ASCO 2024 | Ascentage Pharma Releases Latest Results from Multiple Clinical Studies of Its Lead Drug Candidates

SUZHOU,ChinaandROCKVILLE,Md.,May 24,2024 -- 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 its four abstracts selected for presentations at the 2024 American Society of Clinical Oncology (ASCO) Annual Meeting are now available on ASCO's official website. These abstracts report on the company's three lead drug candidates,including olverembatinib (HQP1351),the first and only China-approved third-generation BCR-ABL inhibitor; lisaftoclax (APG-2575),a BCL-2 selective inhibitor; and APG-2449,a FAK/ALK/ROS1 inhibitor.

Updated results from the four studies will be presented in Oral Reports or Posters at the ASCO Annual Meeting taking place on May 31 - June 4,2024 in Chicago,IL. The ASCO Annual Meeting showcases the most cutting-edge research in clinical oncology and state-of-the-art advanced cancer therapies and is the world's most influential and prominent scientific gathering of the clinical oncology community.

"It is our pleasure to present the latest data on our key drug candidates at the ASCO Annual Meeting for the seventh consecutive year," said Dr. Yifan Zhai,Chief Medical Officer of Ascentage Pharma. "These encouraging results once again highlight Ascentage Pharma's robust capabilities in global innovation and clinical development. Going forward,we will further expedite our clinical development programs globally in the hope of benefitting more patients in China and around the world as soon as possible."

These four clinical studies to be presented at this year's ASCO Annual Meeting are as follows:

Drug Candidates

Abstract Title

Abstract#

Format

Olverembatinib (HQP1351)

Updated efficacy results of olverembatinib (HQP1351) in patients with tyrosine kinase inhibitor (TKI)-resistant succinate dehydrogenase (SDH)-deficient gastrointestinal stromal tumor (GIST) and paraganglioma.

#11502

Oral

Report

Lisaftoclax

（APG-2575）

Safety and efficacy of lisaftoclax,a novel BCL-2 inhibitor,in combination with azacitidine in patients with treatment-naïve or relapsed or refractory acute myeloid leukemia.

#6541

Poster Presentation

Updated efficacy and safety results of BCL-2 inhibitor lisaftoclax (APG-2575) alone or combined with ibrutinib or rituximab in patients (pts) with Waldenström macroglobulinemia (WM).

#7078

Poster Presentation

APG-2449

Updated study results of novel FAK/ALK/ROS1 inhibitor APG-2449 in patients (pts) with non-small-cell lung cancer (NSCLC) resistant to second-generation ALK inhibitors.

#3124

Poster Presentation

The details of these abstracts are as follows:

Oral Report

Olverembatinib (HQP1351)

Updated efficacy results of olverembatinib (HQP1351) in patients with tyrosine kinase inhibitor (TKI)-resistant succinate dehydrogenase (SDH)-deficient gastrointestinal stromal tumor (GIST) and paraganglioma

Abstract#:11502

Session Title:Sarcoma

Date and Time:June 3,2024,Monday,3:00 PM – 6:00 PM (Central Time)

First Author:Haibo Qiu,MD,PhD,Sun Yat-sen University Cancer Center,Guangzhou,Guangdong,China.

Highlights:

Background: SDH-deficient GIST is a rare type of GIST,mainly observed in the stomach of children,adolescents,and young adults under 30 years of age. No active targeted therapies have been identified in this subset of GIST. Olverembatinib,approved in China for the treatment of patients with chronic myeloid leukemia,has shown promising clinical efficacy in SDH-deficient GIST. In this abstract,the study reports updated efficacy data of olverembatinib in SDH-deficient GIST and preliminary efficacy data in paraganglioma,an SDH-deficient-related tumor.

Introduction: The aim of this study was to evaluate the safety and efficacy (per RECIST v1.1) of olverembatinib in patients with SDH-deficient GIST and other solid tumors. Olverembatinib was administered orally once every other day (QOD) in 28-day cycles.

