A Phase 2a Study to Assess Safety, Daily Symptoms, PK, and Biomarkers of YPL-001 in COPD Patients

A TEAE was defined as an AE that was starting or worsening at the time of or after study drug administration. All AEs collected by the clinics and recorded in the CRF were captured in the database and were listed in by-patient data listings.

A TEAE was defined as an AE that was starting or worsening at the time of or after study drug administration. All AEs collected by the clinics and recorded in the CRF were captured in the database and were listed in by-patient data listings.

When a patient experienced the same AE at more than one level of severity, the patient was counted once under the highest severity.

When a patient experienced the same AE at more than one level of severity, the patient was counted once under the highest severity.

The PEF assessments are made daily prior to each dose from Day 1 of the Run-in Period to Day 56 of the Treatment Period. Three measurements were made at each time point using a hand held PEF meter. Readings not performed in the clinical research unit (CRU) were recorded in the patient e-diary. All PEF assessments were performed before administration of a bronchodilator where possible. Baseline is Day 1 predose measurement.

Patient is asked to record the major (sputum quality, color, consistency) and minor (cough, wheeze, sore throat, nasal congestion, discharge, and body temperature above 100°F) symptoms of COPD exacerbation via the e-diary before each dosing. Baseline is Day 1 predose measurement

• Breathlessness(Dyspnea) Screen: 0(None)-10(Extreme): 0: better condition, 10: worse condition
• Sputum Quantity Screen: None(better)-greater than 1/4 cup(worse)
• Sputum Color Screen: White(better)-Brown(condition)
• Sputum Consistency Screen: Watery(better)-Thick(worse)
• Peak Flow Measurement Screen: 60(better)-800(worse)
• Symptoms Screen: (Temperature over 100F / Cough/Wheeze/Sore Throat/ Nasal Congestion)
• Nasal Discharge Screen(Yes/No) * quantitative data were summarized including sample size, arithmetic mean, standard deviation, CV, min and max.

Symptom score catecorizes normal(0-0.5), mild(1-1.5), moderate(2-2.5), severe(3-3.5)

Severity level of patient's dyspnea is accessed via the modified Borg dyspnea scale programmed within the e-diary. The modified Borg dyspnea scale is a self-administered categorical scale with a score from 0 to 10, where 0 (as a measure of dyspnea) corresponds to the sensation of normal breathing (absence of dyspnea) and 10 corresponds to the patient's maximum possible sensation of dyspnea.

Patient's functional capacity and activity status were accessed via the DASI programmed within the e-diary. DASI is a self-administered 12-item questionnaire that assesses daily activities such as personal care, ambulation, household tasks, sexual function and recreation with respective metabolic costs. Each item has a specific weight based on the metabolic cost. The final score ranges between 0 and 58.2 points.

The higher score shows the better the functional capacity.

Forced expiratory volume in 1 second (FEV1) is the amount of air that can be exhaled in one second. FEV1 is measured by spirometry performed at approximately the same time of day on each visit to avoid diurnal variation. A positive change from baseline in FEV1 indicates improvement in lung function.

Inspiratory capacity (IC) is the maximum volume of air that can be inhaled into the lungs from the normal resting position after breathing out normally. IC is measured by spirometry performed at approximately the same time of day on each visit to avoid diurnal variation.

The ratio is calculated as the amount of air expelled from the lungs in one second after a full inspiration (FEV1) divided by the volume of air that can forcibly be blown out after a full inspiration (FVC).

Dyspnea at baseline (Day -1) will be assessed with the Baseline Dyspnea Index (BDI). This instrument has 3 domains (functional impairment, magnitude of task and magnitude of effort) with the values added for a combined focal score. Functional impairment determines the impact of breathlessness on the ability to carry out activities; magnitude of task determines the type of task that causes breathlessness, magnitude of effort establishes the level of effort that results in breathlessness. The BDI scores range from 0 (very severe impairment) to 4 (no impairment) for each domain with the baseline focal score consisting of the sum of each domain (0 to 12). Dyspnea throughout the study will be performed at the time points. The change from baseline is measured by the Transition Dyspnea Index (TDI) score which ranges from -3 (major deterioration) to +3 (major improvement) for each domain with the TDI focal score consisting in the sum of each domain (-9 to +9).

The chronic obstructive pulmonary disease assessment test (CAT) is a short and simple questionnaire of 8 items completed by patients to be performed at the time points. Scores for each of the 8 items are summed to give a single, final score ranging from 0 (no impact on daily activities) to 40 (very high impact on daily activity).

The bronchoalveolar lavage (BAL) samples were collected at baseline and again at the completion of the study for pharmacodynamics (PD) assessments of biomarkers. BAL samples are at analyzed for total cell count (cells/mL) of white blood cell, macrophages, lymphocytes, neutrophils, and eosinophils as a percentage of total cells.

The bronchoalveolar lavage (BAL) samples are collected at baseline and again at the completion of the study for pharmacodynamics (PD) assessments of biomarkers. BAL samples are analyzed for concentrations of tumor necrosis factor (TNF)-alpha, interleukin (IL)-1β, IL-4, IL-5, IL-6, IL-8, IL-13, Myeloperoxidase (MPO), neutrophil elastase (ELA2), monocyte chemotactic protein-1 (MCP-1), myeloperoxidase(MPO), and matrix metalloproteinase-9 (MMP-9).

The blood samples are collected at the the time points of the study for pharmacodynamics (PD) assessments of biomarkers. The blood samples are analyzed for inflammatory markers (total and differential cell counts as absolute and percentage for neutrophils, macrophages, eosinophils and lymphocytes).

The blood samples are collected at the the time points of the study for pharmacodynamics (PD) assessments of biomarkers. The blood samples are analyzed for concentrations of C-reactive protein (CRP), fibrinogen, TNF-α, IL-1β, IL-4, IL-5, IL-6, IL-8, IL-13, MCP-1, and MMP-9. Baseline is Day 1 predose measurement.

Number of COPD exacerbation during 8-week treatment. COPD exacerbations are defined as a new onset or worsening of at least one respiratory symptom (i.e. dyspnea, cough, sputum purulence or volume, or wheeze) present for at least 3 consecutive days, documented change or increase in COPD-related treatment due to worsening symptoms or documented COPD-related hospitalizations or emergency room visits.

Forced vital capacity (FVC) is the volume of air which can be forcibly exhaled from the lungs after taking the deepest breath possible. FVC is measured by spirometry performed at approximately the same time of day on each visit to avoid diurnal variation. A positive change from baseline in FVC indicates improvement in lung function.