A Phase 2a Randomized, Placebo-Controlled Clinical Study to Evaluate the Efficacy and Safety of MK-5475 in Adults With Pulmonary Hypertension Associated With Chronic Obstructive Pulmonary Disease.

The primary objective of this Phase 2a randomized, placebo-controlled clinical study is to evaluate the effect of **MK-5475** versus placebo on the 6-minute walk distance (6MWD) at Week 24 in adults with pulmonary hypertension associated with chronic obstructive pulmonary disease (PH-COPD). This measure is clinically relevant as it assesses the functional exercise capacity of patients, which is a critical indicator of disease progression and patient quality of life.

Secondary objectives include:

• Evaluating the effect of MK-5475 versus placebo on 6MWD at Week 12.
• Assessing the effect on N-terminal pro B-type natriuretic peptide (NT-proBNP) levels at Week 12 and Week 24, which are biomarkers of cardiac stress and heart failure.
• Evaluating the effect on the World Health Organization (WHO) Functional Class at Week 12 and Week 24, which categorizes the severity of symptoms and physical limitations.
• Assessing the safety and tolerability of MK-5475, which is crucial for determining the risk-benefit profile of the treatment.

The clinical trial involves a total of **100 participants** diagnosed with **pulmonary hypertension associated with chronic obstructive pulmonary disease (PH-COPD)**. The study population includes both male and female subjects, aged between 40 and 85 years. Participants were selected based on specific criteria, including a confirmed diagnosis of Group 3.1 PH-COPD, as defined by the Clinical Classification of Pulmonary Hypertension. The general health status of participants requires stable and optimized chronic, baseline COPD-specific therapy, and if applicable, stable use of supplemental oxygen, PDE5 inhibitors, antihypertensives, diuretics, or anticoagulants. The trial population is characterized by a WHO Functional Class assessment of Class II to IV. Lifestyle considerations such as diet and physical activity are not specified, but the stability of medical regimens is emphasized. The trial includes a vulnerable population, ensuring comprehensive evaluation across diverse health backgrounds.

The clinical trial is a **randomized**, **placebo-controlled** study designed to evaluate the efficacy and safety of MK-5475 in adults with **pulmonary hypertension** associated with **chronic obstructive pulmonary disease** (PH-COPD). The trial is structured as a **double-blind** study, ensuring that neither the participants nor the investigators know which treatment the participants are receiving, thereby minimizing bias. The primary objective is to assess the effect of MK-5475 versus placebo on the 6-minute walk distance (6MWD) at Week 24. Secondary endpoints include changes in 6MWD and N-terminal pro B-type natriuretic peptide (NT-proBNP) at Weeks 12 and 24, as well as the percentage of participants whose World Health Organization (WHO) Functional Class does not worsen relative to baseline at these time points.

The trial is expected to last until October 2026, with participant recruitment having commenced in December 2022. Participants will be involved in the study for a maximum treatment period of 102 weeks. The study includes several key visits: an initial screening visit to confirm eligibility based on criteria such as age, sex, and medical history, including right heart catheterization and pulmonary function testing. Follow-up visits will occur at regular intervals to monitor the participants' health status, adherence to the treatment regimen, and any adverse events. The end-of-study visit will conclude the trial for each participant, during which final assessments will be conducted.

Participants may be withdrawn from the study early if they experience significant adverse events, fail to adhere to the study protocol, or if the investigator deems it necessary for their safety. The trial is conducted under strict ethical guidelines, ensuring that all participants provide informed consent and that their health and safety are prioritized throughout the study duration.

The clinical trial involves the administration of **MK-5475**, an investigational medication formulated as an **inhalation powder**. The active substance in MK-5475 is **3-(4-{(5S)-4-amino-2-[6-chloro-1-(3,3,4,4,4-pentafluorobutyl)-1H-indazol-3-yl]-5-methyl-6-oxo6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-5-yl}phenyl)propanoic acid**, which is of chemical origin. The medication is administered via **inhalation use**. The maximum daily dose is 380 micrograms, with a total maximum dose of 271,320 micrograms over a treatment period of 102 days. The administration schedule is designed to ensure consistent dosing, and participant compliance is monitored throughout the study.

The study also includes a **placebo** group, where participants receive a placebo designed to match the MK-5475 inhalation powder in appearance and administration method. The placebo is used to maintain the study's double-blind design, ensuring that neither the participants nor the investigators know which treatment is being administered. This allows for an unbiased assessment of the efficacy and safety of MK-5475 in comparison to the placebo. The placebo is administered with the same frequency and route as the active treatment to ensure consistency across the study arms.

The efficacy of MK-5475 in the treatment of **pulmonary hypertension associated with chronic obstructive pulmonary disease (PH-COPD)** will be assessed through a randomized, placebo-controlled clinical trial. The primary endpoint for evaluating efficacy is the mean change from baseline in the 6-minute walk distance (6MWD) at Week 24. This measure will provide insight into the improvement in exercise capacity of participants receiving the treatment compared to those receiving a placebo.

Secondary endpoints include the mean change from baseline in 6MWD at Week 12, as well as the mean change from baseline in N-terminal pro B-type natriuretic peptide (NT-proBNP) at both Week 12 and Week 24. Additionally, the percentage of participants whose World Health Organization (WHO) Functional Class does not worsen relative to baseline at Weeks 12 and 24 will be evaluated. Safety will also be monitored by assessing the percentage of participants experiencing one or more adverse events (AEs) and those who discontinue the study treatment due to an AE.