Orelabrutinib, an irreversible inhibitor of Bruton’s tyrosine kinase, for the treatment of systemic lupus erythematosus: a randomised, double-blind, placebo-controlled, phase Ib/IIa study

Orelabrutinib, an irreversible inhibitor of Bruton’s tyrosine kinase, for the treatment of systemic lupus erythematosus: a randomised, double-blind, placebo-controlled, phase Ib/IIa study | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Article Orelabrutinib, an irreversible inhibitor of Bruton’s tyrosine kinase, for the treatment of systemic lupus erythematosus: a randomised, double-blind, placebo-controlled, phase Ib/IIa study Xue Li, Ru Li, Xiaoxia Zhu, Shengyun Liu, Xiao Zhang, Changhao Xie, and 6 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-7058001/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract Orelabrutinib is a highly selective, irreversible inhibitor of Bruton’s tyrosine kinase (BTK). It has shown promising results in animal models, indicating potential for treating systemic lupus erythematosus (SLE). A multicentre, double-blind, randomised, placebo-controlled, phase Ib/IIa trial (NCT04305197) was conducted. Sixty SLE patients were randomised 1:1:1:1 to receive oral orelabrutinib (50, 80, 100 mg) or placebo once daily for 12 weeks. A total of 55 patients completed the trial. In all evaluable patients, the 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. 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%). Adverse events were mostly mild or moderate in the study. In summary, orelabrutinib was effective and well-tolerated in SLE patients. Health sciences/Rheumatology/Rheumatic diseases/Systemic lupus erythematosus Biological sciences/Immunology/Immunotherapy/Immunosuppression Figures Figure 1 Introduction Systemic lupus erythematosus (SLE) is a systemic autoimmune disease characterized by inflammation and immune-mediated injury affecting multiple organs, including the skin, joints, and kidneys. 1–3 Standard-of-care (SoC) therapies for SLE encompass immunosuppressants/ immunomodulators, antimalarials, corticosteroids, and nonsteroidal anti-inflammatory drugs. 4 Despite these therapeutic options, there are unmet needs in the treatment of SLE, particularly for patients who do not respond to SoC. 5 B cell hyperactivity leading to autoantibody formation is a well-known mechanism associated with SLE. 6- 8 Consequently, targeting B cells represents a potential treatment approach due to their pivotal role in disease pathogenesis through the development of autoreactive B cells. 9 Bruton’s tyrosine kinase (BTK) plays an important role in B cell signalling upon antigen binding to the B cell receptor (BCR), as well as in B cell development and activation processes. 10,11 Overexpression of BTK can result in abnormal activation of B cells and contribute to autoimmune disorders. 1 2 Therefore, BTK is implicated in B cell signalling pathways that are potentially crucial for the pathogenesis of SLE. Orelabrutinib is an oral, irreversible BTK inhibitor with high potency and exceptional kinase selectivity for BTK. In a kinase screening assay against a panel of 456 kinases, orelabrutinib at a concentration of 1 μM inhibited only BTK to significant levels > 90%, with minimal off-target binding to other tyrosine kinases. In addition, orelabrutinib at doses of ≥ 50 mg/day exhibited high BTK target occupancy maintained at nearly 100% over 24 hours in healthy subjects. 1 3 Moreover, orelabrutinib has demonstrated potent inhibitory effects on human primary B cell proliferation and activation in peripheral blood mononuclear cells (PBMCs). In a six-month study utilizing the MRL/lpr spontaneous SLE mouse model, orelabrutinib exhibited notable anti-inflammatory properties by significantly improving survival rates and kidney function in treated animals. Similarly, in the pristane-induced SLE mouse model, orelabrutinib showed dose-dependent efficacy in inhibiting lupus-related arthritis and improving kidney function (data not shown). Here, we report the findings of a randomised, double-blind, placebo-controlled, phase Ib/IIa clinical trial which evaluated the efficacy and safety of once daily oral orelabrutinib at 50 mg, 80 mg, or 100 mg in the treatment of patients with active SLE receiving SoC treatment. Methods Study design This study was a multicentre, double-blind, randomised, placebo-controlled, parallel-group, phase Ib/IIa clinical study of orelabrutinib 50 mg, 80 mg, or 100 mg versus placebo in patients with active SLE receiving standard therapy over 12 weeks (Figure S1). The trial was conducted across 11 centres in China. The study was done in accordance with the ethical principles of the Declaration of Helsinki and Good Clinical Practice guidelines. All participating sites obtained approval from the appropriate authorized institutional review board or ethics committee. Participants Eligible patients included individuals aged 18 to 75 years who had a confirmed clinical diagnosis of SLE for at least six months prior to screening by fulfilling at least four out of the 11 revised American College of Rheumatology 1997 criteria for the classification of SLE; at baseline, patients were required to have active disease evidenced by a Systemic Lupus Erythematosus Disease Activity Index 2000 (SLEDAI-2K) score ranging from 5 to 12 and to test positive for at least one of the following antibodies: antinuclear antibody (ANA), anti-dsDNA, or anti-Smith. Patients were excluded if they had severe active lupus nephritis, severe active central nervous system lupus, recent clinically serious infection, and selected laboratory abnormalities. A comprehensive list of inclusion and exclusion criteria can be found in the Supplementary (pages 4-6). All patients provided written informed consent. Randomisation and masking Participants who met all criteria for enrolment were randomised 1:1:1:1 to receive oral orelabrutinib at 50 mg, 80 mg, and 100 mg or placebo once daily (QD) for 12 weeks, respectively. A randomisation table was generated by an unblinded statistician independent of the study, and an interactive website response system (IWRS) was used for randomisation. Orelabrutinib and placebo were packaged uniformly to have identical appearances to maintain masking. Patients, investigators, and anyone involved in patient evaluation and trial implementation were masked to group assignment. Procedures Participants maintained their usual SoC for SLE during the study and had been treated for at least three months before screening. The SoC treatment included corticosteroids (stable dose of 40 mg or less per day of prednisone or equivalent), and/or antimalarials, and/or immunosuppressants (such as azathioprine, methotrexate, mycophenolate mofetil, sodium mycophenolate, cyclosporine, leflunomide, tacrolimus, sirolimus, mizoribine, 6-mercaptopurine, iguratimod, or thalidomide). All patients were monitored during the treatment period (for a period of 12 weeks), and the 28-day follow-up visit was completed after the treatment period. Outcomes The primary outcome was safety and tolerability as measured by treatment-emergent adverse events (TEAEs), treatment-related adverse events (TRAEs), serious adverse events (SAEs), vital signs, electrocardiogram (ECG), and laboratory findings. The second endpoint was the proportion of patients achieving a Systemic Lupus Erythematosus Responder Index-4 (SRI-4) response and SRI-6 response at week 8 or 12. SRI-4/6 response is defined as a reduction of at least 4 or 6 points from baseline in SLEDAI-2K score, no worsening in British Isles Lupus Assessment Group (BILAG) A or B disease activity scores (no new BILAG A score or no more than one new BILAG B score), and no worsening (defined as an increase of ≥ 0·3 points [10 mm] from baseline) in the Physician’s Global Assessment of Disease Activity (PGA). Other secondary endpoints were the proportion of patients with proteinuria ≤ 0·5 g/24 h or a decrease of ≥ 25% from baseline at week 12 in patients with baseline proteinuria > 0·5 g/24 h, the proportion of patients achieving a reduction of 4 points or more from baseline in SLEDAI-2K score, and the proportion of patients at week 12 whose arthritis and/or rash have resolved relative to baseline (as measured by SLEDAI-2K). We also analysed the BTK occupancy rate of orelabrutinib and effect on SLE biomarkers. Statistical analysis The primary endpoint of this study was AEs that occurred after oral administration of orelabrutinib, as well as vital signs, ECG, and laboratory tests. The sample size was based on clinical trial experience rather than formal statistical hypothesis or power calculation. It was planned to randomise 60 patients in parallel into the placebo group (n=15) and into three dose groups of orelabrutinib (50 mg [n=15], 80 mg [n=15], and 100 mg [n=15]) once daily. All safety analyses included all subjects who received at least one dose of study drug and had at least one post-baseline safety assessment. The efficacy analysis was conducted in all the evaluable patients, who received at least one dose of study drug and had efficacy assessment at 12 weeks (Per Protocol Set, PPS). These participants strictly adhered to the study protocol and completed all required assessments, thereby minimizing bias from deviations and non-adherence. Additionally, a sensitivity analysis was performed in all the treated patients, which included all randomised subjects who received at least one dose of study drug (Full Analysis Set, FAS), to assess the robustness of the findings. The number and proportion of subjects reaching the efficacy endpoint was calculated for each dose group. All statistical analyses were conducted using SAS software, version 9·4 (SAS Institute, Inc.). Descriptive statistics was mainly used in statistical analysis. This trial is registered with ClinicalTrials.gov (NCT04305197). Role of the funding source The funder of the study had a role in study design, data analysis, data interpretation, and writing of the report, but had no role in data collection. Results Patients were recruited from July 9, 2020 to September 29, 2021. 92 patients were screened for eligibility, and 60 were randomly assigned to receive a once daily dose of orelabrutinib at 50 mg (n=15), 80 mg (n=15), 100 mg (n=16), or placebo (n=14) on top of SoC treatments. No patients were excluded from the efficacy and safety analyses. A total of 55 patients (92%) completed the 12-week double-blind treatment period, and 5 (8%) discontinued treatment during this period (Figure S1). There were no major protocol deviations reported in this study. A summary of protocol deviations is provided in the appendix (Table S1). Baseline demographics and disease activity were similar among groups. The mean age at baseline was 33·7 ± 9·8 years, and 58 (97%) patients were female. At baseline, the median duration of SLE was 6·0 years (interquartile range [IQR], 2·6-11·8 years), and patients had a baseline mean SLEDAI-2K score of 8·5 ± 2·1. At baseline, 54 (90%) patients were receiving glucocorticoids with a mean prednisone (or equivalent) dose of 10·1 ± 5·3 mg per day; 50 (83%) were receiving antimalarials; and 41 (68%) were receiving immunosuppressants. Mycophenolate mofetil was the main immunosuppressant (52%). Patients with ANA titre ≥ 1:40 comprised 87%, anti-Smith antibody positive 48%, anti-dsDNA antibody positive 37%, low C3 65%, and low C4 47%, all of which were evenly distributed among all groups. Additional baseline characteristics, disease activity, and biomarkers are given in Table 1. Among all evaluable patients (PPS), the SRI-4 response rates at week 12 were 50%, 62%, and 64% in patients treated with orelabrutinib at 50 mg (n=14), 80 mg (n=13), and 100 mg (n=14), respectively, compared with 36% in patients treated with placebo (n=14), indicating a trend of dose-dependent improvement (Figure 1a). The SRI-6 response rates at week 12 were 36%, 39%, and 21% in patients treated with orelabrutinib at 50 mg (n=14), 80 mg (n=13), and 100 mg (n=14), respectively, compared with 7% in patients treated with placebo (n=14) (Figure 1b). Among the subgroup of patients with SLEDAI-2K > 8 at screening, there was a significant difference observed in SRI-4 response rate in the patients with orelabrutinib at 50 mg (80%, p=0·048), 80 mg (83%, p=0·048) and 100 mg (100%, p=0·029) compared with placebo (0%) at week 12 (Figure 1c). Same trends were also observed in all treated patients (Figure 1d-1f). The remission rate of arthritis, as measured by the SLEDAI-2K score at 12 weeks, was 100%, 71%, and 100% in the orelabrutinib 50 mg, 80 mg, and 100 mg groups, respectively, compared to 50% in the placebo group (Table 2). Orelabrutinib showed a tendency of alleviating arthritis when compared to placebo. Remission rates of rash measured by SLEDAI-2K score at week 12 were 40%, 75%, and 36% in the orelabrutinib groups of 50 mg, 80 mg, and 100 mg, respectively, compared to 33% in the placebo group (Table 2). All patients with baseline proteinuria > 0·5 g/24 h were in the orelabrutinib treatment groups (6 patients at 50 mg, 7 patients at 80 mg, and 4 patients at 100 mg), with none in the placebo group. At week 12, the proportions of patients achieving proteinuria remission based on SLEDAI-2K score were two (33%) at 50 mg, two (29%) at 80 mg, and three (75%) at 100 mg in the orelabrutinib groups, as shown in Table 2. Participants who achieved proteinuria remission or proteinuria ≤ 0·5 g/24 h or ≥ 25% reduction from baseline at week 12 included three (50%) at 50 mg, four (57%) at 80 mg, and three (75%) at 100 mg in the orelabrutinib groups, showing a dose-related improvement (Table 2). At 12 weeks, reduced anti-dsDNA antibody was observed in all orelabrutinib dose groups, particularly at 50 mg and 80 mg. Trends of increased C4, decreased IgG, and decreased IgM were also observed across all dose groups. C3 increased noticeably from baseline in the orelabrutinib 80 mg group but did not change significantly in the 50 mg and 100 mg groups (Figure 1g-1k). Trends of decreased SLEDAI-2K score from baseline were also observed in all dose group (Table 3). Furthermore, nearly complete (100%) BTK occupancy was achieved at four hours after administration across all dose groups, and the occupancy was sustained for 24 hours without any decrease (Figure 1l). TEAEs occurred in 54 (90%) of all patients. At least one TEAE was reported in 80%, 93%, and 100% of orelabrutinib-treated patients at 50 mg, 80 mg, and 100 mg QD, respectively, versus 86% in the placebo group. Most events were mild or moderate in severity. SAEs were reported in six patients and were considered related to orelabrutinib treatment in three patients. No deaths were reported. Treatment discontinuation rates due to AEs were low and are summarized in Table 4. Compared to the TRAEs in the placebo group, there was a higher incidence of decreased lymphocytes and anaemia reported in the orelabrutinib 80 mg treatment group and of decreased lymphocytes, upper respiratory tract infection, and petechia reported in the orelabrutinib 100 mg treatment group. All other TRAEs were similar between orelabrutinib treatment and placebo groups. Safety data are described further in Table 4 and Table S2. Discussion Unlike numerous other autoimmune diseases, where outcomes, including mortality rates, have shown improvement due to the approval and adoption of targeted therapies, SLE continues to exhibit poor outcomes. 