Preventive and Therapeutic Effects of a Novel JAK Inhibitor SHR0302 in Acute Graft-Versus-Host Disease

Sun, Xi; He, Qi‐Chang; Yang, Jun; Wang, Yuzhuo; Zhang, Fang; Qiu, Huiying; Zhou, Kun; Wang, Pengran; Ding, Xiaodan; Xiao, Yuan; Li, Huajun; Zhang, Yan; Song, Xianmin

doi:10.1177/09636897211033778

Cited by 12 publications

(14 citation statements)

References 42 publications

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“…Interestingly, baricitinib was superior to ruxolitnib in preventing GVHD-induced mortality. More recently, Sun and colleagues utilized a highly selective JAK1 inhibitor (SHR0302) (62) and demonstrated improved overall survival when compared to vehicle treated controls (63). SHR0302 also reduced the infiltration of immune cells into the GI tract through reduction of CXCR3 expression on donor T cells as well as mitigated the release of the proinflammatory cytokines, IL-6, IFN-g, and TNF-a.…”

Section: Janus Kinase Inhibitionmentioning

confidence: 99%

Translational Clinical Strategies for the Prevention of Gastrointestinal Tract Graft Versus Host Disease

Rayasam

Drobyski

2021

Front. Immunol.

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Graft versus host disease (GVHD) is the major non-relapse complication associated with allogeneic hematopoietic stem cell transplantation (HSCT). Unfortunately, GVHD occurs in roughly half of patients following this therapy and can induce severe life-threatening side effects and premature mortality. The pathophysiology of GVHD is driven by alloreactive donor T cells that induce a proinflammatory environment to cause pathological damage in the skin, gastrointestinal (GI) tract, lung, and liver during the acute phase of this disease. Recent work has demonstrated that the GI tract is a pivotal target organ and a primary driver of morbidity and mortality in patients. Prevention of this complication has therefore emerged as an important goal of prophylaxis strategies given the primacy of this tissue site in GVHD pathophysiology. In this review, we summarize foundational pre-clinical studies that have been conducted in animal models to prevent GI tract GVHD and examine the efficacy of these approaches upon subsequent translation into the clinic. Specifically, we focus on therapies designed to block inflammatory cytokine pathways, inhibit cellular trafficking of alloreactive donor T cells to the GI tract, and reconstitute impaired regulatory networks for the prevention of GVHD in the GI tract.

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Section: Janus Kinase Inhibitionmentioning

confidence: 99%

Translational Clinical Strategies for the Prevention of Gastrointestinal Tract Graft Versus Host Disease

Rayasam

Drobyski

2021

Front. Immunol.

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“…Currently, SHR0302 is undergoing a phase III study (NCT04333771) of treatment for RA patients at once‐daily doses of 4 or 8 mg. In addition to the indication of RA mentioned in this article, SHR0302 is also being developed for the treatment of various other autoimmune inflammatory disorders 6–8 …”

Section: Introductionmentioning

confidence: 99%

“…In addition to the indication of RA mentioned in this article, SHR0302 is also being developed for the treatment of various other autoimmune inflammatory disorders. [6][7][8] In a phase I single ascending dose study, SHR0302 demonstrated a favourable safety profile at a dose range of 1-100 mg in healthy subjects. The plasma exposure of SHR0302 increased in an approximately dose-proportional manner across the evaluated dose range, indicating linear pharmacokinetic (PK) characteristics of the drug.…”

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confidence: 99%

Effect of CYP3A4 induction and inhibition on the pharmacokinetics of SHR0302 in healthy subjects

