Live from ASCO 2024 | Updated Data of Bcl-2 Inhibitor Lisaftoclax Combined with Azacitidine in Patients with AML Demonstrate Promising Efficacy and Manageable Safety

SUZHOU, China and ROCKVILLE, Md., June 4, 2024 /PRNewswire/ -- Ascentage Pharma (6855.HK), a global biopharmaceutical company engaged in developing novel therapies for cancer, chronic hepatitis B (CHB), and age-related diseases, announced today that it has released the latest results from a Phase Ib/II study of its Bcl-2 inhibitor lisaftoclax (APG-2575) in combination with azacitidine (AZA) in patients with treatment-naïve (TN) or relapsed/refractory (R/R) acute myeloid leukemia (AML), in a poster presentation at the 60th American Society of Clinical Oncology (ASCO) Annual Meeting taking place in Chicago, IL.

The ASCO Annual Meeting showcases the most cutting-edge research in clinical oncology and state-of-the-art advanced cancer therapies and is the world's most influential and prominent scientific gathering of the clinical oncology community. Presenting clinical development progress at the ASCO Annual Meeting for the seventh consecutive year, Ascentage had four clinical studies of three of the company's proprietary drug candidates selected for presentations, including an oral report, at ASCO 2024.

The data of lisaftoclax combined with AZA in elderly/unfit TN patients with AML who were intolerant of standard induction chemotherapies and patients with R/R AML showed excellent therapeutic potential and a favorable safety profile in terms of tumor lysis syndrome (TLS), low incidence of neutropenic fever, and low early mortality.

"As a proprietary novel Bcl-2 inhibitor, lisaftoclax has shown treatment responses comparable to the approved Bcl-2 inhibitor and a better safety profile," said Prof. Jie Jin, a principal investigator of the study from the First Affiliated Hospital, Zhejiang University School of Medicine. "The improved safety offered by lisaftoclax means lower treatment-related mortality, fewer dose adjustments, and earlier start of sequential chemotherapies that should contribute to patients' long-term survival."

"The introduction of Bcl-2 inhibitors represents a major breakthrough for the treatment of AML. However, the hematologic safety issues associated with the approved Bcl-2 inhibitor have limited the clinical adoption and the long-term efficacy," said Dr. Huafeng Wang, PhD, from the First Affiliated Hospital, Zhejiang University School of Medicine, and the presenter of the poster. "As a novel drug, lisaftoclax was frequently presented and attracted broad interest. When combined with chemotherapies, lisaftoclax showed a rate of hematologic adverse events that was lower than that of the approved Bcl-2 inhibitor. More importantly, its hematologic adverse events were relatively mild and easy to manage. Its hematologic toxicity-related serious adverse events such as neutropenic fever and 30-/60-day mortalities were very low. This suggests that lisaftoclax-associated hematologic toxicities are transient, less serious, easier to manage, and therefore would have less negative impact on sequential chemotherapies. Overall, lisaftoclax has already shown a highly favorable clinical potential."

"These efficacy and safety data of lisaftoclax combined with AZA in patients with AML are very encouraging because they reaffirmed the drug's global best-in-class potential as a hopeful new treatment option for patients with AML, a hematologic malignancy commonly associated with a poor prognosis," said Dr. Yifan Zhai, Chief Medical Officer of Ascentage Pharma. "A global registrational Phase III study of lisaftoclax in AML is already underway. Remaining committed to the mission of addressing unmet clinical needs in China and around the world, we will accelerate the clinical development of lisaftoclax and bring this novel therapeutic to the broad population of patients with AML as soon as possible."

Highlights of these data presented at ASCO 2024 are as follows:

Safety and efficacy of lisaftoclax, a novel BCL-2 inhibitor, in combination with azacitidine in patients with treatment-naïve or relapsed or refractory acute myeloid leukemia

Abstract#: 6541

Session Title: Hematologic Malignancies—Leukemia, Myelodysplastic Syndromes, and Allotransplant

Date and Time: June 3, 2024, Monday, 9:00 AM – 12:00 PM (Central Time)

First Author: Huafeng Wang, MD, PhD, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China.

Highlights:

Background and introduction: Early studies showed that lisaftoclax in combination with various agents can synergistically induce apoptosis in AML. This poster presents follow-up safety and efficacy data from a Phase Ib/II study of lisaftoclax combined with AZA in adults with AML.

Patient enrollment and methods:

• This study enrolled elderly (≥75 years)/unfit TN patients with AML who were intolerant of standard induction chemotherapies and patients (≥18 years) with R/R AML. Lisaftoclax (400/600/800 mg) was administered orally once daily in 28-day cycles. In the first treatment cycle, a daily ramp up schedule was used to prevent TLS. AZA was administered once daily on D1-D7 at 75 mg/m².
• As of January 25, 2024, 76 patients with AML were enrolled, including 37 patients with R/R AML and 39 elderly/unfit patients with TN AML who were intolerant of standard induction chemotherapies. The median (range) age was 66 (20-81) years.