14 Approximately a quarter to a third of SLE patients demonstrate inadequate disease control. Mortality rates in SLE have not seen any advancements in the first two decades of this century and it remains one of the leading causes of death among young adult females. 15 Positive pivotal trials have led to regulatory approval for belimumab and telitacicept, providing strong evidence for the involvement of B cells in the pathogenesis of SLE. 16 , 17 However, several other trials have yielded negative results, highlighting an urgent need for new and convenient therapeutic options. 18 Given the unmet need for effective treatments in SLE, our study explores the potential of orelabrutinib as a novel therapeutic strategy. We present findings on both the safety and efficacy of orelabrutinib, offering new insights into their potential role in managing this challenging. In this phase Ib/IIa study, the majority of TRAEs observed during treatment were DMID Grade 1–2, and only a small proportion of patients (three patients, 5%) experienced treatment-related serious adverse events (SAEs), all of which resolved completely. These findings indicate that orelabrutinib demonstrated overall good safety and tolerability. Furthermore, the safety profile of the orelabrutinib 50 mg QD group was comparable to or even better than that of the placebo group. Only decreased lymphocytes, upper respiratory tract infection, petechia, and anemia had a trend of higher incidence rates in the higher orelabrutinib dose groups (80 mg QD, 100 mg QD) compared to the placebo arm. Orelabrutinib demonstrated an acceptable safety profile in this study consistent with its approval for hematologic malignancies. 19 Orelabrutinib exhibited apoptotic effects on B lymphocytes and inhibited their proliferation. Although a decrease in lymphocyte count was observed in both the 80 mg QD and 100 mg QD groups as anticipated, only the 100 mg group had a higher incidence of upper respiratory tract infection compared to placebo. Anaemia and abnormal liver function were primarily observed in the orelabrutinib treatment groups; however, given the limited number of patients in each dose group along with multiple confounding factors present, further observation with a larger sample size is warranted. Bleeding is one of the most concerning side effects associated with BTK inhibitors. This study reported cutaneous mucous bleeding including petechiae, ecchymosis, and nosebleeds, which were mostly mild without decreased platelet counts and predominantly found in the 100 mg group. In addition to infection and bleeding concerns commonly associated with BTK inhibitors, the trial patients had a low incidence rate (3%) of diarrhoea. No adverse events such as atrial fibrillation or headache were reported. In the present study, a dose-dependent increase in the SRI-4 response rate was observed among all patients with mild to moderate SLE in both the FAS and PPS. Importantly, significantly higher SRI-4 responses were noted with orelabrutinib than with placebo in subgroups with baseline SLEDAI scores > 8. Our results also demonstrated improvements of proteinuria upon orelabrutinib treatment at all dose levels with relatively short treatment duration of 12 weeks, decreases in anti-dsDNA, IgG, and IgM levels, as well as an increase in complement C4 levels following treatment with orelabrutinib. The superior efficacy results observed with orelabrutinib as early as week 12 support further evaluation through larger sample sizes and long-term clinical trials which may unveil more substantial improvements. There are other BTK inhibitors are under clinical development for SLE. Phase 2 trials of fenebrutinib and evobrutinib did not meet the primary efficacy endpoint (SRI-4) despite promising results from multiple preclinical SLE animal models. 20 , 21 Preclinical investigations on evobrutinib have shown that 80% BTK target occupancy could potentially lead to near complete disease inhibition in SLE model. 22 Unfortunately, these treatment groups only demonstrated a marginal increase in the response rate of SRI-4. 21 In the MS study of evobrutinib, only 48% of patients achieved > 95% occupancy at 75 mg QD, 23 suggesting that inadequate BTK target occupancy may be one contributing factor to evobrutinib’s lack of efficacy in the SLE clinical study. Of note, orelabrutinib achieved nearly 100% BTK occupancy at a dose of 50 mg QD at four hours after administration and lasted for 24 hours. This may be the key to the improved efficacy observed in this orelabrutinib SLE phIb/IIa trial. There remains a critical need for effective SLE therapies. Preliminary efficacy results from this study suggest orelabrutinib may offer a promising option for SLE patients, particularly given that phase 2 studies of BTK inhibitors fenebrutinib and evobrutinib did not yield positive outcomes despite preclinical efficacy. This study is the first to demonstrate the encouraging efficacy of BTK inhibitors in patients with SLE, albeit with limitations, including a small sample size and short duration of follow-up. Larger, longer trials are needed to further explore optimal dosing of orelabrutinib for SLE. References Siegel CH, Sammaritano LR. Systemic Lupus Erythematosus A Review. JAMA 2024; 331 (17):1480-1491. Hoib A, Igel T. Systemic lupus erythematosus. Lancet 2024; 403 : 2326-2338. Rose T, Dörner T. Drivers of the immunopathogenesis in systemic lupus erythematosus. Best Pract Res Clin Rheumatol 2017; 31: 321–33. Kostopoulou M, Chetan B M, George B, et al. Management of systemic lupus erythematosus: a systematic literature review informing the 2023 update of the EULAR recommendations. Ann Rheum Dis 2024; 0 : 1-13. Allen ME, Rus V, et al. Leveraging Heterogeneity in Systemic Lupus Erythematosus for New Therapies. Trends Mol Med 2021; 27 : 152-171. Chan O, Shlomchik MJ. A new role for B cells in systemic autoimmunity: B cells promote spontaneous T cell activation in MRL-lpr/lpr mice. J Immunol 1998; 160: 51–59. Dörner T, Lipsky PE. The essential roles of memory B cells in the pathogenesis of systemic lupus erythematosus. Nat Rev Rheumatol 2024; 2 0: 770-782. Dörner T, Giesecke C, Lipsky PE. Mechanisms of B cell autoimmunity in SLE. Arthritis Res Ther 2011; 13: 243. Ding Q, Zhou Y. Bruton's tyrosine kinase: A promising target for treating systemic lupus erythematosus. Int Immunopharmacol 2024; 142 : 113040. Satterthwaite AB. Bruton's Tyrosine Kinase, a Component of B Cell Signaling Pathways, Has Multiple Roles in the Pathogenesis of Lupus. Front Immunol 2018; 8 : 1986. Fan Y, Gao D, Zhang Z. Telitacicept, a novel humanized, recombinant TACI-Fc fusion protein, for the treatment of systemic lupus erythematosus. Drugs Today (Barc) 2022; 58: 23–32. Cool A, Nong T, et al. BTK inhibitors: past, present, and future. Trends Pharmacol Sci 2024; 45 :691-707 Zhang B, Zhao R, Liang R, et al. Abstract CT132: Orelabrutinib, a potent and selective Bruton's tyrosine kinase inhibitor with superior safety profile and excellent PK/PD properties. Cancer Res 2020; 80: CT132. Jorge AM, Lu N, Zhang Y, Rai SK, Choi HK. Unchanging premature mortality trends in systemic lupus erythematosus: a general population-based study (1999-2014). Rheumatology (Oxford) 2018; 57: 337–44. Yen EY, Singh RR. Lupus—an unrecognized leading cause of death in young females: a population-based study using nationwide death certificates, 2000-2015. Arthritis Rheumatol 2018; 70: 1251–55. Dhillon S. Telitacicept: First approval. Drugs. 2021; 81: 1671–75. Navarra SV, Guzmán RM, Gallacher AE, et al. Efficacy and safety of belimumab in patients with active systemic lupus erythematosus: a randomised, placebo-controlled, phase 3 trial. Lancet 2011; 377: 721–31. Petri M, Bruce IN, Dörner T, et al. Baricitinib for systemic lupus erythematosus: a double-blind, randomised, placebo-controlled, phase 3 trial (SLE-BRAVE-II). Lancet 2023; 401: 1011–19. Deng LJ, Zhou KS, et al. Orelabrutinib for the treatment of relapsed or refractory MCL: a phase 1/2, open-label, multicenter, single-arm study. Blood Advances 2023; V7:4349-4357 Isenberg D, Furie R, et al. Efficacy, Safety, and Pharmacodynamic Effects of the Bruton's Tyrosine Kinase Inhibitor Fenebrutinib (GDC-0853) in Systemic Lupus Erythematosus: Results of a Phase II, Randomized, Double-Blind, Placebo-Controlled Trial. Arthritis Rheumatol 2021; 73 :1835-1846 Wallace DJ, Dörner T, et al. Efficacy and Safety of the Bruton's Tyrosine Kinase Inhibitor Evobrutinib in Systemic Lupus Erythematosus: Results of a Phase II, Randomized, Double-Blind, Placebo-Controlled Dose-Ranging Trial. ACR Open Rheumatol 2023; 5 :38-48 Haselmayer P, Camps M, Liu-Bujalski L, et al. Efficacy and pharmacodynamic modeling of the BTK inhibitor evobrutinib in autoimmune disease models. J Immunol 2019; 202: 2888–906. Montalban X, Arnold DL, Weber MS, et al. Clinical relapse rates in relapsing MS patients treated with the BTK inhibitor evobrutinib: results of an open-label extension to a Phase II study. Presented at the European Charcot Foundation 28th Annual Meeting; November 15-19, 2020. Tables Table 1. Baseline characteristics and disease activity. Placebo (N=14) Orelabrutinib 50 mg (N=15) Orelabrutinib 80 mg (N=15) Orelabrutinib 100 mg (N=16) Total Demographics Age (years) 31.1 (7.4) 33.0 (11.5) 36.7 (12.1) 33.9 (7.3) 33.7 (9.8) Female 14 (100%) 14 (93%) 14 (93%) 16 (100%) 58 (97%) Ethnic Han 13 (93%) 15 (100%) 15 (100%) 15 (94%) 58 (97%) Weight (kg) 59.7 (11.3) 62.0 (13.5) 58.5 (11.9) 56.2 (9.1) 59.1 (11.4) Body mass index (kg/m 2 ) 22.8 (3.6) 24.0 (5.4) 22.6 (3.5) 21.3 (3.4) 22.6 (4.1) Duration of SLE (years) 7.3 (2.2, 10.1) 4.8 (2.2, 8.7) 5.3 (2.3, 10.1) 11.9 (3.0, 17.9) 6.0 (2.6, 11.8) Disease activity SLEDAI score 8.2 (1.8) 8.5 (2.1) 9.1 (2.6) 8.0 (1.8) 8.5 (2.1) <5 0 0 0 0 0 5-7 4 (29%) 4 (27%) 4 (27%) 5 (31%) 17 (28%) 8-12 10 (71%) 11 (73%) 10 (67%) 11 (69%) 42 (70%) ≥ 13 0 0 1 (7%) 0 1 (2%) SLEDAI-2K organ system involvement Vasculitis 1 (7%) 0 0 0 1 (2%) Arthritis 6 (43%) 4 (27%) 7 (47%) 5 (31%) 22 (37%) Hematuria 0 3 (20%) 2 (13%) 1 (6%) 6 (10%) Proteinuria 0 6 (40%) 7 (47%) 4 (25%) 17 (28%) Pyuria 1 (7%) 2 (13%) 2 (13%) 0 5 (8%) Alopecia 8 (57%) 7 (47%) 5 (33%) 9 (56%) 29 (48%) Rash 9 (64%) 5 (33%) 4 (27%) 11 (69%) 29 (48%) Mucosal ulcers 1 (7%) 0 1 (7%) 1 (6%) 3 (5%) Low complement 10 (71%) 10 (67%) 11 (73%) 12 (75%) 43 (72%) Increased DNA binding 11 (79%) 12 (80%) 11 (73%) 11 (69%) 45 (75%) Leukopenia 1 (7%) 0 0 0 1 (2%) BILAG A or B organ domain scores at baseline Mucocutaneous 10 (71%) 5 (33%) 4 (27%) 11 (69%) 30 (50%) Renal 1 (7%) 6 (40%) 7 (47%) 4 (25%) 18 (30%) Blood system 1 (7%) 0 0 0 0 Musculoskeletal 1 (7%) 4 (27%) 3 (20%) 2 (13%) 10 (17%) Mean proteinuria (g/24 h) 0.2 (0.1) 0.5 (0.7) 0.8 (0.9) 0.5 (0.8) 0.5 (0.7) >0.5 g/24 h 0 6 (40%) 7 (47%) 4 (25%) 17 (28%) Biomarkers Anti-dsDNA positive 7 (50%) 6 (40%) 4 (27%) 5 (31%) 22 (37%) ANA ≥ 1:40 14 (100%) 13 (87%) 12 (80%) 13 (81%) 52 (87%) Anti-Smith positive 6 (43%) 6 (40%) 8 (53%) 9 (56%) 29 (48%) Low C3 9 (64%) 8 (53%) 11 (73%) 11 (69%) 39 (65%) Low C4 6 (43%) 7 (47%) 8 (53%) 7 (44%) 28 (47%) IgG (g/L) 14.7 (4.1) 14.1 (3.1) 14.4 (3.2) 14.7 (4.0) 14.5 (3.5) IgA (g/L) 3.3 (1.5) 2.5 (1.5) 2.8 (0.9) 3.2 (1.2) 2.9 (1.3) IgM (g/L) 0.9 (0.6) 0.8 (0.3) 0.9 (0.4) 1.1 (0.7) 0.9 (0.5) Concomitant medications for SLE Corticosteroids 12 (86%) 14 (93%) 14 (93%) 14 (88%) 54 (90%) Mean prednisone, mg/day 9.8 (5.4) 12.7 (6.2) 8.0 (4.3) 10.0 (4.7) 10.1 (5.3) Prednisone, ≥ 7.5 mg/day 9 (64%) 11 (73%) 6 (40%) 9 (56%) 35 (58%) Antimalarials 12 (86%) 12 (80%) 13 (87%) 13 (81%) 50 (83%) Immunosuppressants 8 (57%) 12 (80%) 9 (60%) 12 (75%) 41 (68%) Mycophenolate mofetil 5 (36%) 10 (67%) 7 (47%) 9 (56%) 31 (52%) Tacrolimus 2 (14%) 0 2 (13%) 1 (6%) 5 (8%) Azathioprine 0 0 0 1 (6%) 1 (2%) Methotrexate 1 (7%) 1 (7%) 1 (7%) 1 (6%) 4 (7%) Cyclosporine 0 1 (7%) 1 (7%) 0 2 (3%) Leflunomide 0 0 1 (7%) 0 1 (2%) SLEDAI-2K = Systemic Lupus Erythematosus Disease Activity Index 2000. BILAG = British Isles Lupus Assessment Group. PGA = Physician’s Global Assessment. (1) Data are number (%) or mean (SD), unless specified otherwise. (2) Percentages are calculated with the number of FAS subjects in each group as the denominator. (3) Age (years) = (date of informed consent - date of birth +1) / 365.25, rounded down. (4) BMI (kg /m 2 ) = weight (kg) / (height (cm)/100) 2 . (5) Baseline is defined as the last non-missing observation before first administration of the investigational drug. (6) SLE diagnosis date: If month is missing, then 6 months will be used to fill in; if the day is missing, it is filled with 1 day; missing years are considered missing. (7) Duration of SLE (years) = (date of first administration - date of SLE diagnosis +1) / 365.25. (8) Steroid dose conversion: methylprednisolone 4 mg = prednisone 5 mg; prednisone 5 mg = prednisone 5 mg. Table 2. Improvement of proteinuria, arthritis, and rash at week 12. Placebo Orelabrutinib 50 mg Orelabrutinib 80 mg Orelabrutinib 100 mg Baseline arthritis (N=22) 6 4 7 5 Arthritis remission* 3 (50%) 4 (100%) 5 (71%) 5 (100%) Baseline rash (N=29) 9 5 4 11 Rash remission** 3 (33%) 2 (40%) 3 (75%) 4 (36%) Baseline proteinuria >0.5 g/24 h (N=17) N=0 N=6 N=7 N=4 Proteinuria remission*** 0 2 (33%) 2 (29%) 3 (75%) Proteinuria remission or proteinuria ≤ 0.5 g/24 h or ≥ 25% reduction from baseline*** 0 3 (50%) 4 (57%) 3 (75%) *Percentages are calculated based on the number of subjects with baseline arthritis. ** Percentages are calculated based on the number of subjects with baseline rash. *** Percentages are calculated based on the number of subjects with baseline proteinuria >0.5 g/24 h. Table 3: Total SLEDAI-2K score and relative baseline change at each visit, FAS (N=60) Visit Placebo Orelabrutinib 50 mg Orelabrutinib 80 mg Orelabrutinib 100 mg Baseline N (miss) 14 (0) 15 (0) 15 (0) 16 (0) Mean (SD) 8.2 (1.76) 8.5 (2.07) 9.1 (2.60) 8.0 (1.79) Median (Q1, Q3) 8.0 (7.0, 10.0) 8.0 (6.0, 10.0) 8.0 (6.0, 12.0) 8.0 (6.0, 9.0) DAY 84 N (miss) 14 (0) 14 (1) 13 (2) 14 (2) Mean (SD) 7.2 (4.26) 5.6 (2.85) 5.2 (2.89) 4.5 (3.06) Median (Q1, Q3) 7.0 (4.0, 10.0) 5.0 (4.0, 6.0) 6.0 (4.0, 6.0) 4.5 (2.0, 6.0) DAY 84 change from baseline N (miss) 14 (0) 14 (1) 13 (2) 14 (2) Mean (SD) -1.0 (3.11) -2.9 (3.48) -4.0 (3.06) -3.2 (3.29) Median (Q1, Q3) 0.0 (-4.0, 0.0) -2.0 (-6.0, 0.0) -4.0 (-6.0, -2.0) -4.0 (-4.0, 0.0) Table 4. Adverse events in the safety population. Placebo (N=14) Orelabrutinib 50 mg (N=15) Orelabrutinib 80 mg (N=15) Orelabrutinib 100 mg (N=16) Total (N=60) Treatment-emergent adverse event 12 (86%) 12 (80%) 14 (93%) 16 (100%) 54 (90%) DMID ≥ 3 treatment-emergent adverse event 0 0 3 (20%) 2 (13%) 5 (8%) Discontinuation 0 0 1 (7%) 1 (6%) 2 (3%) Death 0 0 0 0 0 Treatment-emergent serious adverse event 0 0 4 (27%) 2 (13%) 6 (10%) Treatment-related adverse event 7 (50%) 10 (67%) 13 (87%) 13 (81%) 43 (72%) DMID ≥ 3 treatment-related adverse event 0 0 1 (7%) 1 (6%) 2 (3%) Discontinuation 0 0 1 (7%) 0 1 (2%) Death 0 0 0 0 0 Treatment-related serious adverse event 0 0 2 (13%) 1 (6%) 3 (5%) Treatment-related adverse event ≥2 (preferred term) Decreased lymphocyte count 1 (7%) 2 (13%) 5 (33%) 5 (31%) 13 (22%) Decreased white blood cell count 2 (14%) 0 3 (20%) 3 (19%) 8 (13%) Petechia 0 1 (7%) 2 (13%) 4 (25%) 7 (12%) Upper respiratory tract infection 1 (7%) 1 (7%) 0 4 (25%) 6 (10%) Elevated blood thyrotropin 2 (14%) 1 (7%) 0 3 (19%) 6 (10%) Anemia 0 0 3 (20%) 2 (13%) 5 (8%) Hypokalemia 1 (7%) 2 (13%) 1 (7%) 0 4 (7%) Abnormal liver function 0 1 (7%) 2 (13%) 1 (6%) 4 (7%) Decreased platelet count 1 (7%) 0 1 (7%) 2 (13%) 4 (7%) Data are presented as n (%). Percentages are calculated based on the number of subjects in safety population. Additional Declarations There is NO Competing Interest. Supplementary Files Supplementary.docx Supplementary Protocol.docx Study Protocol StatisticalAnalysisPlan.docx Statistical Analysis Plan Cite Share Download PDF Status: Posted Version 1 posted You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. Our growing team is made up of researchers and industry professionals working together to solve the most critical problems facing scientific publishing. Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-7058001","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Article","associatedPublications":[],"authors":[{"id":486981472,"identity":"3e9b5787-38ca-4a99-90cc-2c0d6eed5ff1","order_by":0,"name":"Xue Li","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAAwElEQVRIiWNgGAWjYBACPgYGNgYJBgY5BnbGBuK0sEG1GDMwk6QFCBIbmIl1GJtEAtsDy5zD6f3NzG3SvDsY5PnFDhDQwnOA3UBy2+HcGYcZgVrOMBjOnJ1AQAt7A5sESEsDWEsbQ4LBbUJamBnAWtLlidcCtSXBgHgtEL+kG248zNhsObdNgrBf+IEh9lhym7W83PH2hzfettnI80sT0ALU9IFZAsJiAdIShJRDAOMHCM38gTj1o2AUjIJRMNIAACA/N1sNUVdzAAAAAElFTkSuQmCC","orcid":"https://orcid.org/0000-0003-2368-812X","institution":"Peking University People’s Hospital","correspondingAuthor":true,"prefix":"","firstName":"Xue","middleName":"","lastName":"Li","suffix":""},{"id":486981473,"identity":"b9c10656-0876-4883-9991-fb01a7ab4841","order_by":1,"name":"Ru Li","email":"","orcid":"","institution":"Peking University People's Hospital","correspondingAuthor":false,"prefix":"","firstName":"Ru","middleName":"","lastName":"Li","suffix":""},{"id":486981474,"identity":"2c56e8ee-0dbc-467e-b816-4ab56254af4f","order_by":2,"name":"Xiaoxia Zhu","email":"","orcid":"","institution":"Division of Rheumatology, Huashan Hospital, Fudan University","correspondingAuthor":false,"prefix":"","firstName":"Xiaoxia","middleName":"","lastName":"Zhu","suffix":""},{"id":486981475,"identity":"a69e916d-baf8-4b08-845c-9a1831fe3be2","order_by":3,"name":"Shengyun Liu","email":"","orcid":"","institution":"The First Affiliated Hospital of Zhengzhou University","correspondingAuthor":false,"prefix":"","firstName":"Shengyun","middleName":"","lastName":"Liu","suffix":""},{"id":486981476,"identity":"00ac3088-2d9f-4e69-ae0d-5fcb834e0dd9","order_by":4,"name":"Xiao Zhang","email":"","orcid":"","institution":"Guangdong Provincial People’s Hospital","correspondingAuthor":false,"prefix":"","firstName":"Xiao","middleName":"","lastName":"Zhang","suffix":""},{"id":486981477,"identity":"4797d2cd-2dc7-4db1-bce3-3d7a1125f5f4","order_by":5,"name":"Changhao Xie","email":"","orcid":"","institution":"Nanjing Medical University","correspondingAuthor":false,"prefix":"","firstName":"Changhao","middleName":"","lastName":"Xie","suffix":""},{"id":486981478,"identity":"8cc837ba-5829-459e-a5b5-aaa1d7fac6ec","order_by":6,"name":"Zili Fu","email":"","orcid":"","institution":"First Hospital of Shanxi Medical University","correspondingAuthor":false,"prefix":"","firstName":"Zili","middleName":"","lastName":"Fu","suffix":""},{"id":486981479,"identity":"f0c3d2a8-f796-4705-a4e5-e6e2971f09fb","order_by":7,"name":"Anbin Huang","email":"","orcid":"","institution":"First Hospital of Shanxi Medical University","correspondingAuthor":false,"prefix":"","firstName":"Anbin","middleName":"","lastName":"Huang","suffix":""},{"id":486981480,"identity":"09337a6d-a3c7-45cd-8624-8b692c2ffe7f","order_by":8,"name":"Lingyun Sun","email":"","orcid":"","institution":"Department of Rheumatology and Immunology, the Affiliated Drum Tower Hospital of Nanjing University Medical School","correspondingAuthor":false,"prefix":"","firstName":"Lingyun","middleName":"","lastName":"Sun","suffix":""},{"id":486981481,"identity":"464e4935-2d3a-4e10-8440-b39d6b4fd840","order_by":9,"name":"Dongzhou Liu","email":"","orcid":"","institution":"Jinan University","correspondingAuthor":false,"prefix":"","firstName":"Dongzhou","middleName":"","lastName":"Liu","suffix":""},{"id":486981482,"identity":"fc89bfbd-a86f-495f-8803-5de9a2149c62","order_by":10,"name":"Jinxia Zhao","email":"","orcid":"","institution":"Department of Rheumatology and Immunology, Peking University Third Hospital","correspondingAuthor":false,"prefix":"","firstName":"Jinxia","middleName":"","lastName":"Zhao","suffix":""},{"id":486981483,"identity":"c564bfd9-e5f6-44ec-ac41-f4b0fc22fe4a","order_by":11,"name":"Zhanguo Li","email":"","orcid":"https://orcid.org/0000-0002-2590-6242","institution":"Peking University People's Hospital, Peking University","correspondingAuthor":false,"prefix":"","firstName":"Zhanguo","middleName":"","lastName":"Li","suffix":""}],"badges":[],"createdAt":"2025-07-06 13:15:10","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-7058001/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-7058001/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":87383276,"identity":"7d0a1636-feaf-47a9-bcc0-e53a17e11a6f","added_by":"auto","created_at":"2025-07-23 08:42:19","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":152599,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eThe Efficacy of Orelabrutinib in Patients with Systemic Lupus Erythematosus.\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003ea.\u003c/strong\u003e SRI-4 response rates at 12 weeks in all evaluable patients.\u003cstrong\u003e b. \u003c/strong\u003eSRI-6 response rates at 12 weeks in all evaluable patients. \u003cstrong\u003ec.\u003c/strong\u003e SRI-4 response rates for subgroups with baseline SLEDAI-2K scores \u0026gt; 8 at 12 weeks in all evaluable patients. \u003cstrong\u003ed. \u003c/strong\u003eSRI-4 response rates at 12 weeks in all treated patients. \u003cstrong\u003ee.\u003c/strong\u003e SRI-6 response rates at 12 weeks in all treated patients. \u003cstrong\u003ef.\u003c/strong\u003e SRI-4 response rates for subgroups with baseline SLEDAI-2K scores \u0026gt; 8 at 12 weeks in all treated patients. Improvements in SLE efficacy biomarkers are shown as follows: anti-dsDNA (\u003cstrong\u003eg\u003c/strong\u003e), IgG (\u003cstrong\u003eh\u003c/strong\u003e), IgM (\u003cstrong\u003ei\u003c/strong\u003e), C4 (\u003cstrong\u003ej\u003c/strong\u003e), and C3 (\u003cstrong\u003ek\u003c/strong\u003e). \u003cstrong\u003el. \u003c/strong\u003eBTK occupancy after administration of orelabrutinib. Anti-dsDNA denotes anti-double stranded DNA, BTK Bruton’s tyrosine kinase, C3 complement 3, C4 complement 4, IgG immunoglobulin G, IgM immunoglobulin M, SLEDAI-2K Systemic Lupus Erythematosus Disease Activity Index 2000, and SRI Systemic Lupus Erythematosus Responder Index. *p\u0026lt;0.05\u003c/p\u003e","description":"","filename":"floatimage1.png","url":"https://assets-eu.researchsquare.com/files/rs-7058001/v1/986f2c2196be9780133c6084.png"},{"id":90116261,"identity":"74bde7f8-0f49-4f5d-a4cd-d6cc9521e500","added_by":"auto","created_at":"2025-08-28 16:18:36","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":1920598,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-7058001/v1/62f4c216-b349-4bfc-8e7e-50e5d52f20f7.pdf"},{"id":87380371,"identity":"ac1109ac-04d8-4aba-b7d0-d6e244ff109b","added_by":"auto","created_at":"2025-07-23 08:34:19","extension":"docx","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":65596,"visible":true,"origin":"","legend":"Supplementary","description":"","filename":"Supplementary.docx","url":"https://assets-eu.researchsquare.com/files/rs-7058001/v1/bf9e261be36ec79e95b3bae1.docx"},{"id":87383277,"identity":"997523c4-0347-46dd-9f88-140726385c1e","added_by":"auto","created_at":"2025-07-23 08:42:19","extension":"docx","order_by":2,"title":"","display":"","copyAsset":false,"role":"supplement","size":187729,"visible":true,"origin":"","legend":"Study Protocol","description":"","filename":"Protocol.docx","url":"https://assets-eu.researchsquare.com/files/rs-7058001/v1/224051e178b9783209970dd0.docx"},{"id":87380369,"identity":"c777efc3-4515-4a11-a1d4-f3b98394a777","added_by":"auto","created_at":"2025-07-23 08:34:19","extension":"docx","order_by":3,"title":"","display":"","copyAsset":false,"role":"supplement","size":145501,"visible":true,"origin":"","legend":"Statistical Analysis Plan","description":"","filename":"StatisticalAnalysisPlan.docx","url":"https://assets-eu.researchsquare.com/files/rs-7058001/v1/88f3d051eca8ccded9daba55.docx"}],"financialInterests":"There is \u003cb\u003eNO\u003c/b\u003e Competing Interest.","formattedTitle":"Orelabrutinib, an irreversible inhibitor of Bruton’s tyrosine kinase, for the treatment of systemic lupus erythematosus: a randomised, double-blind, placebo-controlled, phase Ib/IIa study","fulltext":[{"header":"Introduction","content":"\u003cp\u003eSystemic lupus erythematosus (SLE) is a systemic autoimmune disease characterized by inflammation and immune-mediated injury affecting multiple organs, including the skin, joints, and kidneys.\u003csup\u003e1\u0026ndash;3\u003c/sup\u003e Standard-of-care (SoC) therapies for SLE encompass immunosuppressants/ immunomodulators, antimalarials, corticosteroids, and nonsteroidal anti-inflammatory drugs.\u003csup\u003e4\u003c/sup\u003e Despite these therapeutic options, there are unmet needs in the treatment of SLE, particularly for patients who do not respond to SoC.\u003csup\u003e5\u003c/sup\u003e B cell hyperactivity leading to autoantibody formation is a well-known mechanism associated with SLE.\u003csup\u003e6-\u003c/sup\u003e\u003csup\u003e8\u003c/sup\u003e Consequently, targeting B cells represents a potential treatment approach due to their pivotal role in disease pathogenesis through the development of autoreactive B cells.\u003csup\u003e9\u003c/sup\u003e\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eBruton\u0026rsquo;s tyrosine kinase (BTK) plays an important role in B cell signalling upon antigen binding to the B cell receptor (BCR), as well as in B cell development and activation processes.\u003csup\u003e10,11\u003c/sup\u003e Overexpression of BTK can result in abnormal activation of B cells and contribute to autoimmune disorders.\u003csup\u003e1\u003c/sup\u003e\u003csup\u003e2\u003c/sup\u003e Therefore, BTK is implicated in B cell signalling pathways that are potentially crucial for the pathogenesis of SLE. \u0026nbsp;\u003c/p\u003e\n\u003cp\u003eOrelabrutinib is an oral, irreversible BTK inhibitor with high potency and exceptional kinase selectivity for BTK. In a kinase screening assay against a panel of 456 kinases, orelabrutinib at a concentration of 1 \u0026mu;M inhibited only BTK to significant levels \u0026gt; 90%, with minimal off-target binding to other tyrosine kinases. In addition, orelabrutinib at doses of \u0026ge; 50 mg/day exhibited high BTK target occupancy maintained at nearly 100% over 24 hours in healthy subjects.\u003csup\u003e1\u003c/sup\u003e\u003csup\u003e3\u003c/sup\u003e Moreover, orelabrutinib has demonstrated potent inhibitory effects on human primary B cell proliferation and activation in peripheral blood mononuclear cells (PBMCs). In a six-month study utilizing the MRL/lpr spontaneous SLE mouse model, orelabrutinib exhibited notable anti-inflammatory properties by significantly improving survival rates and kidney function in treated animals. Similarly, in the pristane-induced SLE mouse model, orelabrutinib showed dose-dependent efficacy in inhibiting lupus-related arthritis and improving kidney function (data not shown). \u0026nbsp;\u003c/p\u003e\n\u003cp\u003eHere, we report the findings of a randomised, double-blind, placebo-controlled, phase Ib/IIa clinical trial which evaluated the efficacy and safety of once daily oral orelabrutinib at 50 mg, 80 mg, or 100 mg in the treatment of patients with active SLE receiving SoC treatment. \u0026nbsp;\u003c/p\u003e"},{"header":"Methods","content":"\u003ch2\u003eStudy design\u0026nbsp;\u003c/h2\u003e\n\u003cp\u003eThis study was a multicentre, double-blind, randomised, placebo-controlled, parallel-group, phase Ib/IIa clinical study of orelabrutinib 50 mg, 80 mg, or 100 mg versus placebo in patients with active SLE receiving standard therapy over 12 weeks (Figure S1). The trial was conducted across 11 centres in China.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eThe study was done in accordance with the ethical principles of the Declaration of Helsinki and Good Clinical Practice guidelines. All participating sites obtained approval from the appropriate authorized institutional review board or ethics committee.\u0026nbsp;\u003c/p\u003e\n\u003ch2\u003eParticipants\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/h2\u003e\n\u003cp\u003eEligible patients included individuals aged 18 to 75 years who had a confirmed clinical diagnosis of SLE for at least six months prior to screening by fulfilling at least four out of the 11 revised American College of Rheumatology 1997 criteria for the classification of SLE; at baseline, patients were required to have active disease evidenced by a Systemic Lupus Erythematosus Disease Activity Index 2000 (SLEDAI-2K) score ranging from 5 to 12 and to test positive for at least one of the following antibodies: antinuclear antibody (ANA), anti-dsDNA, or anti-Smith. Patients were excluded if they had severe active lupus nephritis, severe active central nervous system lupus, recent clinically serious infection, and selected laboratory abnormalities. A comprehensive list of inclusion and exclusion criteria can be found in the Supplementary (pages 4-6).\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eAll patients provided written informed consent.\u0026nbsp;\u003c/p\u003e\n\u003ch2\u003eRandomisation and masking\u0026nbsp;\u003c/h2\u003e\n\u003cp\u003eParticipants who met all criteria for enrolment were randomised 1:1:1:1 to receive oral orelabrutinib at 50 mg, 80 mg, and 100 mg or placebo once daily (QD) for 12 weeks, respectively. A randomisation table was generated by an unblinded statistician independent of the study, and an interactive website response system (IWRS) was used for randomisation.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eOrelabrutinib and placebo were packaged uniformly to have identical appearances to maintain masking. Patients, investigators, and anyone involved in patient evaluation and trial implementation were masked to group assignment.\u0026nbsp;\u003c/p\u003e\n\u003ch2\u003eProcedures\u0026nbsp;\u003c/h2\u003e\n\u003cp\u003eParticipants maintained their usual SoC for SLE during the study and had been treated for at least three months before screening. The SoC treatment included corticosteroids (stable dose of 40 mg or less per day of prednisone or equivalent), and/or antimalarials, and/or immunosuppressants (such as azathioprine, methotrexate, mycophenolate mofetil, sodium mycophenolate, cyclosporine, leflunomide, tacrolimus, sirolimus, mizoribine, 6-mercaptopurine, iguratimod, or thalidomide). All patients were monitored during the treatment period (for a period of 12 weeks), and the 28-day follow-up visit was completed after the treatment period.