ASH 2021 | Ascentage Pharma to Release Latest Data from Two Studies of Its Bcl-2-Selective Inhibitor Lisaftoclax (APG-2575), Including a Chinese Study Demonstrating Complete Response

SUZHOU,China,and ROCKVILLE,MD.,Nov. 5,2021 --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 abstracts on six studies of the company's three drug candidates (olverembatinib [HQP1351],lisaftoclax [APG-2575],and pelcitoclax [APG-1252]) have been selected for poster presentations and one oral presentation at the 63rd American Society of Hematology (ASH) Annual Meeting. These data include two clinical studies of the company's novel Bcl-2-selective inhibitor lisaftoclax and one preclinical study of the dual Bcl-2/Bcl-xL inhibitor pelcitoclax.

Drug Candidate

Abstract Title

Abstract#

Format

Olverembatinib (HQP1351)

Updated Safety and Efficacy Results of Phase 1 Study of Olverembatinib (HQP1351),a Novel Third-Generation BCR-ABL Tyrosine Kinase Inhibitor (TKI),in Patients with TKI-Resistant Chronic Myeloid Leukemia (CML)

311

Oral Presentation

Updated Results of Pivotal Phase 2 Trials of Olverembatinib (HQP1351) in Patients (Pts) with Tyrosine Kinase Inhibitor (TKI)-Resistant BCR-ABL1T315I-Mutated Chronic- and Accelerated-Phase Chronic Myeloid Leukemia (CML-CP and CML-AP)

3598

Poster Presentation

Trial in Progress: Phase 1b Bridging Study of the Pharmacokinetic (PK),Safety,and Efficacy of Orally Administered Olverembatinib (HQP1351) in Patients with Refractory Chronic Myeloid Leukemia (CML) and Philadelphia Chromosome-Positive Acute Lymphoblastic Leukemia (Ph+ ALL)

2551

Poster Presentation

Lisaftoclax (APG-2575)

A Phase 1 Study to Evaluate the Safety,Pharmacokinetics (PK) and Pharmacodynamics (PD) of Lisaftoclax (APG-2575),a Novel BCL-2 Inhibitor (BCL-2i),in Patients (pts) with Certain Relapsed or Refractory (R/R) Hematologic Malignancies (HMs)

3730

Poster Presentation

Trial in Progress: Phase 1b Study of Lisaftoclax (APG-2575) As a Single Agent or Combined with Other Therapeutic Agents in Patients with Relapsed and/or Refractory Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma (R/R CLL/SLL)

1554

Poster Presentation

Pelcitoclax (APG-1252)

Antitumor Activity of Dual BCL-2/BCL-xl Inhibitor Pelcitoclax (APG-1252) in Natural Killer/T-Cell Lymphoma (NK/TCL)

2062

Poster Presentation

Among those studies,the multicenter,open-label Phase I study of lisaftoclax in patients with hematologic malignancies has demonstrated favorable tolerability of lisaftoclax,without evidence of tumor lysis syndrome (TLS). As of data cutoff on July 27,2021,9 of the 25 patients who had received at least one tumor evaluation (of 31 enrolled patients) achieved complete response (CR) or partial response (PR). At doses ≥ 200 mg,all 6 patients with chronic lymphocytic lymphoma (CLL) achieved objective responses,including 1 with CR and 5 with PR.

"For the first time,we are presenting data of lisaftoclax and pelcitoclax,two key drug candidates of our apoptosis-targeted pipeline,at the ASH Annual Meeting,amid widespread interest in the therapeutic utility and potential clinical advantages of these two drug candidates," said Dr. Yifan Zhai,Chief Medical Officer of Ascentage Pharma. "We are very encouraged by those promising data to be reported at this year's ASH Annual Meeting,especially the poster showing impressive potential efficacy and safety of lisaftoclax. Lisaftoclax is the first China-developed Bcl-2-selective inhibitor entering clinical development in China. We will accelerate the clinical development of this drug candidate in hematologic indications to allow patients in China and around the world to benefit from it as soon as possible."

The ASH Annual Meetingis one of the largest gatherings of the international hematology field,bringing together the latest and most cutting-edge research and development in hematology. The 63rd ASH Annual Meeting will take place on December 11-14,both virtually and in-person in Atlanta,Georgia,United States (information on these abstracts of olverembatinibare available in a separate press release published in parallel).

