GR1501-007 (NCT05881785) was a phase III, multicenter, randomized, double-blind, placebo-controlled trial conducted over 48 weeks, consisting of a 16-week core treatment period, a 16-week maintenance period, and a 16-week follow-up period. Patients in the placebo group were re-randomized to receive xeligekimab 100 mg or 200 mg at week 16. During the 16-week maintenance phase, all patients received xeligekimab, while in the 16-week follow-up period, subjects underwent routine follow-up without receiving xeligekmab. Patient enrollment and data collection were conducted at 40 sites across China.

Chinese patients aged ≥ 18 years with r-axSpA were enrolled in the study. Eligible patients had a history of back pain lasting at least 3 months, with onset before age 45 years, and met the Assessment of Spondyloarthritis International Society (ASAS) classification criteria [14]. Radiographic evidence of sacroiliitis was required, with grades ≥ 2 bilaterally or grades 3–4 unilaterally according to the modified New York criteria [15]. Patients were required to have active disease, defined by a baseline Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) score of ≥ 4 and a spinal pain score (BASDAI Question 2) of ≥ 4 [16].

Patients had to demonstrate an inadequate response to NSAIDs for at least 4 weeks or have a history of NSAIDs intolerance or contraindications. Those using NSAIDs as part of their ongoing therapy were required to maintain a stable dose for at least 2 weeks prior to randomization. Stable doses of systemic corticosteroids (prednisone ≤ 10 mg or an equivalent dose), methotrexate (7.5–25 mg/week), or sulfasalazine (≤ 3 g/day) were permitted for 4 weeks before the study. Additionally, patients who had previously used no more than two TNFi therapies were eligible for enrollment.

Exclusion criteria included total spinal ankylosis (defined as the fusion of all vertebrae in the spine), active inflammatory bowel disease, active or recent infection (defined as receiving oral anti-infective medication within the past 2 weeks, requiring intravenous anti-infective therapy or undergoing hospital treatment within the past 8 weeks), active tuberculosis (based on clinical symptoms, signs, laboratory examination, computed tomography (CT) examination, and medical history), systemic inflammatory diseases such as systemic lupus erythematosus, vasculitis, rheumatoid arthritis, etc. and a history of lymphoproliferative or malignant disease. Patients with a history of JAKi use were eligible for enrollment but were required to discontinue the medication for at least 4 weeks before enrollment. However, subjects with a history of IL-17i use were not eligible to participate. Details are available in the Online Supplementary Material.

The study protocol (NCT05881785) and its amendments were reviewed and approved by the independent ethics committee or Institutional Review Board (IRB) at each center. The study was conducted in accordance with the principles outlined in the Declaration of Helsinki and the Council of International Organizations of Medical Sciences International Ethical Guidelines. Written informed consent was obtained from all enrolled patients.

Patients were randomly assigned (1:1:1) to receive subcutaneous administration of xeligekimab 100 mg, xeligekimab 200 mg, or placebo from week 0 to week 16. Patients were initially administered either 100 mg or 200 mg once every 2 weeks (Q2W) for the first three doses, followed by administration every 4 weeks. Randomization was stratified by medication history (biologic-experienced vs. biologic-naïve) and weight (≥ 70 kg vs. < 70 kg) and was conducted using an interactive Web Response System.

Throughout the treatment period, patients, investigators, and the sponsor’s trial team remained blinded to the treatment allocation. All patients received the same frequency and number of injections, irrespective of their treatment arm. Patients initially receiving placebo were re-randomized to xeligekimab 100 mg or 200 mg at week 16, while those already on xeligekimab continued with their assigned treatment regimens until the study’s end.

The primary endpoint of the trial was the proportion of patients achieving ASAS20 at week 16, comparing each xeligekimab dosing regimen to placebo. ASAS20 is defined as a relative improvement of ≥ 20% and an absolute improvement of ≥ 1 unit in at least three of the first four main ASAS domains, with no worsening of ≥ 20% and ≥ 1 unit in the remaining domain. The six main ASAS domains include patient global assessment, spinal pain, Bath Ankylosing Spondylitis Functional Index (BASFI), the average of the last two questions of the BASDAI, Bath Ankylosing Spondylitis Metrology Index (BASMI), and high sensitive-C-reactive protein (hs-CRP) [16].

The secondary endpoints included demonstrating the efficacy of xeligekimab based on the following parameters:(1) the proportion of patients achieving ASAS20 at weeks 2, 4, 8, 12, 20, 24, 28, 32, 36, and 48; (2) the proportion of patients achieving ASAS40 (improvement of ≥ 40% and absolute improvement of ≥ 2 units in at least three of the first four main ASAS domains, with no worsening in the remaining domain) at each visit; (3) the proportion of patients achieving ASAS5/6 (≥ 20% improvement in five of the six ASAS domains) at weeks 16, 32, and 48; (4) change from baseline in physician and patient global assessments at weeks 16, 32, and 48; (5) change from baseline in Ankylosing Spondylitis Disease Activity Score based on C-reactive protein (ASDAS-CRP) or erythrocyte sedimentation rate (ASDAS-ESR) at weeks 16, 32, and 48; (6) change from baseline in BASDAI, BASFI, BASMI, and Maastricht Ankylosing Spondylitis Enthesis Score (MASES) [17] at weeks 16, 32, and 48; (7) change from baseline in Work Productivity and Activity Impairment (WPAI) [18], Ankylosing Spondylitis Quality of Life (ASQoL) [19], and Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-F) [20] at weeks 16, 32, and 48.

The overall safety and tolerability of xeligekimab were assessed by monitoring adverse events (AEs), serious AEs, laboratory assessments, vital signs, electrocardiography, and the Columbia Suicide Severity Rating Scale (C-SSRS) [21].

Sample size calculations for the trial determined that a total of 465 patients were needed, accounting for a 20% dropout rate. A sample of 372 patients (124 per group) was sufficient to achieve 90% power to test the superiority of xeligekimab over placebo for the ASAS20 outcome at week 16, with a two-sided 2.5% type I error rate. This calculation assumed ASAS20 response rates of 62% for xeligekimab and 39% for placebo, based on clinical trials of secukinumab in Chinese patients with AS and previous results of xeligekimab in AS. The power calculation focused solely on the primary objective and did not account for other comparisons.

The primary estimand assessed the treatment policy strategy, with treatment effect expressed as the difference in ASAS20 responder proportions between xeligekimab and placebo with 95% confidence intervals (CIs). Secondary endpoints were analyzed under the same strategy, with categorical variables summarized as responder proportions and continuous variables as least-square mean changes, each with 95% CIs. Other exploratory efficacy outcomes were analyzed descriptively.

The safety analysis was conducted in the Safety Analysis Set (SS), which included all patients who received at least one dose of the study drug, analyzed according to their treatment group. Safety data were summarized by the frequency of events occurring in each treatment group during the core treatment period. Statistical analyses were performed using SAS version 9.4.