Ascentage Pharma's Bcl-2 Inhibitor Lisaftoclax in Combinations Demonstrates Potential Clinical Benefit in Patients with Prior Exposure to Venetoclax

Ascentage Pharma (6855.HK), a global biopharmaceutical company engaged in discovering, developing, and commercializing therapies to address global unmet medical needs primarily for malignancies, today announced that it has released the latest clinical data of lisaftoclax (APG-2575) as a monotherapy or in combinations in patients with chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL), in a Poster Presentation at the 66th American Society of Hematology (ASH) Annual Meeting, taking place in San Diego, CA, the United States. Dr. Matthew Davids, from Dana-Farber Cancer Institute in the US, is the principal investigator of the study.

The ASH Annual Meeting is one of the largest gatherings of the international hematology community, bringing together the most cutting-edge scientific research and latest data of investigational therapies that represent leading scientific and clinical advances in the global hematology field. Garnering growing interest from the global research community, results from multiple clinical and preclinical studies on four of Ascentage Pharma's drug candidates (olverembatinib, lisaftoclax, APG-2449, and APG-5918) have been selected for presentations, including two Oral Reports, at this year's ASH Annual Meeting.

These data once again highlighted the therapeutic magnitude of Ascentage Pharma's Bcl-2 selective inhibitor lisaftoclax, as a monotherapy and in combinations, in patients with relapsed/refractory (R/R) CLL/SLL, particularly the clinical benefit of lisaftoclax in combination with acalabrutinib in patients with prior exposure to venetoclax, including those who progressed on or were intolerant/refractory to venetoclax. Furthermore, no drug-drug interactions (DDIs) or new safety signals were observed in patients treated with lisaftoclax monotherapy or combinations.

Dr. Matthew S. Davids commented, "Lisaftoclax continues to demonstrate very strong efficacy in multiple patient subgroups, including those who previously progressed on venetoclax or BTK inhibitors.  The drug also has excellent tolerability and the convenience of a daily dose ramp-up to reach the target effective dose. Based on the promising early phase results, the GLORA global registrational study has now launched and is actively enrolling."

"Results released at this year's ASH Annual Meeting reaffirmed the therapeutic potential of lisaftoclax in CLL/SLL," said Dr. Yifan Zhai, Chief Medical Officer of Ascentage Pharma. "In China, a New Drug Application (NDA) for lisaftoclax has already been accepted and granted the Priority Review designation by the Center for Drug Evaluation (CDE) of China's National Medical Products Administration (NMPA), potentially leading lisaftoclax to become the second Bcl-2 inhibitor approved anywhere in the world. In the US, a global registrational Phase III study that was cleared by the US Food and Drug Administration (FDA) is currently underway. Fulfilling our mission of addressing unmet clinical needs in China and around the world, we will expedite the global clinical development of our key drug candidates such as lisaftoclax to bring more safe and effective therapies to patients as soon as possible."

Highlights of the data this study reported at ASH 2024 are as below:

Lisaftoclax (APG-2575) Demonstrates Activity and Safety When Given With Accelerated Ramp-up and Then Combined With Acalabrutinib or Rituximab in Patients (pts) With Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma (CLL/SLL), Including Those With Prior Exposure to Venetoclax
Format: Poster Presentation
Abstract#: 4614
Session: 642. Chronic Lymphocytic Leukemia: Clinical and Epidemiological: Poster III

Highlights:

Background: Bcl-2 inhibition with venetoclax (ven) was a major advance in CLL treatment, but the 5-week dose ramp-up to mitigate the risk of tumor lysis syndrome (TLS) and DDIs challenge treatment optimization. Lisaftoclax is an investigational, oral Bcl-2i with a short half-life, allowing it to be ramped-up on a daily schedule.

Introduction: This poster presents updated clinical data of lisaftoclax alone or combined with acalabrutinib or rituximab in patients with treatment-naïve (TN), R/R, or prior ven-treated CLL/SLL.

Enrolled Patients and Study Methods:

• From March 20, 2020, to June 27, 2024, 176 patients were enrolled: 46 in monotherapy and 39 and 91 in the rituximab and acalabrutinib combination cohorts, respectively; 87.5% (154/176) of patients were R/R and 12.5% (22/176) were TN. The median (range) age was 63 (34-80) years; 67% were male; 25.6% had del(17p) and/or TP53 mutation.