These two abstracts on lisaftoclax that have been selected for presentations at the 2021 ASH Annual Meeting are as follows:

A Phase 1 Study to Evaluate the Safety,in Patients (pts) with Certain Relapsed or Refractory (R/R) Hematologic Malignancies (HMs)

Format: Poster Presentation

Abstract: 3730

Session: 642. Chronic Lymphocytic Leukemia: Clinical and Epidemiological: Poster III

Time: Monday,December 13,2021; 6:00 PM – 8:00 PM EDT

Highlights:

This Chinese,multicenter,open-label,single-agent,Phase I trial is evaluating the safety (including dose-limiting toxicity [DLT] and maximum tolerated dose [MTD]),efficacy,PK,and PD of lisaftoclax in adults with R/R chronic lymphocytic leukemia (CLL) or non-Hodgkin's lymphoma (NHL).

As of July 27,31 patients had been enrolled and treated with lisaftoclax at doses ranging from 20 to 800 mg. Patients had a median (range) of 4 (1-14) prior lines of treatment and diagnoses of CLL/SLL (n=9),mantle cell lymphoma (MCL; n=6),marginal zone lymphoma (MZL; n=3),follicular lymphoma (n=8),diffuse large B-cell lymphoma (n=2),lymphoplasmacytic lymphoma/Waldenstrom macroglobulinemia (n=1),angioimmunoblastic T-cell lymphoma (n=1),or mycosis fungoides (MF; n=1). DLT,MTD,and laboratory/clinical tumor lysis syndrome (TLS) have not been observed. The recommended Phase II dose (RP2D) is 600 mg.

Lisaftoclax was generally well tolerated. Treatment-related adverse events (TRAEs) reported in 28 patients (87.5%) were mostly grade 1 or 2. Any grade TRAEs in > 10% of patients included thrombocytopenia (34.4%),anemia (28.1%),neutropenia (21.9%),leukopenia (21.9%),diarrhea (15.6%),hyperuricemia (15.6%),hyperphosphatemia (12.5%),and hypertriglyceridemia (12.5%). Grade 3-4 TRAEs were reported in 7 patients (21.9%),including thrombocytopenia (18.8%),neutropenia (12.5%),leukopenia (9.4%),and anemia (6.3%). Serious TRAEs occurred in 1 patient and included anemia and thrombocytopenia (in 3.1% each).

Among the 25 patients who have received at least one tumor evaluation,9 achieved CR or PR,with a median (range) time to response of 2 (2-4) cycles. The highest response rates were seen in patients with CLL/SLL (ORR 66.7% [6/9]). At lisaftoclax doses ≥ 200 mg,an ORR of 100% (6/6 including 1 CR and 5 PRs) was observed. Responses were also observed in MZL,with a PR in 2 of 3 patients (ORR,66.7%),and MCL,with a PR in 1 of 4 patients (ORR,25%). In 1 patient with MF,skin tumor shrinkage was observed after 1 lisaftoclax treatment cycle. Favorable absolute lymphocyte count (ALC) profiles included reductions at lisaftoclax doses as low as 100 mg/day.

The preliminary PK profile showed that exposures increased with lisaftoclax doses from 20 to 800 mg,with an average half-life of 4 to 6 hours. On BH3 profiling,lisaftoclax rapidly triggered changes in BCL-2 complex in CLL/SLL patient samples,which were consistent with rapid clinical reductions in ALCs.

Conclusions: Lisaftoclax was well tolerated up to 800 mg/day. No TLS was observed,even with the daily ramp-up schedule. There were no significant new or unmanageable safety findings. Lisaftoclax showed single-agent antitumor activity in CLL/SLL,MZL,and MCL. The BCL-2i lisaftoclax offers a treatment alternative for patients with R/R HMs,with a daily ramp-up schedule that may be more patient friendly with a favorable preliminary safety profile.

Trial in Progress: Phase 1b Study of Lisaftoclax (APG-2575) As a Single Agent or Combined with Other Therapeutic Agents in Patients with Relapsed and/or Refractory Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma (R/R CLL/SLL)

Format: Poster Presentation

Abstract: 1554

Session: 642. Chronic Lymphocytic Leukemia: Clinical and Epidemiological

Time: Saturday,December 11,2021; 5:30 PM - 7:30 PM EDT

Highlights:

This new study is a global,two-part Phase Ib dose escalation and dose expansion study to assess the safety and tolerability of lisaftoclax (Part 1) and lisaftoclax combined with rituximab or acalabrutinib (Part 2).

In a standard "3+3" dose escalation design (Part 1),lisaftoclax is being administered orally once daily in a 28-day cycle,with full doses of 200 to 1,200 mg (by 200-mg increments at 4 dose levels [400,600,800,and 1,000 mg]) in parallel. To lower the risk of TLS,lisaftoclax was administered with a daily dose ramp-up.

