A Study to Investigate the Safety, Tolerability, and Pharmacokinetics of Inhaled CHF6333 After Single Doses in Healthy Volunteers and After Single and Repeated Doses in Subjects With Bronchiectasis

HV Inclusion Criteria:

1. Signed and dated informed consent obtained prior to any study-related procedure;

2. Healthy male or female subject ≥18 and ≤60 years of age at screening;

3. Ability to understand the study procedures and the risks involved, and to be trainedto use inhalers correctly and to generate sufficient peak inspiratory flow (PIF) (atleast 40 L/min) using the In-Check Dial set as per "GenuAir" inhaler resistance, atscreening;

4. Body mass index (BMI) ≥18 and ≤35 kg/m2 at screening;

5. Non-smokers or ex-smokers who smoked <5 pack-years and stopped smoking >1 year priorto screening;

6. Good physical and mental status, determined via assessment of medical history andclinical examination, at screening and prior to randomisation;

7. Vital signs within normal limits at screening and prior to randomisation: diastolicblood pressure (DBP) ≥40 and ≤89 mmHg, and systolic blood pressure (SBP) ≥90 and ≤139 mmHg; body temperature <37.5°C;

8. Triplicate 12-lead electrocardiogram (ECG) considered as normal (40 ≤ heart rate ≤110 bpm, 120 ms ≤ PR ≤210 ms, QRS ≤120 ms, Fridericia corrected QT interval [QTcF] ≤450 ms for males and QTcF ≤470 ms for females) at screening and prior torandomisation;

9. Lung function measurements within limits at screening and prior to randomisation:forced expiratory volume in 1 second (FEV1) >80% predicted and FEV1/forced vitalcapacity (FVC) ratio >0.70;

10. Male subjects willing to use a male condom throughout the study if they have womenof childbearing potential (WOCBP) partners; male subjects with non-WOCBP partners orwho are sterile do not have contraception requirements;

11. Female subjects (if WOCBP) and/or their partners (if fertile) must be willing to usea highly effective birth control method, preferably with low user dependency,throughout the study; female subjects who are non-WOCBP or who have non-fertilepartners do not have contraception requirements.

HV Exclusion Criteria:

1. Participation in another clinical study where investigational drug was received andthe last investigations were performed less than 3 months prior to randomisation;

2. Clinically relevant and uncontrolled respiratory, cardiac, hepatic,gastrointestinal, renal, endocrine, hematologic, metabolic, neurological, orpsychiatric disorders that may interfere with successful completion of thisprotocol, according to the investigator's judgment;

3. Clinically relevant abnormal laboratory values at screening suggesting an unknowndisease and requiring further clinical investigation or which may impact the safetyof the subject or the evaluation of the results of the study, according to theinvestigator's judgment;

4. History of respiratory diseases;

5. Positive human immunodeficiency virus (HIV) 1 or HIV2 serology results at screening;

6. Hepatitis serology results which indicate acute or chronic hepatitis B (HB) orhepatitis C virus (HCV) at screening;

7. Documented coronavirus disease 2019 (COVID-19) diagnosis within 2 weeks prior toscreening or prior to randomisation, or associated complications/symptoms, whichhave not resolved within 2 weeks prior to screening;

8. Blood donation or blood loss (equal or more than 450 mL) less than 2 months prior toscreening or prior to randomisation;

9. Abnormal liver enzymes at screening or prior to randomisation (alanineaminotransferase [ALT] or aspartate aminotransferase [AST] or bilirubin: >1.5× upperlimit of normal [ULN]);

10. Positive urine test for cotinine at screening or prior to randomisation;

11. Documented history of alcohol abuse within 12 months prior to screening or apositive alcohol breath test at screening or prior to randomisation;

12. Documented history of drug abuse within 12 months prior to screening or a positiveurine drug screen at screening or prior to randomisation;

13. Treatment with prohibited concomitant medications or if the subject is expected totake prohibited concomitant medications during the study;

14. Presence of any current infection, or previous infection that resolved less than 7days prior to screening or prior to randomisation;

15. Known intolerance and/or hypersensitivity to any of the excipients contained in theformulation used in the study;

16. Unsuitable veins for repeated venepuncture;

17. Heavy caffeine drinker;

18. For females only: pregnant or lactating women, where pregnancy is defined as thestate of a female after conception and until termination of the gestation, confirmedby a positive serum human chorionic gonadotropin laboratory test. A serum pregnancytest is to be performed at screening and a urine pregnancy test is to be performedprior to randomisation;

19. Use of any kind of electronic smoking devices within 6 months prior to screening.

Part I BE subjects Inclusion Criteria:

1. Signed and dated informed consent obtained prior to any study-related procedure;

2. Male or female subject ≥18 and ≤80 years of age at screening;

3. Clinical history consistent with BE (cough, chronic sputum production, and/orrecurrent respiratory infections) that is confirmed by chest computed tomography (CT) demonstrating BE affecting 1 or more lobes (confirmation may be based on priorchest CT); subjects whose past chest radiographic image records or report are notavailable will undergo chest CT scan during screening;

4. Post-bronchodilator FEV1 ≥50% of the predicted value at screening;

5. If currently receiving treatment for BE, this treatment should be administered at astable dose;

6. Subjects in a stable clinical condition with no exacerbation of BE for at least 4weeks prior to randomisation. A pulmonary exacerbation is defined as a deteriorationin three or more of the key symptoms for at least 48 hours (cough, sputum volumeand/or consistency, sputum purulence, breathlessness and/or exercise tolerance,fatigue and/or malaise, haemoptysis) AND a clinician-prescribed course ofantibiotics;

7. Vital signs within normal limits at screening and prior to randomisation: DBP ≥40and ≤89 mmHg, and SBP ≥90 and ≤150 mmHg; body temperature <37.5°C;

8. Ability to understand the study procedures and the risks involved, and the abilityto be trained to use the inhalers correctly and to generate sufficient PIF (at least 40 L/min) using the In-Check Dial set as per "GenuAir" inhaler resistance, atscreening;

9. Male subjects willing to use a male condom throughout the study if they have WOCBPpartners; male subjects with non-WOCBP partners or who are sterile do not havecontraception requirements;

10. Female subjects (if WOCBP) and/or their partners (if fertile) must be willing to usea highly effective birth control method, preferably with low user dependency,throughout the study; female subjects who are non-WOCBP or who have non-fertilepartners do not have contraception requirements.

