A Phase II Study of Ensifentrine in Non-Cystic Fibrosis Bronchiectasis

Inclusion Criteria:

• Males are eligible to participate if they agree to use contraception as described inthe contraceptive guidance from Screening and throughout the study and for at least 30 days after the last dose of blinded study medication.

• Females are eligible to participate if they are not pregnant, not breastfeeding, and 1 of the following conditions apply:

1. Not a woman of childbearing potential (WOCBP) OR

2. A WOCBP who agrees to follow the contraceptive guidance from Screeningthroughout the study and for at least 30 days after the last dose of blindedstudy medication.

• Clinical history consistent with bronchiectasis (cough, chronic sputum production,and/or recurrent respiratory infections) confirmed by chest CT demonstratingbronchiectasis affecting 1 or more lobes. Confirmation may be based on prior chestCT within the prior 5 years; subjects whose past CT image records are not availablewill require chest CT scan during screening. Notes: If a subject has no clinicalhistory consistent with bronchiectasis, they may not be re-screened.

• Current sputum producer with a history of chronic expectoration and able to providesputum sample spontaneously at the clinic during screening.

• ≥ 1 documented pulmonary exacerbation defined by an antibiotic prescription by aphysician for the signs and symptoms of respiratory infections in the past 12 monthsbefore screening.

• Capable of using the study nebulizer correctly.

• Ability to perform acceptable spirometry in accordance with American ThoracicSociety and European Respiratory Society guidelines

Exclusion Criteria:

• A diagnosis of COPD or a primary diagnosis of asthma, as judged by the investigator.

• Bronchiectasis due to cystic fibrosis, hypogammaglobulinemia common variableimmunodeficiency, severe immunodeficiency, or requirement for treatment withintravenous immunoglobulin.

• Current smoker defined as by the Centers for Disease Control and Prevention (CDC).

• Former cigarette smokers with a history of cigarette smoking ≥ 10 pack years atScreening [number of pack years = (number of cigarettes per day / 20) × number ofyears smoked (e.g., 20 cigarettes per day for 10 years, or 10 cigarettes per day for 20 years)]. Pipe and/or cigar use cannot be used to calculate pack-year history.Former smokers are defined as those who have stopped smoking for at least 6 monthsprior to Screening.

• A diagnosis of primary ciliary dyskinesia.

• Current treatment for nontuberculous mycobacterial lung infection, allergicbronchopulmonary aspergillosis, or tuberculosis.

• Presence of acute exacerbation or another acute infection that required antibiotictreatment within 4 weeks of screening (or within 12 weeks of screening if theantibiotic prescription is a macrolide).

• Use of the following prohibited medications within the designated time periods:

1. Immunomodulatory agents (e.g., bortezomib, ixazomib, thalidomide, dupilumab)within 3 months prior to signing the ICF.

2. CFTR modulators (e.g., ivacaftor, lumacaftor, tezacaftor) within 1 week priorto signing the ICF.

3. Treated with doses of cyclic antibiotics 90 days prior to signing the ICF.

4. Theophylline and PDE4 inhibitors (e.g., roflumilast, apremilast, crisaborole)within 48 hours prior to signing the ICF.

5. Brensocatib within 3 months or 5 half-lives, whichever is longer, prior tosigning the ICF.

6. Ohtuvayre at any time prior to signing the ICF.

• Initiated or altered therapy with oral or inhaled antibiotics as chronic treatmentfor NCFBE within 3 months prior to signing the ICF.

• Initiated or altered therapy with ICS within 4 weeks prior to Screening.

• Unable to withhold short-acting beta-agonists or short-acting muscarinic antagonistsfor ≥ 4 hours prior to spirometry.

• Significant hemoptysis (≥ 300 mL or requiring blood transfusion) within 6 weeksprior to Day 1.

• Currently participating in or scheduled to participate in an intensive pulmonaryrehabilitation program (a maintenance rehabilitation program is allowed if theirschedule and procedure will be consistent for the duration of the study).

• Current or chronic history of unstable liver disease defined by the presence ofascites, encephalopathy, coagulopathy, hypoalbuminemia, esophageal or gastricvarices or persistent jaundice, cirrhosis, or known hepatic or biliary abnormalitiesexcept for Gilbert syndrome or asymptomatic gallstones. Note: Chronic stablehepatitis B and C is not exclusionary if the subject otherwise meets study entrycriteria.

• History of or current malignancy of any organ system, treated or untreated withinthe past 5 years, except for localized basal or squamous cell carcinoma of the skin.

• Estimated glomerular filtration rate (eGFR) < 30 mL/min.

• Alanine aminotransferase (ALT) ≥ 2 × upper limit of normal (ULN), aspartateaminotransferase (AST) ≥ 2 × ULN, alkaline phosphatase and/or bilirubin > 1.5 × ULN (isolated bilirubin > 1.5 × ULN is acceptable if fractionated bilirubin < 35%).

• Participation in any other interventional, clinical studies (drugs or devices)within 3 months before Day 1, or 5 half-lives, whichever is longer.

• Intolerance of or hypersensitivity to ensifentrine or any of itsexcipients/components.

• Current or history of drug or alcohol abuse within the past 5 years.

• Significantly abnormal ECG finding