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Orelabrutinib for systemic lupus erythematosus: A randomised, double-blind, placebo-controlled study
Ru Li1, Xue Li1, Xiaoxia Zhu2
1Department of Rheumatology & Immunology, Peking University People's Hospital, Beijing, China.
Objectives:
Orelabrutinib is an oral, highly selective, irreversible inhibitor of Bruton's tyrosine kinase (BTK). Preclinical mechanistic studies have demonstrated its therapeutic potential in systemic lupus erythematosus (SLE).
Methods:
A multicentre, double-blind, randomised, placebo-controlled, parallel-group, phase Ib/IIa study was conducted in 11 centres in China. Patients diagnosed with SLE were randomised 1:1:1:1 to receive oral orelabrutinib at 50 mg, 80 mg, and 100 mg or placebo once daily for 12 weeks, respectively. This trial is registered with ClinicalTrials.gov, NCT04305197.
Results:
Between July 9, 2020 and September 29, 2021, 60 patients were randomised, with 55 patients who completed 12 weeks of treatment. Adverse events (AEs) were mostly mild or moderate. In all evaluable patients, the SLE Response Index (SRI)-4 rates at week 12 were 50%, 62%, and 64% for orelabrutinib at 50 mg, 80 mg, and 100 mg, respectively, compared with 36% for placebo, indicating dose-dependent improvement. Among patients with baseline SLEDAI-2K > 8, significantly higher SRI-4 responses were noted with orelabrutinib at 50 mg (80%, p = 0·048), 80 mg (83%, p = 0·048), and 100 mg (100%, p = 0·029) compared to placebo (0%). SRI-6 responses at week 12 were 36%, 39%, and 21% for orelabrutinib at 50 mg, 80 mg, and 100 mg, respectively, compared with 7% for placebo. Reduced proteinuria, anti-dsDNA, IgG, and IgM and increased C4 were observed with orelabrutinib treatment.
Conclusions:
Orelabrutinib was well tolerated and potentially efficacious in patients with SLE.
Insights
Orelabrutinib shows promise in treating systemic lupus erythematosus (SLE). This phase Ib/IIa study found the oral Bruton
Area of Science:
- Immunology
- Rheumatology
- Pharmacology
Background:
- Orelabrutinib is an oral, selective, irreversible Bruton's tyrosine kinase (BTK) inhibitor.
- Preclinical studies suggest therapeutic potential for orelabrutinib in systemic lupus erythematosus (SLE).
- BTK signaling plays a crucial role in B-cell function and autoimmune responses relevant to SLE pathogenesis.
Purpose of the Study:
- To evaluate the safety, tolerability, and preliminary efficacy of orelabrutinib in patients with SLE.
- To determine the optimal dose of orelabrutinib for further clinical investigation in SLE.
- To assess the effect of orelabrutinib on clinical and biomarker endpoints in SLE patients.
Main Methods:
- A multicenter, double-blind, randomized, placebo-controlled, phase Ib/IIa study.
- 60 SLE patients randomized to receive oral orelabrutinib (50 mg, 80 mg, 100 mg) or placebo once daily for 12 weeks.
- Primary endpoints included safety and tolerability; secondary endpoints included SLE Response Index (SRI)-4 and SRI-6 scores, and biomarker changes.
Main Results:
- Orelabrutinib was generally well-tolerated with mild to moderate adverse events.
- SRI-4 response rates at week 12 were dose-dependent: 50% (50 mg), 62% (80 mg), 64% (100 mg) vs. 36% for placebo.
- Significant improvements in SRI-4 were observed in patients with severe SLE (SLEDAI-2K > 8) treated with orelabrutinib compared to placebo. Biomarker changes included reduced proteinuria, anti-dsDNA, IgG, IgM, and increased C4.
Conclusions:
- Orelabrutinib demonstrated a favorable safety profile and potential efficacy in SLE patients.
- The study supports further investigation of orelabrutinib as a treatment for systemic lupus erythematosus.
- Dose-dependent improvements in clinical response and relevant biomarkers were observed.
