Live from ASH 2023 | Ascentage Pharma Presents the First Dataset of Bcl-2 inhibitor Lisaftoclax in Patients with AML, Demonstrating Favorable Efficacy and Safety

SUZHOU, China and ROCKVILLE, Md., Dec. 11, 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 released the results of lisaftoclax (APG-2575), one of the company's key drug candidates, in patients with treatment-naïve or relapsed/refractory (R/R) acute myeloid leukemia (AML) or other myeloid neoplasms, in a Poster Presentation at the 65th American Society of Hematology (ASH) Annual Meeting, taking place in San Diego, CA, the United States. This is the first data readout of lisaftoclax for the treatment of patients with AML.

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, multiple studies of Ascentage Pharma's key drug candidates (lisaftoclax and olverembatinib) have been selected for presentations at this year's ASH Annual Meeting, including two Oral Presentations.

These data in patients with AML or other myeloid neoplasms indicate the strong therapeutic potential of lisaftoclax in the treatment of hematologic malignancies. Results showed an overall response rate (ORR) of 75% and a composite response rate (CRc=complete remission [CR]+CR with incomplete blood count recovery [CRi]) of 44.4% in the 36 efficacy-evaluable patients with R/R AML who were treated with lisaftoclax combined with azacitidine (AZA); and an ORR of 71.4% and a CRc of 47.6% in the 21 efficacy-evaluable elderly patients with treatment-naïve AML who were treated with lisaftoclax combined with AZA. The study did not report any tumor lysis syndrome (TLS), and the low incidence of TLS is consistent with observations of an earlier study in patients with chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL).

Prof. Jie Jin of the First Affiliated Hospital of Zhejiang University and the Principal Investigator of the study, commented, "As a novel Bcl-2 inhibitor, lisaftoclax showed favorable clinical benefit and tolerability in the treatment of multiple hematologic malignancies. It has the potential as a new treatment option much anticipated by patients and clinicians."

Prof. Huafeng Wang of the First Affiliated Hospital of Zhejiang University and the presenter of this abstract, noted, "In the treatment of AML, lisaftoclax has demonstrated response rates and a duration of response that are comparable to the best results observed in studies of the only approved Bcl-2 inhibitor. On safety, particularly hematologic adverse events, those reported by patients who received lisaftoclax were low in incidence and severity, and mostly transient, thus indicating the favorable efficacy and safety of this novel Bcl-2 inhibitor."

Dr. Yifan Zhai, Chief Medical Officer of Ascentage Pharma, said, "The study accessing lisaftoclax for the treatment of patients with CLL/SLL has long attracted strong interest from the hematology community. In AML, a common subtype of leukemia in adults that is often associated with very poor prognoses, Bcl-2 inhibitors hold strong potential in bringing much needed breakthroughs and improved treatment outcomes. At this year's ASH Annual Meeting, we presented clinical data of lisaftoclax in patients with AML or other myeloid neoplasms that showed encouraging therapeutic potential and favorable tolerability, reaffirming the global best-in-class potential of lisaftoclax. Remaining committed to the mission of addressing unmet clinical needs in China and around the world, we will expedite our clinical development programs to bring safe and effective therapies to patients in need."

Highlights of the study presented at ASH 2023:

Safety and Efficacy of Lisaftoclax (APG-2575), a Novel BCL-2 Inhibitor (BCL-2i), in Relapsed or Refractory (R/R) or Treatment-Naïve (TN) Patients (Pts) with Acute Myeloid Leukemia (AML), Myelodysplastic Syndrome (MDS), or Other Myeloid Neoplasms

Format: Poster Presentation
Abstract: #2925 
Session: 616. Acute Myeloid Leukemias: Investigational Therapies, Excluding Transplantation and Cellular Immunotherapies: Poster II
Time: December 10, 2023, Sunday, 6:00 PM – 8:00 PM (Pacific Time) / December 11, 2023, Monday, 10:00 AM – 12:00 PM (Beijing Time)
Highlights:
Background: Novel Bcl-2 selective inhibitor lisaftoclax has shown antileukemic activity in patients with CLL. For the first time, we are presenting findings on the efficacy and safety of lisaftoclax alone or combined with AZA or homoharringtonine (HHT) in adult patients with AML, MDS, or other myeloid neoplasms.

