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Background Orelabrutinib is an oral, highly-selective, irreversible inhibitor of Bruton’s tyrosine kinase (BTK). Orelabrutinib has been approved for the treatment of B cell malignancies in China. Two distinct lupus animal models showed significant efficacy of orelabrutinib in reducing disease activity, which supported the clinical development of orelabrutinib in Systemic Lupus Erythematosus (SLE).

Objectives This phase Ib/IIa, randomized, double-blind, placebo-controlled, dose-finding study aimed to evaluate the safety, tolerability, pharmacokinetics (PK), pharmacodynamics (PD), preliminary efficacy and biomarkers of orelabrutinib in patients with mild to moderate SLE who received standard of care (SoC) therapy.

Methods Patients diagnosed with SLE by the ACR classification criteria for ≥ 6 months, who had a SLEDAI-2K score ≥5 at screening, and were autoantibody-positive, were randomized 1:1:1:1 to receive oral orelabrutinib at 50mg, 80mg, 100mg or placebo once daily for 12 weeks, respectively.

Results This study randomized 60 patients with 55 patients who completed 12-week treatment. Age at baseline was 33.7±9.8 years and 96.7% were female. Baseline disease characteristics were generally balanced across treatment groups. Adverse events (AEs) were reported in 80%, 93.3% and 100% of orelabrutinib treated patients at doses of 50mg, 80mg and 100mg QD respectively versus 85.5% in placebo group. AEs were mostly mild or moderate. Treatment-related SAEs were reported in 3 patients treated with orelabrutinib, only 1 of which was grade 3. No deaths were reported. The plasma exposure of orelabrutinib (AUC and Cmax) was proportionally increased with doses. Nearly complete BTK occupancy was achieved at all dose levels, and the occupancy lasted for 24 hours without any decrease compared to that at 4 hour post-dosing. In all evaluable patients, the SLE Response Index (SRI)-4 response rates at week 12 were 50.0%, 61.5% and 64.3% in patients treated with orelabrutinib at 50mg (n=14), 80mg (n=13) and 100mg (n=14) respectively, compared with 35.7% in patients treated with placebo (n=14), which indicated the trend of dose-dependent improvement. Among the subgroup of patients with SLEDAI-2K≥8 at screening, SRI-4 response occurred in 70%, 70% and 66.7% of patients treated with orelabrutinib at 50mg (n=10), 80mg (n=10) and 100mg (n=9), respectively, compared with 30% who received placebo (n=10). Trends of reduced proteinuria, anti-dsDNA and IgG, total B cells and increased complements C4 were also observed following orelabrutinib treatment.

Conclusion Orelabrutinib was generally safe and well tolerated in patients with SLE. Preliminary results also suggested encouraging efficacy which supports further development of orelabrutinib in larger and longer trials for SLE.

Table 1.

Efficacy results at week 12.

Figure 1.

SRI-4 response rates at week 12.

Disclosure of Interests Ru Li: None declared, Xiaoxia Zhu: None declared, Shengyun Liu: None declared, Xiao Zhang: None declared, Changhao Xie: None declared, Zili Fu: None declared, Anbin Huang: None declared, Lingyun Sun: None declared, Dongzhou Liu: None declared, Jinxia Zhao: None declared, Lin Wu: None declared, Zhoushuai Qin Employee of: InnoCare Pharma Limited., Sichen Li Employee of: InnoCare pharma Limited., Yaorong Liu Employee of: InnoCare pharma Limited., Zhanguo Li: None declared

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