\u0026nbsp;\u003c/p\u003e\n\u003ch2\u003eOutcomes\u0026nbsp;\u003c/h2\u003e\n\u003cp\u003eThe primary outcome was safety and tolerability as measured by treatment-emergent adverse events (TEAEs), treatment-related adverse events (TRAEs), serious adverse events (SAEs), vital signs, electrocardiogram (ECG), and laboratory findings. The second endpoint was the proportion of patients achieving a Systemic Lupus Erythematosus Responder Index-4 (SRI-4) response and SRI-6 response at week 8 or 12. SRI-4/6 response is defined as a reduction of at least 4 or 6 points from baseline in SLEDAI-2K score, no worsening in British Isles Lupus Assessment Group (BILAG) A or B disease activity scores (no new BILAG A score or no more than one new BILAG B score), and no worsening (defined as an increase of \u0026ge; 0\u0026middot;3 points [10 mm] from baseline) in the Physician\u0026rsquo;s Global Assessment of Disease Activity (PGA). Other secondary endpoints were the proportion of patients with proteinuria \u0026le; 0\u0026middot;5 g/24 h or a decrease of \u0026ge; 25% from baseline at week 12 in patients with baseline proteinuria \u0026gt; 0\u0026middot;5 g/24 h, the proportion of patients achieving a reduction of 4 points or more from baseline in SLEDAI-2K score, and the proportion of patients at week 12 whose arthritis and/or rash have resolved relative to baseline (as measured by SLEDAI-2K). \u0026nbsp;\u003c/p\u003e\n\u003cp\u003eWe also analysed the BTK occupancy rate of orelabrutinib and effect on SLE biomarkers.\u0026nbsp;\u003c/p\u003e\n\u003ch2\u003eStatistical analysis\u0026nbsp;\u003c/h2\u003e\n\u003cp\u003eThe primary endpoint of this study was AEs that occurred after oral administration of orelabrutinib, as well as vital signs, ECG, and laboratory tests. The sample size was based on clinical trial experience rather than formal statistical hypothesis or power calculation. It was planned to randomise 60 patients in parallel into the placebo group (n=15) and into three dose groups of orelabrutinib (50 mg [n=15], 80 mg [n=15], and 100 mg [n=15]) once daily. All safety analyses included all subjects who received at least one dose of study drug and had at least one post-baseline safety assessment.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eThe efficacy analysis was conducted in all the evaluable patients, who received at least one dose of study drug and had efficacy assessment at 12 weeks (Per Protocol Set, PPS). These participants strictly adhered to the study protocol and completed all required assessments, thereby minimizing bias from deviations and non-adherence. Additionally, a sensitivity analysis was performed in all the treated patients, which included all randomised subjects who received at least one dose of study drug (Full Analysis Set, FAS), to assess the robustness of the findings. The number and proportion of subjects reaching the efficacy endpoint was calculated for each dose group.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eAll statistical analyses were conducted using SAS software, version 9\u0026middot;4 (SAS Institute, Inc.). Descriptive statistics was mainly used in statistical analysis.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eThis trial is registered with ClinicalTrials.gov (NCT04305197).\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eRole of the funding source\u003c/strong\u003e\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eThe funder of the study had a role in study design, data analysis, data interpretation, and writing of the report, but had no role in data collection.\u003c/p\u003e"},{"header":"Results","content":"\u003cp\u003ePatients were recruited from July 9, 2020 to September 29, 2021. 92 patients were screened for eligibility, and 60 were randomly assigned to receive a once daily dose of orelabrutinib at 50 mg (n=15), 80 mg (n=15), 100 mg (n=16), or placebo (n=14) on top of SoC treatments. No patients were excluded from the efficacy and safety analyses. A total of 55 patients (92%) completed the 12-week double-blind treatment period, and 5 (8%) discontinued treatment during this period (Figure S1). There were no major protocol deviations reported in this study. A summary of protocol deviations is provided in the appendix (Table S1).\u003c/p\u003e\n\u003cp\u003eBaseline demographics and disease activity were similar among groups. The mean age at baseline was 33\u0026middot;7 \u0026plusmn; 9\u0026middot;8 years, and 58 (97%) patients were female. At baseline, the median duration of SLE was 6\u0026middot;0 years (interquartile range [IQR], 2\u0026middot;6-11\u0026middot;8 years), and patients had a baseline mean SLEDAI-2K score of 8\u0026middot;5 \u0026plusmn; 2\u0026middot;1. At baseline, 54 (90%) patients were receiving glucocorticoids with a mean prednisone (or equivalent) dose of 10\u0026middot;1 \u0026plusmn; 5\u0026middot;3 mg per day; 50 (83%) were receiving antimalarials; and 41 (68%) were receiving immunosuppressants. Mycophenolate mofetil was the main immunosuppressant (52%). Patients with ANA titre \u0026ge; 1:40 comprised 87%, anti-Smith antibody positive 48%, anti-dsDNA antibody positive 37%, low C3 65%, and low C4 47%, all of which were evenly distributed among all groups. Additional baseline characteristics, disease activity, and biomarkers are given in Table 1.\u003c/p\u003e\n\u003cp\u003eAmong all evaluable patients (PPS), the SRI-4 response rates at week 12 were 50%, 62%, and 64% in patients treated with orelabrutinib at 50 mg (n=14), 80 mg (n=13), and 100 mg (n=14), respectively, compared with 36% in patients treated with placebo (n=14), indicating a trend of dose-dependent improvement (Figure 1a). The SRI-6 response rates at week 12 were 36%, 39%, and 21% in patients treated with orelabrutinib at 50 mg (n=14), 80 mg (n=13), and 100 mg (n=14), respectively, compared with 7% in patients treated with placebo (n=14) (Figure 1b). Among the subgroup of patients with SLEDAI-2K \u0026gt; 8 at screening, there was a significant difference observed in SRI-4 response rate in the patients with orelabrutinib at 50 mg (80%, p=0\u0026middot;048), 80 mg (83%, p=0\u0026middot;048) and 100 mg (100%, p=0\u0026middot;029) compared with placebo (0%) at week 12 (Figure 1c). Same trends were also observed in all treated patients (Figure 1d-1f).\u003c/p\u003e\n\u003cp\u003eThe remission rate of arthritis, as measured by the SLEDAI-2K score at 12 weeks, was 100%, 71%, and 100% in the orelabrutinib 50 mg, 80 mg, and 100 mg groups, respectively, compared to 50% in the placebo group (Table 2). Orelabrutinib showed a tendency of alleviating arthritis when compared to placebo. Remission rates of rash measured by SLEDAI-2K score at week 12 were 40%, 75%, and 36% in the orelabrutinib groups of 50 mg, 80 mg, and 100 mg, respectively, compared to 33% in the placebo group (Table 2).\u003c/p\u003e\n\u003cp\u003eAll patients with baseline proteinuria \u0026gt; 0\u0026middot;5 g/24 h were in the orelabrutinib treatment groups (6 patients at 50 mg, 7 patients at 80 mg, and 4 patients at 100 mg), with none in the placebo group. At week 12, the proportions of patients achieving proteinuria remission based on SLEDAI-2K score were two (33%) at 50 mg, two (29%) at 80 mg, and three (75%) at 100 mg in the orelabrutinib groups, as shown in Table 2. Participants who achieved proteinuria remission or proteinuria \u0026le; 0\u0026middot;5 g/24 h or \u0026ge; 25% reduction from baseline at week 12 included three (50%) at 50 mg, four (57%) at 80 mg, and three (75%) at 100 mg in the orelabrutinib groups, showing a dose-related improvement (Table 2).\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eAt 12 weeks, reduced anti-dsDNA antibody was observed in all orelabrutinib dose groups, particularly at 50 mg and 80 mg. Trends of increased C4, decreased IgG, and decreased IgM were also observed across all dose groups. C3 increased noticeably from baseline in the orelabrutinib 80 mg group but did not change significantly in the 50 mg and 100 mg groups (Figure 1g-1k). Trends of decreased SLEDAI-2K score from baseline were also observed in all dose group (Table 3). Furthermore, nearly complete (100%) BTK occupancy was achieved at four hours after administration across all dose groups, and the occupancy was sustained for 24 hours without any decrease (Figure 1l).\u003c/p\u003e\n\u003cp\u003eTEAEs occurred in 54 (90%) of all patients. At least one TEAE was reported in 80%, 93%, and 100% of orelabrutinib-treated patients at 50 mg, 80 mg, and 100 mg QD, respectively, versus 86% in the placebo group. Most events were mild or moderate in severity. SAEs were reported in six patients and were considered related to orelabrutinib treatment in three patients. No deaths were reported. Treatment discontinuation rates due to AEs were low and are summarized in Table 4.\u003c/p\u003e\n\u003cp\u003eCompared to the TRAEs in the placebo group, there was a higher incidence of decreased lymphocytes and anaemia reported in the orelabrutinib 80 mg treatment group and of decreased lymphocytes, upper respiratory tract infection, and petechia reported in the orelabrutinib 100 mg treatment group. All other TRAEs were similar between orelabrutinib treatment and placebo groups. Safety data are described further in Table 4 and Table S2.\u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003eUnlike numerous other autoimmune diseases, where outcomes, including mortality rates, have shown improvement due to the approval and adoption of targeted therapies, SLE continues to exhibit poor outcomes.\u003csup\u003e\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e\u003c/sup\u003e Approximately a quarter to a third of SLE patients demonstrate inadequate disease control. Mortality rates in SLE have not seen any advancements in the first two decades of this century and it remains one of the leading causes of death among young adult females.\u003csup\u003e\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e\u003c/sup\u003e Positive pivotal trials have led to regulatory approval for belimumab and telitacicept, providing strong evidence for the involvement of B cells in the pathogenesis of SLE.\u003csup\u003e\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e,\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e\u003c/sup\u003e However, several other trials have yielded negative results, highlighting an urgent need for new and convenient therapeutic options.\u003csup\u003e\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e\u003c/sup\u003e\u003c/p\u003e\u003cp\u003eGiven the unmet need for effective treatments in SLE, our study explores the potential of orelabrutinib as a novel therapeutic strategy. We present findings on both the safety and efficacy of orelabrutinib, offering new insights into their potential role in managing this challenging.\u003c/p\u003e\u003cp\u003eIn this phase Ib/IIa study, the majority of TRAEs observed during treatment were DMID Grade 1\u0026ndash;2, and only a small proportion of patients (three patients, 5%) experienced treatment-related serious adverse events (SAEs), all of which resolved completely. These findings indicate that orelabrutinib demonstrated overall good safety and tolerability. Furthermore, the safety profile of the orelabrutinib 50 mg QD group was comparable to or even better than that of the placebo group. Only decreased lymphocytes, upper respiratory tract infection, petechia, and anemia had a trend of higher incidence rates in the higher orelabrutinib dose groups (80 mg QD, 100 mg QD) compared to the placebo arm.\u003c/p\u003e\u003cp\u003eOrelabrutinib demonstrated an acceptable safety profile in this study consistent with its approval for hematologic malignancies.\u003csup\u003e\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e\u003c/sup\u003e Orelabrutinib exhibited apoptotic effects on B lymphocytes and inhibited their proliferation. Although a decrease in lymphocyte count was observed in both the 80 mg QD and 100 mg QD groups as anticipated, only the 100 mg group had a higher incidence of upper respiratory tract infection compared to placebo. Anaemia and abnormal liver function were primarily observed in the orelabrutinib treatment groups; however, given the limited number of patients in each dose group along with multiple confounding factors present, further observation with a larger sample size is warranted. Bleeding is one of the most concerning side effects associated with BTK inhibitors. This study reported cutaneous mucous bleeding including petechiae, ecchymosis, and nosebleeds, which were mostly mild without decreased platelet counts and predominantly found in the 100 mg group. In addition to infection and bleeding concerns commonly associated with BTK inhibitors, the trial patients had a low incidence rate (3%) of diarrhoea. No adverse events such as atrial fibrillation or headache were reported.\u003c/p\u003e\u003cp\u003eIn the present study, a dose-dependent increase in the SRI-4 response rate was observed among all patients with mild to moderate SLE in both the FAS and PPS. Importantly, significantly higher SRI-4 responses were noted with orelabrutinib than with placebo in subgroups with baseline SLEDAI scores\u0026thinsp;\u0026gt;\u0026thinsp;8. Our results also demonstrated improvements of proteinuria upon orelabrutinib treatment at all dose levels with relatively short treatment duration of 12 weeks, decreases in anti-dsDNA, IgG, and IgM levels, as well as an increase in complement C4 levels following treatment with orelabrutinib. The superior efficacy results observed with orelabrutinib as early as week 12 support further evaluation through larger sample sizes and long-term clinical trials which may unveil more substantial improvements.\u003c/p\u003e\u003cp\u003eThere are other BTK inhibitors are under clinical development for SLE. Phase 2 trials of fenebrutinib and evobrutinib did not meet the primary efficacy endpoint (SRI-4) despite promising results from multiple preclinical SLE animal models.\u003csup\u003e\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e,\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e\u003c/sup\u003e Preclinical investigations on evobrutinib have shown that 80% BTK target occupancy could potentially lead to near complete disease inhibition in SLE model.\u003csup\u003e\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e\u003c/sup\u003e Unfortunately, these treatment groups only demonstrated a marginal increase in the response rate of SRI-4.\u003csup\u003e\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e\u003c/sup\u003e In the MS study of evobrutinib, only 48% of patients achieved\u0026thinsp;\u0026gt;\u0026thinsp;95% occupancy at 75 mg QD,\u003csup\u003e\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e\u003c/sup\u003e suggesting that inadequate BTK target occupancy may be one contributing factor to evobrutinib\u0026rsquo;s lack of efficacy in the SLE clinical study. Of note, orelabrutinib achieved nearly 100% BTK occupancy at a dose of 50 mg QD at four hours after administration and lasted for 24 hours. This may be the key to the improved efficacy observed in this orelabrutinib SLE phIb/IIa trial.\u003c/p\u003e\u003cp\u003eThere remains a critical need for effective SLE therapies. Preliminary efficacy results from this study suggest orelabrutinib may offer a promising option for SLE patients, particularly given that phase 2 studies of BTK inhibitors fenebrutinib and evobrutinib did not yield positive outcomes despite preclinical efficacy. This study is the first to demonstrate the encouraging efficacy of BTK inhibitors in patients with SLE, albeit with limitations, including a small sample size and short duration of follow-up. Larger, longer trials are needed to further explore optimal dosing of orelabrutinib for SLE.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n \u003cli\u003eSiegel CH, Sammaritano LR.\u0026nbsp;Systemic Lupus Erythematosus\u0026nbsp;A Review.\u0026nbsp;\u003cem\u003eJAMA\u003c/em\u003e 2024; \u003cstrong\u003e331\u003c/strong\u003e(17):1480-1491.