This is a Phase 2 study of the efficacy, safety, tolerability and pharmacokinetics of two doses of EXPD-101 in participants with COPD. Study participants will be randomized to receive either study drug or placebo administered once daily for 52 weeks.

Inclusion Criteria:

1. Provided written informed consent for the study

2. Body mass index (BMI) ≥ 18.5 kg/m2 and < 35 kg/m2 at screening (weight ≥ 50 kg for males and ≥ 45 kg for females)

3. Diagnosis of COPD for at least 1 year

4. COPD with physician-confirmed diagnosis of chronic bronchitis (persistent, productive cough and sputum for at least 3 months in the past year)

5. At least 2 moderate or > 1 severe exacerbation within 12 months prior to screening

6. Current or ex-tobacco smokers with history of ≥ 10 pack-years (1 pack year = 20 cigarettes smoked per day for 1 year);

7. Stable maintenance therapy with either dual or triple inhaled therapy for ≥ 3 months prior to enrollment per below:

   1. Dual therapy: long-acting beta-2 agonist/muscarinic antagonist (LABA/LAMA) or inhaled corticosteroids (ICS)/LAMA, or ICS/LABA OR
   2. Triple therapy: ICS/LAMA/LABA

8. Post-BD FEV1/FVC < 0.7 and post-BD FEV1(% predicted) ≥ 40% at Screening

9. COPD Assessment Test (CAT) score ≥ 10 at Screening

10. If participant is of childbearing potential, must commit to practicing highly effective methods of birth control and not donating eggs during the study and at least 14 days after the last dose.

11. Male participants commit to the following during the study and for at least 14 days after the last dose:

    1. Practice true sexual abstinence (refrain from heterosexual intercourse)
    2. Use a condom with any female partner of childbearing potential and ensure that the partner uses a highly effective contraceptive method (eg, IUD/IUS, combined hormonal contraception, progestogen-only contraception, or bilateral tubal occlusion).
    3. Be vasectomized (≥ 3 months prior to screening)
    4. Refrain from donating sperm during the Treatment Period and for at least 14 days after the last dose of the IP

Exclusion Criteria:

1. COPD exacerbation within the 4 weeks prior to randomization.

2. Clinically important pulmonary disease other than COPD (eg, asthma, active lung infection, clinically significant bronchiectasis, pulmonary fibrosis, cystic fibrosis, lung cancer, alpha-1 antitrypsin deficiency, tuberculosis).

3. Significant immunodeficiency and/or positive serological tests for hepatitis B, hepatitis C, or known human immunodeficiency virus (HIV) infection.

4. Pneumonia requiring antibiotics or antiviral medication within 28 days prior to Visit 1.

5. History of clinically significant infection (excluding pneumonia), acute upper or lower respiratory infection, requiring antibiotics or antiviral medication within 14 days prior to Visit 1.

6. Evidence of active liver disease (with or without ongoing treatment)

7. Participants with a QT interval, from the ECG conducted at Screening Visit 1, corrected with Fridericia's formula (QTcF) > 450 msec (or QTcF > 480 msec in participants with bundle branch block).

8. Current or history, within the past year of Visit 1, of substance and/or alcohol abuse.

9. History of cancer except:

   1. Participants who have had basal cell carcinoma, localized squamous cell carcinoma of the skin or in situ carcinoma of the cervix are eligible to participate in the study provided that curative therapy was completed at least 12 months prior to Visit 1
   2. Participants who have had other malignancies are eligible provided that curative therapy was completed at least 5 years prior to Visit 1

10. Any clinically significant abnormal findings in physical examination, vital signs, hematology, clinical chemistry, or urinalysis during Screening Period, which in the opinion of the investigator, may put the participant at risk because of his/her participation in the study, or may influence the results of the study, or the participant's ability to complete the entire duration of the study.

11. Known history of allergy or reaction to any component of the investigational product formulation

12. Current treatment with biologic drugs for COPD (eg, dupilumab, mepolizumab) or use of Therapeutics, biologics within 5 half-lives or 4 months, whichever is longer, from randomization

13. Current long-term treatment with oxygen therapy > 12 hours per day

14. Use of immunoglobulin or blood products in 30 days prior to Screening

15. Received a live attenuated vaccine within 30 days prior to Screening

16. Participants who are participating in the acute phase of a pulmonary rehabilitation program, i.e. who started rehabilitation < 4 weeks prior to screening (Note: participants in the maintenance phase of a rehabilitation program can be included).

17. History or active conditions associated with the onset of non-hereditary palmoplantar keratosis:

18. Have any tooth that can potentially cause pain or infection as noted in the oral exam unless they are corrected before the study

19. Has active periodontal disease and are either:

    1. Currently treated by a dentist for this condition or
    2. Expected to have periodontal disease-related procedures within the study period

20. Are scheduled to have tooth extraction that will occur during the study period

Individual participant data will not be shared externally. Data collected in this study will be used solely for internal analysis and regulatory submission purposes, consistent with participant confidentiality protections and sponsor data governance policies.