Live from ASH 2022 | Ascentage Pharma Presents Latest Data of APG-2575, Including Encouraging Results of the Combination with BTKi in Patients with R/R CLL/SLL

SUZHOU, China and ROCKVILLE, Md. , Dec. 13, 2022 /PRNewswire/ -- Ascentage Pharma (6855.HK), a global biopharmaceutical company engaged in developing novel therapies for cancers, chronic hepatitis B (CHB), and age-related diseases, today announced that it has released preliminary results from a global Phase II study of lisaftoclax (APG-2575), a key member of the company's apoptosis-targeting pipeline, as a monotherapy or in combination with CALQUENCE® (acalabrutinib) or rituximab in patients with relapsed or refractory chronic lymphocytic leukemia/small lymphocytic lymphoma (R/R CLL/SLL), in an oral presentation at the  American Society of Hematology (ASH) 64^th  Annual Meeting & Exposition (New Orleans, LA).

The ASH Annual Meeting is one of the largest gatherings of the international hematology field, featuring world-class advances on cutting-edge scientific and clinical research in hematology.  As a leading member of the Chinese hematology and oncology research community that has been increasingly active on the global stage, Ascentage Pharma had results from 5 of its clinical trials selected for 4 oral presentations at this year's ASH Annual Meeting, attracting widespread interest at the event. In total, Ascentage Pharma will have 8 presentations at ASH 2022, including 4 oral and 4 poster presentations including 3 poster presentations submitted independently by investigators based on Real World Evidence.

In the results reported in the oral presentation, the Company's investigational Bcl-2-selective inhibitor lisaftoclax showed promising therapeutic potential, both as a single agent and in combinations. In particular, the combinations showed high objective response rates (ORRs), on the order of 98% (56/57) when combined with acalabrutinib in patient with R/R CLL/SLL. In terms of tumor lysis syndrome (TLS), the combination regimens showed low incidences comparable to that of lisaftoclax monotherapy. In addition, unlike the 5-week dose-escalation applied in trials of other Bcl-2 inhibitors, this study of lisaftoclax adopted a daily dose ramp-up that allowed dose-escalation to be completed in only 4 to 6 days, allowing the patients to receive the full therapeutic dose earlier.

Acalabrutinib is a next-generation Bruton tyrosine kinase inhibitor (BTKi). In June 2020, Ascentage Pharma entered into a clinical collaboration with Acerta Pharma B.V., the hematology research and development center of excellence of AstraZeneca, to evaluate the combination of Ascentage Pharma's investigational Bcl-2 inhibitor, lisaftoclax, and Acerta's BTKi, acalabrutinib. The oral presentation at the 2022 ASH Annual Meeting marks the first ever data release on the combination regimen.

The combination of lisaftoclax with the BTK inhibitor acalabrutinib resulted in an ORR of 98%," according to principal investigator Matthew S. Davids, MD, MMSc of Dana-Farber Cancer Institute (Boston, MA). "Given an encouraging safety profile, with limited TLS despite a daily dose ramp-up, these findings signal the potential clinical utility of this new Bcl-2 inhibitor in patients with CLL/SLL."

"Results reported at this year's ASH Annual Meeting have again shown lisaftoclax's exciting therapeutic potential for the treatment of R/R CLL/SLL," according to Dr. Yifan Zhai, Chief Medical Officer of Ascentage Pharma. "Combined use of Bcl-2 and BTK inhibitors has received much interest in recent years. For the first time, we announced the efficacy data of lisaftoclax plus acalabrutinib, with an ORR that is indeed very encouraging."

"At this year's ASH Annual Meeting, clinical researchers delivered four Company-sponsored oral presentations on lisaftoclax as well as our BCR-ABL1 inhibitor olverembatinib, which has been approved in China for the management of treatment-resistant chronic myeloid leukemia," according to Dr. Zhai. "We are very proud of this accomplishment as another validation of our robust global innovation capabilities. Ascentage Pharma remains committed to our founding mission of addressing unmet clinical needs in China and around the world for the benefit of more patients, and we will continue to accelerate our clinical development programs to bring well tolerated and effective therapeutics to patients as soon as possible."

