Long-Term Safety Evaluation of Inhaled Imatinib (AV-101) in Patients with Pulmonary Arterial Hypertension Following Completion of Study AV-101-002

The primary objective of the study is to establish the long-term **safety** of AV-101 in subjects with **Pulmonary Arterial Hypertension (PAH)** who have completed the AV-101-002 study. This is clinically relevant as it aims to ensure that the prolonged use of AV-101 does not result in adverse effects, thereby supporting its potential as a sustainable treatment option for PAH. Additionally, the study will assess the long-term effects of AV-101 on efficacy measures, including the six-minute walk distance (6MWD), N-terminal pro b-type natriuretic peptide (NT-proBNP), and cardiac echocardiography. These assessments are crucial for understanding the therapeutic impact of AV-101 on functional capacity and cardiac health in PAH patients over an extended period.

The clinical trial for **Pulmonary Arterial Hypertension (PAH)** involves a total of 257 participants. The study population includes both male and female subjects, with an age range that encompasses adults and older adults. Participants were selected based on their successful completion of a prior placebo-controlled 24-week study, AV-101-002, and their consent to participate in the long-term extension (LTE) study. The trial includes individuals who are considered part of a vulnerable population. Female participants of childbearing potential are required to use a highly effective form of contraception during the study and for at least 30 days after completing or discontinuing the study treatment. The trial aims to assess the long-term safety and efficacy of AV-101, with a focus on measures such as the 6-minute walk distance (6MWD), NT-proBNP levels, and cardiac echocardiography. The sponsor has not provided specific information regarding the general health status or lifestyle considerations of the participants.

The clinical trial is designed to evaluate the long-term safety and efficacy of **AV-101** in subjects with **Pulmonary Arterial Hypertension (PAH)** who have completed a prior placebo-controlled study. This trial is a multi-center, long-term extension study, categorized as a Phase 5 trial. The study employs a randomized, double-blind, controlled design to ensure the reliability and validity of the results. The trial is expected to conclude by December 31, 2025, with recruitment having commenced on November 6, 2022.

Participants will undergo a series of study visits, beginning with an inclusion visit to confirm eligibility based on the successful completion of the previous study and agreement to use effective contraception if applicable. The primary objective is to assess the safety and tolerability of AV-101, with secondary objectives including changes from baseline in the six-minute walk distance (6MWD), NT-proBNP levels, and right ventricular function as measured by transthoracic echocardiography. The study will also monitor the time to clinical worsening events.

The trial will involve regular follow-up visits to monitor the participants' health and response to the treatment. These visits will include assessments of the primary and secondary endpoints. The end-of-study visit will mark the conclusion of the participant's involvement, which is expected to last up to 165 days. Conditions that may lead to early termination from the study include adverse events, withdrawal of consent, or non-compliance with study procedures.

The clinical trial involves the administration of **AV-101 (imatinib)**, a tyrosine kinase inhibitor, in the form of a **capsule**. The active substance, **imatinib**, is of chemical origin and is provided by Aerovate Therapeutics, Inc. The trial includes three different dosing regimens of AV-101, each with a distinct maximum daily dose and total dose over the treatment period. The first regimen involves a maximum daily dose of 140 mg, with a total dose of 161,700 mg over a maximum treatment period of 165 days. The second regimen allows for a maximum daily dose of 20 mg, with a total dose of 23,100 mg over the same period. The third regimen includes a maximum daily dose of 70 mg, with a total dose of 80,850 mg over 165 days. All doses are administered via **inhalation** using the AV-101 DPI, a non-integral dry powder inhaler that is CE marked as a Class 1 medical device.

In addition to the experimental treatment, the study may include non-experimental treatments such as standard-of-care therapy, placebo, or comparator treatment, although specific details are not provided in the source data. Participant compliance with the dosing schedule will be monitored throughout the trial to ensure adherence to the prescribed regimen. The primary objective of the study is to establish the long-term safety of AV-101, with secondary assessments on efficacy measures such as the 6-minute walk distance (6MWD), NT-proBNP levels, and cardiac echocardiography.

The efficacy of AV-101 in the clinical trial for **Pulmonary Arterial Hypertension (PAH)** will be assessed through several primary endpoints. These include the change from baseline in the 6-Minute Walk Distance (6MWD), which measures the distance a patient can walk in six minutes as a test of aerobic capacity and endurance. Additionally, changes from baseline in NT-proBNP levels, a biomarker indicative of heart failure, will be evaluated. The time to clinical worsening events will also be monitored, providing insight into the progression of the disease. Furthermore, changes from baseline in transthoracic echocardiography parameters of right ventricular function will be assessed to evaluate cardiac performance.

The collection and analysis of these efficacy parameters will be conducted at specified intervals throughout the trial. The trial is designed as a long-term extension study, with a focus on both safety and efficacy over an extended period. The use of validated scales and laboratory tests will ensure the reliability and accuracy of the data collected. The study will utilize the AV-101 device, a non-integral dry powder inhaler (DPI), which is CE marked as a Class 1 medical device, to administer the investigational product. The trial aims to provide comprehensive data on the long-term effects of AV-101 in subjects who have completed the initial placebo-controlled study.