Long-Term Safety and Tolerability of Inhaled Pirfenidone in Progressive Pulmonary Fibrosis and Idiopathic Pulmonary Fibrosis: An Open-Label Extension Study

The primary objective of this study is to evaluate the long-term **safety** and **tolerability** outcomes of subjects receiving Avalyn nebulized antifibrotic medications. This is clinically relevant as it aims to ensure that the treatment is safe for prolonged use in patients with **progressive pulmonary fibrosis** and **idiopathic pulmonary fibrosis**, conditions characterized by progressive scarring of lung tissue that can lead to severe respiratory impairment.

Secondary objectives include:

• Evaluating the long-term effect of Avalyn nebulized antifibrotic medications on lung function. This is important for understanding the potential benefits of the treatment in maintaining or improving respiratory capacity over time.

The clinical trial involves a total of **220 participants** who have been diagnosed with **progressive pulmonary fibrosis** or **idiopathic pulmonary fibrosis**. The study population includes both male and female subjects, aged 18 years and older, who have previously participated in an Avalyn-sponsored inhaled antifibrotic clinical study. Participants were selected based on their prior involvement in such studies and their ability to provide written informed consent. The trial does not include a vulnerable population. Participants are required to adhere to specific lifestyle considerations, including the use of highly effective contraception methods for both male and female subjects of childbearing potential. The study aims to evaluate the long-term safety and tolerability outcomes of Avalyn nebulized antifibrotic medications in this population.

The clinical trial is designed to evaluate the long-term safety and tolerability of **pirfenidone** solution for inhalation in subjects with **idiopathic pulmonary fibrosis** (IPF) or **progressive pulmonary fibrosis** (PPF). This is a Phase 4, open-label extension study involving participants who have previously completed an Avalyn-sponsored inhaled antifibrotic clinical study. The trial employs a non-randomized, open-label design, allowing all eligible participants to receive the investigational product. The study is expected to run until December 31, 2031, with recruitment starting on April 30, 2025. The maximum treatment period for each participant is 364 days, with a daily dose of 200 mg of pirfenidone administered via inhalation using the eFlow Nebulizer System.

Participants will undergo a series of study visits, beginning with a screening visit to confirm eligibility based on criteria such as previous participation in a related study, age, and willingness to comply with study requirements. Following the screening, participants will attend regular follow-up visits to monitor safety and efficacy outcomes, including the incidence of treatment-emergent adverse events (TEAEs), serious adverse events (SAEs), and changes in clinical laboratory tests and vital signs. The primary endpoints focus on the incidence of TEAEs, SAEs, and respiratory deaths, while secondary endpoints include changes in forced vital capacity (FVC) at six-month intervals and the annual rate of decline in FVC.

The end-of-study visit will conclude the participant's involvement, during which final assessments will be conducted to evaluate the long-term effects of the treatment. Participants are expected to remain in the study for the full duration unless conditions arise that necessitate early termination, such as the occurrence of significant adverse events or withdrawal of consent. The study aims to provide comprehensive data on the long-term use of pirfenidone inhalation solution in managing IPF and PPF, contributing valuable insights into its safety profile and therapeutic potential.

The clinical trial involves the administration of **Pirfenidone Solution for Inhalation**, an investigational medication developed by Avalyn Pharma, Inc. This medication is presented in the form of an **inhalation solution** and is intended for use in subjects who have participated in previous studies of inhaled antifibrotic agents. The active substance, **pirfenidone**, is of chemical origin and is delivered via inhalation using the eFlow Nebulizer System. The maximum daily dose of pirfenidone is 200 mg, and the treatment period can extend up to 364 days. The solution is administered through inhalation, ensuring direct delivery to the lungs, which is facilitated by the eFlow Nebulizer System, a CE-marked device specifically designed for this purpose. Detailed instructions for the use, storage, cleaning, and maintenance of the nebulizer system are provided to both subjects and study personnel.

In this study, no non-experimental treatments such as standard-of-care therapy, placebo, or comparator treatments are utilized. The focus is solely on evaluating the long-term safety and tolerability of the investigational antifibrotic medication. Participant compliance with the dosing schedule is monitored throughout the study to ensure adherence to the prescribed regimen. The study does not include a pediatric formulation, and the investigational product is not classified as an orphan drug. The trial is designed to assess the outcomes of subjects receiving the nebulized antifibrotic medication over an extended period, contributing valuable data on its safety profile.

Efficacy in this clinical trial will be assessed through several primary and secondary endpoints. The primary endpoints include the incidence of treatment-emergent adverse events (TEAEs) and serious adverse events (SAEs), the incidence of adverse events of special interest (AESIs), the incidence of treatment-emergent all-cause deaths, the incidence of treatment-emergent respiratory deaths, the incidence of exacerbation of **pulmonary fibrosis**, and changes from baseline in clinical laboratory tests and vital signs. These parameters will provide a comprehensive evaluation of the treatment's impact on patient safety and disease progression.

Secondary endpoints focus on pulmonary function, specifically the change from baseline in forced vital capacity (FVC) measured in milliliters at intervals of 6 months, and the annual rate of decline in FVC. These measurements will be collected and analyzed to assess the long-term efficacy of the treatment in maintaining or improving lung function. The use of validated scales and laboratory tests will ensure the accuracy and reliability of the data collected throughout the study period.