ROCKVILLE,Md. and SUZHOU,China,Sept. 14,2024 -- Ascentage Pharma (6855.HK),a global biopharmaceutical company engaged in discovering,developing and commercializing therapies to address global unmet medical needs primarily for malignancies,today announced that it has released the clinical data of olverembatinib (HQP1351),the company's novel drug candidate,in patients with succinate dehydrogenase- (SDH-) deficient gastrointestinal stromal tumor (GIST),in a Mini Oral at the 2024 European Society of Medical Oncology (ESMO) Congress.

These data of olverembatinib,presented in the Mini Oral at ESMO 2024,showed sustained clinical benefit in patients with SDH-deficient GIST. As of March 12,2024,six of the 26 patients with SDH-deficient GIST enrolled in the study achieved partial responses (PRs). The objective response rate (ORR) was 23.1%,and the median progression-free survival (PFS) was 22 months. Furthermore,studies on mechanism of action (MOA) revealed that olverembatinib exerts its antitumor activity by modulating multiple signaling pathways involved in angiogenesis,apoptosis,proliferation,and survival.

Olverembatinib,a novel orally-administered tyrosine kinase inhibitor (TKI) developed by Ascentage Pharma,is the first approved third-generation BCR-ABL inhibitor in China. To date,olverembatinib has been approved for two indications in China,including adult patients with TKI-resistant chronic-phase chronic myeloid leukemia (CML-CP) or accelerated-phase CML (CML-AP) harboring the T315I mutation; and adult patients with CML-CP resistant to and/or intolerant of first-and second-generation TKIs. Olverembatinib is jointly commercialized in China by Ascentage Pharma and Innovent Biologics. This is a study of an investigational drug not yet approved by the US Food and Drug Administration (FDA).

In addition to hematologic indications,olverembatinib is also being clinically evaluated for the treatment of GIST. To date,olverembatinib has already been granted a Breakthrough Therapy Designation by the Center for Drug Evaluation (CDE) of China's National Medical Products Administration (NMPA) for the treatment of patients with SDH-deficient GIST who had received first-line treatment. Recently,olverembatinib was cleared by the China CDE to enter a registrational Phase III study in patients with SDH-deficient GIST.

Prof. Haibo Qiu,of Sun Yat-Sen University Cancer Center,and the presenter of the report,commented,"SDH-deficient GIST is an extremely rare type of cancer. According to Chinese and International clinical guidelines,there are currently no standard treatment options for unresectable SDH-deficient GIST. In this Phase I study,we have observed encouraging clinical benefit data and further explored the MOA of olverembatinib. Supported by existing data,we will soon initiate a registrational Phase III study in efforts to bring a new treatment option to more patients with SDH-deficient GIST."

Dr. Yifan Zhai,Chief Medical Officer of Ascentage Pharma,said,"Clinical data presented in the Mini Oral reaffirmed olverembatinib's clinical benefit and favorable tolerability in patients with SDH-deficient GIST,thus indicated another potential breakthrough for an indication with a huge unmet medical need. We will actively advance this clinical development program which hopefully will soon offer patients a safe and effective new treatment option."

As one of the world's leading and most influential oncology congresses,the ESMO Congress showcases the latest results in some of the most cutting-edge cancer research from around the world.

Highlights of the data on olverembatinib presented at this year's ESMO Congress are as follows:

Updated efficacy results of olverembatinib (HQP1351) in patients with succinate dehydrogenase (SDH)-deficient gastrointestinal stromal tumors (GIST) and potential mechanisms of action (MOA)

Format: Mini oral

Presentation#: 1722MO

Category: Sarcoma

Date & Time: Friday September 13,16:30 - 16:35 CEST

Speaker: Haibo Qiu,MD,PhD,Sun Yat-sen University Cancer Center

Highlights:

Background: SDH-deficient GIST is a rare disease with limited treatment options. The oncogenic mechanism of SDH deficiency has not been elucidated. Olverembatinib,already approved in China for the treatment of adult patients with TKI-resistant chronic-phase CML (CML-CP) or accelerated-phase CML (CML-AP),with or without the T315I mutation,has shown promising clinical efficacy in SDH-deficient GIST. This report provides the most updated Phase I efficacy data and translational data of olverembatinib in SDH-deficient GIST.

Methods: This study (HQP1351-SJ0003; NCT03594422) was designed to evaluate the safety and efficacy of olverembatinib in patients (≥12 years of age) with GIST or other solid tumors. Olverembatinib was administered orally every other day (QOD). The study evaluated the clinical efficacy of olverembatinib and analyzed the drug's MOA using multiple in vitro and in vivo assays including a SDHB knock-down rat pheochromocytoma PC12 (#5F7)-derived mouse xenograft model.

Enrolled Patients: As of March 12,a total of 26 patients with SDH-deficient GIST (confirmed by IHC) were treated with olverembatinib,including 25 (96.2%) who had received 1 to 4 TKIs and 13 (50.0%) who had received ≥3 TKIs.

Efficacy and Safety Results: Olverembatinib was well tolerated at doses of 30 to 50 mg. In all,6 (23.1%) patients achieved partial responses (PRs) and the median PFS was 22.0 months (range: 12.9-38.6).

Preclinical Results: Olverembatinib had superior antiproliferative activity (vs. other approved TKIs) in SDHB-deficient cell lines (IC50,0.129-5.132 μM). In PC12#5F7 (SDHB knock-down) cells,olverembatinib decreased HIF 2α,VEGFA,and FGFR1 protein levels and inhibited phosphorylation of FGFR1,IGF 1R,SRC,AKT,and ERK1/2. In PC12#5F7-derived xenograft models,olverembatinib demonstrated dose dependent antitumor activity at 10 and 20 mg/kg (QOD).

Conclusions: Olverembatinib showed sustained clinical efficacy in SDH-deficient GIST,indicating potential benefit of this treatment as well as providing a benchmark for future studies in this rare subtype of GIST. MOA studies revealed that olverembatinib exerts antitumor activity by modulating multiple signaling pathways involved in angiogenesis,and survival.

About Ascentage Pharma

Ascentage Pharma (6855.HK) is a global,integrated biopharmaceutical company engaged in discovering,developing and commercializing therapies to address global unmet medical needs primarily in malignancies. 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.

The company has built a rich pipeline of innovative drug candidates that includes 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 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 has conducted more than 40 clinical trials in the US,Australia,Europe,and China,including 11 registrational studies (completed/ ongoing/planned).

Olverembatinib,the company's first lead asset developed for the treatment of drug-resistant chronic myeloid leukemia (CML) and the company's first approved product in China,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 National Reimbursement Drug List (NRDL). Furthermore,olverembatinib has been granted Orphan Drug Designations (ODDs) 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 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 and other relationships with numerous leading biotechnology and pharmaceutical companies such as Takeda,AstraZeneca,Merck,Pfizer and Innovent; and research and development relationships with leading research institutions such as Dana-Farber Cancer Institute,Mayo Clinic,MD Anderson Cancer Center,National Cancer Institute and the University of Michigan.

The company has built a talented team with a wealth of global experience in the discovery and development of innovative drugs and fully functional 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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