Methods:

• In part one, lisaftoclax as a single agent was orally administered once daily at 200, 400, 600, or 800 mg, using a "3+3" dose escalation design.
• In part two, patients with R/R AML, mixed-phenotype acute leukemia (MPAL), blastic plasmacytoid dendritic cell neoplasm (BPDCN), or chronic myelomonocytic leukemia (CMML) were enrolled in Cohorts A, B, and C; while patients with higher-risk MDS were enrolled in Cohort D; and older (≥ 75 years) or chemotherapy-ineligible (unfit) patients with treatment-naïve (TN) AML were enrolled in Cohort E.
• Lisaftoclax was administered orally once daily in 28-day cycles (or 14-day cycles for patients with MDS). A daily ramp-up schedule was adopted in the first cycle to prevent TLS.
• In part two, Cohort A was treated with lisaftoclax combined with low-dose HHT (1 mg daily on days [d] 1-14); Cohort B was treated with lisaftoclax combined with standard-dose HHT (2 mg/m² daily on d1-7); and Cohorts C, D, and E were treated with lisaftoclax combined with AZA (75 mg/m² daily on d1-7).

Patients: As of July 19, 2023, a total of 115 patients were enrolled, including 89 with AML (64 R/R; 25 TN older/unfit), 22 with MDS (7 R/R MDS; 15 TN MDS), 2 MPAL, 1 CMML, and 1 BPDCN. The median (range) age was 62.0 (18-81) years, and 57.4% (66/115) of patients were male. A total of 13 patients received lisaftoclax monotherapy, and 102 patients received combination regimens.

Efficacy results:

• In patients treated with lisaftoclax monotherapy in part one, the ORR and CRc were each 8.3% (1/12).
• Lisaftoclax at 600 mg and 800 mg were chosen as exploratory doses for combination therapies.
• Among the 21 efficacy evaluable patients with TN AML in Cohort E, the ORR and CRc were 71.4% and 47.6%, respectively, and the median (range) time to CR/CRi/the morphologic leukemia-free state (MLFS) was 1.05 (95% CI, 0.99-NR) months.
• Among the 36 efficacy evaluable patients with R/R AML or myeloid neoplasm in Cohort C, the ORR and CRc were 75.0% and 44.4%, respectively; the median (range) time to CR/CRi/MLFS was 1.25 (95% CI, 1.02-2.17) months; and the median PFS was 10.22 months.
• Among patients in Cohort B, the ORR and CRc were both 75.0%.
• Among patients in Cohort D, the ORR was 70.0%, and the CR + marrow CR rate was 60.0%.

Safety results:

• Common treatment-emergent adverse events (TEAEs) observed in this study included hematologic toxicity, electrolyte imbalances, and diarrhea. No TLS was reported during the study, and DLTs (pneumonia, respiratory failure, and heart failure) were observed in 1 patient in Cohort C.
• 13 patients who received lisaftoclax monotherapy experienced TEAEs (all grade ≥3), and 4 (30.8%) patients experienced serious AEs (SAEs).
• In the 14 patients treated with lisaftoclax combined with HHT, 12 (85.7%) experienced TEAEs (all grade ≥3), and 2 (14.3%) experienced SAEs.
• In the 75 patients treated with lisaftoclax combined with AZA, 100% of patients experienced TEAEs, including 55 (73.3%) who experienced grade ≥3 TEAEs and 18 (24.0%) SAEs.

Pharmacokinetics (PK): Increased systemic exposure of lisaftoclax was discerned as the dosage escalated from 200 to 800 mg. Compared to lisaftoclax monotherapy, no significant difference was observed in the pharmacokinetic profile of lisaftoclax combined with AZA or HHT.

Conclusions: Lisaftoclax showed favorable tolerability as monotherapy and when combined with AZA or HHT, and exhibited encouraging clinical efficacy among patients with R/R AML or MDS and older/unfit patients with TN AML.

* Lisaftoclax (APG-2575) is an investigational drug that has not been approved in any country and region.

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 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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SOURCE Ascentage Pharma