EFFICACY AND SAFETY OF TELITACICEPT IN PATIENTS WITH REFRACTORY PRIMARY MEMBRANOUS NEPHROPATHY AFTER ANTI-CD20 MONOCLONAL ANTIBODY THERAPY FAILURE: A SINGLE-ARM, OPEN-LABEL STUDY WITH DOSE-TAPERING REGIMEN

Primary membranous nephropathy (PMN) is a major cause of nephrotic syndrome in adults. Anti-CD20 monoclonal antibodies (e.g., rituximab) work for some patients with PMN, but many do not respond well to this treatment. Telitacicept is a new TACI-Fc fusion protein that blocks B-lymphocyte stimulator (BLyS) and a proliferation-inducing ligand (APRIL). It offers a different way to treat PMN by targeting specific B-cell pathways. This study focused on testing the effectiveness and safety of telitacicept using a dose-tapering method in patients with refractory PMN who did not respond to anti-CD20 therapy.

This was a prospective, single-center, open-label, single-arm clinical trial. Patients with PLA2R-positive PMN who did not respond well to anti-CD20 monoclonal antibody therapy were included. They were aged 18-70, had 24-hour urinary protein (UTP) ≥3.5g despite at least 3 months of optimized RAS blockade, and an eGFR ≥45mL/min/1.73m². Participants received subcutaneous injections of telitacicept using a dose-tapering regimen. First, they got 240 mg weekly for 8 weeks (induction phase). Then, they received 160 mg weekly for 8 weeks, followed by 160 mg every 10 days for 8 weeks. After that, they got 80 mg weekly for 8 weeks, 80 mg every 10 days for 8 weeks, 80 mg every 15 days for 8 weeks, and finally 80 mg monthly as maintenance therapy. The primary endpoint was the change in 24-hour proteinuria at week 48. Complete remission was defined as UTP <0.5g/24h, and partial remission as UTP between 0.5-3.5g/24h or a ≥50% reduction from baseline. Secondary endpoints included changes in eGFR, serum albumin, hemoglobin, and immunoglobulin levels.

This interim analysis included 12 patients with refractory PMN. Treatment with telitacicept showed strong and ongoing effectiveness across multiple measures. 24-hour urinary protein (UTP) dropped steadily from baseline (around 11 g/L) to 3 g/L at week 48, with significant reductions starting at week 16 (p<0.05). The decrease in proteinuria was especially notable after week 20, showing lasting benefits during the dose-tapering phase.

Serum albumin levels improved gradually from baseline (around 32 g/L) to 42.5 g/L at week 48, with significant increases starting at week 20 (p<0.05). This improvement shows that protein balance was restored and nephrotic syndrome symptoms were resolved.

Kidney function, measured by eGFR, improved from baseline (around 68 mL/min/1.73m²) to 82.5 mL/min/1.73m² at week 48, with significant improvements at weeks 32 and 48 (p<0.05). This indicates not only that the disease was stabilized but also that kidney function recovered.

Serum IgG levels showed a two-phase pattern: they stayed stable from baseline (around 5.5 g/L) through week 24 (around 5.0 g/L), then increased significantly to around 10 g/L at week 48 (p<0.05 at weeks 32 and 48). This pattern suggests a complex immune regulatory effect rather than simple suppression, with the dose-tapering regimen possibly allowing immune recovery while keeping the disease under control.

Telitacicept was well-tolerated. All reported side effects (AEs) were mild (CTCAE Grade 1), with no Grade 2 or higher AEs, serious AEs, or AEs leading to study withdrawal or dose changes. Two AEs were reported: one case of abdominal pain and vomiting (not linked to the study drug) and one case of itching that went away without medication. No opportunistic infections or severe low immunoglobulin levels were seen, even with the long treatment period.

In this study, telitacicept with a dose-tapering regimen showed strong and ongoing effectiveness in reducing proteinuria, improving kidney function, and normalizing serum albumin levels in patients with refractory primary membranous nephropathy who did not respond to anti-CD20 monoclonal antibody therapy. The treatment had a favorable safety profile, and the unique biphasic pattern of immunoglobulin modulation—first staying stable and then increasing significantly—suggests a complex immune regulatory mechanism. This mechanism allows for disease control while maintaining and potentially boosting immune function. The dose-tapering strategy seems to balance efficacy and safety well for long-term management, possibly supporting immune recovery during the maintenance phase. These results indicate that telitacicept is a promising treatment for refractory PMN, offering hope for patients who do not benefit from standard anti-CD20 therapy, and justify further research in larger randomized controlled trials.