Efficacy results:

• In patients with R/R AML treated with lisaftoclax combined with AZA, the overall response rate ([ORR]=CR + CRi + morphologic leukemia-free state [MLFS] + PR) was 72.7%, and the composite complete remission rate (CRc = CR + CRi) was 45.5%. In the 600 mg cohort (n=30), the median duration of treatment was 3.8 months, the ORR was 76.7%, the CRc was 50.0%, the median time to CRc was 2.5 months, the median PFS was 10.2 months, and the median overall survival (OS) was 14.7 months.
• Among patients with TN AML treated with lisaftoclax combined with AZA, the ORR was 64.1%, and the CRc was 51.3%. In the 600 mg cohort (n=29), the median duration of treatment was 3.3 months, and the median time to CRc was 1.9 months. The median PFS and median OS were not reached.
• 600 mg lisaftoclax combined with AZA was established as the recommended Phase II dose (RP2D)

Safety results: All patients treated with lisaftoclax combined with AZA reported treatment-emergent adverse events (TEAEs), with 89.5% experiencing grade 3/4 TEAEs and 43.4% experiencing serious adverse events (SAEs). Common Grade ≥ 3 TEAEs reported in ≥ 10% of patients included neutropenia (57.9%), thrombocytopenia (50.0%), anemia (27.6%), pneumonia (17.1%), and febrile neutropenia (10.5%). No TLS was reported. The 30-day mortality rate was 1.3%.

Conclusions: These data support a promising role for the new Bcl-2 inhibitor lisaftoclax combined with AZA for the treatment of elderly/unfit TN patients with AML intolerant of standard induction chemotherapies and patients with R/R AML, especially given a potentially favorable safety profile in terms of TLS, the incidence of neutropenic fever, and low early mortality. A Phase III randomized, double-blind study is being conducted to determine whether lisaftoclax combined with AZA improves the survival of elderly/unfit TN patients with AML intolerant of standard induction chemotherapies.

*Lisaftoclax is an investigational drug that has not been approved in any country and region.

Appendix: The four clinical studies of Ascentage Pharma's three drug candidates, including lisaftoclax, presented at this year's ASCO Annual Meeting.

About Ascentage Pharma

Ascentage Pharma (6855.HK) is a globally focused biopharmaceutical company engaged in developing novel therapies for cancers, chronic hepatitis B, and age-related diseases. On October 28, 2019, Ascentage Pharma was listed on the Main Board of the Stock Exchange of Hong Kong Limited with the stock code 6855.HK.

Ascentage Pharma focuses on developing therapeutics that inhibit protein-protein interactions to restore apoptosis, or programmed cell death. The company has built a pipeline of 9 clinical drug candidates, including novel, highly potent Bcl-2, and dual Bcl-2/Bcl-xL inhibitors, as well as candidates aimed at IAP and MDM2-p53 pathways, and next-generation tyrosine kinase inhibitors (TKIs). Ascentage Pharma is also the only company in the world with active clinical programs targeting all three known classes of key apoptosis regulators. The company is conducting more than 40 Phase I/II clinical trials, including 5 global registrational phase III studies, in the US, Australia, Europe, and China. Ascentage Pharma has been designated for multiple Major National R&D Projects, including five Major New Drug Projects, one New Drug Incubator status, four Innovative Drug Programs, and one Major Project for the Prevention and Treatment of Infectious Diseases.

Olverembatinib, the company's core drug candidate developed for the treatment of drug-resistant chronic myeloid leukemia (CML) and the company's first approved product in China, has been granted Priority Review Designations and Breakthrough Therapy Designations by the Center for Drug Evaluation (CDE) of China National Medical Products Administration (NMPA). To date, the drug had been included into the China 2022 National Reimbursement Drug List (NRDL). Furthermore, olverembatinib has been granted an Orphan Drug Designation (ODD) and a Fast Track Designation (FTD) by the US FDA, and an Orphan Designation by the EMA of the EU. To date, Ascentage Pharma has obtained a total of 16 ODDs from the US FDA and 1 Orphan Designation from the EMA of the EU for 4 of the company's investigational drug candidates.

Leveraging its robust R&D capabilities, Ascentage Pharma has built a portfolio of global intellectual property rights and entered into global partnerships with numerous renowned biotechnology and pharmaceutical companies and research institutes such as UNITY Biotechnology, MD Anderson Cancer Center, Mayo Clinic, Dana-Farber Cancer Institute, MSD, and AstraZeneca. The company has built a talented team with global experience in the discovery and development of innovative drugs and is setting up its world-class commercial manufacturing and Sales & Marketing teams. One pivotal aim of Ascentage Pharma is to continuously strengthen its R&D capabilities and accelerate its clinical development programs, in order to fulfil its mission of addressing unmet clinical needs in China and around the world for the benefit of more patients.

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