Efficacy and Safety Evaluation of XXB750 in Heart Failure Patients with LVEF < 50% on Standard Care Including ACEI/ARB or Sacubitril/Valsartan

The primary objective of this study is to evaluate the **efficacy** and dose-response relationship of three XXB750 target dose levels compared to placebo in reducing N-terminal prohormone B-type natriuretic peptide (NT-proBNP) from baseline to Week 16 in symptomatic heart failure (HF) patients with left ventricular ejection fraction (LVEF) less than 50%, who are treated with standard of care, including angiotensin-converting enzyme inhibitors (ACEI)/angiotensin receptor blockers (ARB) or sacubitril/valsartan. This is clinically relevant as NT-proBNP is a biomarker used to assess the severity and prognosis of heart failure, and its reduction is associated with improved clinical outcomes.

Secondary objectives include:

• Evaluating the treatment effect of the highest XXB750 target dose level compared to placebo in reducing NT-proBNP from baseline to Week 16 in symptomatic HF patients with LVEF less than 50% treated with standard of care, including ACEI/ARB or sacubitril/valsartan.
• Evaluating the treatment effect of combined two highest XXB750 target dose levels administered in addition to a background of ACEI/ARB versus conversion from ACEI/ARB to sacubitril/valsartan, in reducing NT-proBNP from baseline to Week 16.
• Evaluating the safety and tolerability of XXB750 up-titration regimens and dose levels.

The clinical trial involves a total of **316 participants** diagnosed with **heart failure**. The study population includes both male and female outpatients aged 18 years and older, presenting with symptoms of heart failure classified as NYHA class II-III. Participants have a left ventricular ejection fraction (LVEF) of less than 50% and elevated levels of N-terminal prohormone B-type natriuretic peptide (NT-proBNP). All participants are required to be on a stable dose of either an ACE inhibitor or an angiotensin receptor blocker, or sacubitril/valsartan, for at least four weeks prior to screening. The trial population was selected based on these criteria to ensure a consistent baseline for evaluating the efficacy and dose-response relationship of the investigational treatment. The study does not include vulnerable populations, and participants are expected to be receiving other guideline-recommended heart failure therapies as appropriate. Lifestyle factors 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- and active-controlled, parallel-group study to evaluate the efficacy, safety, and tolerability of the investigational drug **XXB750** in patients with **heart failure**. The trial will span a total duration of 24 weeks, with the primary objective being to assess the change in N-terminal prohormone B-type natriuretic peptide (NT-proBNP) levels from baseline to Week 16. Participants will be randomly assigned to receive one of three target dose levels of XXB750 or a placebo, with all groups receiving standard care, including ACE inhibitors (ACEI) or angiotensin receptor blockers (ARB) or sacubitril/valsartan.

The study will include several key visits: an initial screening visit, regular follow-up visits, and an end-of-study visit. During the **screening** visit, eligibility will be confirmed based on criteria such as age, symptoms of heart failure, left ventricular ejection fraction (LVEF), and NT-proBNP levels. Participants must be on a stable dose of ACEI or ARB or sacubitril/valsartan for at least four weeks prior to screening. Follow-up visits will occur at regular intervals to monitor safety, efficacy, and any adverse events. The end-of-study visit will conclude the trial, with final assessments of NT-proBNP levels and other safety parameters.

Participant involvement is expected to last for the full 24-week duration unless early termination is warranted. Conditions that may lead to early termination include significant adverse events, withdrawal of consent, or non-compliance with the study protocol. The trial aims to provide valuable insights into the dose-response relationship of XXB750 and its potential benefits in managing heart failure.

The clinical trial involves the administration of **XXB750**, an experimental medication, which is a solution for injection. The active substance is a protein of other origin, and the pharmaceutical form is a solution for injection. The maximum daily dose is 240 mg, administered subcutaneously. The treatment period is up to 16 weeks. Participant compliance will be monitored through regular assessments and documentation of dosing schedules.

In addition to the experimental medication, a **placebo** is used as a comparator in the study. The placebo is designed to match the XXB750 solution for injection in appearance but contains no active substance. It is administered subcutaneously in the same manner as the experimental drug to maintain blinding in the study.

Participants in the trial may also receive standard-of-care therapy, which includes medications such as **lisinopril dihydrate**, **azilsartan medoxomil**, **candesartan**, **trandolapril**, **fosinopril sodium**, **perindopril tert-butylamine**, **quinapril hydrochloride**, **captopril**, **eprosartan mesilate**, **ramipril**, **valsartan**, **valsartan and sacubitril**, **zofenopril calcium**, **cilazapril**, **olmesartan medoxomil**, **imidapril hydrochloride**, **enalapril maleate**, **telmisartan**, **losartan potassium**, and **hydrochlorothiazide**. These medications are administered orally, and their dosing is determined based on standard clinical guidelines for the treatment of heart failure.

All medications, including the experimental drug, placebo, and standard-of-care therapies, are administered according to a predefined schedule. Participant adherence to the dosing regimen is monitored through regular follow-up visits and medication logs. The trial aims to evaluate the efficacy, safety, and tolerability of XXB750 in comparison to placebo and standard treatments in patients with heart failure.

The efficacy of the clinical trial will be assessed by evaluating the change in **N-terminal prohormone B-type natriuretic peptide (NT-proBNP)** levels from baseline to Week 16. This primary endpoint will be measured to determine the efficacy of the investigational product, XXB750, in patients with heart failure and a left ventricular ejection fraction (LVEF) of less than 50%. The trial will also monitor secondary endpoints, which include changes in NT-proBNP levels from baseline to Week 16, as well as adverse events, safety laboratory parameters, and vital signs from baseline to the end of the study.

The measurement of NT-proBNP will be conducted at specified time points, with the primary focus on the change from baseline to Week 16. The trial is designed as a multi-center, randomized, placebo- and active-controlled, parallel-group study, which will last for 24 weeks. The study will include patients who are receiving standard care, including ACE inhibitors (ACEI), angiotensin receptor blockers (ARB), or sacubitril/valsartan. The trial aims to establish a dose-response relationship for three target dose levels of XXB750 compared to placebo.