\u003c/li\u003e\n \u003cli\u003eHoib A,\u0026nbsp;Igel\u0026nbsp;T. Systemic lupus erythematosus. \u003cem\u003eLancet\u0026nbsp;\u003c/em\u003e2024;\u0026nbsp;\u003cstrong\u003e403\u003c/strong\u003e\u003cstrong\u003e:\u0026nbsp;\u003c/strong\u003e2326-2338.\u003c/li\u003e\n \u003cli\u003eRose T, D\u0026ouml;rner T. Drivers of the immunopathogenesis in systemic lupus erythematosus. \u003cem\u003eBest Pract Res Clin Rheumatol\u003c/em\u003e 2017; \u003cstrong\u003e31:\u0026nbsp;\u003c/strong\u003e321\u0026ndash;33.\u003c/li\u003e\n \u003cli\u003eKostopoulou M, Chetan B M, George B, et al. 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Mechanisms of B cell autoimmunity in SLE. \u003cem\u003eArthritis Res Ther\u0026nbsp;\u003c/em\u003e2011; \u003cstrong\u003e13:\u0026nbsp;\u003c/strong\u003e243.\u003c/li\u003e\n \u003cli\u003eDing\u0026nbsp;Q,\u0026nbsp;Zhou Y.\u0026nbsp;Bruton\u0026apos;s tyrosine kinase: A promising target for treating systemic lupus erythematosus. \u003cem\u003eInt Immunopharmacol\u0026nbsp;\u003c/em\u003e2024;\u0026nbsp;\u003cstrong\u003e142\u003c/strong\u003e\u003cstrong\u003e:\u0026nbsp;\u003c/strong\u003e113040.\u003c/li\u003e\n \u003cli\u003eSatterthwaite\u0026nbsp;AB. Bruton\u0026apos;s Tyrosine Kinase, a Component of B Cell Signaling Pathways, Has Multiple Roles in the Pathogenesis of Lupus. \u003cem\u003eFront Immunol\u003c/em\u003e\u003cem\u003e\u0026nbsp;\u003c/em\u003e2018;\u0026nbsp;\u003cstrong\u003e8\u003c/strong\u003e\u003cstrong\u003e:\u0026nbsp;\u003c/strong\u003e1986.\u003c/li\u003e\n \u003cli\u003eFan Y, Gao D, Zhang Z. Telitacicept, a novel humanized, recombinant TACI-Fc fusion protein, for the treatment of systemic lupus erythematosus. \u003cem\u003eDrugs Today (Barc)\u003c/em\u003e 2022; \u003cstrong\u003e58:\u0026nbsp;\u003c/strong\u003e23\u0026ndash;32.\u003c/li\u003e\n \u003cli\u003eCool\u0026nbsp;A,\u0026nbsp;Nong T, et al.\u0026nbsp;BTK inhibitors: past, present, and future.\u0026nbsp;\u003cem\u003eTrends Pharmacol Sci\u003c/em\u003e 2024; \u003cstrong\u003e45\u003c/strong\u003e:691-707\u003c/li\u003e\n \u003cli\u003eZhang B, Zhao R, Liang R, et al. Abstract CT132: Orelabrutinib, a potent and selective Bruton\u0026apos;s tyrosine kinase inhibitor with superior safety profile and excellent PK/PD properties. Cancer Res 2020; 80: CT132.\u003c/li\u003e\n \u003cli\u003eJorge AM, Lu N, Zhang Y, Rai SK, Choi HK. Unchanging premature mortality trends in systemic lupus erythematosus: a general population-based study (1999-2014). \u003cem\u003eRheumatology (Oxford)\u0026nbsp;\u003c/em\u003e2018; \u003cstrong\u003e57:\u0026nbsp;\u003c/strong\u003e337\u0026ndash;44.\u003c/li\u003e\n \u003cli\u003eYen EY, Singh RR. Lupus\u0026mdash;an unrecognized leading cause of death in young females: a population-based study using nationwide death certificates, 2000-2015. \u003cem\u003eArthritis Rheumatol\u0026nbsp;\u003c/em\u003e2018; \u003cstrong\u003e70:\u0026nbsp;\u003c/strong\u003e1251\u0026ndash;55.\u003c/li\u003e\n \u003cli\u003eDhillon S. Telitacicept: First approval. \u003cem\u003eDrugs.\u0026nbsp;\u003c/em\u003e2021; \u003cstrong\u003e81:\u0026nbsp;\u003c/strong\u003e1671\u0026ndash;75.\u0026nbsp;\u003c/li\u003e\n \u003cli\u003eNavarra SV, Guzm\u0026aacute;n RM, Gallacher AE, et al. Efficacy and safety of belimumab in patients with active systemic lupus erythematosus: a randomised, placebo-controlled, phase 3 trial. \u003cem\u003eLancet\u0026nbsp;\u003c/em\u003e2011; \u003cstrong\u003e377:\u0026nbsp;\u003c/strong\u003e721\u0026ndash;31.\u003c/li\u003e\n \u003cli\u003ePetri M, Bruce IN, D\u0026ouml;rner T, et al. Baricitinib for systemic lupus erythematosus: a double-blind, randomised, placebo-controlled, phase 3 trial (SLE-BRAVE-II). \u003cem\u003eLancet\u0026nbsp;\u003c/em\u003e2023; \u003cstrong\u003e401:\u003c/strong\u003e 1011\u0026ndash;19.\u0026nbsp;\u003c/li\u003e\n \u003cli\u003eDeng LJ, Zhou KS, et al. Orelabrutinib for the treatment of relapsed or refractory MCL: a phase 1/2, open-label, multicenter, single-arm study.\u003cem\u003eBlood Advances\u003c/em\u003e 2023; V7:4349-4357\u003c/li\u003e\n \u003cli\u003eIsenberg\u0026nbsp;D, Furie R, et al. Efficacy, Safety, and Pharmacodynamic Effects of the Bruton\u0026apos;s Tyrosine Kinase Inhibitor Fenebrutinib (GDC-0853) in Systemic Lupus Erythematosus: Results of a Phase II, Randomized, Double-Blind, Placebo-Controlled Trial.\u0026nbsp;\u003cem\u003eArthritis Rheumatol\u0026nbsp;\u003c/em\u003e2021;\u003cstrong\u003e73\u003c/strong\u003e:1835-1846\u003c/li\u003e\n \u003cli\u003eWallace DJ, D\u0026ouml;rner T, et al. Efficacy and Safety of the Bruton\u0026apos;s Tyrosine Kinase Inhibitor Evobrutinib in Systemic Lupus Erythematosus: Results of a Phase II, Randomized, Double-Blind, Placebo-Controlled Dose-Ranging Trial.\u003cem\u003e\u0026nbsp;\u003c/em\u003e\u003cem\u003eACR Open Rheumatol\u0026nbsp;\u003c/em\u003e2023;\u003cstrong\u003e5\u003c/strong\u003e:38-48\u003c/li\u003e\n \u003cli\u003eHaselmayer P, Camps M, Liu-Bujalski L, et al. Efficacy and pharmacodynamic modeling of the BTK inhibitor evobrutinib in autoimmune disease models. \u003cem\u003eJ Immunol\u003c/em\u003e 2019; \u003cstrong\u003e202:\u0026nbsp;\u003c/strong\u003e2888\u0026ndash;906.\u003c/li\u003e\n \u003cli\u003eMontalban X, Arnold DL, Weber MS, et al. Clinical relapse rates in relapsing MS patients treated with the BTK inhibitor evobrutinib: results of an open-label extension to a Phase II study. Presented at the European Charcot Foundation 28th Annual Meeting; November 15-19, 2020.\u003c/li\u003e\n\u003c/ol\u003e"},{"header":"Tables","content":"\u003cp\u003e\u003cstrong\u003eTable 1.\u003c/strong\u003e \u003cstrong\u003eBaseline characteristics and disease activity.\u003c/strong\u003e\u003c/p\u003e\n\u003cdiv align=\"\"\u003e\n \u003ctable border=\"1\" cellspacing=\"0\" cellpadding=\"0\" width=\"100%\"\u003e\n \u003cthead\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 24px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 14px;\"\u003e\n \u003cp\u003e\u003cstrong\u003ePlacebo\u003cbr\u003e\u0026nbsp;(N=14)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 15px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eOrelabrutinib 50 mg\u003cbr\u003e\u0026nbsp;(N=15)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 15px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eOrelabrutinib 80 mg\u003cbr\u003e\u0026nbsp;(N=15)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 15px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eOrelabrutinib 100 mg\u003cbr\u003e\u0026nbsp;(N=16)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 15px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eTotal\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/thead\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 24px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eDemographics\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 14px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 15px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 15px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 15px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 15px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 24px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eAge (years)\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 14px;\"\u003e\n \u003cp\u003e31.1 (7.4)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 15px;\"\u003e\n \u003cp\u003e33.0 (11.5)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 15px;\"\u003e\n \u003cp\u003e36.7 (12.1)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 15px;\"\u003e\n \u003cp\u003e33.9 (7.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 15px;\"\u003e\n \u003cp\u003e33.7 (9.8)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 24px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eFemale\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 14px;\"\u003e\n \u003cp\u003e14 (100%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 15px;\"\u003e\n \u003cp\u003e14 (93%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 15px;\"\u003e\n \u003cp\u003e14 (93%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 15px;\"\u003e\n \u003cp\u003e16 (100%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 15px;\"\u003e\n \u003cp\u003e58 (97%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 24px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eEthnic Han\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 14px;\"\u003e\n \u003cp\u003e13 (93%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 15px;\"\u003e\n \u003cp\u003e15 (100%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 15px;\"\u003e\n \u003cp\u003e15 (100%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 15px;\"\u003e\n \u003cp\u003e15 (94%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 15px;\"\u003e\n \u003cp\u003e58 (97%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 24px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eWeight (kg)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 14px;\"\u003e\n \u003cp\u003e59.7 (11.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 15px;\"\u003e\n \u003cp\u003e62.0 (13.5)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 15px;\"\u003e\n \u003cp\u003e58.5 (11.9)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 15px;\"\u003e\n \u003cp\u003e56.2 (9.1)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 15px;\"\u003e\n \u003cp\u003e59.1 (11.4)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 24px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eBody mass index (kg/m\u003csup\u003e2\u003c/sup\u003e)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 14px;\"\u003e\n \u003cp\u003e22.8 (3.6)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 15px;\"\u003e\n \u003cp\u003e24.0 (5.4)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 15px;\"\u003e\n \u003cp\u003e22.6 (3.5)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 15px;\"\u003e\n \u003cp\u003e21.3 (3.4)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 15px;\"\u003e\n \u003cp\u003e22.6 (4.1)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 24px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eDuration of SLE (years)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 14px;\"\u003e\n \u003cp\u003e7.3 (2.2, 10.1)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 15px;\"\u003e\n \u003cp\u003e4.8 (2.2, 8.7)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 15px;\"\u003e\n \u003cp\u003e5.3 (2.3, 10.1)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 15px;\"\u003e\n \u003cp\u003e11.9 (3.0, 17.9)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 15px;\"\u003e\n \u003cp\u003e6.0 (2.6, 11.8)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 24px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eDisease activity\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 14px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 15px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 15px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 15px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 15px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 24px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eSLEDAI score\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 14px;\"\u003e\n \u003cp\u003e8.2 (1.8)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 15px;\"\u003e\n \u003cp\u003e8.5 (2.1)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 15px;\"\u003e\n \u003cp\u003e9.1 (2.6)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 15px;\"\u003e\n \u003cp\u003e8.0 (1.8)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 15px;\"\u003e\n \u003cp\u003e8.5 (2.1)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 24px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026lt;5\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 14px;\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 15px;\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 15px;\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 15px;\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 15px;\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 24px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e5-7\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 14px;\"\u003e\n \u003cp\u003e4 (29%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 15px;\"\u003e\n \u003cp\u003e4 (27%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 15px;\"\u003e\n \u003cp\u003e4 (27%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 15px;\"\u003e\n \u003cp\u003e5 (31%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 15px;\"\u003e\n \u003cp\u003e17 (28%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 24px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e8-12\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 14px;\"\u003e\n \u003cp\u003e10 (71%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 15px;\"\u003e\n \u003cp\u003e11 (73%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 15px;\"\u003e\n \u003cp\u003e10 (67%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 15px;\"\u003e\n \u003cp\u003e11 (69%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 15px;\"\u003e\n \u003cp\u003e42 (70%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 24px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026ge;\u003c/strong\u003e\u003cstrong\u003e13\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 14px;\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 15px;\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 15px;\"\u003e\n \u003cp\u003e1 (7%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 15px;\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 15px;\"\u003e\n \u003cp\u003e1 (2%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"6\" valign=\"top\" style=\"width: 100px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eSLEDAI-2K organ system involvement\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 24px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eVasculitis\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 14px;\"\u003e\n \u003cp\u003e1 (7%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 15px;\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 15px;\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 15px;\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 15px;\"\u003e\n \u003cp\u003e1 (2%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 24px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eArthritis\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 14px;\"\u003e\n \u003cp\u003e6 (43%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 15px;\"\u003e\n \u003cp\u003e4 (27%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 15px;\"\u003e\n \u003cp\u003e7 (47%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 15px;\"\u003e\n \u003cp\u003e5 (31%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 15px;\"\u003e\n \u003cp\u003e22 (37%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 24px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eHematuria\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 14px;\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 15px;\"\u003e\n \u003cp\u003e3 (20%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 15px;\"\u003e\n \u003cp\u003e2 (13%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 15px;\"\u003e\n \u003cp\u003e1 (6%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 15px;\"\u003e\n \u003cp\u003e6 (10%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 