SHR0302, A JAK1 Inhibitor, Shows Promise for Rheumatoid Arthritis in Phase 3 Study

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Findings from a phase 3 study are shining light on the efficacy and safety of SHR0302 in patients with moderate to severe active rheumatoid arthritis (RA) who had an inadequate response to conventional synthetic disease-modifying anti-rheumatic drugs (csDMARDs).¹

Results showed patients treated with SHR0302 4 mg or 8 mg achieved greater improvements in American College of Rheumatology response criteria (ACR20) at week 24 compared to patients in the placebo arm, also besting placebo across outcomes for Disease Activity Score-28 for Rheumatoid Arthritis with CRP (DAS28-CRP), Health Assessment Questionnaire-Disability Index (HAQ-DI), and 36-Item Short Form Health Survey (SF-36).¹

A potent selective Janus kinase (JAK)1 inhibitor, SHR0302 has previously demonstrated efficacy and safety in treating patients with active RA in a phase 2 trial.² The present phase 3 trial was led by Xiaofeng Zeng, MD, professor of medicine and chief of the department of rheumatology and immunology at Peking Union Medical College Hospital, to assess its efficacy and safety in patients with active RA and an inadequate response to csDMARDs.¹

For inclusion, patients were required to be 18 to 75 years of age and diagnosed with RA according to the 2010 ACR/European Alliance of Associations for Rheumatology (EULAR) criteria, additionally exhibiting moderately to severely active disease with a history of inadequate response to csDMARDS. In total, 566 patients were randomly assigned in a 1:1:1 ratio to receive SHR0302 4 mg, 8 mg, or placebo administered orally once daily for 24 weeks. Of note, randomization was stratified by concomitant csDMARDs use at baseline:

• Methotrexate at a dose of ≥15 mg/week or leflunomide at 20 mg/day
• Methotrexate at <15 mg/week or leflunomide at <20 mg/day
• No usage of either methotrexate or leflunomide

Participants who were initially assigned to the placebo group were switched to receive SHR0302 4 mg for an additional 28 weeks, while those originally assigned to SHR0302 continued with their initial dosage.¹

The primary endpoint was the proportion of pts who achieved a 20% improvement in the ACR response criteria (ACR20) at week 24.¹

Investigators noted baseline demographics and disease characteristics were balanced across treatment arms. Of the 566 patients randomly assigned to treatment and who received ≥ dose of the study drug, 524 (92.6%) completed the 24-week treatment and 496 (87.6%) completed the 52-week treatment.¹

At week 24, ACR20 response rates were significantly greater among patients receiving SHR0302 4 mg (70.4%; P <.0001) and 8 mg (75.1%; P <.0001) compared to those on placebo (40.4%), with an apparent rapid onset of action as more patients in the SHR0302 arms achieved ACR20 at week 2 than placebo. Investigators also noted significant improvements in ACR50 and ACR70 responses with both SHR0302 doses versus placebo.¹

Additionally, at week 24, a significantly greater proportion of patients achieved a DAS28-CRP of < 2.6 and ≤ 3.2 in the SHR0302 4 mg (29.6% and 46.0%; nominal P <.0001) and SHR0302 8 mg (39.2% and 57.1%; nominal P <.0001) groups compared to the placebo group (4.8% and 15.4%). Investigators also pointed out greater changes from baseline in HAQ-DI scores in the SHR0302 4 mg (least squares mean change, -0.45; nominal P <.0001) and 8 mg (-0.51; nominal P <.0001) groups at week 24 compared with placebo (-0.21).¹

Changes from baseline in the SF-36 score at week 24 were numerically greater in patients treated with SHR0302 (least squares mean change in physical component summary [PCS], 5.62 for 4 mg and 6.43 for 8 mg; mental component summary (MCS), 2.85 for 4 mg and 4.04 for 8 mg; all nominal P <.0001) compared to those receiving placebo (PCS, 1.78; MCS, -0.22). Investigators noted these trends in improvements were sustained over an additional 28 weeks.¹

Throughout the 24-week treatment period, the incidences of treatment-emergent adverse events (TEAEs) were 81.5% in the SHR0302 4 mg group, 90.5% in the SHR0302 8 mg group, and 79.3% in the placebo group. The incidence of infection-related TEAEs was greater in the SHR0302 groups (4 mg, 40.2%; 8 mg, 40.7%) than in the placebo group (34.0%). No deaths, tuberculosis cases, or gastrointestinal perforations were reported during the trial, and no new safety issues were identified.¹

“Both doses of SHR0302 (4 mg and 8 mg) demonstrated significant and sustained improvements in clinical signs and symptoms in pts with moderately to severely active RA who had an inadequate response to csDMARDs, and exhibited a generally acceptable safety profile,” investigators concluded.¹

References:

1. ^{Zeng X, Liu J, Jiang Y, et al. OP0037 A MULTICENTER, RANDOMIZED, PLACEBO-CONTROLLED, DOUBLE-BLIND, PHASE 3 STUDY OF SHR0302, A SELECTIVE JANUS KINASE 1 INHIBITOR, IN PATIENTS WITH ACTIVE RHEUMATOID ARTHRITIS AND INADEQUATE RESPONSE TO CONVENTIONAL SYNTHETIC DISEASE-MODIFYING ANTI-RHEUMATIC DRUGS. Annals of the Rheumatic Diseases 2024. https://doi.org/10.1136/annrheumdis-2024-eular.1908}
2. ^{Clinicaltrials.gov. Study of SHR0302 Tablets (SHR0302) as Monotherapy in Active Rheumatoid Arthritis (RA) Patients. Study Record. September 30, 2021. Accessed June 20, 2024. https://clinicaltrials.gov/study/NCT03254966}