A-319, a T-cell engager (TCE), is showing early promise in treating severe and refractory systemic lupus erythematosus (SLE). Data from a phase 1 trial (NCT06400537) presented at the American College of Rheumatology (ACR) Convergence 2024 indicate that A-319 led to improvements in patients with SLE and was well-tolerated, without evidence of cytokine release syndrome (CRS) or immune effector cell-associated neurotoxicity syndrome (ICANS).
The trial, led by Qiubai Li, MD, PhD, Chief, Department of Rheumatology and Immunology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, enrolled participants with moderate to severe refractory SLE. Participants received A-319 at 0.05μg/kg/day on days 1, 3, and 5 via 24-hour IV infusion in week 1, and 0.3μg/kg/day on days 1, 3, and 5 via 6-hour IV infusion in week 2.
Early Clinical Data
The data presented included six participants with Systemic Lupus Erythematosus Disease Activity Index 2000 (SLEDAI-2K) scores ranging from 8 to 16 at baseline. The median duration of severe/refractory SLE among these patients was 7.5 years (range, 0.5-10). One patient had severe SLE with lupus nephritis (LN) and encephalopathy, two had disease overlap with systemic sclerosis and rheumatoid arthritis, and five had concomitant LN.
Investigators reported that all participants experienced low-grade fevers related to A-319 during treatment, but no other drug-related adverse events, including CRS, ICANS, myelotoxicities, hypogammaglobulinemia, or infections, were observed.
Observed Immunological Responses
Researchers noted rapid CD19+ B cell depletion in peripheral blood during the first week. In one patient, CD19+ B cells recovered to over 10% of baseline at weeks 2 and 4, accompanied by a marked decrease in anti-nuclear antibodies (ANAs), anti-dsDNA, Sm, SSA, ribosomal P protein, chromatin, SCL-70, RNP 68, and other autoantibody levels by week 8. C4 and IgE levels normalized by Day 15, and C3 and urinary total protein levels normalized by week 8.
Clinical Improvement
SLEDAI-2K scores improved from 12 at baseline to 4 at week 8 in patient 1, 8 to 0 at week 2 in patient 2, and 16 to 4 at week 2 in patient 3. Disease Activity Score-28 scores improved from 5.83 at baseline to 1.96 at week 2 in patient 2, and SLE-related vasculitis improved in patient 3 by week 2.
Comparison with CAR-T Therapy
Li noted the potential advantages and disadvantages of both CAR-T and TCE therapies, suggesting that patients may eventually have two different cell therapy treatment options for SLE. Another early CAR-T trial is investigating MC-1-50 chimeric antigen receptor (CAR) T cells in pediatric SLE. Data from a phase 1/2 study presented during October’s American Society of Nephrology (ASN) Kidney Week 2024 showed that doses of the CD19-targeted CAR T-cells ranging from 0.3×10^5/kg cells to 3×10^5/kg cells resulted in grade 1 CRS in 9 participants (81.8%) and grade 1 ICANS in 2 participants (18.2%). In 5 participants with follow-up for over 3 months, 4 achieved Systemic Lupus Erythematosus Responder Index (SRI-4) responses.