Part 2 includes a further standard 3+3 dose escalation of lisaftoclax combined with rituximab,or acalabrutinib (in separate cohorts),with a further planned dose expansion at RP2D of these combination regimens.

As of July 19,71 patients have been enrolled (of 144 planned).

The abstract of pelcitoclax selected for presentations at 2021 ASH Annual Meeting is as follows:

Antitumor Activity of Dual BCL-2/BCL-Xl Inhibitor Pelcitoclax (APG-1252) in Natural Killer/T-Cell Lymphoma (NK/TCL)

Format: Poster Presentation

Abstract: 2062

Session: 203. Lymphocytes and Acquired or Congenital Immunodeficiency Disorders

Time: Sunday,December 12,2021; 6:00 PM - 8:00 PM EST

Highlights:

This study evaluated the potential antitumor effect of pelcitoclax in preclinical models of NK/TCL. Cell-based antiproliferation studies showed activity of pelcitoclaxand its more potent metabolite APG-1252-M1 toward NK/TCL cell lines that overexpressed BCL-xL. Half-maximal inhibitory concentrations (IC) for pelcitoclax in SNK-1,SNK-6,and SNK-8 (EBV-positive NK/TCL) cell lines were 2.652 ± 2.606 μM,1.568 ± 1.109 μM,and 0.557 ± 0.383μM,respectively. Corresponding values for APG-1252-M1 were 0.133 ± 0.056 μM,0.064 ±0.014 μM,and 0.020 ± 0.008 μM,respectively.

Mechanistic studies demonstrated that pelcitoclax and the APG-1252-M1 metabolite disrupted the complex of BCL-xL/BCL-2-associated X protein (Bax) and BCL-xL/BCL-2 homologous antagonist killer protein (Bak) in SNK-6 cells,thereby liberating these proapoptotic proteins and further activating downstream apoptosis pathways by cleaving poly-ADP ribose polymerase-1 (PARP-1) and caspase-3. In an SNK-6xenograft model,administration of pelcitoclax at 65 mg/kg and 100 mg/kg either twice or once weekly resulted in significant antitumor effects,with tumor growth rate (T/C%) values ranging from 13.7% to 30.7%.

Furthermore,the combination of pelcitoclax with histone deacetylase (HDAC) inhibitor chidamide or DDGP (dexamethasone,cisplatin,gemcitabine,and pegaspargase) chemotherapy demonstrated synergistic effects. Pharmacokinetic assessment in mice showed that pelcitoclax had a long half-life in plasma (127 hours) and tumor tissues (25.2hours),justifying intermittent dosing schedules used in vivo. Importantly,the transformation of pelcitoclax to APG-1252-M1 was 16 times higher in tumor tissues compared to plasma (22% vs. 1.3%) after administration of pelcitoclax,thereby suggesting that pelcitoclax can reduce platelet toxicity caused by APG-1252-M1 in plasma.

Conclusion: Pelcitoclax has promising antitumor effects in NK/TCL,either as a single agent or in combination with an HDAC inhibitor or chemotherapy. These findings provide evidence to further evaluate APG-1252 as a potential treatment for NK/TCL.

About Lisaftoclax (APG-2575)

Lisaftoclax is a novel,orally administered small-molecule Bcl-2‒selective inhibitor being developed by Ascentage Pharma to treat hematologic malignancies and solid tumors by selectively blocking antiapoptotic protein Bcl-2 and hence restoring the normal apoptosis process in cancer cells. Lisaftoclax is the first China-developed Bcl-2 inhibitor entering clinical development in China.

Lisaftoclax is being studied in multiple clinical studies in countries and regions including the U.S.,Australia,and the European Union,for a range of hematologic malignancies and solid tumors such as chronic lymphocytic leukemia,acute myeloid leukemia,and breast cancer. Lisaftoclax has been granted Orphan Drug Designations for five indications including Waldenström macroglobulinemia,chronic lymphocytic leukemia,multiple myeloma,and follicular lymphoma.

About Pelcitoclax (APG-1252)

Pelcitoclax is a novel,highly potent,small-molecule drug designed to restore apoptosis through selective inhibition of Bcl-2 and Bcl-xL proteins. In preclinical animal models of EGFR-mutant non-small cell lung cancer,pelcitoclax plus osimertinib has demonstrated synergistic effects in models that were either sensitive or resistant to osimertinib,thus suggesting that pelcitoclax has the potential to become a new treatment option for this patient population.

About Ascentage Pharma (6855.HK)

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 eight 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,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. 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 12 ODDs from the US FDA 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. A pivotal aim of Ascentage Pharma is to continuously strengthen its R&D capabilities and accelerate its clinical development programs 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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