Efficacy and Safety Evaluation of TX000045 in Pulmonary Hypertension Secondary to Heart Failure with Preserved Ejection Fraction: A Randomized, Placebo-Controlled Study

The primary objective of this study is to evaluate the effect of **TX000045** versus placebo on mean pulmonary vascular resistance (PVR) in participants with pulmonary hypertension secondary to heart failure with preserved ejection fraction (PH-HFpEF). This is clinically relevant as reducing PVR can potentially improve hemodynamic parameters and outcomes in patients with PH-HFpEF, a condition characterized by increased pressure in the pulmonary arteries and associated with significant morbidity and mortality.

Secondary objectives include:

• Evaluating the effect of TX000045 on mean PVR in the subset of participants with PVR ≥3 Wood units.
• Assessing the effect of TX000045 on exercise capacity in participants with PH-HFpEF.
• Evaluating the effect of TX000045 on exercise capacity in participants with PH-HFpEF and PVR ≥3 Wood units.
• Assessing the effect of TX000045 versus placebo on pulmonary capillary wedge pressure (PCWP) in participants with PH-HFpEF.

The clinical trial involves a total of **54 participants** diagnosed with **Pulmonary Hypertension** with Heart Failure with Preserved Ejection Fraction (PH-HFpEF). The study population includes both male and female subjects of non-childbearing potential, aged between 18 and 80 years. Participants were selected based on specific criteria, including a diagnosis of PH-HFpEF confirmed by echocardiogram and right heart catheterization, and a New York Heart Association (NYHA) functional class II-III heart failure classification. All participants are required to have a stable medication regimen for heart failure or cardiovascular disease for at least 30 days prior to screening, with exceptions for diuretics and anticoagulants. The trial does not include a vulnerable population, and participants must be able to adhere to the study visit schedule and comply with protocol requirements. Lifestyle considerations such as diet and physical activity are not specified in the trial data provided.

The clinical trial is designed as a **randomized**, **double-blind**, **placebo-controlled** study to evaluate the efficacy and safety of the investigational product TX000045 in patients with **pulmonary hypertension** secondary to heart failure with preserved ejection fraction (PH-HFpEF). The trial will span a duration of 24 weeks, during which participants will be randomly assigned to receive either TX000045 or a placebo. The primary objective is to assess the mean change from baseline to Week 24 in pulmonary vascular resistance (PVR) as measured by right heart catheterization (RHC). Secondary endpoints include changes in the 6-minute walk test (6MWT) distance and pulmonary capillary wedge pressure (PCWP).

Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on specific criteria, such as age, diagnosis of PH-HFpEF, and stable medication use. The screening process will include echocardiograms and RHC to establish baseline measurements. Following randomization, participants will attend regular follow-up visits to monitor safety and efficacy outcomes, including assessments of adverse events, laboratory tests, and physical examinations. The end-of-study visit will occur at Week 24, where final evaluations will be conducted to determine the overall impact of the treatment.

The expected length of participant involvement is approximately 24 weeks, with conditions for early termination including the occurrence of serious adverse events or non-compliance with the study protocol. Participants are required to adhere to the visit schedule and protocol requirements, and they must agree not to participate in other investigational studies during the trial period. The trial aims to provide valuable insights into the treatment of PH-HFpEF, contributing to the understanding of TX000045's therapeutic potential.

The clinical trial involves the administration of **TX000045**, a biologic investigational product, formulated as a **solution for injection/infusion**. The active substance, also named TX000045, is a protein of other origin. The pharmaceutical form is specifically designed for subcutaneous administration. Participants will receive a maximum daily dose of 300 mg, with a total maximum dose of 3600 mg over the course of the study. The treatment period is set for 24 weeks. The investigational product is manufactured by Tectonic Therapeutic, Inc., and is identified by the sponsor product code TX000045. Compliance with the dosing schedule will be monitored throughout the trial to ensure adherence to the protocol.

In addition to the investigational product, a **sterile isotonic solution** will be used as a placebo comparator. The placebo is intended to mimic the administration of the investigational product without containing the active substance. The placebo will be administered in the same manner as the investigational product, ensuring blinding of the study. The use of a placebo control is essential for maintaining the integrity of the double-blind, randomized study design, allowing for an unbiased assessment of the efficacy and safety of TX000045 in patients with pulmonary hypertension secondary to heart failure with preserved ejection fraction (PH-HFpEF).

The efficacy of TX000045 in the treatment of **Pulmonary Hypertension Secondary to Heart Failure With Preserved Ejection Fraction (PH-HFpEF)** will be assessed through a series of primary and secondary endpoints. The primary efficacy endpoint is the mean change from baseline to Week 24 in pulmonary vascular resistance (PVR), as measured by right heart catheterization (RHC), in participants receiving TX000045 compared to those receiving placebo. Secondary endpoints include the mean change from baseline to Week 24 in PVR in the subset of participants with PVR ≥3 Wood units, the mean change in 6-minute walk test (6MWT) distance, and the mean change in pulmonary capillary wedge pressure (PCWP) as measured by RHC.

These efficacy parameters will be collected and analyzed at baseline and at Week 24. The RHC will be utilized to measure PVR and PCWP, while the 6MWT will assess functional exercise capacity. The study will ensure that these measurements are conducted using standardized and validated methods to maintain consistency and reliability of the data. The analysis will compare the changes in these parameters between the treatment and placebo groups to determine the efficacy of TX000045 in improving clinical outcomes for patients with PH-HFpEF.