Live from ASCO 2023 | Updated Data of Olverembatinib in SDH-Deficient GIST including a CBR of 93.8% Signals a Potential Clinical Breakthrough

SUZHOU,China and ROCKVILLE,Md.,June 5,2023 --Ascentage Pharma (6855.HK),a global biopharmaceutical company engaged in developing novel therapies for cancer,chronic hepatitis B (CHB),and age-related diseases,announced today that it has released updated clinical results of olverembatinib (HQP1351),a third-generation tyrosine kinase inhibitor (TKI),in patients with TKI-resistant succinate dehydrogenase (SDH)-deficient gastrointestinal stromal tumor (GIST),in a Poster Presentation at the 59th American Society of Clinical Oncology (ASCO) Annual Meeting. This is the second consecutive year in which clinical data on olverembatinib were selected for presentations at the ASCO Annual Meeting.

Showcasing progress in clinical development at the ASCO Annual Meeting for six consecutive years,Ascentage Pharma had clinical results from four clinical studies of four of the company's lead drug candidates selected for presentations in 2023. Among these results,the updated data of olverembatinib reaffirmed efficacy and safety in patients with TKI-resistant SDH-deficient GIST,with a clinical benefit rate (CBR) of 93.8%.

GIST is a type of malignancy that arises in the mesenchymal tissues of the gastrointestinal tract,and most patients with GIST harbor KIT or PDGFRA mutations. The introduction of TKIs has significantly improved the prognosis of these patients. However,patients with SDH-deficient GIST,a rare subtype of GIST,still have considerable unmet medical needs. It is known to the research community that patients with SDH-deficient GIST are commonly insensitive to existing TKIs. Although patients with early-stage localized disease can benefit from surgical treatment,most of them eventually experience relapse.1-5 At present,there is no standard of care treatment for patients with relapsed or advanced SDH-deficient GIST,whose 5-year event-free survival (EFS) is only 24%.1-5

Olverembatinib,a third-generation TKI being jointly commercialized in China by Ascentage Pharma and Innovent Biologics,is the first and only third-generation BCR-ABL1 inhibitor approved in China for the treatment of adult patients with TKI-resistant chronic-phase chronic myeloid leukemia (CML-CP) or accelerated-phase CML (CML-AP) harboring the T315I mutation. While being clinically developed and adopted for the treatment of hematologic malignancies,olverembatinib is also being investigated in preclinical and clinical studies for the treatment of GIST,having already shown potent antitumor activity against GIST in multiple preclinical models. Very recently,olverembatinib was granted a Breakthrough Therapy Designation (BTD) for the SDH-deficient GIST indication by the Center for Drug Evaluation (CDE) of China National Medical Products Administration (NMPA). (Olverembatinib is an investigational drug that has not been approved for any indication outside the Chinese mainland)

"Olverembatinib may offer a new treatment option to patients with SDH-deficient GIST,a highly rare subtype of GIST that currently lacks standard of care treatment," said Prof. Ruihua Xu,the principal investigator of this study,President of the Chinese Society of Clinical Oncology(CSCO) and Director of Sun Yat-Sen University Cancer Center. "The drug's impressive efficacy and manageable safety signal a potential breakthrough in the treatment of SDH-deficient GIST."

"This year,we presented updated clinical results that further validated olverembatinib's clinical potential in SDH-deficient GIST,a rare subtype representing an urgent treatment gap in GIST," said Dr. Yifan Zhai,Chief Medical Officer of Ascentage Pharma. "We are truly excited by the prospect of a novel therapeutic that could potentially address an urgent clinical need and bring renewed hope to patients. Remaining committed to the mission of addressing unmet clinical needs in China and around the world,we will press forward with this clinical development program in order to bring a safe and effective new treatment option to patients as soon as possible."

Highlights of the poster on olverembatinib presented at this year's ASCO Annual Meeting:

Antitumor activity of olverembatinib (HQP1351) in patients (pts) with tyrosine kinase inhibitor- (TKI)- resistant succinate dehydrogenase- (SDH-) deficient gastrointestinal stromal tumor (GIST)

Abstract#: 11540

Poster Board#: 474

Session Title: Sarcoma

Highlights:

This open-label,multicenter Phase Ib/II study in China was designed to evaluate the safety,tolerability,pharmacokinetics (PK),and antitumor activity of olverembatinib in patients with TKI-resistant locally advanced or metastatic GIST.

As of January 15,2023,a total of 20 patients with SDH-deficient GIST were enrolled in the study. The median (range) age of these patients was 30 (14-56) years. Olverembatinib,at doses ranging from 20 to 50 mg (50 mg cohort [n=6]; 40 mg cohort [n=8]; 30 mg cohort [n=6]),was administered once every other day (QOD) in 28-day cycles.

Efficacy Results: The median (range) duration of treatment in the 20 patients with SDH-deficient GIST was 7.8 (1.81-42.3) months. A total of 5 of these patients achieved partial responses (PRs). Of the 16 evaluable patients who were treated with olverembatinib for 16 weeks or longer,the clinical benefit rate (CBR = complete responses [CRs] + PRs + stable disease [SD] > 16 weeks) was 93.8% (15/16) and the longest treatment duration was 42 months.

