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Background <p>KL130008 is a selective Janus kinase 1/2 inhibitor with encouraging preclinical efficacy. Phase I trials in healthy volunteers and patients with rheumatoid arthritis (RA) showed favorable pharmacokinetics, dose-dependent inhibition of phosphorylated signal transducer and activator of transcription 3, good tolerability, and no clinically meaningful pharmacokinetic interaction with methotrexate, supporting further evaluation in active RA.</p> Methods <p>In this double-blind, placebo-controlled phase II trial at 24 centers in China, RA patients were randomized (1:1:1:1) to receive placebo or KL130008 capsules (0.5, 1 or 2&#xa0;mg) once daily for 12&#xa0;weeks. Week 13–24, the placebo group was switched 1:1 to KL130008 at 0.5&#xa0;mg or 1&#xa0;mg, while other groups continued their original doses. All patients received 7.5–25&#xa0;mg methotrexate once weekly throughout 24&#xa0;weeks. The primary outcome was the proportion of patients who achieved at least 20% improvement in American College of Rheumatology criteria (ACR20) after 12&#xa0;weeks of treatment. Secondary outcomes included ACR50/70 responses, Disease Activity Score 28 (DAS28) changes, safety assessments and pharmacokinetic properties.</p> Results <p>By week 12, the proportion of patients achieving ACR20 was significantly lower in the placebo group (26.8%) than in the groups receiving KL130008 at 1&#xa0;mg (55.0%, <i>p</i> = 0.011) or 2&#xa0;mg (64.1%, <i>p</i> = 0.001). KL130008 at 2&#xa0;mg also significantly outperformed placebo for ACR50 or ACR70 responses, DAS28-C-reactive protein, DAS28- erythrocyte sedimentation rate, and the Health Assessment Questionnaire Disability Index scores. The clinical benefits of KL130008 persisted through week 24 and were associated with markedly lower levels of tumor necrosis factor-a and interleukin-6 in blood, without affecting levels of interleukin-15. The oral drug showed linear pharmacokinetics and mild accumulation. During the 24-week treatment, drug-related treatment-emergent adverse events occurred in approximately half of the patients receiving KL130008 (52.5%, 50.0%, and 56.4% in the 0.5, 1, and 2&#xa0;mg groups), and the most frequent events were anemia and hyperlipidemia.</p> Conclusions <p>KL130008 demonstrated potential for sustained efficacy and safety in the treatment of RA.</p> Trial registration <p>Registered in the Chinese Clinical Trial Register (ChiCTR2100042141).</p>

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Efficacy and safety of Janus kinase 1/2 inhibitor KL130008 in active rheumatoid arthritis: a randomized, double-blind, placebo-controlled phase II trial

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年12月9日

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  • Yue Cheng,
  • Honghu Tang,
  • Yufeng Qing,
  • Yuan Liu,
  • Lei Yang,
  • Wantai Dang,
  • Jing Yu,
  • Rongbin Li,
  • Huaxiang Liu,
  • Zhenyu Jiang,
  • Hongsheng Sun,
  • Songlou Yin,
  • Jianzhao Cheng,
  • Zhijun Li,
  • Wenqiang Fan,
  • Hong Zhang,
  • Hongwei Du,
  • Zili Fu,
  • Xinmei Ma,
  • Jian Wu,
  • Lihua Duan,
  • Rong Zhang,
  • Jinying Lin,
  • Zhanyun Da,
  • Wei Wei,
  • Qianxun Zhai,
  • Bingjie Wu,
  • Xiaowei Yi,
  • Xiaoping Jin,
  • Junyou Ge,
  • Ping Feng,
  • Yi Liu

摘要

Background

KL130008 is a selective Janus kinase 1/2 inhibitor with encouraging preclinical efficacy. Phase I trials in healthy volunteers and patients with rheumatoid arthritis (RA) showed favorable pharmacokinetics, dose-dependent inhibition of phosphorylated signal transducer and activator of transcription 3, good tolerability, and no clinically meaningful pharmacokinetic interaction with methotrexate, supporting further evaluation in active RA.

Methods

In this double-blind, placebo-controlled phase II trial at 24 centers in China, RA patients were randomized (1:1:1:1) to receive placebo or KL130008 capsules (0.5, 1 or 2 mg) once daily for 12 weeks. Week 13–24, the placebo group was switched 1:1 to KL130008 at 0.5 mg or 1 mg, while other groups continued their original doses. All patients received 7.5–25 mg methotrexate once weekly throughout 24 weeks. The primary outcome was the proportion of patients who achieved at least 20% improvement in American College of Rheumatology criteria (ACR20) after 12 weeks of treatment. Secondary outcomes included ACR50/70 responses, Disease Activity Score 28 (DAS28) changes, safety assessments and pharmacokinetic properties.

Results

By week 12, the proportion of patients achieving ACR20 was significantly lower in the placebo group (26.8%) than in the groups receiving KL130008 at 1 mg (55.0%, p = 0.011) or 2 mg (64.1%, p = 0.001). KL130008 at 2 mg also significantly outperformed placebo for ACR50 or ACR70 responses, DAS28-C-reactive protein, DAS28- erythrocyte sedimentation rate, and the Health Assessment Questionnaire Disability Index scores. The clinical benefits of KL130008 persisted through week 24 and were associated with markedly lower levels of tumor necrosis factor-a and interleukin-6 in blood, without affecting levels of interleukin-15. The oral drug showed linear pharmacokinetics and mild accumulation. During the 24-week treatment, drug-related treatment-emergent adverse events occurred in approximately half of the patients receiving KL130008 (52.5%, 50.0%, and 56.4% in the 0.5, 1, and 2 mg groups), and the most frequent events were anemia and hyperlipidemia.

Conclusions

KL130008 demonstrated potential for sustained efficacy and safety in the treatment of RA.

Trial registration

Registered in the Chinese Clinical Trial Register (ChiCTR2100042141).