24px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eProteinuria\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 14px;\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 15px;\"\u003e\n \u003cp\u003e6 (40%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 15px;\"\u003e\n \u003cp\u003e7 (47%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 15px;\"\u003e\n \u003cp\u003e4 (25%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 15px;\"\u003e\n \u003cp\u003e17 (28%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 24px;\"\u003e\n \u003cp\u003e\u003cstrong\u003ePyuria\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 14px;\"\u003e\n \u003cp\u003e1 (7%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 15px;\"\u003e\n \u003cp\u003e2 (13%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 15px;\"\u003e\n \u003cp\u003e2 (13%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 15px;\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 15px;\"\u003e\n \u003cp\u003e5 (8%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 24px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eAlopecia\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 14px;\"\u003e\n \u003cp\u003e8 (57%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 15px;\"\u003e\n \u003cp\u003e7 (47%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 15px;\"\u003e\n \u003cp\u003e5 (33%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 15px;\"\u003e\n \u003cp\u003e9 (56%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 15px;\"\u003e\n \u003cp\u003e29 (48%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 24px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eRash\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 14px;\"\u003e\n \u003cp\u003e9 (64%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 15px;\"\u003e\n \u003cp\u003e5 (33%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 15px;\"\u003e\n \u003cp\u003e4 (27%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 15px;\"\u003e\n \u003cp\u003e11 (69%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 15px;\"\u003e\n \u003cp\u003e29 (48%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 24px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eMucosal ulcers\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 14px;\"\u003e\n \u003cp\u003e1 (7%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 15px;\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 15px;\"\u003e\n \u003cp\u003e1 (7%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 15px;\"\u003e\n \u003cp\u003e1 (6%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 15px;\"\u003e\n \u003cp\u003e3 (5%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 24px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eLow complement\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 14px;\"\u003e\n \u003cp\u003e10 (71%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 15px;\"\u003e\n \u003cp\u003e10 (67%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 15px;\"\u003e\n \u003cp\u003e11 (73%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 15px;\"\u003e\n \u003cp\u003e12 (75%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 15px;\"\u003e\n \u003cp\u003e43 (72%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 24px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eIncreased DNA\u003c/strong\u003e \u003cstrong\u003ebinding\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 14px;\"\u003e\n \u003cp\u003e11 (79%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 15px;\"\u003e\n \u003cp\u003e12 (80%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 15px;\"\u003e\n \u003cp\u003e11 (73%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 15px;\"\u003e\n \u003cp\u003e11 (69%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 15px;\"\u003e\n \u003cp\u003e45 (75%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 24px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eLeukopenia\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 14px;\"\u003e\n \u003cp\u003e1 (7%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 15px;\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 15px;\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 15px;\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 15px;\"\u003e\n \u003cp\u003e1 (2%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 24px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eBILAG A or B organ domain scores at baseline\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 14px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 15px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 15px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 15px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 15px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 24px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eMucocutaneous\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 14px;\"\u003e\n \u003cp\u003e10 (71%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 15px;\"\u003e\n \u003cp\u003e5 (33%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 15px;\"\u003e\n \u003cp\u003e4 (27%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 15px;\"\u003e\n \u003cp\u003e11 (69%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 15px;\"\u003e\n \u003cp\u003e30 (50%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 24px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eRenal\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 14px;\"\u003e\n \u003cp\u003e1 (7%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 15px;\"\u003e\n \u003cp\u003e6 (40%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 15px;\"\u003e\n \u003cp\u003e7 (47%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 15px;\"\u003e\n \u003cp\u003e4 (25%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 15px;\"\u003e\n \u003cp\u003e18 (30%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 24px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;Blood system\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 14px;\"\u003e\n \u003cp\u003e1 (7%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 15px;\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 15px;\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 15px;\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 15px;\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 24px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eMusculoskeletal\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 14px;\"\u003e\n \u003cp\u003e1 (7%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 15px;\"\u003e\n \u003cp\u003e4 (27%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 15px;\"\u003e\n \u003cp\u003e3 (20%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 15px;\"\u003e\n \u003cp\u003e2 (13%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 15px;\"\u003e\n \u003cp\u003e10 (17%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 24px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eMean proteinuria (g/24 h)\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 14px;\"\u003e\n \u003cp\u003e0.2 (0.1)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 15px;\"\u003e\n \u003cp\u003e0.5 (0.7)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 15px;\"\u003e\n \u003cp\u003e0.8 (0.9)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 15px;\"\u003e\n \u003cp\u003e0.5 (0.8)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 15px;\"\u003e\n \u003cp\u003e0.5 (0.7)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 24px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026gt;0.5 g/24 h\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 14px;\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 15px;\"\u003e\n \u003cp\u003e6 (40%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 15px;\"\u003e\n \u003cp\u003e7 (47%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 15px;\"\u003e\n \u003cp\u003e4 (25%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 15px;\"\u003e\n \u003cp\u003e17 (28%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 24px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eBiomarkers\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 14px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 15px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 15px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 15px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 15px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 24px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eAnti-dsDNA positive\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 14px;\"\u003e\n \u003cp\u003e7 (50%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 15px;\"\u003e\n \u003cp\u003e6 (40%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 15px;\"\u003e\n \u003cp\u003e4 (27%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 15px;\"\u003e\n \u003cp\u003e5 (31%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 15px;\"\u003e\n \u003cp\u003e22 (37%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 24px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eANA\u0026nbsp;\u003c/strong\u003e\u003cstrong\u003e\u0026ge;\u003c/strong\u003e\u003cstrong\u003e1:40\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 14px;\"\u003e\n \u003cp\u003e14 (100%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 15px;\"\u003e\n \u003cp\u003e13 (87%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 15px;\"\u003e\n \u003cp\u003e12 (80%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 15px;\"\u003e\n \u003cp\u003e13 (81%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 15px;\"\u003e\n \u003cp\u003e52 (87%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 24px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eAnti-Smith positive\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 14px;\"\u003e\n \u003cp\u003e6 (43%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 15px;\"\u003e\n \u003cp\u003e6 (40%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 15px;\"\u003e\n \u003cp\u003e8 (53%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 15px;\"\u003e\n \u003cp\u003e9 (56%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 15px;\"\u003e\n \u003cp\u003e29 (48%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 24px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eLow C3\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 14px;\"\u003e\n \u003cp\u003e9 (64%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 15px;\"\u003e\n \u003cp\u003e8 (53%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 15px;\"\u003e\n \u003cp\u003e11 (73%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 15px;\"\u003e\n \u003cp\u003e11 (69%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 15px;\"\u003e\n \u003cp\u003e39 (65%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 24px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eLow C4\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 14px;\"\u003e\n \u003cp\u003e6 (43%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 15px;\"\u003e\n \u003cp\u003e7 (47%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 15px;\"\u003e\n \u003cp\u003e8 (53%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 15px;\"\u003e\n \u003cp\u003e7 (44%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 15px;\"\u003e\n \u003cp\u003e28 (47%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 24px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eIgG (g/L)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 14px;\"\u003e\n \u003cp\u003e14.7 (4.1)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 15px;\"\u003e\n \u003cp\u003e14.1 (3.1)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 15px;\"\u003e\n \u003cp\u003e14.4 (3.2)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 15px;\"\u003e\n \u003cp\u003e14.7 (4.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 15px;\"\u003e\n \u003cp\u003e14.5 (3.5)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 24px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eIgA (g/L)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 14px;\"\u003e\n \u003cp\u003e3.3 (1.5)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 15px;\"\u003e\n \u003cp\u003e2.5 (1.5)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 15px;\"\u003e\n \u003cp\u003e2.8 (0.9)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 15px;\"\u003e\n \u003cp\u003e3.2 (1.2)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 15px;\"\u003e\n \u003cp\u003e2.9 (1.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 24px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eIgM (g/L)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 14px;\"\u003e\n \u003cp\u003e0.9 (0.6)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 15px;\"\u003e\n \u003cp\u003e0.8 (0.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 15px;\"\u003e\n \u003cp\u003e0.9 (0.4)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 15px;\"\u003e\n \u003cp\u003e1.1 (0.7)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 15px;\"\u003e\n \u003cp\u003e0.9 (0.5)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 24px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eConcomitant medications for SLE\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 14px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 15px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 15px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 15px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 15px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 24px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eCorticosteroids\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 14px;\"\u003e\n \u003cp\u003e12 (86%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 15px;\"\u003e\n \u003cp\u003e14 (93%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 15px;\"\u003e\n \u003cp\u003e14 (93%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 15px;\"\u003e\n \u003cp\u003e14 (88%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 15px;\"\u003e\n \u003cp\u003e54 (90%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 24px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eMean prednisone, mg/day\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 14px;\"\u003e\n \u003cp\u003e9.8 (5.4)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 15px;\"\u003e\n \u003cp\u003e12.7 (6.2)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 15px;\"\u003e\n \u003cp\u003e8.0 (4.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 15px;\"\u003e\n \u003cp\u003e10.0 (4.7)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 15px;\"\u003e\n \u003cp\u003e10.1 (5.