Zhang

Gao

Zhang

et al. 2023

Brit J Clinical Pharma

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Aims SHR0302 is a selective Janus kinase (JAK) 1 inhibitor under clinical investigation for the treatment of rheumatoid arthritis (RA). As SHR0302 is metabolized mainly by cytochrome P450 (CYP) 3A4, clinical studies were performed to evaluate the effects of a strong CYP3A4 inducer, rifampin, and a strong CYP3A4 inhibitor, itraconazole, on the pharmacokinetics of SHR0302 in healthy subjects. Methods Two phase I, open‐label, fixed‐sequence drug interaction studies enrolled 28 subjects. In Study A, 14 subjects received 8 mg SHR0302 on Days 1 and 10, and 600 mg rifampin once daily on Days 3–11. In Study B, 14 subjects received 4 mg SHR0302 on Days 1 and 8, and 200 mg itraconazole once daily on Days 4–10. Blood samples were collected to measure SHR0302 concentrations. Pharmacokinetic parameters were calculated using non‐compartmental analysis. Treatment comparisons were made using mixed‐effect models. Results Co‐administration with rifampin decreased the exposures of SHR0302 with geometric mean ratios (GMRs) (90% confidence intervals [CIs]) for AUC0‐inf of 0.51 (0.49, 0.54) and Cmax of 0.91 (0.84, 0.98). Co‐administration with itraconazole increased the exposures of SHR0302 with GMR (90% CIs) for AUC0‐inf of 1.48 (1.41, 1.56) and Cmax of 1.06 (0.982, 1.14). Single oral doses of SHR0302 administered with or without rifampin or itraconazole were generally safe. Conclusions Strong CYP3A4 induction and inhibition both resulted in a weak effect on the clinical exposures of SHR0302. These present studies provided valuable information that helps inform SHR0302 dosing instructions and concomitant medication precautions.

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“…SHR0302 is an oral and highly selective Janus kinase 1 (JAK1) inhibitor. JAK1 is an intracellular tyrosine kinase that controls many functions of innate and adaptive immunity by sending signals from extracellular cytokines (e.g., interleukin‐2 and ‐6 and interferons) and activating downstream cascades via the JAK–STAT pathway 1–3 . By inhibiting JAK1, SHR0302 has the potential to control autoimmune or immune‐mediated disorders, including rheumatoid arthritis (RA) 4 and atopic dermatitis (AD) 1 .…”

Section: Introductionmentioning

confidence: 99%

Effect of SHR0302 on the pharmacokinetics of CYP3A4, CYP2C8, CYP2C9 and CYP2C19 probe substrates in healthy volunteers: A cocktail analysis

Luo

Feng

et al. 2023

Brit J Clinical Pharma

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AimThis study evaluated the effects of SHR0302 on the pharmacokinetics of cytochrome P450 (CYP) probe substrates.MethodsWe performed a single‐center, open‐label, three‐period drug‐drug interaction (DDI) study in 24 healthy subjects (NCT05392127). Subjects received a single oral dose of 5 mg warfarin (CYP2C9), 20 mg omeprazole (CYP2C19), and 15 mg midazolam (CYP3A4) on day 1, 8, and 22, and received 0.5 mg repaglinide (CYP2C8) on day 7, 14, and 28. Multiple oral doses of 8 mg SHR0302 were administered once daily from day 8 to day 28.ResultsThe exposure of S‐warfarin and repaglinide were comparable before and after SHR0302 administration. AUC of midazolam was not affected by SHR0302, whereas the administration of SHR0302 slightly decreased the Cmax of midazolam by 7.6% (single dose) and 15.7% (once daily for 14 days). The AUC0‐t, AUC0‐inf, and Cmax of omeprazole were slightly decreased after a single dose of SHR0302 by 19.2%, 21.8%, and 23.5%, respectively. In the presence of SHR0302 for 14 days, the AUC0‐t, AUC0‐inf, and Cmax of omeprazole were marginally reduced by 3.0%, 16.4%, and 8.3%, respectively. According to the induction mechanism of the CYP enzyme, for the investigation of the induction effect, the results of multiple administration of the perpetrator were more reliable than those of the single dose.ConclusionThe results demonstrated that co‐administration of SHR0302 8mg once daily is unlikely to have a clinically meaningful effect on the exposure of drugs metabolized by CYP3A4, CYP2C8, CYP2C9, and CYP2C19 in healthy subjects.

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Preventive and Therapeutic Effects of a Novel JAK Inhibitor SHR0302 in Acute Graft-Versus-Host Disease

Cited by 12 publications

References 42 publications

Translational Clinical Strategies for the Prevention of Gastrointestinal Tract Graft Versus Host Disease

Translational Clinical Strategies for the Prevention of Gastrointestinal Tract Graft Versus Host Disease

Effect of CYP3A4 induction and inhibition on the pharmacokinetics of SHR0302 in healthy subjects

Effect of SHR0302 on the pharmacokinetics of CYP3A4, CYP2C8, CYP2C9 and CYP2C19 probe substrates in healthy volunteers: A cocktail analysis

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