These data of lisaftoclax reported in the oral presentation at this year's ASH Annual Meeting are as follows (for details of those oral presentations on olverembatinib, please refer to other two press releases to be published during ASH 2022):

Lisaftoclax (APG-2575) Safety and Activity as Monotherapy or Combined with Acalabrutinib or Rituximab in Patients (pts) with Treatment-Naïve, Relapsed or Refractory Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma (R/R CLL/SLL): Initial Data from a Phase 2 Global Study

• Format: Oral Presentation
• Abstract: 160386
• Session: 642. Chronic Lymphocytic Leukemia: Clinical and Epidemiological: Drugs in Development and COVID-19
• Highlights:

• Lisaftoclax, a specific Bcl-2 inhibitor, is active in patients with R/R CLL/SLL, including patients whose disease harbored del(17p) and had progressive disease (PD) after BTKi therapies. This is the first report of lisaftoclax combined with acalabrutinib or rituximab in patients with CLL/SLL.
• Patients with R/R CLL/SLL were treated daily with oral lisaftoclax (400, 600, and
  800 mg) alone or combined with continuous acalabrutinib or rituximab for six 28-day cycles. Primary objectives were to determine the recommended Phase II dose (RP2D), safety, and efficacy, including ORRs of lisaftoclax alone and combined with acalabrutinib or rituximab. Patients underwent lisaftoclax daily ramp-up over 4 to 6 days, with the monitoring of TLS. Dose ramp-up was followed by Cycle 1 Day 1 (C1D1) of lisaftoclax target doses of 400, 600, or 800 mg. Patients in the combination groups completed ramp-up, as well as an additional 7 days of lead-in of lisaftoclax at the target dose, before acalabrutinib or rituximab was added on C1D8, and then treated until PD or unacceptable toxicity was observed.
• As of December 5, 2022, 164 patients had been enrolled. The lisaftoclax monotherapy cohort enrolled a total of 46 patients, with a median age of 60.5 (range, 41-80) years. The rituximab combination cohort enrolled a total of 39 patients, with a median age of 64 (34-75). The acalabrutinib combination cohort enrolled a total of 79 patients, with a median age of 64 (18-80). Of all patients, 16 (9.8%) were treatment-naïve and 19 (11.6%) had received prior treatment with BTKis. In the combination cohorts (n = 118), 25 patients had the TP53 mutation and/or del(17p), and 34 patients had unmutated IGHV. Median treatment duration with lisaftoclax monotherapy was 16.5 (range, 1-36) cycles, 11 (range, 0-21) cycles for the rituximab combination, and 11 (range, 1-24) cycles for the acalabrutinib combination.
• Safety: Common adverse events (AEs) of any grade in all cohorts included neutropenia, diarrhea, and infections. Common AEs of grade ≥ 3 in the lisaftoclax monotherapy cohort included neutropenia (30.3%), COVID-19 infections (28%), anemia (15%), thrombocytopenia (6.5%), and pneumonia (6.5%). Common AEs of grade ≥ 3 in the rituximab combination cohort mainly included neutropenia (21%) and anemia (8%), thrombocytopenia (5%). Common AEs of grade ≥ 3 in the acalabrutinib combination cohort mainly included neutropenia (23%), COVID-19 infections (11.5%), anemia (10%), and thrombocytopenia (6.4%). First onset of grade ≥ 3 cytopenias mainly occurred during ramp-up or C1 and infrequently after C2. Grade ≥ 3 neutropenia was manageable with growth factor support. A total of 4 patients met Howard criteria for TLS (2 clinical TLS/2 laboratory TLS), and 2 with clinical TLS fully recovered and showed responses at 600 mg. No dose-limiting toxicities (DLTs) were observed, and no drug-drug interactions were observed in either combination group.
• Preliminary efficacy: ORRs were 67% (29/43) in the monotherapy group, including 67% (4/6) in patients who were BTKi resistant or intolerant; 98.6% (72/73) in the acalabrutinib combination cohort, including 98% (56/57) in relapsed/refractory patients, 100% (16/16) in treatment-naïve patients，and 88% (7/8) in prior BTKi resistant or intolerant patients; and 79% (27/34) in the rituximab combination cohort.
• Conclusions: Initiated with a daily dose ramp-up, lisaftoclax alone or combined with acalabrutinib or rituximab had a manageable safety profile and favorable clinical activity in patients with treatment-naïve or R/R CLL/SLL.

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 1/2 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), 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. A New Drug Application (NDA) for HQP1351 has been submitted and subsequently granted Priority Review status and a Breakthrough Therapy Designation (BTD) by the Center for Drug Evaluation (CDE) in China. 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 four 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.

Forward-Looking Statements

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