Study to Compare the Pharmacokinetics and Pharmacodynamics of ASA Powder for Oral Inhalation With Non-enteric-coated Chewable Aspirin in Adult Subjects With Obstructive or Restrictive Pulmonary Function

A Single-dose, Open-label, Multi-center, Randomized, 2-treatment Crossover Study to Compare the Pharmacokinetics, Pharmacodynamics, Safety and Tolerability of Acetylsalicylic Acid Powder for Oral Inhalation With Non-enteric-coated Chewable Aspirin in Adult Subjects With Obstructive or Restrictive Pulmonary Function

The goal of this clinical trial is to compare the pharmacokinetics (PK) pharmacodynamics (PD), safety and tolerability of acetylsalicylic acid powder for oral inhalation (I-ASA) with non-enteric-coated chewable aspirin (C-ASA) in adult subjects with obstructive or restrictive pulmonary function.

In the first treatment period, subjects will be randomized to receive either a single dose (100 mg) of I-ASA powder via a Dry Powder Inhaler (DPI) OR a single dose (162 mg) of C-ASA tablets. After a washout period, subjects will be crossed over to receive the other treatment in the second treatment period. All subjects will receive both treatments during the study. Each single dose treatment will be followed by up to 24 hours of serial post-dose PK, PD, and safety/tolerability assessments.

Up to 16 adult males and females subjects are planned for enrollment in this study, to achieve a minimum of 10 subjects with evaluable PD/PK, safety, and tolerability data:

• 5 subjects with obstructive lung function [i.e., diagnosed with chronic obstructive pulmonary disease (COPD)]; and
• 5 subjects with restrictive lung function

Inclusion Criteria:

All Cohorts

• Subjects must meet all of the following criteria to be included in the study:
• Male or female, ≥ 40 years of age.
• BMI >18.0 and <35.0 kg/m2 and body weight ≥50.0 kg for males and ≥45.0 kg for females.
• Clinically stable as determined by medical history, physical examination, vital signs, and clinical laboratory evaluation.
• Female subjects of non-childbearing potential must be: post-menopausal; or surgically sterile at least 3 months prior to first dosing.
• Sexually active female subjects of childbearing potential must be willing to use an acceptable contraceptive method throughout the study as detailed in protocol.
• Smoker (no more than 25 cigarettes or equivalent daily) or non-smoker.

Obstructive Pulmonary Function Cohort

• Subject with a smoking history of at least 10 pack-years.
• Subject with an established diagnosis of COPD at least 12 months prior to the screening visit AND confirmed at screening by spirometry, with a post bronchodilator FEV1 greater than 40% and equal to or less than 70% of the subject's normal predicted value and a post-bronchodilator FEV1 greater than 40% and equal to or less than 70% of the subject's normal predicted value and a post-bronchodilator FEV1/ FVC ratio < 0.70.
• Subject on stable uninterrupted maintenance COPD therapy for at least 3 months prior to screening as per SoC and without any history of moderate or severe exacerbations within 6 months prior to screening.
• Non-symptomatic subject on stable uninterrupted maintenance COPD therapy, such that, in the judgement of the Investigator, on the day of dosing in each period, it would be safe to withhold the morning dose of the maintenance treatment until 2 hours post-dose and to withhold PRN short acting rescue bronchodilators from 1 hour pre-dose until 2 hours post-dose.

Restrictive Pulmonary Function Cohort

• Subject with a history and documented prior diagnosis of underlying chronic respiratory or cardiac disease with restrictive pulmonary function as confirmed at the screening visit by:
• FEV1/FVC ≥ 0. 7 and
• FVC < LLN (or < 80% predicted) and
• TLC < 5th percentile predicted (or < 80% predicted) and
• DLCO ≤ 75% to ≥ 35% predicted
• Continued uninterrupted SoC therapy for underlying disease for at least 12 consecutive weeks immediately prior to screening.
• Stable patient, such that, in the judgement of the Investigator, on the day of dosing in each period, it would be safe to withhold the morning dose of the maintenance treatment until 2 hours post-dose and to withhold short acting rescue bronchodilators, if any, from 1 hour pre-dose until 2 hours post-dose.

Exclusion Criteria:

All Cohorts:

• Presence of clinically significant uncontrolled or unstable cardiovascular, pulmonary, hepatic, renal, endocrinological, hematological, immunologic, metabolic, psychological, neurological, or gastrointestinal disease.
• Any new clinically significant abnormal finding at physical examination at screening.
• Positive serology test results for HBsAg, HCV antibody, or HIV antigen and antibody, or TB test at screening.
• Positive pregnancy test or lactating female subject.
• Positive urine drug screen or alcohol breath test.
• Positive test for active COVID-19.
• Known allergic reactions, hypersensitivity or contraindications to ASA, ibuprofen, other NSAID, or other related drugs, or to any excipient in the formulation.
• Known lack of response (lack of effect) to aspirin in the past.
• Clinically significant ECG abnormalities or vital signs abnormalities at screening.
• Clinically significant abnormal laboratory parameters at screening
• Presence of active or latent tuberculosis.
• History of asthma, including childhood asthma, syndrome of asthma, rhinitis (including allergic rhinitis), nasal polyps, angioedema, urticaria, angioedema, or bronchospasm that in investigator's opinion is not suitable to participate in the study.
• Subject with current asthma defined as post-bronchodilator FEV1 > 12% increase AND >200 ml absolute increase from pre-bronchodilator values.
• History of non-trauma related hemorrhage.

Restrictive Pulmonary Function Cohort

• Subject had lung surgery, with lung removal, as the reason for restrictive pulmonary function.
• Subject receiving systemic corticosteroid treatment of prednisone > 10 mg/day or equivalent within 3 months of screening.
• Subject suffers from restrictive pulmonary function, co-existent with obstructive pulmonary function disease.
• Subject has baseline resting oxygen saturation of < 89% on room air.
• Subject in need of continuous oxygen use and/or prescribed long-term continuous home oxygen therapy.

Other Protocol defined I/E criteria that apply