Ascentage's Lisaftoclax Cracks Venetoclax Resistance in Leukemia

ORLANDO, FL – December 07, 2025 – In the bustling halls of the American Society of Hematology (ASH) Annual Meeting, where the future of blood cancer treatment is debated and defined, a compelling story of scientific persistence and strategic positioning is unfolding. Ascentage Pharma, a dual-listed biopharmaceutical firm with ambitions stretching from Suzhou to Rockville, has presented data that does more than just update a clinical trial; it signals a potential paradigm shift in treating some of the most stubborn forms of myeloid malignancies.

The data, from a Phase Ib/II study of its investigational drug Lisaftoclax, addresses one of the most significant challenges in modern leukemia therapy: resistance to venetoclax, a blockbuster drug that has become a standard of care. The results presented here suggest Ascentage may have found a key to unlock responses in patients who have run out of options, a development that carries profound implications for patients, clinicians, and investors alike.

The Clinical Choke Point: Overcoming Venetoclax Resistance

Venetoclax, co-marketed by AbbVie and Genentech, transformed the treatment landscape for Acute Myeloid Leukemia (AML), particularly for older patients unfit for intensive chemotherapy. As a Bcl-2 inhibitor, it reactivates the natural process of cell death, or apoptosis, in cancer cells. Yet, for all its success, a formidable challenge remains: many patients either fail to respond or eventually develop resistance, their cancer evolving to evade the drug's mechanism.

For patients who fail venetoclax-based regimens, the outlook is grim, with median overall survival often plummeting to less than three months. This clinical dead-end represents a major unmet need and a focal point for the next wave of oncologic innovation.

This is the context that makes Ascentage's ASH presentation so significant. In a cohort of 22 evaluable patients with relapsed or refractory (R/R) AML who had previously been treated with and failed venetoclax, the combination of Lisaftoclax and the chemotherapy agent azacitidine achieved an overall response rate (ORR) of 31.8%. Nearly a quarter of these heavily pre-treated patients (22.7%) achieved a complete response. While the numbers are from an early-stage study, they represent the first clinical evidence of a Bcl-2 inhibitor demonstrating the ability to overcome resistance to another drug in its own class.

"These data suggest that this combination regimen has substantial therapeutic potential for the treatment of newly diagnosed or venetoclax–exposed patients," said Dr. Yifan Zhai, Chief Medical Officer of Ascentage Pharma, in a statement accompanying the data release. "We hope that Lisaftoclax will bring a breakthrough to the clinical management of myeloid malignancies."

De-Risking the Pipeline: The Strategic Value for Ascentage

Beyond the clinical implications, this data is a cornerstone event for Ascentage Pharma's corporate strategy. For a company building a global presence from its base in China, positive data on a key pipeline asset is the currency of progress. The results significantly de-risk the massive investment Ascentage is pouring into Lisaftoclax's global development program, which includes four separate registrational Phase III trials.

Ascentage is already a commercial-stage entity, with two drugs approved in China: Olverembatinib for chronic myeloid leukemia and Lisaftoclax itself for a different indication, chronic lymphocytic leukemia (CLL). The latest data provides powerful validation for expanding Lisaftoclax into the much larger and more complex myeloid malignancy market. The company isn't just developing another drug; it is building a differentiated franchise asset with a clear line of attack against the market leader's primary weakness.

This strategic nuance is critical for investors. Rather than going head-to-head with venetoclax across the board, Ascentage is carving out a high-value niche in the resistance setting while simultaneously demonstrating competitive strength in other patient populations. The 80% overall response rate seen in newly diagnosed, high-risk myelodysplastic syndromes (HR-MDS) and chronic myelomonocytic leukemia (CMML) patients is a prime example. This figure is highly competitive when compared to the historical 40-50% ORR for azacitidine alone and positions the combination favorably against other emerging venetoclax-based regimens in this front-line setting.

The Science of Apoptosis: A Sharper Tool in the Bcl-2 Arsenal

The promising results naturally raise the question of why Lisaftoclax might be succeeding where venetoclax fails. Both are selective Bcl-2 inhibitors, but as a novel, internally developed compound, Lisaftoclax may possess distinct structural or binding properties that allow it to be effective against cancer cells that have adapted to sidestep venetoclax. The ability to restore apoptosis in these resistant cells is the holy grail for next-generation Bcl-2 inhibitors.

Furthermore, the drug's safety profile adds to its strategic value. The study of 103 patients reported no dose-limiting toxicities, a crucial finding for any drug intended for combination therapy. The most common severe adverse events were hematologic—such as neutropenia and thrombocytopenia—which are expected and generally manageable for this class of therapy. A clean safety profile is essential for securing a role in complex, multi-drug regimens that are becoming the standard in oncology.

The strong performance in newly diagnosed HR-MDS, where the median overall survival was not even reached in the study period, suggests a broad potential. This indication is the focus of the company's GLORA-4 Phase III trial, and the ASH data provides a powerful tailwind for that study's rationale and eventual recruitment.

The Road Ahead: From ASH Data to Global Market

For Ascentage Pharma, the data presented in Orlando is not a finish line but a well-marked checkpoint on a long road. The focus now shifts squarely to execution on its ambitious Phase III program. These larger, global studies will be required to confirm the early promise of Lisaftoclax and provide the definitive evidence needed for regulatory approvals by the FDA and other global health authorities.

While AbbVie's venetoclax remains the undisputed giant in the field, Ascentage's strategy appears less about direct confrontation and more about intelligent flanking. By proving its value in the venetoclax-failure setting, Lisaftoclax could establish an anchor market from which to expand. The impressive front-line MDS data suggests it has the potential to compete more broadly as well.

This weekend’s news solidifies Ascentage Pharma's position as a serious player in the global hematology space. The company has moved beyond simply presenting data and is now telling a coherent strategic story, connecting scientific innovation with a clear understanding of unmet clinical and market needs. For Ascentage, the path from promising data to market approval is demanding, but the coordinates laid out in Orlando point toward a significant destination in the landscape of modern oncology.