POS0214 A MULTICENTER, RANDOMIZED, DOUBLE-BLIND, PLACEBO-CONTROLLED, PHASE 2/3 STUDY OF SHR0302, A SELECTIVE JANUS KINASE 1 INHIBITOR, IN PATIENTS WITH ACTIVE ANKYLOSING SPONDYLITIS

Background:

JAK inhibitors are effective in treating signs and symptoms of AS. However, with regard to the side effects, specific JAK1 inhibitors emerge as the most promising target.

Objectives:

This phase 3 study investigated the efficacy and safety of SHR0302, a potent selective JAK1 inhibitor, for the treatment of patients with active AS.

Methods:

This is a randomized, double-blind, adaptive, seamless, phase 2/3 study (NCT NCT04481139). Eligible patients had active AS, and had inadequate responses to ≥2 NSAIDs administered at the therapeutic dose range for ≥ 4 weeks. In the phase 2 period, patients were randomized (1:1:1:1) to receive oral SHR0302 at doses of 2 mg, 4 mg, or 8 mg, or placebo, once daily for 12 weeks. Patients assigned placebo group were re-randomized (1:1:1) to receive SHR0302 2 mg, 4 mg, or 8 mg for an additional 12-week extension treatment period. A pre-planned interim analysis was performed after all patients completed assessment at week 12, and SHR0302 4 mg was determined to be the recommended phase 3 dose per independent data monitoring committee. In the phase 3 period, patients were randomized (1:1) to receive oral SHR0302 4 mg or placebo, once daily for 12 weeks; from week 12, all patients received SHR0302 4 mg during the extension treatment period. The primary efficacy endpoint was the Assessment of SpondyloArthritis international Society ≥20% improvement (ASAS20) at Week 12.

Results:

Throughout the phase 2 and phase 3 periods, 187 patients were randomized to receive SHR0302 4 mg and 186 patients to the placebo group, with all patients receiving at least one dose of the study treatment. Of these, 350 (93.8%) patients completed the 12-week treatment, and 304 (81.5%) completed the 24-week treatment. At week 12, the ASAS20 response rates were significantly higher in patients receiving SHR0302 at a dose of 4 mg (48.7%, one-sided P=0.0001) compared to those on placebo (29.0%). Obvious improvements were also observed with SHR0302 4 mg compared to placebo in measures of ASAS40 (32.1% vs. 18.3%, nominal P=0.0011) and ASAS5/6 responses (42.8% vs. 15.6%; nominal P<0.0001) (Figure 1A). Changes from baseline in BASDAI score (least squares mean change -2.21 vs -1.43; nominal P<0.0001), BASFI score (-1.33 vs. -0.79; nominal P=0.0007), BASMI linear score (-0.40 vs. -0.29; nominal P=0.0289), ASQoL score (-3.13 vs. -2.18; nominal P=0.0052), SF-36 PCS score (4.43 vs. 3.33; nominal P=0.0217), and SF-36 MCS score (2.32 vs. 0.97; nominal P=0.0285) at Week 12 were numerically greater in patients treated with SHR0302 compared to those receiving placebo (Figure 1B and 1C and Table 1). These trends in improvements were sustained over an additional 12-week extension treatment period (Table 1). During the initial 12-week treatment period, 79.7% of patients in the SHR0302 4 mg group and 65.6% in the placebo group experienced treatment-emergent adverse events (TEAEs). Similar incidences of serious TEAEs (1.1% in the SHR0302 4 mg group vs. 2.2% in the placebo group) and infection-related TEAEs (28.9% vs. 25.3%) were reported within Weeks 0-12. Throughout the trial, there were no reported deaths, tuberculosis cases, major cardiovascular events, thromboembolic events, or newly diagnosed malignancies, and no new safety issues were identified.

Conclusion:

SHR0302 4 mg demonstrated significant and sustained improvements in reducing disease activity and signs and symptoms in patients with active AS who had an inadequate response or contraindication to NSAIDs, and was well tolerated through 24 weeks of treatment.

REFERENCES:

NIL.

Acknowledgements:

NIL.

Disclosure of Interests:

Zhanguo Li: None declared, Xu Liu: None declared, Cheng Zhao: None declared, Shengyun Liu: None declared, Lingyun Sun: None declared, Lei Yang: None declared, Xiaoyan Xu: None declared, Rui Wu: None declared, Xiumei Liu: None declared, Jing Zhang: None declared, Shengqian Xu: None declared, Ping Zhu: None declared, Haiying Chen: None declared, Xiaoxia Wang: None declared, Changsong Lin: None declared, Jin Lin: None declared, Feng Zhan: None declared, Hua Wei: None declared, Qingchun Huang: None declared, Huaxiang Liu: None declared, Xinmei Ma: None declared, Guixiu Shi: None declared, Hui Wang I am employed at Jiangsu Hengrui Pharmaceuticals Co., Ltd., Pan Liu I am employed at Jiangsu Hengrui Pharmaceuticals Co., Ltd.