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Clinical Trial
. 2023 Dec;75(12):2185-2194.
doi: 10.1002/art.42652.

Obexelimab in Systemic Lupus Erythematosus With Exploration of Response Based on Gene Pathway Co-Expression Patterns: A Double-Blind, Randomized, Placebo-Controlled, Phase 2 Trial

Joan T Merrill  1 , Joel Guthridge  1 , Miles Smith  1 , Joshua June  2 , Fotios Koumpouras  3 , Wambui Machua  4 , Anca Askanase  5 , Arezou Khosroshahi  6 , Saira Z Sheikh  7 , Gaurav Rathi  8 , Bart Burington  8 , Paul Foster  8 , Mark Matijevic  9 , Sujata Arora  9 , Xiaodong Wang  9 , Minggeng Gao  9 , Stephen Wax  9 , Judith A James  1 , Debra J Zack  8
Affiliations
Clinical Trial

Obexelimab in Systemic Lupus Erythematosus With Exploration of Response Based on Gene Pathway Co-Expression Patterns: A Double-Blind, Randomized, Placebo-Controlled, Phase 2 Trial

Joan T Merrill et al. Arthritis Rheumatol. 2023 Dec.

Abstract

Objective: Obexelimab is an investigational, bifunctional, noncytolytic monoclonal antibody that binds CD19 and FcyRIIb to inhibit B cells, plasmablasts, and plasma cells. This trial evaluated the efficacy and safety of obexelimab in the treatment of patients with systemic lupus erythematosus (SLE).

Methods: During screening, patients with active, non-organ-threatening SLE received corticosteroid injections to ameliorate symptoms while immunosuppressants were withdrawn (≤10 mg/day prednisone equivalent and ≤400 mg/day hydroxychloroquine allowed). Patients with improved disease activity were randomized 1:1 to obexelimab 5 mg/kg intravenously or placebo once every 2 weeks until week 32 or loss of improvement (LOI).

Results: In this study, 104 patients were randomized. Analysis of the primary endpoint, proportion of patients reaching week 32 without LOI, used an efficacy-evaluable (EE) population defined as patients who completed the study or withdrew for flare or treatment-related toxicity. This endpoint did not reach statistical significance: 21 of 50 obexelimab-treated patients (42.0%) versus 12 of 42 patients (28.6%) treated with a placebo (P = 0.183). Time to LOI was increased in obexelimab-treated patients versus patients treated with a placebo in the EE (hazard ratio [HR] 0.53, P = 0.025) and intention-to-treat (HR 0.59, P = 0.062) populations. In obexelimab-treated patients, B cells decreased approximately 50%, and trough concentration and inclusion in baseline gene expression clusters with high B cell pathway modules were associated with increased time to LOI. Obexelimab was associated with infusion reactions but was generally safe and well-tolerated.

Conclusion: Although the primary endpoint was not reached, secondary analysis showed time to LOI was significantly increased in obexelimab-treated patients, and analysis of patient subsets defined by gene expression patterns at baseline suggests a responding subpopulation.

Trial registration: ClinicalTrials.gov NCT02725515.

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References

REFERENCES

    1. Merrill JT. Connective tissue diseases: is SLE many single-organ diseases or an overlapping spectrum? Nat Rev Rheumatol 2015;11:385-386.
    1. Kim M, Merrill J, Kalunian K et al. Brief report: longitudinal patterns of response to standard of care for systemic lupus erythematosus: implications for clinical trial design. Arthritis Rheumatol 2017;69:785-790.
    1. Mok CC. Therapeutic monitoring of the immuno-modulating drugs in systemic lupus erythematosus. Expert Rev Clin Immunol 2017;13:35-41.
    1. Thanou A, Merrill JT. Treatment of systemic lupus erythematosus: new therapeutic avenues and blind alleys. Nat Rev Rheumatol 2014;10:23-34.
    1. Fleischer SJ, Daridon C, Fleischer V et al. Enhanced tyrosine phosphatase activity underlies dysregulated B cell receptor signaling and promotes survival of human lupus B cells. Arthritis Rheumatol 2016;68:1210-1221.

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