ASH 2023 | Ascentage Pharma to Present Results from Three Clinical Studies of Bcl-2 Inhibitor Lisaftoclax (APG-2575), Including the First Data in AML and MM

SUZHOU, China, and ROCKVILLE, Md., Nov. 3, 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 results from three clinical studies of lisaftoclax (APG-2575), a key candidate drug in the Company's pipeline, have been selected for presentations at the 65^th American Society of Hematology (ASH) Annual Meeting, marking the second consecutive year in which clinical results of lisaftoclax were selected. This year, results from multiple clinical studies on two of Ascentage Pharma's lead drug candidates (olverembatinib and lisaftoclax) have been selected for presentations at the ASH Annual Meeting.

Developed by Ascentage Pharma, lisaftoclax is an orally available Bcl-2 inhibitor with a wide therapeutic window in multiple hematologic malignancies and solid tumors. The investigational clinical data of lisaftoclax in patients with chronic lymphocytic leukemia (CLL), to be presented at the ASH Annual Meeting this year, once again demonstrate the drug's efficacy and favorable tolerability in patients with CLL who were heavily pretreated and had prior exposure to BTK inhibitors. In two other abstracts on lisaftoclax, results were disclosed from clinical studies of the drug as a single agent and in combination regimens in multiple hematologic malignancies, including relapsed/refractory (R/R) multiple myeloma (MM) and acute myeloid leukemia (AML).

The ASH Annual Meeting is one of the largest gatherings of the international hematology community, bringing together the latest and most cutting-edge scientific research in the pathogenesis and clinical treatment of hematologic diseases. The 65^th ASH Annual Meeting will take place on December 9-12, 2023, both online and in-person, in San Diego, CA (United States).

"Lisaftoclax is the first Bcl-2 inhibitor in China and the second globally that has demonstrated promising efficacy. Clinical results to be presented at the ASH Annual Meeting this year further validate the drug's potential as an alternative treatment option for a number of hematologic malignancies, including R/R CLL," said Dr. Yifan Zhai, Chief Medical Officer of Ascentage Pharma. "In addition, we will also present data of a few more clinical studies that will underscore our broad progress in new drug discovery and clinical development. Moving forward, we will continue to expeditiously advance our clinical development programs globally for the benefit of patients in China and around the world."

Studies of Ascentage Pharma's Drug Candidates to be presented at ASH 2023.

The abstracts of lisaftoclax presented at the 2023 ASH Annual Meeting are as follows (for details on the abstracts featuring olverembatinib, please refer to a separate press release published at the same time):

Updated Efficacy and Safety Results of Lisaftoclax (APG-2575) in Patients (pts) with Heavily Pretreated Chronic Lymphocytic Leukemia (CLL): Pool Analysis of Two Clinical Trials

Format: Poster Presentation
Abstract: #1900
Session: 642. Chronic Lymphocytic Leukemia: Clinical and Epidemiological: Poster I
Time: Saturday, December 9, 2023, 5:30 PM - 7:30 PM (Pacific Time) / Sunday, December 10, 2023, 9:30 AM – 11:30 AM (Beijing Time)

Highlights:

• This abstract reported updated data from long-term follow-ups in two Phase 1b/2 studies of lisaftoclax (APG-2575-CN001 [NCT03913949] and APG-2575-CC101 [NCT04494503]) in patients with CLL.
  
  
• In the 2 studies, lisaftoclax was administered orally once daily in 28-day cycles, in 100 mg, 200 mg, 400 mg, 600 mg, and 800 mg dose cohorts. Under close monitoring for prevention and early detection of tumor lysis syndrome (TLS), patients were treated (with a daily dose ramp-up schedule) until disease progression, intolerable toxicity, death, or any other reason for termination.
  
  As of April 27, 2023, a total of 47 patients with CLL were enrolled. The median (range) duration of follow-up was 14.06 (0.70-30.2) months. The median (range) age was 58 (34-80) years. At enrolment, 53.2% of patients were in Rai stage III/IV, and 48.9% of patients were in Binet stage C. 44.7% of patients had received ≥3 lines of treatment; 66.0% of patients had received ≥2 lines of treatment; 23.4% of patients were treated with Bruton tyrosine kinase inhibitors (BTKis); and 55.3% were treated with a CD20 monoclonal antibody. 68.1% (32) of patients discontinued the study due to disease progression (51.1%), consent withdrawal (6.4%), adverse events (AEs) (2.1%), investigator's decision (2.1%), poor compliance (2.1%), protocol deviation (2.1%), and other reasons (2.1%).
  
  
• The overall response rate (ORR) in patients with CLL was 73.3% (33/45), and the complete response (CR)/incomplete hematological recovery (Cri) rate was 24.4% (11/45).
  
  
• In total, 76.6% (36) of patients experienced grade ≥3 treatment-emergent adverse events (TEAEs); 27.7% (13) experienced serious AEs (SAEs). Treatment-related adverse events (TRAEs) were observed in 95.7% (45) of patients, of whom 68.1% (32) experienced grade ≥3 TRAEs and 14.9% (7) experienced SAEs. One incident of TLS was reported.
  
