Ascentage Pharma to Present Six Abstracts at 2020 AACR Annual Meeting

SUZHOU, China, and ROCKVILLE, Md., May 15, 2020 /PRNewswire/ -- Ascentage Pharma (6855.HK), a globally focused, clinical-stage biotechnology company engaged in developing novel therapies for cancers, chronic hepatitis B (CHB), and age-related diseases, today announced that the latest research progress of the company will be presented at the 2020 American Association for Cancer Research (AACR) Annual Meeting. Because of concerns about the current coronavirus (COVID-19) pandemic, this year's AACR annual meeting is being held in two sessions in a virtual format. The first session was April 27-28, and the second session, in which Asentage Pharma is set to present, will be June 22-24.

As the most comprehensive and critically important basic-science cancer research meeting in the world, the AACR annual congress covers the latest discoveries across the spectrum of cancer research.

Ascentage Pharma will report six research results involving multiple cancer types in poster presentations during the meeting. Among them, APG-3526, the company's newest drug candidate, will be presented for the first time.

"The research results we're presenting at AACR represent our further progress in research and development aimed to address unmet clinical needs. The results provide scientific rationale for exploring combination therapies in different mechanisms of action with drug candidates in our apoptosis-targeting pipeline, including APG-2575, APG-115 and APG-1252," said Dr. Yifan Zhai, Chief Medical Officer of Ascentage Pharma. "Combination therapy is playing an increasingly important role in cancer treatment. We hope to make more research and development progress and benefit patients sooner."

Development of APG-3526 as a novel and highly efficacious
MCL-1 inhibitor

    --  Abstract: #2349
    --  Background: MCL-1 is an important anti-death BCL-2 family protein and
        plays a key role in blocking apoptosis in cancer cells. The MCL-1 gene
        is located in one of the most frequently amplified loci in various
        hematologic malignancies and solid tumors. MCL-1 overexpression is
        implicated as a resistance factor for multiple therapies including
        widely prescribed microtubule-targeted agents for breast cancers.
        Therefore, MCL-1 is an attractive therapeutic target for the treatment
        of cancers. This study explored the chemical synthesis optimization and
        both the potent antiproliferative and antitumor activity of the lead
        preclinical compound APG-3526 using multiple in vitro and xenograft
    --  Results: We have discovered the novel and highly potent MCL-1 selective
        inhibitor APG-3526, which displays clinically relevant pharmacokinetic
        properties and elicits potent antiproliferative and antitumor activities
        via disrupting MCL-1 complex and triggering caspase activation,
        especially in MCL-1 driven MM models. These results support APG-3526 as
        a promising MCL-1 inhibitor for further clinical development.

APG-2575, a clinical stage BCL-2 selective inhibitor, sensitizes estrogen receptor-positive breast cancers to
standard therapies in the preclinical models

    --  Abstract: #3472
    --  Background: Breast cancer is a heterogeneous disease with at least four
        categories according to the presence or absence of estrogen receptor
        (ER), progesterone receptor (PR), and human epidermal growth factor
        receptor 2 (HER2) expression. In ER(?) breast cancer, anti-estrogen
        therapies with tamoxifen, or CDK4/6 plus aromatase inhibitors, remain
        the standard endocrine therapies, whereas the combination of
        CDK4/6-targeted therapy plus fulvestrant (an ER degrader) follows when
        the disease progresses on the hormonal therapy. However, drug resistance
        to the current therapies frequently emerges. Developing more effective
        treatments becomes an urgent need. Among four subsets of breast cancer,
        ER? breast cancer exhibits the highest BCL-2 expression. Thus,
        inhibition of BCL-2 which triggers apoptosis of cancer cells may become
        an effective therapy synergizes the current therapies. APG-2575 is a
        BCL-2 selective inhibitor currently in clinical trials in patients with
        hematologic malignancies. Here, in preclinical xenograft models of ER(+)
        breast cancer in mice, we evaluated whether APG-2575 enhanced the
        sensitivity to tamoxifen or CDK4/6-targeted (i.e., palbociclib or
        palbociclib plus fulvestrant) therapy.
    --  Results: We demonstrated that Combining APG-2575 with tamoxifen or
        palbociclib therapies substantially enhanced antitumor activity and
        overcomes tamoxifen resistance in the preclinical models of ER(+) breast
        cancer, suggesting a novel strategy for the clinical development of
        BCL-2 inhibitors in ER(+) breast cancers.

Combination of BCL-2/BCL-xL dual inhibitor APG-1252 and chemotherapeutics overcomes resistance to osimertinib in EGFR mutant NSCLC in preclinical models

    --  Abstract: #3631
    --  Background: Osimertinib (AZD9291) is the first-line treatment for
        EGFR-mutated non-small-cell lung cancer (NSCLC); however, the majority
        of patients inevitably develop resistance due to de novo genomic
        abnormalities, such as C797S mutation, EGFR exon 20 insertion, MET
        amplification and other unknown mechanisms. Hence, effective therapies
        to overcome acquired resistance are urgently needed. Inhibition of
        BCL-2/BCL-xL has been reported to enhance apoptosis in EGFR-TKI
        resistant cells with low sensitivity to EGFR inhibition. In this study,
        we evaluated whether the combination of a dual BCL-2/BCL-xL inhibitor
        APG-1252 and chemotherapeutics could overcome osimertinib resistance in
        preclinical xenograft models.
    --  Results: Combination therapy with APG-1252 and cisplatin or docetaxel
        exhibited synergistic antitumor activity. The APG-1252 plus docetaxel
        combination achieved 100% tumor partial regression (PR). Similar results
        were demonstrated in a patient-derived xenograft (PDX) tumor model
        derived from an osimertinib-resistant patient with NSCLC harboring
        19del-T790M-C797S mutation. Furthermore, the combinations also exhibited
        enhanced antitumor activity in an osimertinib-resistant PDX model that
        the resistant mechanism remained unknown. In summary, these results
        suggest that the combination treatment with APG-1252 and
        chemotherapeutics can overcome acquired resistance to osimertinib and
        the combination deserves further clinical evaluations.

