The safety of JAK-1 inhibitors

Clarke, Benjamin D; Yates, Mark; Adas, Maryam A; Bechman, Katie; Galloway, James

doi:10.1093/rheumatology/keaa895

Cited by 80 publications

(58 citation statements)

References 27 publications

(26 reference statements)

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“…Compared with the other groups in Study 2, baseline platelet counts were lower in the 90‐mg group, which may have contributed to a higher proportion of these patients experiencing transient thrombocytopenia. Several reviews on the overall safety of JAK inhibitors have been published recently 54–56 …”

Section: Discussionmentioning

confidence: 99%

Janus kinase 1 inhibitor INCB054707 for patients with moderate‐to‐severe hidradenitis suppurativa: results from two phase II studies*

et al. 2022

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Summary Background Janus kinase (JAK)‐mediated cytokine signalling contributes to local and systemic inflammation in hidradenitis suppurativa (HS). Objectives To describe the safety and efficacy results from two multicentre phase II trials of the JAK1 inhibitor INCB054707 in patients with moderate‐to‐severe HS. Methods Patients received open‐label INCB054707 15 mg once daily (QD; Study 1) or were randomized to INCB054707 30, 60 or 90 mg QD or placebo (3 : 1 within each cohort; Study 2) for 8 weeks. Eligible patients were aged 18–75 years and had moderate‐to‐severe HS (Hurley stage II/III disease), lesions present in at least two anatomical locations, and a total abscess and inflammatory nodule count ≥ 3. The primary endpoint for both studies was safety and tolerability. Secondary endpoints included HS Clinical Response (HiSCR) and other efficacy measures. Results Ten patients were enrolled in Study 1 (15 mg INCB054707) and 35 in Study 2 (INCB054707: 30 mg, n = 9; 60 mg, n = 9; 90 mg, n = 8; placebo, n = 9). Overall, 70% of patients in Study 1 and 81% of patients receiving INCB054707 in Study 2 experienced at least one treatment‐emergent adverse event; 30% and 42% of patients, respectively, had at least one treatment‐related adverse event. Among the evaluable patients, three (43%) in Study 1 and 17 (65% overall: 30 mg, 56%; 60 mg, 56%; 90 mg, 88%) receiving INCB054707 vs. 4 patients (57%) receiving placebo in Study 2 achieved HiSCR at week 8. Conclusions INCB054707 was well tolerated, with responses observed in patients with moderate‐to‐severe HS. The safety and efficacy findings from these studies demonstrate proof of concept for JAK1 inhibition in HS. The studies are registered on http://clinicaltrials.gov (NCT03569371 and NCT03607487).

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Section: Discussionmentioning

confidence: 99%

Janus kinase 1 inhibitor INCB054707 for patients with moderate‐to‐severe hidradenitis suppurativa: results from two phase II studies*

et al. 2022

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“…Given the lack of direct comparison in head-to-head studies between JAK inhibitors, we are limited in drawing conclusions regarding the relative risk of HZ with UPA as compared with other JAK inhibitors (tofacitinib, baricitinib and filgotinib). 35 Differences in study design, length of follow-up, inclusion and exclusion criteria, study sites and data analysis limit the ability to compare data across clinical trials. With those limitations in mind, the incidence rates described within the UPA programme are similar to those described in the RA programmes for tofacitinib and baricitinib, with the highest rates in all three programmes observed in the Asian region.…”

Section: Discussionmentioning

confidence: 99%

Incidence and risk factors for herpes zoster in patients with rheumatoid arthritis receiving upadacitinib: a pooled analysis of six phase III clinical trials

