A-319 in active SLE: Phase I trial results

Results from an open-label, dose-escalation, phase I trial (NCT06400537) evaluating A-319, a CD3 × CD19 bispecific antibody T-cell engager, in 12 patients with systemic lupus erythematosus (SLE) were published in Nature Medicine by Xu et al. Patients were assigned to receive A-319 0.3 μg/kg (Cohort 1; n = 6), 0.6 μg/kg (Cohort 2; n = 3), or 1.2 μg/kg (Cohort 3; n = 3). The primary endpoint was safety and tolerability, assessed by adverse events (AEs) and dose-limiting toxicities (DLTs). 

Key data: Overall, 4 serious adverse events (SAEs) were reported, including Grade 3 pruritic rash, a lymphatic fistula, disease flare requiring hospitalization, and nephrolithiasis; none were considered related to A-319 exposure. No deaths, immune effector cell-associated neurotoxicity syndrome (ICANS), or immune effector cell-associated hemophagocytic lymphohistiocytosis-like syndromes (IEC-HS) occurred. Grade 1 and 2 cytokine release syndrome (CRS) were reported in 11 patients and 1 patient, respectively; no Grade ≥3 CRS events were reported. Grade ≥3 lymphopenia was reported in all patients during treatment. B-cell recovery kinetics were dose-dependent, with reconstruction beginning at Week 6 in Cohort 1 and depletion remaining through Month 3 in Cohorts 2 and 3. Infections occurred in 58.3% of patients and were predominantly low-grade. At Month 12, mean Systemic Lupus Erythematosus Disease Activity Index-2000 (SLEDAI-2K) declined from 13.1 at baseline to 1.7, daily glucocorticoid dose was reduced by 67%, 8 patients achieved Lupus Low Disease Activity State (LLDAS; n = 10), and 6 patients achieved Definition of Remission in SLE (DORIS; n = 10). 

Key learning: In a phase I trial, A-319 demonstrated safety, feasibility, and preliminary efficacy in patients with active SLE, supporting further investigation in randomized controlled trials with longer follow-up.