Evaluation of AV-101 (Imatinib) Efficacy and Safety in Pulmonary Arterial Hypertension: A Randomized, Double-Blind, Placebo-Controlled Phase 2b/3 Trial

The primary objective of the IMPAHCT study is to determine the optimal dose of **AV-101** (imatinib) for patients with **Pulmonary Arterial Hypertension (PAH)**. This will be primarily assessed by evaluating the change in pulmonary vascular resistance (PVR) through right heart catheterization (RHC) and examining the safety and tolerability of AV-101 during the Phase 2b part of the study. The optimal dose identified will then be used in the Phase 3 part of the study, where the primary endpoint will be the placebo-corrected change in the six-minute walk distance (6MWD) after 24 weeks of treatment. This objective is clinically relevant as it aims to improve the management of PAH by optimizing the therapeutic dose of AV-101, potentially enhancing patient outcomes and quality of life.

The clinical trial involves a total of **257 participants** diagnosed with **Pulmonary Arterial Hypertension (PAH)**. The study population includes both male and female subjects, aged between 18 and 75 years. Participants were selected based on specific inclusion criteria, including a diagnosis of PAH as per the NICE classification of Group 1, excluding those with Portopulmonary Hypertension. The trial includes individuals with World Health Organization (WHO) Functional Class II, III, or IV symptoms, who are capable of walking a distance of at least 100 meters but no more than 475 meters during the screening 6-minute walk test. The trial population is characterized by a diverse range of health statuses, and the selection process ensures the inclusion of a vulnerable population. Lifestyle factors such as diet, physical activity, and habits are not specified in the available data.

The clinical trial is a **randomized**, **double-blind**, **placebo-controlled** study designed to evaluate the safety and efficacy of AV-101 in patients with **Pulmonary Arterial Hypertension (PAH)**. The trial is structured in two phases: Phase 2b and Phase 3, with a total duration of 24 weeks for each phase. The primary objective is to establish an optimal dose of AV-101 based on the change in pulmonary vascular resistance (PVR) and to assess the placebo-corrected change in the 6-minute walk distance (6MWD) after 24 weeks of treatment.

Participants will undergo a series of study visits, beginning with a screening visit to confirm eligibility based on criteria such as age, diagnosis of PAH, and ability to perform a 6-minute walk test. Following randomization, participants will attend regular follow-up visits to monitor safety, tolerability, and efficacy outcomes. The end-of-study visit will occur at the conclusion of the 24-week treatment period, where final assessments will be conducted.

The expected length of participant involvement is approximately 24 weeks, with conditions for early termination including adverse events, withdrawal of consent, or non-compliance with study procedures. The trial will utilize a dry powder inhaler (DPI) device for the administration of AV-101, which is a **tyrosine kinase inhibitor**. The study aims to provide valuable insights into the treatment of PAH, with primary endpoints focusing on changes in PVR and 6MWD, and secondary endpoints including changes in NT-proBNP levels, incidence of clinical worsening events, and improvements in WHO Functional Class and quality of life.

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 medication is delivered via **inhalation** using the AV-101 DPI, a non-integral dry powder inhaler (DPI) that is CE marked as a Class 1 medical device. The trial includes three different dosing regimens of AV-101: a maximum daily dose of 140 mg, 70 mg, and 20 mg, with corresponding maximum total doses of 23,520 mg, 11,760 mg, and 3,360 mg, respectively. Each dosing regimen is administered over a maximum treatment period of 24 weeks. Participant compliance is monitored through regular assessments to ensure adherence to the dosing schedule.

The study also includes a **placebo** group to serve as a comparator. The placebo is administered in a manner consistent with the experimental treatment to maintain the double-blind nature of the trial. The placebo does not contain any active substance and is used to evaluate the efficacy and safety of AV-101 by comparing outcomes between the treatment and placebo groups. The placebo administration follows the same inhalation route and schedule as the active treatment to ensure consistency across study arms.

The efficacy of AV-101 in patients with **Pulmonary Arterial Hypertension (PAH)** will be assessed through a series of primary and secondary endpoints over a 24-week period. The primary endpoint for Phase 2b is the placebo-corrected change from baseline at Week 24 in Pulmonary Vascular Resistance (PVR), assessed by right heart catheterization (RHC). For Phase 3, the primary endpoint is the placebo-corrected change from baseline at Week 24 in the 6-minute walk distance (6MWD).

Secondary endpoints for Phase 2b include changes from baseline at Week 24 in N-terminal pro b-type Natriuretic Peptide (NT-proBNP), 6MWD, incidence of clinical worsening events, improvement in World Health Organization (WHO) Functional Class, change in REVEAL Lite 2.0 risk score, and quality of life (QoL). In Phase 3, secondary endpoints will also include changes from baseline at Week 24 in NT-proBNP, time to clinical worsening events, improvement in WHO Functional Class, change in REVEAL Lite 2.0 risk score, and QoL.

These efficacy parameters will be measured and collected at baseline and at the 24-week mark using validated scales and laboratory tests. The analysis will focus on the comparison of changes from baseline to Week 24 between the treatment and placebo groups, ensuring a comprehensive evaluation of AV-101's efficacy in treating PAH.