Bronchodilator Effect of RPL554 Administered in Addition to Tiotropium/Olodaterol in Patients With COPD

RPL554 is a dual inhibitor of phosphodiesterase 3 (PDE3) and phosphodiesterase 4 (PDE4) which
are known to have a role in modulating the inflammatory airway response in respiratory
diseases, including COPD. PDE3 inhibitors act as bronchodilators whilst PDE4 inhibitors have
anti-inflammatory properties and there is also evidence to suggest that combined inhibition
of PDE3 and PDE4 can have additive or synergistic anti-inflammatory and bronchodilator. The
two doses of RPL554 (1.5 mg and 6 mg)have been selected based on the results from prior
studies investigating single and multiple ascending doses in healthy subjects, single doses
in asthmatics, single/multiple ascending doses in COPD patients, and 3 days of dosing in COPD
patients. These doses were demonstrated to be both effective as a bronchodilator and well
tolerated.

The purpose of the study is to investigate if RPL554 has an additive bronchodilator effect
when administered in combination with a commonly used anticholinergic/β-agonist combination
medication, tiotropium/olodaterol (Respimat), in this patient population measured by the peak
forced expiratory volume in one second (FEV1), and forced vital capacity (FVC).

Inclusion Criteria:

1. Written informed consent

2. Male or female aged 40 and 80 years

3. For males, not to donate sperm and either be sexually abstinent or use contraception
as specified by the protocol. For females, be of non-childbearing potential or use a
highly effective form of contraception

4. 12-lead ECG with heart rate between 45 and 90 beats per minute, QTcF ≤450 msec for
males, and ≤ 470 msec for females, QRS interval ≤120 msec and no clinically
significant abnormality including morphology

5. Screening Holter report with a minimum of 18 hours recording that is able to be
evaluated for rhythm analysis showing no abnormality which indicates a significant
impairment of patient safety or which may significantly impair interpretation

6. Capable of complying with all study restrictions and procedures including ability to
use the study nebulizer and Respimat® correctly.

7. Body mass index (BMI) between 18 and 36 kg/m2 and minimum weight of 45 kg.

8. COPD diagnosis for at least 1 year and clinically stable COPD for 4 week

9. Post-bronchodilator (two puffs of salbutamol/albuterol followed by two puffs of
ipratropium) spirometry at Screening:

- Post-bronchodilator FEV1/forced vital capacity (FVC) ratio of ≤0.70

- Post-bronchodilator FEV1 ≥30 % and ≤70% of predicted normal

- Demonstrates ≥150 mL increase from pre-bronchodilator FEV1

10. A chest X-ray showing no abnormalities, which are both clinically significant and
unrelated to COPD.

12. Meet the concomitant medication restrictions and be expected to do so for the rest of
the study.

13. Current and former smokers with smoking history of ≥10 pack years. 14. Capable of
withdrawing from long acting bronchodilators for the duration of the study, and short
acting bronchodilators for 8 hours prior to dosing.

Exclusion Criteria:

1. A history of life-threatening COPD including Intensive Care Unit admission and/or
requiring intubation.

2. COPD exacerbation requiring oral or parenteral steroids, or lower respiratory tract
infection requiring antibiotics, in the last 3 months

3. A history of one or more hospitalizations for COPD in the last 12 months

4. Intolerance or hypersensitivity to tiotropium, olodaterol, atropine, ipratropium, or
RPL554.

5. Evidence of cor pulmonale or clinically significant pulmonary hypertension.

6. Other respiratory disorders

7. Previous lung resection or lung reduction surgery.

8. Use of oral COPD medications, except mucolytics, in the last 3 months

9. Pulmonary rehabilitation, unless such treatment has been stable in the last 4 weeks

10. History of, or reason to believe a patient has, drug or alcohol abuse within the past
5 years.

11. Inability to perform acceptable spirometry or whole body plethysmography

12. Received an experimental drug within 30 days or five half lives, whichever is longer.

13. Patients with uncontrolled disease that the Investigator believes are clinically
significant. This includes any hepatic disease, or an alanine aminotransferase or
aspartate aminotransferase>2 x upper limit of normal (ULN).

14. Documented cardiovascular disease: arrhythmias, angina, recent (<1 year) or suspected
myocardial infarction, congestive heart failure, unstable or uncontrolled
hypertension, or diagnosis of hypertension in the last 3 months

15. Use of non-selective oral β-blockers.

16. Major surgery (requiring general anesthesia) in the last 6 weeks or will not have
fully recovered from surgery, or planned surgery through the end of the study.

17. A disclosed history or one known to the Investigator, of significant non compliance in
previous investigational studies or with prescribed medications.

18. Required use of oxygen therapy, even on an occasional basis.

19. Symptomatic prostatic hyperplasia or bladder-neck obstruction or with narrow-angle
glaucoma.

20. History of malignancy of any organ system within 5 years, with the exception of
localized skin cancers (basal or squamous cell).

21. Clinically significant abnormal values for safety laboratory tests (hematology,
biochemistry, virology or urinalysis) as determined by the Investigator

22. Any other reason that the Investigator considers makes the patient unsuitable to
participate.