16 mg/kg in the 24-week treatment period, followed by a 28-week follow-up. The primary end point was the incidence and severity of treatment-emergent adverse events (TEAEs).

Results: A total of 31 patients were enrolled and received felzartamab. Twenty-seven patients (87.1%) had TEAEs, including infusion-related reactions (IRRs) (29.0%), hypogammaglobulinemia (25.8%), peripheral edema (19.4%), and nausea (16.1%). Five patients (16.1%) had serious TEAEs that all resolved. Immunologic response (anti-PLA2R titer reduction ≥50%) was achieved by 20 of 26 efficacy-evaluable patients (76.9%) (C1, 13/15 [86.7%]; C2, 7/11 [63.6%]). Anti-PLA2R titer reductions were rapid (week 1 response, 44.0%; response 7 months after last felzartamab dose [end of study, EOS], 53.8%). Partial proteinuria remission (urine protein-to-creatinine ratio [UPCR] reduction ≥50%, UPCR <3.0 g/g, and stable estimated glomerular filtration rate [eGFR]) was achieved by 9 of 26 patients (34.6%) (C1, 7/15 [46.7%]; C2, 2/11 [18.2%]) before or at EOS (median follow-up, 366 days). Serum albumin increased from baseline to EOS in 20 of 26 patients (76.9%) (C1, 12/15 [80.0%]; C2, 8/11 [72.7%]).

Conclusion: In this population with high-risk anti-PLA2R+ PMN, felzartamab was tolerated and resulted in rapid partial and complete immunologic responses and partial improvements in proteinuria and serum albumin in some patients.

Keywords: MOR202; clinical trial; felzartamab; phase 2; phospholipase A2 receptor; primary membranous nephropathy.

Graphical abstract

Figure 1

Median (± IQR) change from baseline to EOS in IgG. EOS, end of study; IQR, interquartile range. Dashed lines indicate the median baseline levels for each cohort (cohort 1, purple; cohort 2, teal). Arrows indicate felzartamab infusions.

Figure 2

Change in anti-PLA2R titer. (a) Percentage change from baseline to week 1 in anti-PLA2R titer in cohorts 1 and 2. (b) Percentage change from baseline to EOT in anti-PLA2R titer in cohorts 1 and 2. (c) Percentage change from baseline to EOS in anti-PLA2R titer in cohorts 1 and 2. (d) Percentage change from baseline to EOT, month 9, and EOS in each patient who was a responder at EOT. Data in all panels are based on the EAS. For EOS evaluations, the median (range) day of last follow-up was 364 (141–393) days. EAS, efficacy analysis set; EOS, end of study; EOT, end of treatment; ICR, immunologic complete response; IPR, immunologic partial response; PLA2R, phospholipase A2 receptor; mo, months. Horizontal dotted lines indicate threshold for IPR (≥50% reduction from baseline in anti-PLA2R titer). ^aICR at the specified time point.

Figure 3

Change in albumin and 24-hour UPCR. (a and b) Comparison of median (± IQR) percentage change from baseline in 24-hour UPCR and serum albumin with median (± IQR) percentage change from baseline in anti-PLA2R titer in cohorts 1 and 2. (c) Percentage change from baseline to EOS in 24-hour UPCR in cohorts 1 and 2. The horizontal dotted line indicates threshold for proteinuria partial response (≥50% reduction from baseline in 24-hour UPCR). (d) Percentage change from baseline to EOS in serum albumin in cohorts 1 and 2. Data in all panels are based on the EAS. For EOS evaluations, the median (range) day of last visit was 364 (141–393) days for albumin and 363.5 (175–432) days for UPCR. Arrows indicate felzartamab infusions. EAS, efficacy analysis set; EOS, end of study; IQR, interquartile range; PLA2R, phospholipase A2 receptor; UPCR, urine protein-to-creatinine ratio.

Figure 4

Change from baseline in health-related quality of life per KDQOL-36. (a) Change from baseline in burden of kidney disease score, (b) effects of kidney disease on daily life score, (c) symptoms/problems score, (d) physical component score, and (e) mental component score. Horizontal white lines represent the medians. Box ends represent the interquartile ranges. Vertical lines represent the ranges. Dots represent individual patients. EOS, end of study; EOT, end of treatment; KDQOL-36, Kidney Disease Quality of Life 36 Survey.