Evaluation of Itepekimab's Mechanism of Action on Airway Inflammation in Chronic Obstructive Pulmonary Disease: A Phase 2a Open-Label Study
- Trial ID
- 2024-512007-39-00
- Protocol
- PDY16967
Trial statistics
Diseases & Conditions
Objectives
The primary objective of this study is to evaluate the **difference in gene expression** between former and current smokers with Chronic Obstructive Pulmonary Disease (COPD) undergoing treatment with itepekimab, an anti-IL-33 monoclonal antibody. This objective is clinically relevant as it aims to elucidate the molecular mechanisms by which itepekimab may modulate airway inflammation, potentially leading to more targeted therapeutic strategies for COPD management.
Secondary objectives include evaluating in former and current smokers with COPD the:
- Effect of itepekimab treatment on prespecified cell type-associated gene expression signatures in endobronchial biopsies.
- Effect of itepekimab on blood eosinophil counts.
- Safety and tolerability of itepekimab.
- Immunogenicity to itepekimab in serum.
- Pharmacokinetic (PK) profile of itepekimab in serum.
Participants
The clinical trial involves a total of **55 participants** diagnosed with **Chronic Obstructive Pulmonary Disease (COPD)**. The study population includes both male and female subjects, aged between **40 to 70 years**. Participants were selected based on a physician's diagnosis of COPD for at least one year, with a smoking history of at least 10 pack-years. The trial includes both former smokers, who have quit smoking at least six months prior to screening, and current smokers, who are not engaged in smoking cessation programs. Participants are required to have a history of chronic bronchitis symptoms and at least one moderate or severe exacerbation in the past five years. All participants must have been on a stable dose of standard-of-care controller therapy for at least one month before screening. Additionally, participants must have a **body mass index (BMI)** of at least 18 kg/m² and have received appropriate vaccination against SARS-CoV-2. The trial includes individuals who are not pregnant or breastfeeding, with women of childbearing potential agreeing to follow contraceptive guidance. The study population is considered vulnerable, and the trial aims to evaluate the difference in gene expression between former and current smokers undergoing itepekimab treatment.
Plans and Procedures
The clinical trial is designed to evaluate the **mechanism of action** of **itepekimab**, an anti-IL-33 monoclonal antibody, on airway inflammation in patients with **Chronic Obstructive Pulmonary Disease (COPD)**. This is a Phase 2a, open-label, two-part study. The trial aims to assess the difference in gene expression between former and current smokers undergoing treatment with itepekimab. The study is expected to run from May 2022 to August 2025, with a maximum treatment period of 19 weeks for each participant.
Participants will be required to attend several study visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as age, smoking history, and a physician diagnosis of COPD. The screening visit will also ensure that participants have a stable treatment regimen and have received appropriate vaccinations. Following the screening, participants will undergo baseline assessments before commencing the treatment phase. During the treatment period, participants will receive itepekimab via subcutaneous injection, with a maximum daily dose of 300 mg and a total dose not exceeding 2700 mg.
Follow-up visits will be scheduled to monitor the pharmacodynamic effects of itepekimab, including changes in pharmacodynamic normalized enrichment scores (NES) in endobronchial biopsies, bronchial brushings, and nasal brushings. Secondary endpoints will include changes in IL-33 treated eosinophil-associated NES, blood eosinophil count, and the incidence of treatment-emergent adverse events. The study will also assess the incidence of anti-itepekimab antibody responses and functional itepekimab concentrations in serum.
The end-of-study visit will conclude the participant's involvement, during which final assessments will be conducted to evaluate the overall impact of the treatment. Participants may be withdrawn from the study early if they experience severe adverse events, fail to comply with study procedures, or if the investigator deems it necessary for their safety. The expected length of participant involvement is approximately 19 weeks, contingent upon adherence to the study protocol and absence of conditions necessitating early termination.
Treatment
The clinical trial involves the administration of **Itepekimab**, a human monoclonal antibody targeting interleukin-33 (IL-33). Itepekimab is provided as a **solution for injection in a pre-filled syringe**. The pharmaceutical form is specifically designed for **subcutaneous injection**. The dosing regimen for Itepekimab involves a maximum daily dose of 300 mg, with a total maximum dose of 2700 mg over the course of the treatment period. The treatment duration is set for a maximum of 19 weeks. The active substance, Itepekimab, is a protein-based therapeutic agent, classified under the category of "Protein - Other." The synonyms for Itepekimab include ANTI-INTERLEUKIN-33 IGG4 HUMAN MONOCLONAL ANTIBODY, HUMAN MONOCLONAL ANTIBODY IGG4 AGAINST HUMAN IL-33, SAR440340, and REGN3500.
