Phase 3 Evaluation of Itepekimab Efficacy and Safety in Adults with Inadequately-Controlled Chronic Rhinosinusitis with Nasal Polyps

The primary objective of this study is to evaluate the **efficacy** of itepekimab compared with placebo on nasal polyps (NP) size and nasal congestion in patients with chronic rhinosinusitis with nasal polyps (CRSwNP). This is clinically relevant as CRSwNP is a condition that significantly impacts patients' quality of life, and effective management of NP size and nasal congestion can lead to improved patient outcomes.

Secondary objectives include:

• Evaluating the long-term efficacy of itepekimab compared with placebo on NP size and nasal congestion.
• Assessing the efficacy of itepekimab on sinus opacification, symptoms of CRSwNP, sense of smell, health-related quality of life, and sleep disturbance.
• Evaluating the ability of itepekimab to reduce the risk of worsening or acute sinusitis requiring treatment with systemic corticosteroids or sinus surgery.
• Assessing the effect of itepekimab on asthma in participants with comorbid asthma and in those with aspirin-exacerbated respiratory disease (AERD).
• Evaluating the safety and tolerability of itepekimab in participants with CRSwNP.
• Assessing the pharmacokinetics and immunogenicity of itepekimab over time compared to placebo.

The clinical trial involves a total of **251 participants** diagnosed with **chronic rhinosinusitis with nasal polyps**. The study population includes both male and female subjects, aged 18 years and older, who have a documented history of the condition for at least one year prior to screening. Participants were selected based on specific criteria, including a history of sinonasal surgery for nasal polyps or recent treatment with systemic corticosteroids due to worsening symptoms. The trial population is characterized by ongoing symptoms such as nasal congestion, loss of smell, or rhinorrhea. Participants are required to have a bilateral Nasal Polyp Score of at least 5 out of a maximum of 8. The study includes individuals from a vulnerable population, and female participants must adhere to specific contraceptive guidelines if of childbearing potential. The trial does not specify any particular lifestyle considerations such as diet or physical activity.

The clinical trial is designed as a **randomized**, **double-blind**, **placebo-controlled** study to evaluate the efficacy, safety, and tolerability of **itepekimab** in adult participants with inadequately-controlled **chronic rhinosinusitis with nasal polyps**. The trial will span a duration of 52 weeks, with participants receiving either itepekimab or a matched placebo via **subcutaneous injection**. The primary objective is to assess changes from baseline in the endoscopic Nasal Polyp Score (NPS) and Nasal Congestion Score (NCS). Secondary endpoints include changes in sinus opacification assessed by CT scan, total symptom scores, and the incidence of treatment-emergent adverse events.

Participants will be involved in the study for the entire 52-week period unless early termination is warranted due to adverse events, withdrawal of consent, or non-compliance with the study protocol. The study begins with a screening visit to confirm eligibility based on criteria such as age, medical history, and symptom severity. Following randomization, participants will attend regular follow-up visits to monitor treatment effects and safety. The end-of-study visit will conclude the trial, where final assessments will be conducted to evaluate the overall impact of the treatment.

Inclusion criteria require participants to be 18 years or older with a documented history of chronic rhinosinusitis with nasal polyps for at least one year. Participants must exhibit ongoing symptoms and have undergone prior sinonasal surgery or systemic corticosteroid treatment. Female participants must adhere to specific contraceptive guidelines if of childbearing potential. The trial excludes individuals who do not meet these criteria or who present with conditions that could interfere with the study outcomes.

The clinical trial involves the administration of **Itepekimab**, an experimental medication, to evaluate its efficacy, safety, and tolerability in adult participants with inadequately-controlled chronic rhinosinusitis with nasal polyps. **Itepekimab** is a **solution for injection** provided in a pre-filled syringe. The active substance is a human monoclonal antibody IgG4 against human interleukin-33, also known by synonyms such as **ANTI-INTERLEUKIN-33 IGG4 HUMAN MONOCLONAL ANTIBODY** and **SAR440340**. The medication is administered via **subcutaneous injection**. The maximum daily dose is 150 mg, with a total treatment period of 52 weeks. The dosing schedule and participant compliance are monitored throughout the trial to ensure adherence to the protocol.

The study also includes a **matched placebo** for the test product, which serves as a comparator treatment. The placebo is designed to mimic the experimental medication in appearance and administration method, ensuring the study remains double-blind. The placebo does not contain any active substance and is used to assess the efficacy of **Itepekimab** by providing a baseline for comparison. Participants receiving the placebo will follow the same administration schedule as those receiving the experimental medication, with compliance monitoring in place to maintain the integrity of the trial results.

The efficacy of **itepekimab** in the treatment of chronic rhinosinusitis with nasal polyps (CRSwNP) will be assessed through a randomized, double-blind, placebo-controlled, parallel-group Phase 3 trial. The primary endpoints for evaluating efficacy include the change from baseline in the endoscopic Nasal Polyp Score (NPS) and the Nasal Congestion Score (NCS). Secondary endpoints encompass a range of measures such as changes from baseline in sinus opacification assessed by CT scan using the Lund-Mackay (LMK) score, Total Symptom Score (TSS), loss of smell severity score using the daily CRSwNP sinonasal symptom eDiary and University of Pennsylvania Smell Identification Test (UPSIT) score, and the Sino-Nasal Outcome Test (SNOT-22) total score. Additional secondary endpoints include the proportion of participants requiring systemic corticosteroids (SCS) or surgery for CRS, annualized rate of SCS courses or surgeries, and time to first SCS or surgery. The trial will also assess changes in pre-bronchodilator forced expiratory volume in one second (FEV1) and Asthma Control Questionnaire (ACQ-5) scores in participants with co-morbid asthma, as well as similar measures in participants with aspirin-exacerbated respiratory disease (AERD).

Data collection will occur at various timepoints throughout the 52-week treatment period. The efficacy parameters will be measured using validated scales and instruments, including endoscopic evaluations, CT scans, and patient-reported outcomes. The trial will also monitor the proportion of NPS responders, defined as participants with an improvement of at least 1 or 2 points in NPS. Additionally, the incidence of treatment-emergent adverse events (TEAEs), serious adverse events (TESAEs), and adverse events of special interest (TEAESIs) will be recorded, along with the concentration of itepekimab in serum and the incidence of treatment-emergent anti-itepekimab antibody (ADA) responses.