Patient enrollment and methods: As of December 27,2023,26 patients with SDH-deficient GIST (confirmed by immunohistochemistry [IHC] assay) had received ≥1 dose of olverembatinib (median [range] age,30 [13-56] years),and 25 of them had received1-4 tyrosine kinase inhibitors (TKIs; 42.3% of patients received ≥3 TKIs). Olverembatinib was administered OQD in doses ranging from 30 to 50 mg (30 mg [n = 6]; 40 mg [n = 14]; 50 mg [n = 6]). This study also enrolled 6 patients with paraganglioma.

Efficacy results:

In the 26 patients with SDH-deficient GIST,the median (range) duration of treatment was 15.6 (1.8-42.3) months. 6 of those patients achieved partial responses (PR); another 18 patients achieved stable diseases (SD) lasting > 4 cycles. The clinical benefit rate (CBR,complete response [CR] + PR + SD > 4 cycles) was 92.3% (24/26) and the longest treatment duration was 40 months. After a median (range) follow-up of 17.0 (4.1-57.5) months,the median (range) progression-free survival (PFS) was 25.7 months (12.1-not reached [NR]).

Among the 6 patients with paraganglioma,5 achieved SDs > 4 cycles,with a CBR of 83.3% and a median (range) PFS of 8.25 (1.87-NR) months.

Safety results: The adverse event profile was the same as previously reported (Qiu H,et al,J Clin Oncol 41:11540),with no newly emergent safety issues observed.

Conclusions: Olverembatinib was well tolerated. In patients with SDH-deficient GIST,olverembatinib demonstrated a CBR exceeding 90% and significantly prolonged the estimated median PFS,indicating the potential benefit of this treatment and providing a benchmark for future studies in this rare subtype of GIST.

Poster Presentations

Lisaftoclax (APG-2575)

Safety and efficacy of lisaftoclax,in combination with azacitidine in patients with treatment-naïve or relapsed or refractory acute myeloid leukemia

Abstract#:6541

Session Title: Hematologic Malignancies—Leukemia,Myelodysplastic Syndromes,and Allotransplant

Date and Time:June 3,9:00 AM – 12:00 PM (Central Time)

First Author:Huafeng Wang,The First Affiliated Hospital,Zhejiang University School of Medicine,Hangzhou,Zhejiang,China.

Highlights:

Background and introduction: Early studies showed that lisaftoclax in combination with various agents can synergistically induce apoptosis in acute myeloid leukemia (AML). This poster presents follow-up safety and efficacy data from a Phase Ib/II study of lisaftoclax combined with azacitidine (AZA) in adults with AML.

Patient enrollment and methods:

This study enrolled elderly (≥75 years)/unfit treatment-naïve (TN) patients withAML who were intolerant of standard induction chemotherapies and patients (≥18 years) with relapsed/refractory (R/R) AML. Lisaftoclax (400/600/800 mg) was administered orally once daily in 28-day cycles. In the first treatment cycle,a daily ramp up schedule was used to prevent tumor lysis syndrome (TLS). AZA was administered once daily on D1-D7 at 75 mg/m2.

As of January 25,76 patients withAML were enrolled,including 37 patients with R/R AML and 39 elderly/unfit patients with TN AML who were intolerant of standard induction chemotherapies. The median (range) age was 66 (20-81) years,and 61.8% of the patients were male.

Efficacy results:

In patients with R/RAML treated with lisaftoclax combined with AZA,the overall response rate ([ORR]=CR + CRi + morphologic leukemia-free state [MLFS] + PR) was 72.7%,the composite complete remission rate (CRc = CR + CRi) was 45.5%. In the 600 mg cohort (n=30),the median duration of treatment was 3.8 months,the ORR was 76.7%,the CRc was 50.0%,the median time to CRc was 2.5 months,the median PFS was 10.2 months,and the median overall survival (OS) was 14.7 months.