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 24px;\"\u003e\n \u003cp\u003e\u003cstrong\u003ePrednisone,\u0026nbsp;\u003c/strong\u003e\u003cstrong\u003e\u0026ge;\u003c/strong\u003e\u003cstrong\u003e7.5 mg/day\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 14px;\"\u003e\n \u003cp\u003e9 (64%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 15px;\"\u003e\n \u003cp\u003e11 (73%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 15px;\"\u003e\n \u003cp\u003e6 (40%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 15px;\"\u003e\n \u003cp\u003e9 (56%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 15px;\"\u003e\n \u003cp\u003e35 (58%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 24px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eAntimalarials\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 14px;\"\u003e\n \u003cp\u003e12 (86%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 15px;\"\u003e\n \u003cp\u003e12 (80%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 15px;\"\u003e\n \u003cp\u003e13 (87%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 15px;\"\u003e\n \u003cp\u003e13 (81%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 15px;\"\u003e\n \u003cp\u003e50 (83%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 24px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eImmunosuppressants\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 14px;\"\u003e\n \u003cp\u003e8 (57%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 15px;\"\u003e\n \u003cp\u003e12 (80%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 15px;\"\u003e\n \u003cp\u003e9 (60%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 15px;\"\u003e\n \u003cp\u003e12 (75%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 15px;\"\u003e\n \u003cp\u003e41 (68%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 24px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eMycophenolate mofetil\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 14px;\"\u003e\n \u003cp\u003e5 (36%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 15px;\"\u003e\n \u003cp\u003e10 (67%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 15px;\"\u003e\n \u003cp\u003e7 (47%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 15px;\"\u003e\n \u003cp\u003e9 (56%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 15px;\"\u003e\n \u003cp\u003e31 (52%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 24px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eTacrolimus\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 14px;\"\u003e\n \u003cp\u003e2 (14%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 15px;\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 15px;\"\u003e\n \u003cp\u003e2 (13%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 15px;\"\u003e\n \u003cp\u003e1 (6%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 15px;\"\u003e\n \u003cp\u003e5 (8%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 24px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eAzathioprine\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 14px;\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 15px;\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 15px;\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 15px;\"\u003e\n \u003cp\u003e1 (6%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 15px;\"\u003e\n \u003cp\u003e1 (2%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 24px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eMethotrexate\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 14px;\"\u003e\n \u003cp\u003e1 (7%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 15px;\"\u003e\n \u003cp\u003e1 (7%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 15px;\"\u003e\n \u003cp\u003e1 (7%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 15px;\"\u003e\n \u003cp\u003e1 (6%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 15px;\"\u003e\n \u003cp\u003e4 (7%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 24px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eCyclosporine\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 14px;\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 15px;\"\u003e\n \u003cp\u003e1 (7%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 15px;\"\u003e\n \u003cp\u003e1 (7%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 15px;\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 15px;\"\u003e\n \u003cp\u003e2 (3%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 24px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eLeflunomide\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 14px;\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 15px;\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 15px;\"\u003e\n \u003cp\u003e1 (7%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 15px;\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 15px;\"\u003e\n \u003cp\u003e1 (2%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n \u003c/table\u003e\n\u003c/div\u003e\n\u003cp\u003eSLEDAI-2K = Systemic Lupus Erythematosus Disease Activity Index 2000. BILAG = British Isles Lupus Assessment Group. PGA = Physician\u0026rsquo;s Global Assessment. (1) Data are number (%) or mean (SD), unless specified otherwise. (2) Percentages are calculated with the number of FAS subjects in each group as the denominator. (3) Age (years) = (date of informed consent - date of birth +1) / 365.25, rounded down. (4) BMI (kg /m\u003csup\u003e2\u003c/sup\u003e) = weight (kg) / (height (cm)/100)\u003csup\u003e2\u003c/sup\u003e. (5) Baseline is defined as the last non-missing observation before first administration of the investigational drug. (6) SLE diagnosis date: If month is missing, then 6 months will be used to fill in; if the day is missing, it is filled with 1 day; missing years are considered missing. (7) Duration of SLE (years) = (date of first administration - date of SLE diagnosis +1) / 365.25. (8) Steroid dose conversion: methylprednisolone 4 mg = prednisone 5 mg; prednisone 5 mg = prednisone 5 mg.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eTable\u0026nbsp;\u003c/strong\u003e\u003cstrong\u003e2.\u003c/strong\u003e \u003cstrong\u003eImprovement of proteinuria, arthritis, and rash at week 12.\u003c/strong\u003e\u003c/p\u003e\n\u003ctable border=\"1\" cellspacing=\"0\" cellpadding=\"0\" width=\"100%\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 32px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 16px;\"\u003e\n \u003cp\u003e\u003cstrong\u003ePlacebo\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 16px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eOrelabrutinib 50 mg\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 16px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eOrelabrutinib 80 mg\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 16px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eOrelabrutinib 100 mg\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 32px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eBaseline\u0026nbsp;\u003c/strong\u003e\u003cstrong\u003earthritis (N=22)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 16px;\"\u003e\n \u003cp\u003e6\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 16px;\"\u003e\n \u003cp\u003e4\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 16px;\"\u003e\n \u003cp\u003e7\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 16px;\"\u003e\n \u003cp\u003e5\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 0px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eArthritis remission*\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 0px;\"\u003e\n \u003cp\u003e3 (50%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 0px;\"\u003e\n \u003cp\u003e4 (100%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 0px;\"\u003e\n \u003cp\u003e5 (71%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 0px;\"\u003e\n \u003cp\u003e5 (100%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 0px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eBaseline rash (N=29)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 0px;\"\u003e\n \u003cp\u003e9\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 0px;\"\u003e\n \u003cp\u003e5\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 0px;\"\u003e\n \u003cp\u003e4\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 0px;\"\u003e\n \u003cp\u003e11\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 0px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eRash remission**\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 0px;\"\u003e\n \u003cp\u003e3 (33%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 0px;\"\u003e\n \u003cp\u003e2 (40%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 0px;\"\u003e\n \u003cp\u003e3 (75%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 0px;\"\u003e\n \u003cp\u003e4 (36%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"bottom\" style=\"width: 32px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eBaseline proteinuria\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026gt;0.5 g/24 h (N=17)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 16px;\"\u003e\n \u003cp\u003eN=0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 16px;\"\u003e\n \u003cp\u003eN=6\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 16px;\"\u003e\n \u003cp\u003eN=7\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 16px;\"\u003e\n \u003cp\u003eN=4\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"bottom\" style=\"width: 0px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eProteinuria remission***\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 0px;\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 0px;\"\u003e\n \u003cp\u003e2 (33%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 0px;\"\u003e\n \u003cp\u003e2 (29%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 0px;\"\u003e\n \u003cp\u003e3 (75%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 0px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eProteinuria remission or proteinuria\u0026nbsp;\u003c/strong\u003e\u003cstrong\u003e\u0026le;\u003c/strong\u003e\u003cstrong\u003e0.5 g/24 h or\u0026nbsp;\u003c/strong\u003e\u003cstrong\u003e\u0026ge;\u003c/strong\u003e\u003cstrong\u003e25% reduction from baseline***\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 0px;\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 0px;\"\u003e\n \u003cp\u003e3 (50%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 0px;\"\u003e\n \u003cp\u003e4 (57%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 0px;\"\u003e\n \u003cp\u003e3 (75%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003e*Percentages are calculated based on the number of subjects with baseline\u0026nbsp;arthritis.\u003c/p\u003e\n\u003cp\u003e** Percentages are calculated based on the number of subjects with baseline\u0026nbsp;rash.\u003c/p\u003e\n\u003cp\u003e*** Percentages are calculated based on the number of subjects with baseline proteinuria \u0026gt;0.5 g/24 h.\u0026nbsp;\u003c/p\u003e\n\u003cp id=\"_Toc151980603\"\u003e\u003cstrong\u003eTable\u0026nbsp;\u003c/strong\u003e\u003cstrong\u003e3: Total SLEDAI-2K score and relative baseline change at each visit, FAS (N=60)\u003c/strong\u003e\u003c/p\u003e\n\u003ctable border=\"1\" cellspacing=\"0\" cellpadding=\"0\" width=\"100%\"\u003e\n \u003cthead\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 23px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eVisit\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 19px;\"\u003e\n \u003cp\u003e\u003cstrong\u003ePlacebo\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 19px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eOrelabrutinib\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e50 mg\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 19px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eOrelabrutinib\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;80 mg\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 19px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eOrelabrutinib\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;100 mg\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/thead\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 23px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eBaseline\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 19px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 19px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 19px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 19px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 23px;\"\u003e\n \u003cp\u003eN (miss)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 19px;\"\u003e\n \u003cp\u003e14 (0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 19px;\"\u003e\n \u003cp\u003e15 (0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 19px;\"\u003e\n \u003cp\u003e15 (0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 19px;\"\u003e\n \u003cp\u003e16 (0)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 23px;\"\u003e\n \u003cp\u003eMean (SD)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 19px;\"\u003e\n \u003cp\u003e8.2 (1.76)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 19px;\"\u003e\n \u003cp\u003e8.5 (2.07)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 19px;\"\u003e\n \u003cp\u003e9.1 (2.60)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 19px;\"\u003e\n \u003cp\u003e8.0 (1.79)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 23px;\"\u003e\n \u003cp\u003eMedian (Q1, Q3)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 19px;\"\u003e\n \u003cp\u003e8.0 (7.0, 10.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 19px;\"\u003e\n \u003cp\u003e8.0 (6.0, 10.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 19px;\"\u003e\n \u003cp\u003e8.0 (6.0, 12.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 19px;\"\u003e\n \u003cp\u003e8.0 (6.0, 9.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 23px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eDAY 84\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 19px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 19px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 19px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 19px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 23px;\"\u003e\n \u003cp\u003eN (miss)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 19px;\"\u003e\n \u003cp\u003e14 (0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 19px;\"\u003e\n \u003cp\u003e14 (1)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 19px;\"\u003e\n \u003cp\u003e13 (2)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 19px;\"\u003e\n \u003cp\u003e14 (2)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 23px;\"\u003e\n \u003cp\u003eMean (SD)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 19px;\"\u003e\n \u003cp\u003e7.2 (4.26)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 19px;\"\u003e\n \u003cp\u003e5.6 (2.85)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 19px;\"\u003e\n \u003cp\u003e5.2 (2.89)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 19px;\"\u003e\n \u003cp\u003e4.5 (3.06)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 23px;\"\u003e\n \u003cp\u003eMedian (Q1, Q3)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 19px;\"\u003e\n \u003cp\u003e7.0 (4.0, 10.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 19px;\"\u003e\n \u003cp\u003e5.0 (4.0, 6.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 19px;\"\u003e\n \u003cp\u003e6.0 (4.0, 6.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 19px;\"\u003e\n \u003cp\u003e4.5 (2.0, 6.