A Phase 2/3, Multicenter, Randomized, Double-blind, Placebo-Controlled, Adaptive Design Study to Evaluate the Efficacy and Safety of MK-5475 in Adults with Pulmonary Arterial Hypertension

The primary objective of this study is to evaluate the effect of **MK-5475** versus placebo on pulmonary vascular resistance (PVR) at Week 12 in the Phase 2 Cohort. This is clinically relevant as PVR is a critical parameter in assessing the severity and progression of pulmonary arterial hypertension (PAH), a condition characterized by elevated blood pressure in the pulmonary arteries, which can lead to right heart failure and other serious complications.

Secondary objectives include:

• Evaluating the effect of MK-5475 versus placebo on the 6-minute walk distance (6MWD) at Week 12 in the Phase 2 Cohort, which is an important measure of exercise capacity and functional status in patients with PAH.
• Assessing the effect of MK-5475 versus placebo on hemodynamic parameters other than PVR at Week 12 in the Phase 2 Cohort, providing a broader understanding of the drug's impact on cardiovascular function.
• Evaluating the effect of MK-5475 versus placebo on 6MWD at Week 24 in the Phase 3 Cohort, further assessing the long-term impact on exercise capacity.
• Assessing the effect of MK-5475 versus placebo on the World Health Organization (WHO) functional PAH class at Week 12 in the Phase 3 Cohort, which is a classification system used to determine the severity of PAH symptoms and their impact on daily activities.
• Evaluating the safety and tolerability of MK-5475 in the Phase 2 and Phase 3 Cohorts independently, ensuring the treatment's risk-benefit profile is acceptable for patients.

The clinical trial involves a total of **121 participants** diagnosed with **pulmonary arterial hypertension (PAH)**, including idiopathic, heritable, drug and toxin-induced, and PAH associated with connective tissue disease, HIV infection, or congenital heart disease. The study population comprises both male and female subjects, with an age range that includes adults and older adults. Participants were selected based on specific inclusion criteria, such as a documented diagnosis of PAH confirmed by right heart catheterization, and meeting certain hemodynamic parameters. The trial includes individuals with a World Health Organization functional class of symptoms between Class II and IV, and a Body Mass Index (BMI) between 18.5 kg/m² and 40 kg/m². Participants are required to have stable concomitant background PAH-specific therapy and demonstrate a 6-minute walk distance between 150 and 500 meters. The trial also considers vulnerable populations, ensuring a comprehensive evaluation of the treatment's effects across diverse demographic groups.

The clinical trial is designed as a **randomized**, **double-blind**, **placebo-controlled** study to evaluate the efficacy and safety of MK-5475 in adults with **pulmonary arterial hypertension** (PAH). The trial employs an adaptive design and is conducted in multiple centers. The study is divided into two phases, Phase 2 and Phase 3, with the primary objective of assessing the effect of MK-5475 on pulmonary vascular resistance (PVR) and 6-minute walk distance (6MWD) over a 12-week period. The trial is expected to conclude by January 19, 2028, with recruitment having commenced on May 19, 2021.

Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as a documented diagnosis of PAH, specific hemodynamic parameters, and stable background therapy. Following randomization, participants will attend regular follow-up visits to monitor safety and efficacy endpoints, including changes in PVR and 6MWD. The end-of-study visit will occur at the conclusion of the treatment period, which is set at 60 days. The total duration of participant involvement is approximately 12 weeks, with conditions for early termination including adverse events or withdrawal of consent.

Key elements of the research methodology include the use of inhalation powder formulations of MK-5475 and placebo, with a maximum daily dose of 380 micrograms and a total dose limit of 684,000 micrograms. The study will assess both primary and secondary endpoints, such as changes in mean right arterial pressure, cardiac index, and stroke volume index, alongside the primary measures of PVR and 6MWD. Participants will be monitored for adverse events, and any discontinuation of the study drug due to adverse events will be documented. The trial aims to provide robust data on the safety and efficacy of MK-5475 in the target population, contributing to the understanding and management of PAH.

The clinical trial involves the evaluation of **MK-5475**, an investigational medication, in adults with **pulmonary arterial hypertension**. MK-5475 is formulated as an **inhalation powder** and is administered via the inhalation route. 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 maximum daily dose is 380 µg, with a total maximum dose of 684,000 µg over a treatment period of up to 60 days. The pharmaceutical form is specifically designed for inhalation, ensuring targeted delivery to the pulmonary system.

In addition to the experimental treatment, a **placebo** is utilized as a comparator in this double-blind, placebo-controlled study. The placebo is designed to mimic the inhalation powder form of MK-5475 but does not contain the active substance. The placebo is administered via the same inhalation route and follows the same dosing schedule as the active treatment to maintain blinding and ensure the integrity of the study results.

The efficacy of MK-5475 in the treatment of **Pulmonary Arterial Hypertension (PAH)** will be assessed through a series of primary and secondary endpoints. The primary endpoints include the change from baseline in pulmonary vascular resistance (PVR) at 12 weeks for the Phase 2 cohort and the change from baseline in the 6-minute walk distance (6MWD) at 12 weeks for the Phase 3 cohort. These endpoints are designed to evaluate the direct impact of the treatment on the physiological and functional capacity of the participants.

Secondary endpoints for the Phase 2 cohort include changes from baseline in 6MWD, mean right arterial pressure (mRAP), cardiac index (CI), and stroke volume index (SVI) at 12 weeks. For the Phase 3 cohort, secondary endpoints include changes from baseline in 6MWD at 24 weeks and changes in World Health Organization Functional Class (WHO-FC) at 12 weeks. Additionally, both Phase 2 and Phase 3 cohorts will assess the number of participants who experience an adverse event and those who discontinue the study drug due to an adverse event.

The efficacy parameters will be measured at specified time points, primarily at 12 weeks, with some assessments extending to 24 weeks. The 6-minute walk distance (6MWD) is a key functional measure, while pulmonary vascular resistance (PVR) and other hemodynamic parameters will be evaluated to assess the physiological impact of the treatment. These assessments will be conducted using validated scales and methods appropriate for the clinical setting, ensuring the reliability and accuracy of the data collected.