Efficacy and Safety of SAR443765 in Adults with High-Risk Asthma Ineligible for Biologic Therapy: A Randomized, Double-Blind, Placebo-Controlled Phase 2 Trial

The primary objective of this study is to evaluate the **efficacy** of lunsekimig compared to placebo on asthma exacerbations. This is clinically relevant as it aims to determine the potential of lunsekimig in reducing the frequency or severity of asthma exacerbations, which are critical events in the management of asthma, particularly in patients with high-risk asthma who are not currently eligible for biologic treatment.

Secondary objectives include:

• Evaluating the effects of lunsekimig compared to placebo on lung function, asthma control, FeNO levels, and loss of asthma control (LOAC) events.
• Assessing the impact on asthma exacerbations requiring hospitalization, emergency room visits, or urgent care visits.
• Investigating the effects on the use of systemic corticosteroid therapy and patient-reported outcomes (PROs).
• Evaluating the pharmacokinetics (PK) and immunogenicity of lunsekimig.
• Assessing the safety of lunsekimig.

The clinical trial involves a total of **1701 participants** diagnosed with **asthma**, specifically targeting individuals with mild-to-moderate asthma as per the Global Initiative for Asthma (GINA) guidelines. The study population includes both male and female subjects, with an age range encompassing children and adolescents. Participants were selected based on specific criteria, including a history of at least one asthma exacerbation in the year prior to screening and a pre-bronchodilator forced expiratory volume in one second (FEV1) of 40% or more of the predicted normal value according to the Global Lung Function Initiative standards. The trial also considers vulnerable populations, ensuring a comprehensive evaluation of the treatment's efficacy across diverse demographic groups. Lifestyle factors such as diet and physical activity were not specified in the available data.

The clinical trial is designed as a **randomized**, Phase 2, **double-blind**, placebo-controlled, parallel-group study to evaluate the efficacy, safety, and tolerability of subcutaneous lunsekimig (SAR443765) in adult participants with high-risk **asthma** who are not currently eligible for biologic treatment. The trial will involve two arms, with participants randomly assigned to receive either the investigational product or a placebo. The primary objective is to assess the efficacy of lunsekimig in reducing the annualized rate of asthma exacerbation events. Secondary endpoints include changes from baseline in pre-bronchodilator forced expiratory volume in 1 second (FEV1), Asthma Control Questionnaire-5 (ACQ-5) scores, and other asthma-related outcomes.

The trial is expected to commence recruitment on April 4, 2025, and conclude by February 16, 2028. Participants will be involved in the study for a duration that includes an initial screening visit, multiple follow-up visits, and an end-of-study visit. The screening visit will confirm eligibility based on criteria such as a physician-diagnosed mild-to-moderate asthma for more than 12 months, at least one asthma exacerbation in the year prior, and a pre-BD FEV1 of 40% or more of predicted normal. Follow-up visits will monitor the participants' response to the treatment, collect data on primary and secondary endpoints, and ensure participant safety. The end-of-study visit will finalize data collection and assess the overall outcomes of the trial.

Participant involvement is expected to last throughout the trial duration unless early termination is warranted. Conditions for early termination include the occurrence of serious adverse events, withdrawal of consent, or any other medical reasons deemed necessary by the investigator. The trial will adhere to rigorous scientific and ethical standards to ensure the integrity of the data and the safety of the participants.

The clinical trial involves the investigation of **lunsekimig** (SAR443765), an experimental medication developed by Sanofi Aventis Recherche et Développement (SAR). Lunsekimig is a pentavalent nanobody consisting of two nanobody building blocks targeting thymic stromal lymphopoietin (TSLP), two nanobody building blocks targeting interleukin-13 (IL-13), and one nanobody building block targeting human albumin. This formulation is designed to be administered subcutaneously. The specific dosage, frequency, and detailed administration schedule are not provided in the available data. The trial aims to evaluate the efficacy, safety, and tolerability of lunsekimig in adult participants with high-risk asthma who are not currently eligible for biologic treatment.

The study also includes a **placebo** group to serve as a comparator for the experimental treatment. The placebo is administered in a manner consistent with the experimental drug to maintain the double-blind nature of the trial. The placebo is used to assess the efficacy of lunsekimig by providing a baseline for comparison. The administration route and frequency for the placebo are aligned with those of the experimental treatment to ensure consistency in the study design. Participant compliance with the dosing schedule is monitored throughout the trial to ensure the integrity of the data collected.

The efficacy of lunsekimig (SAR443765) in the clinical trial will be assessed primarily by evaluating the **annualized rate of asthma exacerbation events**. This primary endpoint will provide a direct measure of the treatment's impact on reducing the frequency of exacerbations in participants with high-risk asthma. Secondary endpoints will include several additional parameters to comprehensively assess efficacy. These include changes from baseline in pre-bronchodilator forced expiratory volume in 1 second (FEV1), Asthma Control Questionnaire-5 (ACQ-5) scores, and fractional exhaled nitric oxide (FeNO) levels. The trial will also measure the annualized rate of loss of asthma control events, the rate of asthma exacerbations requiring hospitalization or emergency care, and total systemic corticosteroid dose exposure. Furthermore, changes from baseline in Asthma Quality of Life Questionnaire Standardized (AQLQ{S}) scores and Asthma Daytime Symptom Diary (ADSD) daily scores will be evaluated.

Serum lunsekimig concentrations and the incidence and titer of anti-drug antibodies (ADA) against lunsekimig will be monitored to assess pharmacokinetics and immunogenicity. The incidence of treatment-emergent adverse events (TEAEs), including local reactions, adverse events of special interest (AESIs), and serious adverse events (SAEs), will also be recorded. These efficacy parameters will be collected and analyzed at specified timepoints throughout the study duration, ensuring a robust evaluation of the treatment's impact on asthma management. The trial is designed as a randomized, double-blind, placebo-controlled, parallel-group study, which will provide high-quality evidence on the efficacy and safety of lunsekimig in the target population.