Global Phase 3 Trial of Lisaftoclax Cleared for Higher-Risk MDS

The FDA and EMA have cleared a global registrational phase 3 study for lisaftoclax (APG-2575), a novel BCL-2 inhibitor.¹ This landmark trial, known as GLORA-4 (NCT06641414), will evaluate the oral agent in combination with azacitidine for the first-line treatment of newly diagnosed adult patients with higher-risk myelodysplastic syndrome (HR-MDS).

This clearance represents a significant regulatory and clinical milestone, as it could potentially provide the first new targeted therapy for this patient population in decades, addressing a critical and long-standing unmet medical need.

“Globally, we still lack targeted therapies for first-line treatment of patients with higher-risk MDS, which represents a huge unmet clinical need. Currently, hypomethylating agents (HMA) and allogeneic hematopoietic stem cell transplantation (allo-HSCT) remain the primary treatment options for higher-risk MDS,” said Yifan Zhai, MD, chief medical officer of Acentage Pharma, in a press release. “In earlier studies, lisaftoclax has demonstrated promising clinical benefit and tolerability. The clearances of the GLORA-4 study by the US FDA and EMA, coinciding with the approval by the China CDE, pave the way for lisaftoclax to potentially become the first BCL-2 inhibitor approved globally for first-line treatment of higher-risk MDS and the first targeted therapy approved for this indication since the introduction of HMA, which fundamentally reshapes the treatment landscape.”

A New Therapeutic Avenue in a High-Need Indication

Higher-risk MDS is a heterogeneous myeloid clonal disease that disproportionately affects older patients, with a median age of diagnosis around 70. This condition is characterized by ineffective hematopoiesis and can progress to acute myeloid leukemia (AML), a transition that occurs in 40% to 60% of higher-risk patients within 5 years. The prognosis for these patients is often poor, with a 5-year survival rate of only 16% to 24%, underscoring the urgent need for more effective treatments.

Currently, HMAs are the standard first-line therapy for HR-MDS. However, HMAs have demonstrated an overall response rate of only 30% to 40% and a median duration of response of 9 to 12 months, highlighting their limitations.

Preclinical Rationale and Preliminary Clinical Data

Lisaftoclax is an orally administered Bcl-2 selective inhibitor. It works by selectively blocking the antiapoptotic protein Bcl-2, thereby restoring the normal process of apoptosis in cancer cells. Preclinical data have shown that lisaftoclax synergistically induces apoptosis when combined with an HMA, providing a strong biological rationale for the GLORA-4 trial design.

The decision by the FDA and EMA to clear this trial is bolstered by compelling data from earlier phase 1b/2 studies. Interim results have shown encouraging efficacy and a manageable safety profile for the lisaftoclax and azacitidine combination. The combination demonstrated a notable 75% overall response rate in patients with MDS, which is a significant improvement over the response rates seen with HMAs alone. Importantly, the combination therapy showed a favorable safety profile with a low incidence of severe hematologic toxicities and neutropenia-related infections, which is a major concern in this patient population, as they often have depleted hematopoietic reserves and multiple comorbidities. The trial also reported no cases of tumor lysis syndrome, a potentially life-threatening complication associated with some apoptosis-targeted therapies.

About GLORA-4

GLORA-4 is a global, randomized, double-blind, placebo-controlled phase 3 study currently enrolling at MD Anderson Cancer Center in Houston, Texas, and Peking University People’s Hospital in Beijing, China.² The primary end point is overall survival, and safety is the secondary end point.

Patients will be randomized to receive lisaftoclax or placebo with azacitidine. Those with newly diagnosed HR-MDS, an ECOG performance status of 2 or less, and adequate organ function are eligible for study enrollment. Those with concomitant malignancies, who have undergone hematopoietic stem cell transplantation, or who have an uncontrolled active infection are not eligible for participation.

The study plans to enroll 464 patients and has an estimated completion date of December 2029.

REFERENCES:

1. Ascentage Pharma Announces Global Registrational Phase III Study of Lisaftoclax for First-line Treatment of Patients with Higher-Risk Myelodysplastic Syndrome Cleared by US FDA and EMA. News release. Ascentage Pharma. August 17, 2025. Accessed August 18, 2025. https://tinyurl.com/yw64zsfm

2. Lisaftoclax (APG-2575) Combined With Azacytidine (AZA) in the Treatment of Patients With Higher-risk Myelodysplastic Syndrome (GLORA-4). ClinicalTrials.gov. Updated February 19, 2025. Accessed August 18, 2025. https://clinicaltrials.gov/study/NCT06641414