Part I BE subjects Exclusion Criteria:

1. History of a clinically meaningful unstable or uncontrolled chronic comorbiditythat, in the opinion of the investigator, might confound the results of the study orpose an additional risk in administering the study drug to the subject;

2. Acute symptomatic respiratory tract infection which constitutes an increase from thesubject's baseline, per the investigator's judgment, within 4 weeks prior torandomisation;

3. Abnormal and clinically significant 12-lead ECG at screening or prior torandomisation that results in an active medical problem, which may impact the safetyof the subject, per the investigator's judgment. Male subjects with QTcF >450 ms andfemale subjects with QTcF >470 ms cannot be enrolled;

4. Clinically significant abnormal laboratory values at screening that, in the opinionof the investigator, may put the subject at risk by participating in the study, orinterfere with the subject's treatment or assessment, or influence the results ofthe study;

5. Participation in another clinical study, where investigational drug was receivedless than 30 days or less than 5 half-lives of the previous administered product (whichever is longer) prior to screening; participation in another clinical study isalso not allowed between screening and randomisation;

6. Primary diagnosis of asthma, as determined by the investigator;

7. Concomitant diagnosis of cystic fibrosis;

8. Diagnosis of chronic obstructive pulmonary disease (COPD) made by a clinician, withairflow obstruction (post-bronchodilator FEV1/FVC ratio <0.7) and at least a 10pack-year smoking history; subjects with documented COPD but without airflowobstruction or smoking history will be permitted;

9. Current smokers; ex-smokers must have stopped for at least 1 year prior to screening (≥6 months for electronic smoking devices);

10. Subjects with an active tuberculous mycobacteria (TM) or non-tuberculousmycobacteria (NTM) infection requiring or receiving antibiotic treatment, an activeallergic bronchopulmonary aspergillosis requiring treatment with corticosteroids oranti-fungal therapy, and/or a connective tissue disease (CTD) receiving animmunosuppressive treatment equivalent to >10 mg prednisolone daily or systemicimmunosuppression;

11. Diagnosis of common variable immunodeficiency (CVID) or other immunodeficienciesrequiring immunoglobulin treatment, based on subject history;

12. Diagnosis of rheumatoid arthritis;

13. Malignancy that has not been in complete remission for at least 1 year or anyuntreated localised carcinomas;

14. History of solid organ/haematological transplantation and receivingimmunosuppressive therapy;

15. Use of any antimicrobials (oral, inhaled, or intravenous) within 4 weeks prior torandomisation, except for subjects who are on stable treatment with macrolideantibiotics (for at least 3 months);

16. Medical history of discontinuation of previous inhaled therapy due to bronchospasmor intolerance;

17. Documented COVID-19 diagnosis within 4 weeks prior to randomisation, or associatedcomplications/symptoms;

18. Diagnosis of alpha-1-antitrypsin (AAT) deficiency defined as an AAT serum level <110mg/dL; a prior test result of AAT serum level to confirm the diagnosis will beacceptable. In the event that a prior result is not available, a new test will beperformed during the screening period and the result considered for the eligibilityat randomisation.

19. Treatment with prohibited concomitant medications or if the subject is expected totake prohibited concomitant medications during the study;

20. Subjects treated with monoclonal antibodies (mAbs) for any respiratory conditions;

21. Subjects with traction BE;

22. For females only: pregnant or lactating women, where pregnancy is defined as thestate of a female after conception and until termination of the gestation, confirmedby a positive serum human chorionic gonadotropin laboratory test. A serum pregnancytest is to be performed at screening, and a urine pregnancy test is to be performedprior to randomisation;

23. Positive HIV1 or HIV2 serology results at screening;

24. Hepatitis serology results which indicate acute or chronic HB or HCV at screening;

25. BMI ≤17 kg/m2 at screening.

Part II BE subjects Inclusion Criteria: the subjects must meet all the inclusion criteria listed in Part I for subjects with BE (Cohort B), except the inclusion criterion below:

4. Post-bronchodilator FEV1 ≥30% of the predicted value at screening.

The subjects must also meet the additional inclusion criteria listed below:

11. Subjects who are regular daily sputum producers and who are able to provide at leastone sputum sample at screening and two sputum samples prior to randomisation; 12.Subjects with active NE level in sputum sample at screening, defined by either apositive bacterial culture in a local laboratory (a positive result for any pathogenwill be accepted for eligibility) or by a positive reading of the NEATstik® in vitrodiagnostic test.

Part II BE subjects Exclusion Criteria:

See the list of criteria in Part I for subjects with BE (Cohort B), except the exclusion criterion below:

15. Use of oral or inhaled antibiotics < 3 months prior to randomization as chronictreatment for BE. Patients on antibiotics as chronic treatment should have been onsuch treatment for ≥ 3 months prior to randomization while meeting all otherinclusion and exclusion criteria.