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 23px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eDAY 84\u003c/strong\u003e\u003cstrong\u003e\u0026nbsp;change from baseline\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 19px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 19px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 19px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 19px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 23px;\"\u003e\n \u003cp\u003eN (miss)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 19px;\"\u003e\n \u003cp\u003e14 (0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 19px;\"\u003e\n \u003cp\u003e14 (1)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 19px;\"\u003e\n \u003cp\u003e13 (2)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 19px;\"\u003e\n \u003cp\u003e14 (2)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 23px;\"\u003e\n \u003cp\u003eMean (SD)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 19px;\"\u003e\n \u003cp\u003e-1.0 (3.11)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 19px;\"\u003e\n \u003cp\u003e-2.9 (3.48)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 19px;\"\u003e\n \u003cp\u003e-4.0 (3.06)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 19px;\"\u003e\n \u003cp\u003e-3.2 (3.29)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 23px;\"\u003e\n \u003cp\u003eMedian (Q1, Q3)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 19px;\"\u003e\n \u003cp\u003e0.0 (-4.0, 0.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 19px;\"\u003e\n \u003cp\u003e-2.0 (-6.0, 0.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 19px;\"\u003e\n \u003cp\u003e-4.0 (-6.0, -2.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 19px;\"\u003e\n \u003cp\u003e-4.0 (-4.0, 0.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eTable\u0026nbsp;\u003c/strong\u003e\u003cstrong\u003e4.\u003c/strong\u003e \u003cstrong\u003eAdverse events in the safety population.\u003c/strong\u003e\u003c/p\u003e\n\u003ctable border=\"1\" cellspacing=\"0\" cellpadding=\"0\" width=\"100%\"\u003e\n \u003cthead\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 0px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 0px;\"\u003e\n \u003cp\u003e\u003cstrong\u003ePlacebo\u003cbr\u003e\u0026nbsp;(N=14)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 0px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eOrelabrutinib 50 mg\u003cbr\u003e\u0026nbsp;(N=15)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 0px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eOrelabrutinib 80 mg\u003cbr\u003e\u0026nbsp;(N=15)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 0px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eOrelabrutinib 100 mg\u003cbr\u003e\u0026nbsp;(N=16)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 0px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eTotal\u003cbr\u003e\u0026nbsp;(N=60)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/thead\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 0px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eTreatment-emergent adverse event\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 0px;\"\u003e\n \u003cp\u003e12 (86%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 0px;\"\u003e\n \u003cp\u003e12 (80%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 0px;\"\u003e\n \u003cp\u003e14 (93%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 0px;\"\u003e\n \u003cp\u003e16 (100%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 0px;\"\u003e\n \u003cp\u003e54 (90%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 0px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eDMID\u0026nbsp;\u003c/strong\u003e\u003cstrong\u003e\u0026ge;\u003c/strong\u003e\u003cstrong\u003e3 treatment-emergent adverse event\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 0px;\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 0px;\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 0px;\"\u003e\n \u003cp\u003e3 (20%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 0px;\"\u003e\n \u003cp\u003e2 (13%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 0px;\"\u003e\n \u003cp\u003e5 (8%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 0px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eDiscontinuation\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 0px;\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 0px;\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 0px;\"\u003e\n \u003cp\u003e1 (7%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 0px;\"\u003e\n \u003cp\u003e1 (6%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 0px;\"\u003e\n \u003cp\u003e2 (3%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 0px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eDeath\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 0px;\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 0px;\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 0px;\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 0px;\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 0px;\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 0px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eTreatment-emergent serious adverse event\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 0px;\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 0px;\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 0px;\"\u003e\n \u003cp\u003e4 (27%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 0px;\"\u003e\n \u003cp\u003e2 (13%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 0px;\"\u003e\n \u003cp\u003e6 (10%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 0px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eTreatment-related adverse event\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 0px;\"\u003e\n \u003cp\u003e7 (50%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 0px;\"\u003e\n \u003cp\u003e10 (67%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 0px;\"\u003e\n \u003cp\u003e13 (87%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 0px;\"\u003e\n \u003cp\u003e13 (81%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 0px;\"\u003e\n \u003cp\u003e43 (72%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 0px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eDMID\u0026nbsp;\u003c/strong\u003e\u003cstrong\u003e\u0026ge;\u003c/strong\u003e\u003cstrong\u003e3 treatment-related adverse event\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 0px;\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 0px;\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 0px;\"\u003e\n \u003cp\u003e1 (7%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 0px;\"\u003e\n \u003cp\u003e1 (6%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 0px;\"\u003e\n \u003cp\u003e2 (3%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 0px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eDiscontinuation\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 0px;\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 0px;\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 0px;\"\u003e\n \u003cp\u003e1 (7%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 0px;\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 0px;\"\u003e\n \u003cp\u003e1 (2%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 0px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eDeath\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 0px;\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 0px;\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 0px;\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 0px;\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 0px;\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 0px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eTreatment-related serious adverse event\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 0px;\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 0px;\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 0px;\"\u003e\n \u003cp\u003e2 (13%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 0px;\"\u003e\n \u003cp\u003e1 (6%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 0px;\"\u003e\n \u003cp\u003e3 (5%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"6\" valign=\"top\" style=\"width: 0px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eTreatment-related adverse event \u0026ge;2 (preferred term)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 0px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eDecreased lymphocyte count\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 0px;\"\u003e\n \u003cp\u003e1 (7%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 0px;\"\u003e\n \u003cp\u003e2 (13%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 0px;\"\u003e\n \u003cp\u003e5 (33%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 0px;\"\u003e\n \u003cp\u003e5 (31%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 0px;\"\u003e\n \u003cp\u003e13 (22%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 0px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eDecreased white blood cell count\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 0px;\"\u003e\n \u003cp\u003e2 (14%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 0px;\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 0px;\"\u003e\n \u003cp\u003e3 (20%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 0px;\"\u003e\n \u003cp\u003e3 (19%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 0px;\"\u003e\n \u003cp\u003e8 (13%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 0px;\"\u003e\n \u003cp\u003e\u003cstrong\u003ePetechia\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 0px;\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 0px;\"\u003e\n \u003cp\u003e1 (7%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 0px;\"\u003e\n \u003cp\u003e2 (13%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 0px;\"\u003e\n \u003cp\u003e4 (25%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 0px;\"\u003e\n \u003cp\u003e7 (12%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 0px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eUpper respiratory tract\u003c/strong\u003e\u003cstrong\u003e\u0026nbsp;infection\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 0px;\"\u003e\n \u003cp\u003e1 (7%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 0px;\"\u003e\n \u003cp\u003e1 (7%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 0px;\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 0px;\"\u003e\n \u003cp\u003e4 (25%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 0px;\"\u003e\n \u003cp\u003e6 (10%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 0px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eElevated blood thyrotropin\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 0px;\"\u003e\n \u003cp\u003e2 (14%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 0px;\"\u003e\n \u003cp\u003e1 (7%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 0px;\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 0px;\"\u003e\n \u003cp\u003e3 (19%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 0px;\"\u003e\n \u003cp\u003e6 (10%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 0px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eAnemia\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 0px;\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 0px;\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 0px;\"\u003e\n \u003cp\u003e3 (20%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 0px;\"\u003e\n \u003cp\u003e2 (13%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 0px;\"\u003e\n \u003cp\u003e5 (8%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 0px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eHypokalemia\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 0px;\"\u003e\n \u003cp\u003e1 (7%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 0px;\"\u003e\n \u003cp\u003e2 (13%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 0px;\"\u003e\n \u003cp\u003e1 (7%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 0px;\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 0px;\"\u003e\n \u003cp\u003e4 (7%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 0px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eAbnormal liver function\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 0px;\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 0px;\"\u003e\n \u003cp\u003e1 (7%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 0px;\"\u003e\n \u003cp\u003e2 (13%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 0px;\"\u003e\n \u003cp\u003e1 (6%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 0px;\"\u003e\n \u003cp\u003e4 (7%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 0px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eDecreased platelet count\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 0px;\"\u003e\n \u003cp\u003e1 (7%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 0px;\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 0px;\"\u003e\n \u003cp\u003e1 (7%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 0px;\"\u003e\n \u003cp\u003e2 (13%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 0px;\"\u003e\n \u003cp\u003e4 (7%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003eData are presented as n (%). Percentages are calculated based on the number of subjects in safety population.\u003c/p\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":true,"hideJournal":true,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"","lastPublishedDoi":"10.21203/rs.3.rs-7058001/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-7058001/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003eOrelabrutinib is a highly selective, irreversible inhibitor of Bruton\u0026rsquo;s tyrosine kinase (BTK). It has shown promising results in animal models, indicating potential for treating systemic lupus erythematosus (SLE). A multicentre, double-blind, randomised, placebo-controlled, phase Ib/IIa trial (NCT04305197) was conducted. Sixty SLE patients were randomised 1:1:1:1 to receive oral orelabrutinib (50, 80, 100 mg) or placebo once daily for 12 weeks. A total of 55 patients completed the trial. In all evaluable patients, the 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. Among patients with baseline SLEDAI-2K\u0026thinsp;\u0026gt;\u0026thinsp;8, significantly higher SRI-4 responses were noted with orelabrutinib at 50 mg (80%, \u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0\u0026middot;048), 80 mg (83%, \u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0\u0026middot;048), and 100 mg (100%, \u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0\u0026middot;029) compared to placebo (0%). Adverse events were mostly mild or moderate in the study. In summary, orelabrutinib was effective and well-tolerated in SLE patients.\u003c/p\u003e","manuscriptTitle":"Orelabrutinib, an irreversible inhibitor of Bruton’s tyrosine kinase, for the treatment of systemic lupus erythematosus: a randomised, double-blind, placebo-controlled, phase Ib/IIa study","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-07-23 08:34:15","doi":"10.21203/rs.3.rs-7058001/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"c7d50186-3e08-4a32-8443-2e5bf56ef0b9","owner":[],"postedDate":"July 23rd, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[{"id":51702880,"name":"Health sciences/Rheumatology/Rheumatic diseases/Systemic lupus erythematosus"},{"id":51702881,"name":"Biological sciences/Immunology/Immunotherapy/Immunosuppression"}],"tags":[],"updatedAt":"2025-08-28T16:10:28+00:00","versionOfRecord":[],"versionCreatedAt":"2025-07-23 08:34:15","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-7058001","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-7058001","identity":"rs-7058001","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}