• Median (range) duration of treatment with lisaftoclax was 16.5 (1-54; monotherapy), 24 (3-39; rituximab), and 27 (1-43; acalabrutinib) cycles. Fourteen (9%) patients relapsed on or were intolerant /refractory to prior treatment with ven. Their median (range) age was 65 (51-78) and 79% were male. 50% of those patients had del (17p), 36% had the TP53 mutation, 64% had del (11q), 38% had a complex karyotype (≥ 3 abnormalities), and 92% had unmutated IGHV.

• Patients were treated with a rapid 4- to 6-day daily ramp-up of lisaftoclax from 20 mg to a target dose of 400, 600, or 800 mg, receiving daily oral lisaftoclax alone or, plus continuous acalabrutinib or 6 cycles of rituximab in 28-day cycles, starting on Cycle 1 Day 8 (C1D8) until disease progression, complete response by C24, or unacceptable toxicity.

Efficacy Results:

The ORR for lisaftoclax plus acalabrutinib in 87 patients was 98%, and the median duration of response (DOR; 95% CI, 31-NE) and median progression-free survival (PFS; 95% CI, 34-NE) of responders were not reached.

• Among patients who received lisaftoclax plus acalabrutinib, 14 have relapsed on or were intolerant/refractory to prior treatment with ven. Their median (range) cycles of treatment were 16 (3-25), the ORR was 86%, the median PFS was not reached (11.3-NE), the 12-month PFS rate was 84%, and the 18-month PFS rate was 73%.

• Among patients who received lisaftoclax plus acalabrutinib, 9 were refractory to ven. Their median (range) cycles of treatment were 16 (3-25), the ORR was 89%. The median PFS was not reached (NE-NE), the 12-month PFS rate was 89%, and the 18-month PFS rate was 89%.

Safety Results:

• Incidence and severity of TEAEs were similar across cohorts.

• Common (≥20%) any-grade TEAEs in all cohorts combined were infection (107 [61%]), neutropenia (67 [38%]), anemia (51 [29%]), diarrhea (51 [29%]), and thrombocytopenia (38 [22%]). Grade ≥ 3 treatment-emergent AEs (TEAEs；≥10%) were neutropenia in 15 (33%), 11 (28%), and 27 (30%) patients; infection in 13 (28%), 4 (10%), and 14 (15%) patients; and anemia in 8 (17%), 4 (10%), and 11 (12%) patients in monotherapy, rituximab, and acalabrutinib combination cohorts, respectively.

• Lisaftoclax, alone or in combination, demonstrated a favorable safety profile and a rate of clinical tumor lysis syndrome (TLS) of 1.1%. No DDIs or new safety signals were observed in patients who received lisaftoclax in combination with acalabrutinib or rituximab.

Conclusions: The presented data suggest that lisaftoclax combined with acalabrutinib was active in patients with TN or R/R CLL, with a reported 98% ORR and a median DOR that was not reached at 22.3 months of median follow-up. Lisaftoclax combined with acalabrutinib was also effective for patients with prior ven exposure, including those who progressed on or were intolerant/refractory to ven. In this updated analysis with longer follow-up, no DDIs or new safety findings were observed in TN or R/R CLL/SLL patients treated with lisaftoclax monotherapy or combinations. Patients with prior ven exposure continue to be accrued in order to further evaluate this promising signal. A global registrational phase III study is recruiting.

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

About Ascentage Pharma

Ascentage Pharma (6855.HK) is a global, integrated biopharmaceutical company engaged in discovering, developing and commercializing therapies to address global unmet medical needs primarily in malignancies. 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.

The company has built a rich pipeline of innovative drug candidates that includes 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 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 has conducted more than 40 clinical trials in the US, Australia, Europe, and China, including 13 registrational studies (completed/ ongoing/planned).

Olverembatinib, the company's first lead asset 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 National Reimbursement Drug List (NRDL). Furthermore, olverembatinib has been granted Orphan Drug Designations (ODDs) 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 and other relationships with numerous leading biotechnology and pharmaceutical companies such as Takeda, AstraZeneca, Merck, Pfizer and Innovent; and research and development relationships with leading research institutions such as Dana-Farber Cancer Institute, Mayo Clinic, National Cancer Institute and the University of Michigan.

The company has built a talented team with a wealth of global experience in the discovery and development of innovative drugs and fully functional 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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