Phase 3 Double-Blind Randomized Study of Lisaftoclax (APG-2575) and Azacitidine in Newly Diagnosed Higher-Risk Myelodysplastic Syndrome Patients

The primary objective of this study is to evaluate the **efficacy** of Lisaftoclax (APG-2575) in combination with Azacitidine (AZA) compared to placebo plus AZA in patients with newly diagnosed higher risk **myelodysplastic syndrome** (HR-MDS). This is clinically relevant as HR-MDS is associated with poor prognosis and limited treatment options, and the study aims to determine if the combination therapy can improve patient outcomes.

Secondary objectives include:

• To compare the effect of the treatment regimen.
• To evaluate the **safety** of the treatment.
• To assess the population **pharmacokinetics** (Pop PK) following treatment.
• To evaluate Patient-Reported Outcome (PRO) measures based on the EORTC QLQ C30 (V3).
• To evaluate Health Economics Outcomes Research (HEOR) measures based on the EuroQol 5 Dimension (EQ-5D).

The clinical trial involves a total of **299 participants** diagnosed with **Newly Diagnosed Higher Risk Myelodysplastic Syndrome**. The study population includes both male and female subjects aged 18 years and older, with an **Eastern Cooperative Oncology Group (ECOG) performance status** of 2 or less, indicating a relatively stable general health status. Participants were selected based on their ability to receive oral medication and adequate organ function, as defined by specific laboratory criteria. The trial includes individuals who are not pregnant and are willing to use effective contraception if of childbearing potential. The study population also encompasses a vulnerable group, ensuring a comprehensive evaluation of the treatment's efficacy across diverse demographics. Lifestyle considerations such as diet and physical activity are not specified, focusing instead on the medical and physiological criteria for inclusion. Participants must have a life expectancy of at least three months and the ability to understand and sign a written informed consent form, demonstrating their willingness to comply with study procedures and follow-up examinations.

The clinical trial is designed as a **randomized**, **double-blind**, controlled study to evaluate the efficacy of **Lisaftoclax** in combination with **Azacitidine** in patients with newly diagnosed higher risk **myelodysplastic syndrome** (HR-MDS). The trial is a Phase 3 study, with an estimated recruitment start date of April 5, 2025, and an estimated end date of January 8, 2030. Participants will be randomly assigned to receive either the active treatment or a placebo, both in combination with Azacitidine. The trial will be conducted over several years, with the duration of individual participant involvement varying based on their response to treatment and overall health status.

Study visits will follow a structured sequence, beginning with an inclusion (screening) visit to assess eligibility based on criteria such as age, performance status, and organ function. Participants must be at least 18 years old, have a life expectancy of at least three months, and be able to receive oral medication. Following the screening, participants will undergo regular follow-up visits to monitor treatment efficacy and safety, as well as to collect data on pharmacokinetics and health economics outcomes. The end-of-study visit will conclude the participant's involvement, during which final assessments will be conducted.

The expected length of participant involvement will depend on individual treatment response and the overall study timeline. Conditions that may lead to early termination from the study include adverse reactions, withdrawal of consent, or any significant protocol deviations. The trial aims to provide comprehensive data on the efficacy and safety of Lisaftoclax in combination with Azacitidine, contributing valuable insights into the treatment of higher risk myelodysplastic syndrome.

The clinical trial involves the administration of **Lisaftoclax**, an experimental medication, in the form of a **tablet**. The active substance, lisaftoclax, is chemically synthesized and is provided by Ascentage Pharma Group Inc. The medication is administered orally. The specific dosage and frequency of administration are not detailed in the provided data. The trial aims to evaluate the efficacy of lisaftoclax in combination with other treatments for patients with newly diagnosed higher-risk myelodysplastic syndrome (HR-MDS).

A **placebo** is also utilized in this study as a comparator treatment. The placebo is designed to mimic the appearance of the lisaftoclax tablet but does not contain any active pharmaceutical ingredients. The placebo is used to maintain the double-blind nature of the trial, ensuring that neither the participants nor the investigators are aware of which treatment the participants are receiving, thereby reducing bias in the study results.

Additionally, the trial includes the administration of **Azacitidine Seacross**, a non-experimental treatment, in the form of a **powder for suspension for injection**. The active substance, azacitidine, is also chemically synthesized and provided by Seacross Pharma (Europe) Ltd. This medication is administered via intravenous, subcutaneous, or intramuscular routes. The specific dosing schedule and monitoring of participant compliance are not specified in the provided data. Azacitidine is a standard-of-care therapy for patients with higher-risk myelodysplastic syndrome and is used in combination with lisaftoclax to assess the potential synergistic effects on treatment efficacy.

The efficacy of the investigational product, **Lisaftoclax** (APG-2575), in combination with Azacitidine, will be assessed in a Phase 3 clinical trial involving patients with newly diagnosed higher-risk myelodysplastic syndrome (HR-MDS). The primary endpoints for evaluating efficacy have not been explicitly detailed in the provided data. However, secondary endpoints include comparing the efficacy of the treatment, evaluating the safety profile, assessing population pharmacokinetics (Pop PK), and measuring Health Economics Outcomes Research (HEOR) using the EuroQol 5 Dimension (EQ-5D) instrument. These assessments will provide comprehensive insights into the therapeutic potential and impact of the treatment regimen.