Safety, Tolerability and Efficacy of Narsoplimab, a Novel MASP-2 Inhibitor for the Treatment of IgA Nephropathy

Abstract

Introduction: Narsoplimab is a human monoclonal antibody against mannan-associated lectin-binding serine protease-2 (MASP-2). Now in a phase 3 study, narsoplimab was evaluated in a staged phase 2 study assessing safety and effectiveness in high-risk patients with IgA nephropathy (IgAN).

Methods: Substudy 1 was a single-arm open-label study of 12 weekly infusions and tapered corticosteroids, with 6 weeks of follow-up. In substudy 2, patients were randomized 1:1 to receive a course of treatment consisting of once-weekly narsoplimab or vehicle infusions for 12 weeks. After 6 weeks of follow-up, both substudy 2 groups could continue in an open-label extension, receiving 1 or more narsoplimab courses at the investigator's discretion.

Results: The most commonly reported adverse events (AEs) included headache, upper respiratory infection, and fatigue. Most AEs were mild or moderate and transient. No treatment-related serious AEs were reported. All 4 patients who were enrolled in substudy 1 had reductions in 24-hour urine protein excretion (UPE) at week 18, ranging from 54% to 95% compared with baseline. In substudy 2, the vehicle and narsoplimab groups had similar proteinuria reductions at week 18. Eight patients (3 vehicle, 5 narsoplimab) continued in the dosing extension; all received narsoplimab. Median reduction in 24-hour UPE in these 8 patients was 61.4% at 31 to 54 weeks postbaseline. Estimated glomerular filtration rates (eGFR) remained stable in both substudies.

Conclusion: This interim analysis suggests that narsoplimab treatment is safe, is well tolerated, and may result in clinically meaningful reductions in proteinuria and stability of eGFR in high-risk patients with advanced IgAN.

Keywords: IgA nephropathy; MASP-2; complement system; lectin pathway; mannan-associated lectin-binding serine protease-2; narsoplimab.

Graphical abstract

Figure 1

Overall study designs for (a) substudy 1 and (b) substudy 2. UPE, urine protein excretion.

Figure 2

Twenty-four-hour urine protein excretion (UPE) at baseline and last follow-up visit in substudy 1. The percent reductions in 24-hour UPE were 54% for patient 1, 81% for patient 2, 63% for patient 3, and 95% for patient 4.

Figure 3

Estimated glomerular filtration rate (eGFR) over time for individual patients in substudy 1 from screening through week 18. CKD-EPI, Chronic Kidney Disease Epidemiology Collaboration.

Figure 4

Consolidated Standards of Reporting Trials (CONSORT) diagram for substudy 2. eGFR, estimated glomerular filtration rate; RAS, renin−angiotensin system; UPE, urine protein excretion.

Figure 5

Twenty-four-hour urine protein excretion (UPE) at baseline through last available follow-up visit for evaluable patients in substudy 2. Dashed lines represent patients who were initially randomized to vehicle; solid lines represent patients who were initially randomized to narsoplimab. By week 18 of follow-up, the median reduction in proteinuria was 18% and 18.4% for the vehicle- and narsoplimab-treated patients, respectively. All patients entering the dosing extension period beyond week 18 received narsoplimab. The median reduction in proteinuria was 61.4% at weeks 31 to 54 for patients in the dosing extension.

Figure 6

Estimated glomerular filtration rate (eGFR) over time for individual evaluable patients in substudy 2 from screening through last measurement during the ongoing dosing extension. Dashed lines represent patients who were initially randomized to vehicle; solid lines represent patients who were initially randomized to narsoplimab.