Type 2 low asthma in obese and non-obese patients treated with Tezepelumab

Rationale: Approximately one third of asthma patients have a T2 low biomarker profile. Patients with a T2 low profile, in particular patients with an obese phenotype, benefit poorly from usual care (i.e. Inhaled Corticosteroids, GINA 2020). Development of new drugs and biologicals are necessary to treat patients with severe T2 low asthma. New drugs for this category of patients will hopefully lead to better control of their asthma and thus lowering the number of exacerbations and the burden of disease. However, developments in T2 low asthma have progressed slowly, due to a poor understanding of T2 low pathways. The recent finding of the possible roles of Thymic Stromal Lymphopoietin (TLSP) in T2 low asthma may shed new light on an old theme. Recent trials suggest a central role of TSLP, as anti-TSLP (Tezepelumab), reduced the exacerbation frequency in patients with non-eosinophilic asthma[1]. A clear understanding of the cellular changes during treatment with anti-TSLP in relation to Asthma severity will benefit future treatment regimens with Tezepelumab. Furthermore, studying the differences between obese and non-obese patients is important as these two T2 low phenotypes may have distinct cellular inflammatory patterns.
Objectives: 1) To identify T2 low biomarkers and 2) to unravel the mechanisms and downstream effects of Tezepelumab in T2 low asthma.
Study design: Explorative, prospective, open-label, intervention trial
Study population: We will include a total of 8 patients (4 obese, BMI ≥ 30 kg/m2 and 4 non-obese, BMI 18.5 - 25 kg/m2), aged 18-65 years with proven asthma for at least 12 months before screening (asthma reversibility of at least 12% and at least 200 mL documented during the 12 months before screening or during run-in, or positive histamine/methacholine provocation test), FEV1 less than 80% of the predicted normal value during the run-in period, T2-low phenotype (peripheral blood eosinophils < 150 cells/μL, FeNO < 20 ppb, no clinically allergy driven asthma and no need for maintenance OCS) with ≥2 exacerbations without hospitalization or ≥1 exacerbations with hospitalization in the past 12 months and an ACQ > 1.5).
Intervention: Patients will be treated (per protocol) with 210mg of Tezepelumab every 4 weeks for a duration of 20 weeks. Blood samples will be collected at baseline and at 20 weeks and analysed with single cell sequencing. ACQ, lung function and FeNO will be measured at every visit. Censored patients will be replaced.
Main study parameters/endpoints: Chromium Single Cell Multiome ATAC + Gene Expression
Nature and extent of the burden and risks associated with participation, benefit and group relatedness: Tezepelumab decreases the exacerbation rate in patients with severe asthma significantly, regardless of eosinophilia[1-4]. Most common adverse events include bronchitis, nasopharyngitis and headaches. Approximately 9% of patients treated with medium dose Tezepelumab developed at least 1 serious event. No treatment related deaths were reported in earlier trials.

Unravel the mechanisms and downstream effect in patients with Type 2 low asthma who are recieve Anti-TSLP (Tezepelumab) treatment, and to find biomarkers to identify patients who will benefit future treatment regimens with Tezepelumab.

• T0: Start of treatment: blood withdrawl for single cell analysis, Tezepelumab 210mg sc, longfunctie, questionaire (ACQ)
• T1: 4 weeks after T0: lung function, Tezepelumab 210mg sc, questionaire (ACQ)
• T2: 4 weeks after T1: lung function, Tezepelumab 210mg sc, questionaire (ACQ)
• T3: 4 weeks after T2: lung function, Tezepelumab 210mg sc, questionaire (ACQ)
• T4: 4 weeks after T3: lung function, Tezepelumab 210mg sc, questionaire (ACQ)
• T5: 4 weeks after T4: lung function, Tezepelumab 210mg sc, questionaire (ACQ)
• T6: 4 weeks after T5, final visit / end of study: blood withdrawl for single cell analysis, lung function, questionaire (ACQ)

210 mg of Tezepelumab s.c. every 4 weeks for 20 weeks.