Ascentage Pharma and AstraZeneca Enter into Clinical Collaboration on the Registrational Phase III Study of Bcl-2 Inhibitor Lisaftoclax in Combination with BTK Inhibitor Acalabrutinib in Treatment-Naïve Patients with First-Line CLL/SLL

SUZHOU, China, and ROCKVILLE, Md., Oct. 16, 2023 /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 entered into a clinical collaboration with AstraZeneca Investment (China) Co., Ltd. (or "AstraZeneca"). The two companies will jointly conduct a registrational Phase III study of the Bcl-2 inhibitor, APG-2575 (lisaftoclax), in combination with AstraZeneca's Bruton's tyrosine kinase (BTK) inhibitor, CALQUENCE® (acalabrutinib), in treatment-naive patients with first-line chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL).

This global multi-center, randomized-controlled, open-label, pivotal Phase III confirmatory trial is designed evaluate the efficacy and safety of lisaftoclax combined with acalabrutinib versus immunochemotherapy in patients with treatment-naïve CLL/SLL.

This collaboration marks another step-forward in the joint clinical development of the lisaftoclax plus acalabrutinib combination by Ascentage Pharma and AstraZeneca. In June 2020, Ascentage Pharma entered into a clinical collaboration with Acerta Pharma, a research and development center of the AstraZeneca Group, to jointly conduct a global Phase II study designed to assess the safety, tolerability, and efficacy of lisaftoclax, Ascentage Pharma's investigational Bcl-2 selective inhibitor, in combination with acalabrutinib, Acerta Pharma's BTK inhibitor. In the study, lisaftoclax combined with acalabrutinib showed strong therapeutic potential, with an objective response rate (ORR) of 98% in patients with relapsed/refractory (R/R) CLL/SLL, an ORR of 100% in treatment-naïve patients with CLL/SLL, and an excellent safety profile that is on par with that of lisaftoclax monotherapy^[1]. Those results were released as an Oral Presentation at the 2022 American Society of Hematology (ASH) Annual Meeting.

CLL/SLL is a hematologic malignancy caused by mature B-cell neoplasms. Primarily affecting older populations, CLL/SLL is among the most common leukemia subtypes in adults and accounts for a quarter of all leukemia cases in the Western World, with over 100,000 new diagnoses reported globally each year^[2]. In China, CLL/SLL is occurring at a rapidly rising incidence rate, with a younger age of onset and higher aggressiveness^[3], thus posing a serious threat to public health in the country. Advancements in basic research and targeted therapies have brought meaningful survival benefit to patients with CLL/SLL. However, CLL/SLL still presents major clinical challenges and urgent medical needs for new treatment options that can offer both efficacy and safety.

Lisaftoclax is a novel, orally administered small-molecule Bcl-2 selective inhibitor being developed by Ascentage Pharma to treat malignancies by selectively blocking the antiapoptotic protein Bcl-2 and hence restoring the normal apoptosis process in cancer cells. With strong global best-in-class potential, lisaftoclax is the first Bcl-2 inhibitor in China and the second anywhere globally that has demonstrated compelling clinical activity and entered a pivotal registrational study. At present, lisaftoclax is being evaluated in multiple clinical studies across the world and more than 300 patients with CLL/SLL have already been treated with the drug. Interim results suggest that lisaftoclax, both as a monotherapy and in combination regimens, offers potent efficacy in patients with CLL/SLL and has the potential as a safer, more efficacious and more patient-friendly treatment option. It is also worth noting that in August 2023, lisaftoclax was cleared by the US Food and Drug Administration (FDA) to enter a global registrational Phase III study designed to assess the efficacy and safety of lisaftoclax combined with a BTK inhibitor in patients with CLL/SLL who have received prior therapies.

Acalabrutinib, a new generation highly selective BTK inhibitor that can specifically inhibit the BTK pathway, is a globally-adopted standard of care treatment for patients with CLL. In 2017, acalabrutinib was approved through the Priority Review process by the US Food and Drug Administration (FDA) for the second-line treatment of patients with mantle cell lymphoma (MCL), and subsequently in 2019, the drug was approved for the additional indication of adult patients with CLL/SLL. Meanwhile, acalabrutinib has been approved in more than 50 countries/regions, such as European Union and Japan until now. In China this year, acalabrutinib was sequentially approved for two indications that include patients with MCL who have received at least one prior therapy; and adult patients with CLL/SLL who have received at least one prior therapy.

Dr. Yifan Zhai, Chief Medical Officer of Ascentage Pharma, said, "Combining Bcl-2 inhibitors and BTK inhibitors as a therapeutic approach has long attracted interest from both the research community and the industry. The Bcl-2 inhibitor lisaftoclax is a key drug candidate in Ascentage Pharma's apoptosis-targeted pipeline. Results from the global Phase II study of lisaftoclax combined with acalabrutinib show that the combination regimen holds the promise as a patient-centric treatment strategy with enormous therapeutic potential. The clinical management of CLL/SLL overseas has already entered an era that is free of chemotherapies, and patients in China also desperately need a safer and more effective Bcl-2 inhibitor that can be combined with BTK inhibitors. Fulfilling our mission of addressing unmet clinical needs in China and around the world, we will work closely with AstraZeneca to actively advance this clinical development program of lisaftoclax and try to bring the drug to market as soon as possible for the benefit of more patients."

Ms. Haiying Yang, Vice President and Head of Medical Affairs at AstraZeneca China, commented, "Phase III results from the ASCENT, ELEVATE-TN, and ELEVATE-RR trials have solidified AstraZeneca's position in the hematology field, while acalabrutinib-based combination regimens have been widely adopted as standard of care treatments. BTK inhibitors offer survival benefits to patients with lymphoma. However, there remains substantial clinical challenges in this therapeutic area and patients are in desperate need for new therapies that are both safe and efficacious, particularly fixed duration therapies. We are confident that acalabrutinib-based combinations can bring more effective and precision-targeting therapies to patients with hematologic malignancies in China as we take further steps in rendering hematologic malignancies into manageable chronic conditions. Through these innovative partnerships with local Chinese companies, we aspire to expand to more therapeutic areas and bring clinical benefit to a broader population of cancer patients in China."

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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 clinical trials 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, 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, 2 FTDs, and 2 Rare Pediatric Disease (RPD) Designations 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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