Clinical Trial to Investigate the Safety and Tolerability of EP395 in Patients With COPD

The aim of this clinical trial is to investigate the safety and tolerability of oral, once-daily EP395 administration in COPD patients for 12 weeks.

This is a randomised, double-blind, placebo-controlled, multicentre study to assess the safety and tolerability of EP395 in COPD patients.

In this study, EP395 will be administered to COPD patients for the first time. Patients will receive either EP395 or placebo as oral capsules once-daily for 12 weeks. Safety and tolerability will be assessed, as well as effect on lung function, lung inflammation and systemic inflammation. Patients' symptoms and quality of life will be assessed with questionnaires. In a sub-set of patients, bronchoscopies will be conducted, to investigate exploratory biomarkers in bronchial brushings and bronchoalveolar lavage.

Eligibility Criteria:
Inclusion Criteria:

1. Willing and able to understand the information on the nature, the scope, and the relevance of the study, and to provide voluntary, written informed consent to participate in the study before any study-related procedures
2. Men and women, aged ≥45 years
3. Women of childbearing potential must:

   1. have a negative pregnancy test (blood) at Screening and (urine) Day 1
   2. agree to use, and be able to comply with, highly effective measures of contraceptive control (failure rate less than 1% per year when used consistently and correctly) without interruption, during study participation and until 90 days after the last investigational product (IP) intake.
   3. agree to abstain from breast feeding during the study participation and for 90 days after the last IP intake.
4. Men must agree to use a condom during sexual intercourse with women of childbearing potential during treatment and for 90 days after the last IP intake and should not donate sperm during this time
5. Diagnosed with COPD for at least 2 years with FEV1/forced vital capacity (FVC) ratio \<0.70 and FEV1 \<70% (post bronchodilator) at Screening
6. Receiving at least one maintenance inhaled therapy (ie, long acting beta-agonist \[LABA\], long acting muscarinic antagonist \[LAMA\], LABA/LAMA, LABA/inhaled corticosteroid \[ICS\], LAMA/ICS, or LABA/LAMA/ICS) for at least 3 months before Screening
7. Able to tolerate the sputum induction procedure and to produce an adequate (volume and sufficient quality for cell count) sputum sample
8. Body mass index of ≥19 and ≤35 kg/m2
9. History of sputum production (bronchitic phenotype) for approximately 3 months (minimum, not consecutive) in a year
10. Up to date COVID-19 vaccination (according to local law and guidelines)

Exclusion Criteria:

1. History or presence of any clinically relevant medical condition including laboratory test abnormality or planned surgery that in the investigator's opinion could affect the patient's safety or interfere with the objectives of the study
2. Exacerbation of COPD in the 3 months before Screening
3. Change in medication for COPD in the 3 months before Screening
4. Lung function at Screening that in the investigator's opinion would indicate not safe to perform sputum induction or bronchoscopy (bronchoscopy applicable only in a subset of patients)
5. History of or active tuberculosis
6. Malignancy within the past 5 years, except removed basal cell carcinoma and resected benign colonic polyps
7. Clinically significant abnormality on 12-lead ECG including prolonged corrected QT interval by Fredericia (QTcF) (\>450 msec in men or \>470 msec in women; based on triplicate) at Screening and Day 1 pre-dose
8. Absolute estimated glomerular filtration rate (\[eGFR cystatin C + eGFR creatinine\]/2) \<60mL/min according to Lund-Malmö equation at Screening
9. Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) \>1.5 x upper limit of normal at Screening
10. Use (including prescription, over-the-counter, herbal or dietary) of cytochrome P450 (CYP) inducers within 28 days before first dosing, or strong or moderate inhibitors of CYP3A4 (including dietary eg, grapefruit juice) or P-glycoprotein (Pgp) inhibitors or oral narrow therapeutic index (TI) Pgp substrates (eg, digoxin) within 14 days before first dosing (substrates, inhibitors, and inducers are listed in https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-drug-interactions-table-substrates-inhibitors-and-inducers)
11. Use of macrolide, roflumilast, or oral corticosteroid (OCS) within 28 days before Screening
12. Ongoing antibiotic treatment at Screening
13. Use of home oxygen or home-based non-invasive ventilation 3 months before Screening
14. Use of a biological therapy within 3 months before Screening
15. Use of herbal remedies within 28 days before first dose until follow-up
16. Live vaccine within 28 days or any other vaccine within 14 days before first dose until 28 days after final dose of the IP (with the exception of COVID-19 booster and flu vaccination; see Previous and concomitant medications and therapies)
17. Positive hepatitis B surface antigen, hepatitis C antibodies, or human immunodeficiency virus 1 or 2 antibodies at Screening
18. Positive test result for severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) on Day 1
19. Positive drugs of abuse test at Screening, including cotinine only in ex-smokers for at least 3 months
20. Use of e-cigarettes and vapes
21. History of alcohol or drug misuse within 12 months before Screening
22. Pregnant and lactating women
23. Prior recovery from recent infection, including but not limited to COVID 19 within the last 30 days before first dosing with IP
24. Known hypersensitivity to macrolides or EP395 or any of the excipients (dicalcium phosphate, croscarmellose sodium, magnesium stearate, microcrystalline cellulose)
25. Participation in a study of an experimental drug within 5 half-lives or 3 months before Screening, whichever is longer
26. Dependent subjects of the sponsor or investigator (eg, employees, relatives)
27. Patients without the capacity to understand the nature and risks of the study