Safety Results: All patients experienced at least one treatment-emergent adverse event (TEAE),most of which were grade 1 or 2; 2 patients experienced grade 3 AEs; and the only hematologic AE with an incidence rate≥20% was anemia (55%). A total of 15 (75%) patients experienced treatment-related adverse events (TRAEs),including 1 patient who experienced a grade 3 TRAE (neutropenia). No serious TRAEs were reported during the study.

Conclusions: Olverembatinib was well tolerated up to 50 mg QOD and showed antitumor activity in patients with TKI-resistant SDH-deficient GIST. A total of 5 (25%) PRs were reported among 20 evaluable patients; the 16 patients treated for ≥ 16 weeks achieved a CBR of 93.8%. These promising findings warrant further investigation.

Appendix: The four posters on Ascentage Pharma's four lead drug candidates,including olverembatinib,presented at this year's ASCO Annual Meeting.

Drug Candidates

Abstract Title

Abstract#

Format

APG-2449

FAK inhibition with novel FAK/ALK inhibitor APG-2449 could overcome resistance in NSCLC patients who are resistant to second-generation ALK inhibitors.

#9015

Poster Discussion

Olverembatinib

(HQP1351)

Antitumor activity of olverembatinib (HQP1351) in patients (pts) with tyrosine kinase inhibitor (TKI)- resistant succinate dehydrogenase (SDH)-deficient gastrointestinal stromal tumor (GIST).

#11540

Poster Presentation

APG-2575

(Lisaftoclax)

Preliminary data of a phase 1b/2 study of BCL-2 inhibitor lisaftoclax (APG-2575) alone or combined with ibrutinib or rituximab in patients (pts) with Waldenström macroglobulinemia (WM).

#7569

Poster

Presentation

APG-115

(Alrizomadlin)

A phase 2 study of alrizomadlin (APG-115) in combination with pembrolizumab in patients with unresectable or metastatic cutaneous melanoma that has failed immuno-oncologic (IO) drugs.

#9559

Poster Presentation

References:

Mantese G. Gastrointestinal stromal tumor: epidemiology,diagnosis,and treatment. Curr Opin Gastroenterol. 2019; 35(6): 555-559.

Call JW,Wang Y,Rothschild S,et al. Treatment responses in SDH-deficient GIST. LRG Science,https://liferaftgroup.org/2019/08/treatmentresponses-in-sdh-deficient-gist.

Nannini M,Rizzo A,Indio V,et al. Targeted therapy in SDH-deficient GIST. Ther Adv Med Oncol. 2021; 13: 17588359211023278.

Weldon CB,Madenci AL,Boikos SA,et al. Surgical Management of Wild-Type Gastrointestinal Stromal Tumors: A Report From the National Institutes of Health Pediatric and Wildtype GIST Clinic. J Clin Oncol. 2017; 35(5): 523-528.

Mullassery D,Weldon CB. Pediatric/"wildtype" gastrointestinal stromal tumors. Semin Pediatr Surg. 2016; 25(5): 305-310.

About Olverembatinib (HQP1351)

Developed by Ascentage Pharma with support from the National Major New Drug Discovery and Manufacturing Program in China,the orally active,third-generation TKI olverembatinib is the first and only China-approved third-generation BCR-ABL inhibitor targeting drug-resistant chronic myeloid leukemia (CML). Olverembatinib can effectively target a spectrum of BCR-ABL mutants,including the T315I mutation.

In November 2021,olverembatinib was granted a conditional approval through the Priority Review process by the China National Medical Products Administration (NMPA) for the treatment of adult patients with tyrosine kinase inhibitor (TKI)-resistant chronic-phase CML (CML-CP) or accelerated-phase CML (CML-AP) harboring the T315I mutation as confirmed by a validated diagnostic test. Subsequently,Olverembatinib was included into the China 2022 National Reimbursement Drug List (NRDL) for the approved indication. In March 2021,olverembatinib was granted a Breakthrough Therapy Designation (BTD) by the CDE for the treatment of patients with CML-CP who are resistant and/or intolerant of first- and second-generation TKIs. In July 2022,an NDA for this inidcation was accepted by the NMPA and subsequentlty granted a BTD that will support a full approval of olverembatinib

In overseas,olverembatinib was cleared by the US FDA in July 2019 to directly enter a Phase Ib study. Since 2018,the clinical results of olverembatinib have been selected for oral presentations at the American Society of Hematology (ASH) Annual Meetings for five consecutive years,and was nominated for "Best of ASH" in 2019. To date,olverembatinib has been granted one Fast Track Designation (FTD) and four Orphan Drug Designations (ODDs) from the US Food and Drug Administration (FDA) for the treatment of CML,acute lymphoblastic leukemia (ALL),acute myeloid leukemia (AML),and gastrointestinal stromal tumour (GIST); and one Orphan Designation from the European Medicines Agency (EMA) of the European Union for the treatment of CML.

In July 2021,Ascentage Pharma (6855.HK) and Innovent Biologics (1801.HK) reached the agreement regarding the joint development and commercialization of olverembatinib in China.

*Olverembatinib is an investigational drug that has not been approved for any indication outside the Chinese mainland)

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 I/II 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) and the company's first approved product,has been granted two Priority Review Designations and two Breakthrough Therapy Designations (BTDs) by the Center for Drug Evaluation (CDE) of China National Medical Products Administration (NMPA). To date,the drug had been included into the China 2022 National Reimbursement Drug List (NRDL). Furthermore,olverembatinib 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. 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 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.

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