ARTEMISIA: a mechanistic study of a novel Janus kinase 1 inhibitor to advance molecular understanding and precision medicine in asthma

Abstract

Background: Patients with uncontrolled asthma despite the use of inhaled corticosteroids (ICS), may have a variety of biological pathways driving their airway inflammation. Londamocitinib (AZD4604), a selective, inhaled, Janus kinase 1 inhibitor, has been designed to target a broad inflammatory cytokine profile including those classically unresponsive to ICS. The ARTEMISIA mechanistic study aims to provide a clear understanding of the pathways impacted by londamocitinib in the lung, determine how this impact is reflected in the nose and periphery, and identify candidate biomarkers of londamocitinib-treatment response in asthma. This article reports the design and objectives of the ARTEMISIA study.

Methods: ARTEMISIA is a placebo-controlled, double-blind study of adults with moderate-to-severe asthma aiming to assess the effects of inhaled londamocitinib on Type 2 (T2) and non-T2 driven inflammatory pathways. Extensive parallel bio-sampling of the lung target tissue, nasal mucosa, blood and urine will be performed prior to the first dose and after 4-weeks of treatment with either londamocitinib or placebo. The main objectives of the study are to evaluate the effect of londamocitinib on gene expression in endobronchial brushings and signal transducer and activator of transcription (STAT) phosphorylation in endobronchial biopsies. Key exploratory objectives include investigating the correlation between inflammatory phenotype-specific bronchial epithelial gene signatures and other biomarkers in the lung and peripheral samples; as well as analysis of transcriptomic, proteomic, and metabolomic biomarkers in the nose, blood, and urine.

Discussion: ARTEMISIA commenced recruitment in 2024 and is poised to deliver a deep understanding of the mechanism of action of londamocitinib and its potential to impact on a population of asthmatics with high unmet need. The multiomic analysis of paired central and peripheral samples may reveal novel insights into the connection and translation between these compartments, deepen understanding of airways disease, and identify novel candidate biomarkers for asthma and JAK activity. In addition to sampling the airway directly, with parallel nasal and peripheral bio-sampling mirrored by the Phase 2a AJAX study (NCT06020014), the ARTEMISIA study may provide a unique link between bronchial assessed mechanisms of action and clinical outcomes.

Trial registration: NCT06435273 (ClinicalTrials.gov). Registered 24th May 2024.

Keywords: Asthma; Bronchoscopy; Gene signatures; Inflammation; Interferon-gamma; Interleukin-6; Janus kinase 1; Signal transducer and activator of transcription (STAT); T2; TH17.

Fig. 1

Proposed mechanism of action of londamocitinib. Janus kinase 1 inhibition reduces STAT1/3/5/6 phosphorylation, suppressing inflammatory pathways relevant in asthma, with broader effects than single cytokine biologics. Londamocitinib, a selective JAK1 inhibitor, therefore, has the potential to benefit patients with asthma, including those with steroid-insensitive inflammation, by targeting T2 and non-T2 airway pathology. IFN: Interferon; IL: Interleukin; JAK1: Janus kinase 1; pSTAT: phosphorylated signal transducer and activator of transcription; T2: Type 2; Th: T-helper; TSLP: thymic stromal lymphopoietin. Created with BioRender.com

Fig. 2

ARTEMISIA study design. Figure to illustrate the design of the ARTEMISIA study. Bronchoscopies will be undertaken to take endobronchial brushings and biopsies. Nasal sampling will consist of nasal lining fluid (nasosorption) and nasal cell (curettage) sampling. Peripheral sampling will consist of venous blood and urine. ACQ: Asthma Control Questionnaire; BID: Twice daily; CAAT: Chronic Airways Assessment Test; FeNO: Fractional exhaled nitric oxide

Fig. 3

ARTEMISIA and AJAX data will be combined to relate lung sample findings with clinical outcomes. The AJAX and ARTEMISIA studies are being performed in parallel to facilitate the development of londamocitinib for moderate-severe asthma. BID: Twice daily; CompEx Asthma - Composite endpoint for asthma exacerbations [10]. Created with BioRender.com

Fig. 4

Sampling and biomarker strategy for both the ARTEMISIA and AJAX studies. Molecular biomarkers in more easily accessible matrices, such as nasal samples, blood, and urine will be correlated to T2 and non-T2 bronchial epithelial gene signatures amenable to londamocitinib modulation. Complementary precision sampling in AJAX and ARTEMISIA will enable the exploration of a link between lung airway mechanisms and clinical efficacy to identify biomarkers predictive of a response to londamocitinib and inform patient subgroups in asthma. CompEx Asthma - Composite endpoint for asthma exacerbations [10]; FeNO: Fractional exhaled nitric oxide; IHC – immunohistochemistry; pSTAT– phosphorylated signal transducer and activator of transcription; RNA: Ribonucleic acid; Seq: Sequencing; SNP: Single nucleotide polymorphism; T2: Type-2

Fig. 5

Processing of bronchoscopic samples. Highly prescriptive sample acquisition and handling protocols were provided to ensure sample handling was consistent across the sites. Created with BioRender.com