et al. 2021

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BackgroundUpadacitinib (UPA) is an oral Janus kinase (JAK) inhibitor approved for the treatment of rheumatoid arthritis (RA). JAK inhibitors have been associated with an increased risk of herpes zoster (HZ) in patients with RA.ObjectivesTo evaluate the incidence and risk factors for HZ in UPA-treated patients with RA from the UPA phase III clinical trial programme.MethodsExposure-adjusted incidence/event rates for HZ were determined in patients receiving UPA (monotherapy or combination therapy) in six randomised phase III trials (data cut-off on 30 June 2020). HZ incidence and event rates were also determined in patients receiving methotrexate (MTX) monotherapy or adalimumab (ADA) + MTX. Multivariable Cox regression analysis was used to identify HZ risk factors in UPA-treated patients.ResultsA total of 5306 patients were included in this analysis. The incidence rate of HZ/100 patient-years (95% CI) was 0.8 (0.3 to 1.9), 1.1 (0.5 to 1.9), 3.0 (2.6 to 3.5) and 5.3 (4.5 to 6.2), in the MTX monotherapy, ADA + MTX, UPA 15 mg and UPA 30 mg groups, respectively. The majority of HZ cases with UPA (71%) involved a single dermatome. Prior history of HZ and Asian region were HZ risk factors in UPA-treated patients.ConclusionIn the UPA phase III RA clinical programme, HZ incidence and event rates were higher with UPA versus ADA + MTX or MTX monotherapy, and higher with the 30 mg versus 15 mg dose. Patients from Asia and those with a history of HZ may be at increased risk of HZ while receiving UPA.

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“… 29 However, systemic JAK1 inhibitor treatment is likely to cause significant immunosuppression and an increased risk of infection as well as herpes zoster reactivation. 30 Local delivery of a selective JAK1 inhibitor to the lungs by inhalation may minimize the potential for systemic immunosuppression while providing maximal therapeutic effect in the inflamed lung tissue.…”

Section: Introductionmentioning

confidence: 99%

Characterization of Selective and Potent JAK1 Inhibitors Intended for the Inhaled Treatment of Asthma

Nilsson¹,

Rhedin²,

Hendrickx³

et al. 2022

DDDT

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Purpose Janus kinase 1 (JAK1) is implicated in multiple inflammatory pathways that are critical for the pathogenesis of asthma, including the interleukin (IL)-4, IL-5, IL-13, and thymic stromal lymphopoietin cytokine signaling pathways, which have previously been targeted to treat allergic asthma. Here, we describe the development of AZD0449 and AZD4604, two novel and highly selective JAK1 inhibitors with promising properties for inhalation. Methods The effects of AZD0449 and AZD4604 in JAK1 signaling pathways were assessed by measuring phosphorylation of signal transducer and activator of transcription (STAT) proteins and chemokine release using immunoassays of whole blood from healthy human volunteers and rats. Pharmacokinetic studies performed on rats evaluated AZD0449 at a lung deposited dose of 52 μg/kg and AZD4604 at 30 µg/kg. The efficacy of AZD0449 and AZD4604 was assessed by evaluating lung inflammation (cell count and cytokine levels) and the late asthmatic response (average enhanced pause [Penh]). Results Both compounds inhibited JAK1-dependent cytokine signaling pathways in a dose-dependent manner in human and rat leukocytes. After intratracheal administration in rats, both compounds exhibited low systemic exposures and medium-to-long terminal lung half-lives (AZD0449, 34 hours; AZD4604, 5 hours). Both compounds inhibited STAT3 and STAT5 phosphorylation in lung tissue from ovalbumin (OVA)-challenged rats. AZD0449 and AZD4604 also inhibited eosinophilia in the lung and reduced the late asthmatic response, measured as Penh in the OVA rat model. Conclusion AZD0449 and AZD4604 show potential as inhibitors of signaling pathways involved in asthmatic immune responses, with target engagement demonstrated locally in the lung. These findings support the clinical development of AZD0449 and AZD4604 for the treatment of patients with asthma.

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The safety of JAK-1 inhibitors

Cited by 80 publications

References 27 publications

Janus kinase 1 inhibitor INCB054707 for patients with moderate‐to‐severe hidradenitis suppurativa: results from two phase II studies*

Janus kinase 1 inhibitor INCB054707 for patients with moderate‐to‐severe hidradenitis suppurativa: results from two phase II studies*

Incidence and risk factors for herpes zoster in patients with rheumatoid arthritis receiving upadacitinib: a pooled analysis of six phase III clinical trials

Characterization of Selective and Potent JAK1 Inhibitors Intended for the Inhaled Treatment of Asthma

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