Evaluation of Response Predictors to Omalizumab and Mepolizumab in Severe Allergic and Eosinophilic Asthma: A Multinational Randomized Controlled Trial

The primary objective of this study is to compare the **rate and magnitude of response** to omalizumab and mepolizumab in patients with severe allergic and eosinophilic asthma, specifically focusing on the annual rate of severe exacerbations. This is clinically relevant as it aims to identify the most effective treatment option for reducing exacerbations in this patient population, thereby potentially improving patient outcomes and quality of life.

Secondary objectives include:

• Determining theranostic features, such as clinical characteristics and biomarkers from blood, urine, and mucosal samples, that can predict a better response to omalizumab or mepolizumab in severe asthma patients eligible for both therapies.
• Comparing the effects of omalizumab and mepolizumab on secondary outcomes, including asthma symptom scores, asthma-related quality of life, lung function, and nasal symptoms.
• Recording the baseline clinical characteristics of severe asthma patients eligible for both biotherapies, compared to those eligible for omalizumab according to the PERSIST study.
• Comparing, in responders, the effects of omalizumab and mepolizumab on clinical and biological features.
• Determining if IgE+ B-cell repertoire, IgE glycosylation patterns, or subsets of T cells (Th2, Tfh2, Tfh13, Tfr) are reliable predictive biomarkers of response to omalizumab or mepolizumab.

The clinical trial involves participants diagnosed with **severe allergic and eosinophilic asthma**. The study population includes both male and female subjects, aged between 18 and 90 years. Participants are required to have a documented physician-diagnosed asthma and must be eligible for treatment with omalizumab and mepolizumab, without prior exposure to these therapies. The trial does not include vulnerable populations. The sponsor has not provided information regarding the total number of participants. Participants are expected to comply with the study protocol, as assessed by the investigator. Lifestyle considerations such as diet, physical activity, or habits are not specified in the available data.

The clinical trial is designed to evaluate the **rate and magnitude of response** to **omalizumab** and **mepolizumab** in patients with severe allergic and eosinophilic asthma. This study is a randomized, controlled, open-label trial with a pragmatic approach, aiming to assess the primary outcome of the annual rate of severe exacerbations. The trial is expected to span from May 2019 to May 2026, with a maximum treatment period of 22 weeks for each participant. Participants will be randomly assigned to receive either omalizumab or mepolizumab, administered via subcutaneous injection.

The study involves several key visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as age, documented physician-diagnosed asthma, and eligibility for the study drugs. Following the screening, participants will undergo regular follow-up visits to monitor their response to treatment and collect data on clinical features and biomarkers. These visits will assess asthma-related outcomes, including disease control, quality of life, and lung function. The end-of-study visit will conclude the participant's involvement, summarizing the treatment's impact and collecting final data.

Participant involvement is expected to last up to 22 weeks, with conditions for early termination including non-compliance with the study protocol or adverse reactions to the treatment. The trial's primary endpoints focus on comparing the rate of severe exacerbations and response rates between the two treatment groups. Secondary endpoints include the evaluation of clinical features and biomarkers for their potential to predict treatment response, as well as other asthma-related outcomes. The trial's design ensures a comprehensive assessment of the therapeutic effects of omalizumab and mepolizumab in the target population.

The clinical trial involves the administration of **mepolizumab**, an experimental medication used to treat severe eosinophilic asthma. Mepolizumab is a monoclonal antibody that targets interleukin-5 (IL-5), a cytokine involved in the growth and activation of eosinophils. The pharmaceutical form of mepolizumab is denoted as PHF00201MIG. It is administered via **subcutaneous injection** with a maximum daily dose of 100 mg. The total dose administered over the treatment period does not exceed 100 mg. The treatment duration is set for a maximum of 22 weeks. Participant compliance with the dosing schedule is monitored throughout the trial to ensure adherence to the protocol.

Another experimental medication used in the trial is **omalizumab**, which is also a monoclonal antibody, but it targets immunoglobulin E (IgE) and is used in the treatment of severe allergic asthma. Omalizumab is provided in the pharmaceutical form PHF00231MIG and is administered via subcutaneous injection. The maximum daily dose for omalizumab is 75 mg, with a total dose not exceeding 600 mg over the course of the 22-week treatment period. As with mepolizumab, participant compliance with the dosing schedule is closely monitored to ensure protocol adherence.

Both medications are administered as part of an open-label, controlled, randomized multinational pragmatic trial aimed at comparing the rate and magnitude of response in patients with severe allergic and eosinophilic asthma. The primary outcome measure is the annual rate of severe exacerbations. No non-experimental treatments, such as standard-of-care therapy, placebo, or comparator treatments, are specified in the trial protocol. The trial is designed to evaluate the efficacy of these treatments in a real-world setting, providing valuable insights into their potential benefits for patients with severe asthma.

Efficacy in this clinical trial will be assessed by comparing the rate and magnitude of response to **omalizumab** and **mepolizumab** in patients with severe allergic and eosinophilic asthma. The primary endpoint is the annual rate of severe exacerbations in patients treated with omalizumab versus mepolizumab. Additionally, the rate of response to each treatment will be evaluated in both the overall and stratified populations.

Secondary endpoints include the analysis of clinical features and biomarkers from blood, mucosal, and urine samples to predict a better response to either omalizumab or mepolizumab. Candidate features for this analysis are age at disease onset, presence of nasal polyps, aspirin hypersensitivity, serum specific/total IgE ratio, and blood eosinophil levels. Other asthma-related outcomes, such as disease control (measured by ACT and ACQ6), asthma-related quality of life (assessed by AQLQ), lung function (FEV1 % predicted and absolute change), and nasal symptoms (VAS and endoscopic scoring for nasal polyps), will also be evaluated in both treatment groups.