In this study, Itepekimab is the sole experimental medication being evaluated, with no additional non-experimental treatments such as standard-of-care therapy, placebo, or comparator treatments being utilized. The trial aims to assess the mechanism of action of Itepekimab on airway inflammation in patients with chronic obstructive pulmonary disease (COPD). Participant compliance with the dosing schedule will be monitored throughout the study to ensure adherence to the treatment protocol. The study is designed to evaluate the difference in gene expression between former and current smokers undergoing treatment with Itepekimab.
Efficacy
Efficacy in this clinical trial will be assessed through a series of primary and secondary endpoints. The primary endpoints focus on the change from baseline in **itepekimab** pharmacodynamic normalized enrichment score (NES) derived from former smokers in endobronchial biopsies, bronchial brushings, and nasal brushings in current smokers with chronic obstructive pulmonary disease (COPD). These measurements will provide insights into the pharmacodynamic effects of itepekimab on airway inflammation.
Secondary endpoints include changes from baseline in IL-33 treated eosinophil-associated NES and mast cell-associated NES in endobronchial biopsies, as well as changes in blood eosinophil count. Additionally, the incidence of treatment-emergent adverse events (TEAEs), adverse events of special interest (AESIs), serious adverse events (SAEs), and adverse events leading to permanent treatment discontinuation will be monitored. The study will also assess the incidence of potentially clinically significant abnormalities in clinical laboratory tests, vital signs, and electrocardiogram (ECG) abnormalities during the treatment-emergent period. Furthermore, the incidence of treatment-emergent anti-itepekimab antibody responses and functional itepekimab concentrations in serum will be evaluated throughout the study.
Inclusion and Exclusion Criteria
Inclusion Criteria
- Participant must be 40 to 70 years of age inclusive
- Physician diagnosis of COPD for at least 1 year (based on the Global Initiative for Chronic Obstructive Lung Disease [GOLD] definition)
- Smoking history of ≥10 pack-years; a) For former smokers: Participants who report that they are not currently smoking, and smoking cessation must have occurred ≥6 months prior to Screening (Visit 1) with an intention to quit permanently, b) For current smokers (not eligible for Part A): Participants who report that they are currently smoking tobacco (participant smoked at least 5 cigarettes per day on average during the past 7 days) at Screening (Visit 1) and at Baseline, and who are not currently participating in, or planning to initiate, a smoking cessation intervention at Screening (Visit 1) or during the screening period
- Participant-reported history of signs and symptoms of chronic bronchitis (chronic productive cough for at least 3 months in the year before screening in a participant in whom other causes of chronic cough [eg, inadequately treated gastroesophageal reflux or chronic rhinosinusitis; or clinical diagnosis of bronchiectasis] have been excluded).
- Documented or self-reported history of exacerbation having had ≥1 moderate or severe exacerbation within the 5 years prior to Screening (Visit 1), with at least 1 exacerbation treated with systemic corticosteroids: a) Moderate exacerbations are defined as an acute worsening of respiratory symptoms that requires either systemic corticosteroids (intramuscular [IM], intravenous [IV], or oral) and/or antibiotics. b) Severe exacerbations are defined as AECOPD that require hospitalization or observation for >24 hours in emergency department/urgent care facility.
- Participants treated with SoC controller therapy for ≥3 months before Screening (Visit 1) and at a stable dose and regimen of controller therapy for at least 1 month before the screening visit AND during the screening period, including either: triple therapy with LAMA + LABA + ICS, or double therapy with ICS + LABA or LABA + LAMA or ICS + LAMA, or monotherapy with LABA or LAMA
- Participants who have received appropriate vaccination according to local recommendations against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), administered a minimum of 1 week prior to Screening (Visit 1)
- Body mass index (BMI) ≥18 kg/m2
- A female participant is eligible to participate if she is not pregnant, not breastfeeding, and at least one of the following conditions applies: a) Not a women of child-bearing potential (WOCBP) or b) A WOCBP who agrees to follow the contraceptive guidance during the intervention period and for at least 20 weeks after the last dose of study intervention
Exclusion Criteria
- Participants are excluded from the study if any of the following criteria apply: - Current diagnosis or previously confirmed diagnosis of asthma according to the Global Initiative for Asthma (GINA) guidelines unless asthma resolved before 18 years of age and has not recurred
- For former smokers (Part A): Active smoking or vaping of any products (eg, nicotine, tetrahydrocannabinol [THC]) within 6 months prior to Screening (Visit 1) or during the screening period. For current smokers (Part B): vaping of any products (eg, nicotine, THC) within 6 months prior to Screening (Visit 1) or during the screening period