Synergy of tyrosine kinase inhibitor HQP1351 and MDM2-p53 antagonist, APG-115, in preclinical models of FLT3 mutant and TP53 wild-type acute myeloid leukemia

    --  Abstract: #3636
    --  Background: HQP1351 is a novel, orally bioavailable multikinase
        inhibitor targeting BCR-ABL, KIT, and FLT3. Currently, HQP1351 is in
        phase II clinical trials in relapsed and refractory chronic myeloid
        leukemia (CML) patients by targeting BCR-ABL. Besides, HQP1351 inhibits
        both wild-type and mutant FLT3 in kinase binding assay. APG-115 is
        another clinical stage, small molecule MDM2 antagonist. In the present
        study, we explored the antitumor effect of the combination of HQP1351
        and APG-115, and the molecular mechanism in FLT3-ITD and TP53 wild-type
        acute myeloid leukemia (AML) in the preclinical setting.
    --  Results: HQP1351 alone exhibited potent antiproliferative activity in
        FLT3-ITD-mutant and TP53 wild-type human AML cell lines, with nanomolar
        IC(50) values. In vivo, HQP1351 single agent demonstrated significant
        antitumor activity evidenced by a markedly reduction of tumor burden and
        prolonged survival in mice. The activity was enhanced when HQP1351 was
        combined with APG-115. The combined treatment synergistically
        downregulated p-FLT3, p-ERK, p-STAT5 and antiapoptotic protein MCL-1,
        and thus enhanced antitumor effects. Taken together, our data provide
        scientific rationale for clinical development of the combination of
        HQP1351 and APG-115 in patients with FLT3-ITD-mutant and TP53-wild-type

Therapeutic potential of IAP inhibitor APG-1387 in combination with PARP- or MEK-targeted therapy, or chemotherapy in pancreatic cancer

    --  Abstract: #3673
    --  Background: Pancreatic cancers are notoriously difficult to treat. While
        poly(ADP-ribose) polymerase (PARP) and mitogen/extracellular
        signal-regulated kinase (MEK) inhibitors are making progresses in the
        clinical development, standard chemotherapy, especially paclitaxel
        protein-bound particles (Abraxane(Ò)) in combination with gemcitabine,
        remains as the first line in pancreatic cancer treatment. To further
        explore the targeted patient populations for APG-1387, a genomic
        biomarker guided avatar mouse trial (n=2) using pancreatic cancer
        patient-derived xenografts (PDXs) was conducted to evaluate the
        combination with PARP inhibitor olaparib in PDXs carrying BRCA1/2
        mutations, MEK inhibitor trametinib in PDXs carrying KRAS mutations, or
        gemcitabine plus abraxane in PDXs with various mutation background.
    --  Results: The results suggest that APG-1387 is promising in pancreatic
        cancer treatment, ascribing to its potential synergistic antitumor
        effect by combining with either PARP inhibitors in BRCA1/2 mutant or MEK
        inhibitors in KRAS mutant pancreatic cancers. In the patients resistant
        to the above combinations, the combination with the standard therapy may
        be explored. Overall, the preclinical study provides the scientific
        rationale for the future clinical development of these combinations in
        patients with pancreatic cancer and distinct genomic alterations.

Co-targeting BCL-xL and HER2 high expression to overcome apoptosis blockade in gastric cancer

    --  Abstract: #5901
    --  Background: Gastric cancer is one of the most prevalent cancers in the
        East Asia population. The five-year survival rate is approximately 20%
        globally. The analysis of gene expression data suggests that
        anti-apoptotic protein BCL-xL may be the oncogenic driver in gastric
        cancer as its expression levels are much higher than BCL-2. In this
        study, we investigated if a clinical stage dual BCL-2/BCL-xL inhibitor
        APG-1252 would elicit therapeutic activity and associated mechanisms
        using a panel of gastric cancer patient-derived xenograft (PDX) models.
        Additionally, we explored if the combination with HER2 inhibition could
        enhance the antitumor activity in HER2? gastric cancer models.

    --  Results: The results demonstrate the on-target antitumor activity of
        APG-1252, the potential of BCL-xL(high) as a predictive biomarker, and
        the resistance mechanism conferred by MCL-1. Furthermore, the data
        provide a scientific rationale for the combined therapy with BCL-xL and
        HER2 inhibitors to achieve better clinical outcomes in a subset of HER2?
        gastric cancers.

About Ascentage Pharma

Ascentage Pharma (6855.HK) is a globally focused, clinical-stage biotechnology company engaged in developing novel therapies for cancers, chronic hepatitis B (CHB), and age-related diseases. The company focuses on developing therapeutics that inhibit protein-protein interactions to restore apoptosis, or programmed cell death. On October 28, 2019, Ascentage Pharma was listed on the Main Board of the Stock Exchange of Hong Kong Limited.

Ascentage Pharma has built a pipeline of eight clinical drug candidates, including a novel, highly potent Bcl-2/Bcl-xL inhibitor, as well as candidates aimed at IAP and MDM2-p53 pathways, and next-generation tyrosine kinase inhibitors. The company is conducting more than 30 Phase I/II clinical trials to evaluate the eight drug candidates in the United States, Australia, and China.

Forward-Looking Statements

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