  
• Conclusions: Lisaftoclax demonstrated significant efficacy and favorable tolerability in patients with CLL who were heavily pretreated and had prior exposure to BTKis.

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:

• This multicenter, open-label, Phase 1 study in China evaluated the efficacy and safety of lisaftoclax alone or combined with azacitidine (AZA) or homoharringtonine (HHT) in patients with treatment-naïve or R/R AML, MDS, or other myeloid neoplasms.
  
  
• Trial design:
  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 or chemotherapy-ineligible (unfit) patients with treatment-naïve 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 to prevent TLS. 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); Cohort C, D, E were treated with lisaftoclax combined with AZA (75 mg/m² daily on d1-7). Dose-limiting toxicity (DLT) was assessed during the first cycle.
  
  
• As of July 19, 2023, a total of 115 patients were enrolled, including 89 patients 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. A total of 13 patients received lisaftoclax monotherapy and 102 patients received combination regimens.
  
  
• Efficacy results: In patients treated with lisaftoclax monotherapy, the ORR and composite remission rate (CRc=complete remission [CR] + CR with incomplete blood count recovery [CRi]) 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. 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 progression-free survival (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%, the CR/marrow CR rate was 60.0%。
  
  
• Safety results: Common TEAEs included hematologic toxicity, electrolyte imbalances, and diarrhea. No TLS was reported during the study and dose-limiting toxicities (DLTs; pneumonia, respiratory failure, and heart failure) were observed in 1 patient in Cohort C. 13 patients who received lisaftoclax monotherapy experienced TEAEs and grade ≥3 TEAEs, and 4 (30.8%) patients experienced SAEs. In patients treated with lisaftoclax combined with HHT, 12 (85.7%) experienced TEAEs and grade ≥3 TEAEs, 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.
  
  
• Increased systemic exposure of lisaftoclax was discerned as the dosage escalated from 200 mg 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, in monotherapy or combination regimens, showed encouraging efficacy and favorable tolerability profiles in patients with R/R AML or MDS and older/unfit patients with TN AML.

First Report on the Effects of Lisaftoclax (APG-2575） in Combination with Novel Therapeutic Regimens in Patients with Relapsed or Refractory Multiple Myeloma (R/R MM） or Immunoglobulin Light-Chain (Amyloid Light-Chain [AL]） Amyloidosis

Format: Poster Presentation
Abstract: #2016
Session: 653. Multiple Myeloma: Prospective Therapeutic Trials: Poster I
Time: December 9, 2023, Saturday, 5:30 PM – 7:30 PM (Pacific Time) / December 10, 2023, Sunday, 9:30 AM – 11:30 AM (Beijing Time)

Highlights:

• This multicenter study was designed to evaluate the safety and efficacy of lisaftoclax combination regimens in patients with R/R MM or R/R AL amyloidosis.
• This study has three treatment arms that included Arm A: lisaftoclax combined with pomalidomide and dexamethasone in patients with R/R MM; Arm B: lisaftoclax combined with daratumumab, lenalidomide, and dexamethasone in patients with R/R MM; and Arm C: lisaftoclax combined with pomalidomide and dexamethasone in patients with R/R amyloidosis. Lisaftoclax was administered orally once daily (QD) at 5 dose levels (400 mg, 600 mg, 800 mg, 1,000 mg, and 1,200 mg) without ramp-up in 28-day cycles. Pomalidomide, daratumumab, and lenalidomide were administered per label use. Dexamethasone 40 mg (20 mg for patients aged >75 years) was administered on Days 1, 8, 15, and 22 of 28-day cycles.
• As of July 3, 2023, a total of 30 patients were enrolled. Among them, 22, 3, and 5 patients were enrolled into Arms A, B, and C, respectively. 66.7% of patients were male and the median (range) age was 70.5 (24-88) years. All patients were previously exposed to multiple lines of treatment, with a median (range) line of prior therapies of 4 (1-19). 18 patients were triple-class-exposed, including 7 who had received pomalidomide and 3 who harbored the t(11;14) chromosomal abnormality.
• Safety results: A total of 19 patients experienced lisaftoclax treatment related AEs, including nausea (16.7%), neutropenia (16.7%); thrombocytopenia, leukopenia, abdominal distension, constipation, or diarrhea (6.7% each). A total of 7 patients experienced grade ≥3 TRAEs, including neutropenia (10.0%), febrile neutropenia (3.3%), iron deficiency anemia (3.3%), thrombocytopenia (3.3%), prolonged electrocardiogram QT interval (3.3%), and acute kidney injury (3.3%). Two patients experienced lisaftoclax-related SAEs, including 1 acute kidney injury and 1 febrile neutropenia.
• Efficacy results: In Arm A, 21 patients with R/R MM were efficacy evaluable, with an ORR (partial response [PR] + very good partial response [VGPR]) of 66.7%. In Arm B, 1 patient with R/R MM achieved PR and another achieved VGPR. In Arm C, 3 patients with R/R amyloidosis achieved a hematologic VGPR. The ORR was 60% and 1 patient experience organ function improvement.
• Conclusions: Lisaftoclax combination regimens were well tolerated and demonstrated potent antitumor activity in patients with R/R MM and R/R amyloidosis.

* 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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