A Study Evaluating the Safety and Efficacy of Inhaled AP01 in Participants With Progressive Pulmonary Fibrosis

This is a randomized, double-blind, placebo-controlled clinical study to evaluate the safety and efficacy of 2 doses of AP01 (pirfenidone solution for inhalation) versus placebo on top of standard of care in participants with PPF over 52 weeks. Up to 300 eligible participants will be randomized to 1 of 3 treatment arms: AP01 high dose, AP01 low dose, or placebo.

Inclusion criteria

• Participant meets criteria for PPF, as follows:
• In subjects with interstitial lung disease (ILD) of known or unknown etiology other than idiopathic pulmonary fibrosis (IPF) who have radiological evidence of pulmonary fibrosis, PPF is defined as:

Physiological evidence of disease progression with at least 1 of the following criteria despite treatment with approved or unapproved medications commonly used in practice (per Investigator):

• Relative decline in FVC ≥10% predicted within the previous 24 months based on documented historical spirometry assessments
• Relative decline in FVC ≥5% to <10% predicted within the previous 24 months based on documented historical spirometry assessments with at least 1 of the 2 following criteria:

• Worsening respiratory symptoms (Note: Changes attributable to comorbidities e.g., infection, heart failure must be excluded) OR
• Radiological (HRCT) evidence of disease progression per a local or central radiologist (from historical HRCT taken up to 24 months prior to Screening Visit 1), for example:

• Increased extent or severity of traction bronchiectasis and bronchiolectasis
• New ground-glass opacity with traction bronchiectasis
• New fine reticulation
• Increased extent or increased coarseness of reticular abnormality
• New or increased honeycombing
• Increased lobar volume loss
• Worsening of respiratory symptoms (Note: Changes attributable to comorbidities e.g., infection, heart failure must be excluded) AND radiological (HRCT) evidence of disease progression per a local or central radiologist

• Meeting all of the following criteria during the Screening Period:

a. FVC ≥45% of predicted normal at Screening Visit 1, b. Forced expiratory volume at 1 second (FEV1)/FVC ≥0.7 or ≥age-adjusted lower limit of normal at Screening Visit 1, c. Diffusing capacity of lung for carbon monoxide (DLCO) ≥30% of predicted, corrected for hemoglobin at Screening Visit 1, d. Acceptability: Participants can perform acceptable spirometry (i.e., meet American Thoracic Society (ATS)/ European Respiratory Society (ERS) acceptability criteria at both Screening Visits).

• For subjects already on nintedanib (up to 30% of subjects): Must have been on nintedanib for at least 6 months prior to Screening with or without dose adjustments and/or drug interruptions during that period. For subjects who have discontinued nintedanib prior to Screening: Must have been off of nintedanib for a minimum of 12 weeks.

Exclusion criteria

• Current treatment with oral pirfenidone or treatment with oral pirfenidone within 3 months prior to Screening.
• Elevated liver enzymes and liver injury at Screening defined as:

• Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) ˃ 3 times the upper limit of normal (ULN)
• Bilirubin >2.0 x ULN
• Renal disease with a creatinine clearance < 30 mL/min, calculated according to the Chronic Kidney Disease Epidemiology Collaboration formula. Retesting is allowed once.
• Diagnosis of idiopathic pulmonary fibrosis (IPF) based on the ATS diagnostic algorithm for IPF. UIP that is not idiopathic, for example related to rheumatoid arthritis (RA), familial interstitial lung disease (ILD), or other is not exclusionary.
• Greater extent of emphysema than of fibrotic ILD on HRCT. Note: CT results must be confirmed through the central over read process.
• Significant clinical worsening of PPF between Screening
• Participants who cannot meet protocol-specified Baseline stability criteria. FVC Baseline stability is defined as the FVC assessments at Visit 3 being within ±12% of the mean of the FVC assessments obtained at the 2 preceding visits. At Visit 3, if the pre-dose FVC is outside of ±12% range, the participant will not be randomized and will be considered a screen failure.