- Participants who are expected to be regularly exposed to environmental (ie, "second hand") tobacco smoke in an indoor setting during the screening or treatment periods (former smokers only)
- Clinically significant new abnormal electrocardiogram (ECG) within 6 months before or at Screening (Visit 1) that may affect the participant’s participation in the study
- Clinically significant and current pulmonary disease other than COPD, eg, sarcoidosis, interstitial lung disease, bronchiectasis (clinical diagnosis), diagnosis of α 1 anti-trypsin deficiency, or another diagnosed pulmonary disease
- Diagnosis of cor pulmonale, evidence of right cardiac failure, or moderate-to-severe pulmonary hypertension
- Participants who require more than 2 L/min of long-term treatment with oxygen at rest. Participants who use up to 4L/min of supplemental oxygen during exercise may enroll. Oxygen during sleep is allowed
- Hypercapnia that requires bi-level positive airway pressure (BiPAP)
- Moderate or severe exacerbation of COPD (AECOPD) within 8 weeks prior to Screening (Visit 1) or during the screening period
- Prior history of pneumonectomy, lobectomy, segmentectomy, or therapeutic bronchoscopy procedure (including bronchoscopic volume reduction). Note: Prior history of surgical lung biopsy or wedge resection are not exclusion criteria
- Any surgery or major procedures (including those requiring conscious sedation) planned to occur during the study. Minor skin procedures are allowed
- Unstable ischemic heart disease, including acute myocardial infarction within 1 year before Screening (Visit 1), or unstable angina within 6 months before Screening (Visit 1) or during the screening period
- Cardiac arrhythmias, including paroxysmal (eg, intermittent) atrial fibrillation. Participants with isolated premature ventricular contractions (PVCs) or premature atrial contractions (PACs) may be considered for inclusion
- Cardiomyopathy, as defined by Stage III-IV (New York Heart Association) cardiac failure, or other relevant cardiovascular disorder that that may affect the participant’s participation in the study
- Any underlying disease requiring the use of prophylaxis for endocarditis
- Uncontrolled hypertension (ie, systolic blood pressure [BP] >180 mm Hg or diastolic BP >110 mm Hg with or without use of antihypertensive therapy)
- Participants with active tuberculosis (TB), latent TB, a history of incompletely treated TB, suspected extrapulmonary TB infection (TBI), or who are at high risk of contracting TB (such as close contact with individuals with active or latent TB) or received Bacillus Calmette Guérin (BCG)-vaccination within 12 weeks before Screening (Visit 1)
- History of human immunodeficiency virus (HIV) infection or positive HIV 1/2 serology at Screening (Visit 1)
- Suspicion of, or confirmed, coronavirus disease 2019 (COVID-19) infection or contact with known exposure to COVID 19 at Screening (Visit 1) or during the screening period; known history of COVID 19 infection within 6 weeks before Screening (Visit 1); history of requiring mechanical ventilation or extracorporeal membrane oxygenation (ECMO) secondary to COVID-19 within 12 months before Screening (Visit 1); participants who have had a COVID-19 infection before Screening (Visit 1) who have not yet sufficiently recovered to participate in the procedures of a clinical trial
- Evidence of acute or chronic infection requiring systemic treatment with antibacterial, antiviral, antifungal, antiparasitic, or antiprotozoal medications within 6 weeks before Screening (Visit 1) or during the screening period, significant viral infections within 6 weeks before Screening (Visit 1) or during the screening period that may not have been treated with antiviral treatment (eg, influenza receiving only symptomatic treatment)
- Participants with active autoimmune disease or participants taking immunosuppressive therapy for autoimmune disease (eg, rheumatoid arthritis, inflammatory bowel disease, primary biliary cirrhosis, systemic lupus erythematosus, multiple sclerosis)
- History of malignancy within 5 years before Screening (Visit 1), or during the screening period, except completely treated in situ carcinoma of the cervix, completely treated and resolved nonmetastatic squamous or basal cell carcinoma of the skin
- Symptomatic herpes zoster within 3 months prior to screening
- Previous use of itepekimab. The above information is not intended to contain all considerations relevant to a patient's potential participation in a clinical trial.
Trial Status by Country
| Country | Status | Start of Recruitment | Planned Patients |
|---|---|---|---|
 Belgium | Not Recruiting | 20 May 2022 | 3 |
 Denmark | Not Recruiting | 20 May 2022 | 11 |
 Germany | Not Recruiting | 20 May 2022 | 34 |
 The Netherlands | Not Recruiting | 20 May 2022 | — |
| Netherlands | — | — | 17 |
Sites & Investigators
Investigational Products
Details about the medicinal products being studied in this clinical trial.
| Product Name | Role in Trial | Formulation | Administration | Max Daily Dose | Treatment Duration | EU MP Number |
|---|---|---|---|---|---|---|
Itepekimab | Test | SOLUTION FOR INJECTION IN PRE-FILLED SYRINGE | SUBCUTANEOUS INJECTION | 300 | 19 | PRD10952832 |