ASH 2021 | Ascentage Pharma Presents Latest Data from Two Studies of Bcl-2-Selective Inhibitor Lisaftoclax (APG-2575), Including a China Study Demonstrating Complete Responses

SUZHOU,China and ROCKVILLE,Md.,Dec. 14,2021 -- 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 it has released the updated data from six studies of the company's three novel drug candidates (olverembatinib,lisaftoclax [APG-2575],and pelcitoclax [APG-1252]) at the 63rd American Society of Hematology (ASH) Annual Meeting.

These results include data from two clinical studies of the company's novel Bcl-2-selective inhibitor lisaftoclax and one preclinical study of its dual Bcl-2/Bcl-xL inhibitor pelcitoclax that were released in poster presentations at the meeting (clinical dataof olverembatinib were also presented in an oral presentation and are available in a separate concurrent press release).

It is worth highlighting that 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 responses (CR) or partial responses (PR). At doses ≥ 200 mg,all 6 patients with chronic lymphocytic lymphoma (CLL) achieved objective responses,including 1 with CR and 5 with PR.

Prof. Jianxiang Wang,MD,Vice President of the Chinese Academy of Medical Sciences' Hematology Hospital (Institute of Hematology Research),and the principal investigator of the Phase I study of lisaftoclax in hematologic malignancies,commented: "We are very encouraged by those data from the China study of lisaftoclax,especially the responses in all patients with CLL who were treated at 200 mg or higher doses. Compared to drugs of the same class approved outside China,lisaftoclax has demonstrated at least comparable efficacy,improved safety in terms of TLS and hematologic toxicity,and the suitability for more convenient dosing. We look forward to seeing more positive clinical data and hope that lisaftoclax will eventually offer a new treatment option to patients."

Dr. Yifan Zhai,Chief Medical Officer of Ascentage Pharma,said: "For the first time,we presented data of lisaftoclax and pelcitoclax,two key drug candidates of our apoptosis-targeted pipeline,at the ASH Annual Meeting. These results,following those of olverembatinib,demonstrated Ascentage Pharma's capabilities in developing novel therapeutics for hematologic malignancies,and the widespread interest in the therapeutic utility and potential clinical advantages of these two drug candidates. These promising data presented at this year's ASH Annual Meeting,especially the poster showing impressive potential efficacy and safety of lisaftoclax,are very encouraging indeed. As the first China-developed Bcl-2-selective inhibitor entering clinical development in China,lisaftoclax is a drug candidate with clear best-in-class potential. We will continue to 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."

These two abstracts on lisaftoclax presented at the 2021 ASH Annual Meeting are as follows:

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)

Format: Poster Presentation

Abstract: 3730

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

Highlights:

This Chinese,multicenter,open-label,single-agent,Phase I trial is designedto evaluatethe safety (including dose-limiting toxicity [DLT] and maximum tolerated dose [MTD]),PK/PD,and preliminary efficacy 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) had not been observed. 600 mg was selected as the recommended Phase II dose (RP2D).

Lisaftoclax was generally well tolerated. Treatment-related adverse events (TRAEs) reported in 28 patients 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,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 (3.1% each).

Among the 25 patients who had received at least one tumor evaluation,9 achieved CR or PR,with a median time to response of 2 cycles. The highest response rates were seen in patients with CLL/SLL (66.7%). Overall Response was observed in all 6 patients with CLL received lisaftoclax at doses ≥ 200 mg,including 1 CR and 5 PR. 2 (66.7%) patients with MZL and 1 (25%) with MCL had achieved PR. 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 patients with CLL/SLL,which were consistent with rapid clinical reductions in ALCs.

Conclusions: Orally-administered Lisaftoclax was well tolerated up to 800 mg/day. No TLS was observed,even in high TLS-risk patients who received the rapid daily ramp-up until the recommended treatment dose. Compared to venetoclax,lisaftoclax did not show any significant new or unmanageable TRAE. Therefore,lisaftoclax has the potential has a safe and effective treatment for patients with R/R HMs.

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: Poster I

Highlights:

This is a global,two-part Phase Ib dose escalation and dose expansion study designed to assess the safety and tolerability of lisaftoclax monotherapy (Part 1) and the lisaftoclax combination therapy (Part 2).

In a standard "3+3" dose escalation design (Part 1),lisaftoclax is being administered orally once daily in a 28-day cycle. Evaluated doses included 400,600,and 800mg. 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 on pelcitoclax presented at the 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: Poster II

Highlights:

This study evaluated the potential antitumor effect of pelcitoclax in preclinical models of NK/TCL. Cell-based antiproliferation studies showed activity of pelcitoclax and 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 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 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,Australia,Europe,and China. Olverembatinib,the company's core drug candidate developed for the treatment of drug-resistant chronic myeloid leukemia (CML),was granted Priority Review status and a Breakthrough Therapy Designation (BTD) by the Center for Drug Evaluation (CDE) of China National Medical Products Administration (NMPA),and is already approved for the indication. In addition,the olverembatinib was also granted an Orphan Drug Designation (ODD) and a Fast Track Designation (FTD) by the US FDA,and an Orphan Designation by the EU. To date,Ascentage Pharma has obtained a total of 12 ODDs from the US FDA and 1 ODD from the EU for four of the company's investigational drug candidates. Ascentage Pharma has been designated for multiple Major National R&D Projects,including five National Major New Drug Discovery and Manufacturing projects,one New Drug Incubator status,four Innovative Drug Programs,and one Major Project for the Prevention and Treatment of Infectious Diseases.

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,AstraZeneca,and Pfizer. 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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