B-CELL–TARGETED THERAPY FOR IDIOPATHIC NEPHROTIC SYNDROME: RESULTS OF THE PHASE III, GLOBAL, MULTICENTER INSHORE TRIAL ASSESSING OBINUTUZUMAB VS MYCOPHENOLATE MOFETIL

Idiopathic nephrotic syndrome (INS) is the most common childhood glomerular disease worldwide. B-cell–depleting monoclonal antibodies have been used for steroid minimization in frequently relapsing nephrotic syndrome (FRNS) or steroid-dependent nephrotic syndrome (SDNS); their efficacy supports a pathogenic role for B cells. The Phase III, randomized, open-label INShore trial (NCT05627557) compared obinutuzumab (OBI), a humanized type II anti-CD20 antibody with mycophenolate mofetil (MMF) in patients (pts) with INS.  

Pts aged 2-25 years with FRNS/SDNS in complete remission (CR: absence of edema; urine protein-to-creatinine ratio [UPCR] ≤0.2 g/g) were randomized (1:1) to OBI (1000 mg or 20 mg/kg if pts <45 kg) on Days 1, 15, 168 (Week [W] 24) and 182 (W26) or MMF (1200 mg/m^2/day; max 2 g/day) for 52 weeks, followed by a 3-month taper. Ongoing glucocorticoids at randomization were tapered (Fig 1). Primary endpoint was sustained CR at 1 year (first morning void [FMV] UPCR ≤0.2 g/g at W52, without relapse or intercurrent event). Ranked key secondary efficacy outcomes included relapse-free survival (RFS), cumulative glucocorticoid dose, number of relapses and sustained CR at W76. The RFS endpoint included events occurring in pts until the clinical cutoff date. Relapse (FMV UPCR ≥2 g/g or dipstick urinalysis protein ≥3+ for 3 consecutive days with most recent UPCR >0.2 g/g or dipstick urinalysis protein ≥3+ on any single day with edema and UPCR >0.2 g/g) was confirmed by a central laboratory.

Pts (N=85; OBI n=44; MMF n=41) were enrolled across 32 sites in 9 countries: 64.7% male; 63.5% <12 years old; 46 months median disease duration; 75.3% had prior non-steroid immunosuppressive therapy; 84.7% receiving glucocorticoids at baseline (BL). One pt (2.3%) receiving OBI and 9 (22.0%) receiving MMF discontinued treatment before W52. The primary and first 3 ranked secondary endpoints were statistically significant and clinically meaningful in favor of OBI. At W52, 95.5% of pts receiving OBI achieved sustained CR vs 73.2% receiving MMF (adjusted difference [AD] 23.36%; P=0.0031). Pts receiving OBI had improved overall RFS (75% reduction in risk of relapse or death; hazard ratio 0.25; P=0.0074; Fig 2), lower cumulative glucocorticoid dose (weight-adjusted median difference −8.86 mg/kg; P=0.0391), fewer relapses from BL to W52 (4 vs 23; adjusted rate ratio 0.07; P=0.0015), and a numerically higher proportion of pts achieved sustained CR at W76 (AD 20.67%; P=0.1399). More pts had adverse events (AEs) in the OBI vs MMF arm (95.5% vs 82.9%; Grade ≥3: 25.0% vs 7.3%, respectively). The most common AEs were infusion-related reactions (IRRs; 36.4% OBI) and upper respiratory tract infection (36.6% MMF vs 29.5% OBI). One pt in each arm discontinued study treatment due to an AE. No new safety signals were seen for OBI or MMF. 

OBI was superior to MMF in achieving sustained CR at 1 year in childhood-onset INS. OBI showed statistically significant and clinically meaningful key secondary endpoints, including overall RFS and reduced glucocorticoid use, with no new safety signals. These encouraging results from the INShore trial suggest OBI as a potential B-cell–targeted intervention in INS.