Among patients with TNAML treated with lisaftoclax combined with AZA,the ORR was 64.1%,the CRc was 51.3%. In the 600 mg cohort (n=29),the median duration of treatment was 3.3 months,the median time to CRc was 1.9 months. The median PFS was not reached.

600 mglisaftoclax combined with AZA was established as the recommended Phase II dose (RP2D).

Safety results: All patients treated with lisaftoclax combined with AZA reported treatment-emergent adverse events (TEAEs),with 89.5% experiencing Grade 3/4 TEAEs and 43.4% experiencing serious adverse events (SAEs). Common TEAEs included neutropenia (60.5%),thrombocytopenia (60.5%),diarrhea (42.1%),hypokalemia (40.8%),pyrexia (35.5%),and vomiting (30.3%). Grade ≥ 3 TEAEs reported in ≥ 10% of patients included neutropenia (57.9%),thrombocytopenia (50.0%),anemia (27.6%),pneumonia (17.1%),and febrile neutropenia (10.5%). No TLS was reported. The 30-/60-day mortality rates were 1.3% and 3.9%,respectively.

Conclusions: These data support a promising role for the new Bcl-2 inhibitor lisaftoclax combined with AZA for the treatment of elderly/unfit TN patients with AML intolerant of standard induction chemotherapies and patients with R/R AML,especially given a potentially favorable safety profile in terms of TLS,the incidence of neutropenic fever,and low early mortality. A Phase III randomized,double-blind study is being conducted to determine whether lisaftoclax combined with AZA improves the survival of elderly/unfit TN patients with AML intolerant of standard induction chemotherapies.

Updated efficacy and safety results of BCL-2 inhibitor lisaftoclax (APG-2575) alone or combined with ibrutinib or rituximab in patients (pts) with Waldenström macroglobulinemia (WM)

Abstract#:7078

Session Title: Hematologic Malignancies—Lymphoma and Chronic Lymphocytic Leukemia

Date and Time:June 3,9:00 AM– 12:00 PM (Central Time)

First Author:Masa Lasica,MBBS,FRACP,FRCPA,St Vincent's Hospital,Melbourne,Victoria,Australia.

Highlights:

Background: Lisaftoclax is a novel,oral,highly selective,potent Bcl-2 inhibitor. Lisaftoclax can overcome resistance to ibrutinib in ibrutinib-insensitive RPCI-WM1 models. In other non-Hodgkin lymphoma (NHL) models (including DOHH2 follicular lymphoma models and OCI-LY1 diffuse large B-cell lymphoma [DLBCL] models),lisaftoclax combined with ibrutinib has a strong synergistic antitumor effect.

Introduction: This is an open-label,multicenter,global Phase Ib/II study designed to evaluate the efficacy,safety,tolerability,and pharmacokinetics (PK) of lisaftoclax monotherapy or in combinations with agents such as ibrutinib/rituximab in patients with WM.

Patient enrollment and methods:

In this study,patients with WM were enrolled in 3 arms,including Arm A: lisaftoclax monotherapy in patients resistant or intolerant to prior treatment with Bruton's tyrosine kinase inhibitors (BTKis); Arm B: lisaftoclax combined with ibrutinib in treatment-naïve patients with WM; and Arm C: lisaftoclax combined with rituximab in BTKi-naïve patients with relapsed/refractory WM.

Lisaftoclax was orally administered once daily in 28-day cycles. Lisaftoclax was gradually escalated from the starting dose of 400 mg to 1,200 mg. As of January 25,a total of 46 patients were enrolled in the study (Arm A [n=14] at doses of up to 1,000 mg; Arm B [n=24] at doses of up to 1,200 mg; Arm C [n=8] at doses of up to 800 mg).

Efficacy results:

The median (range)durations of treatment were 11 (1-28),23.5 (1-34),and 11.5 (5-33) months for Arms A,B,and C,respectively.

The objective response rates (ORRs; PR,very good partial response [VGPR],CR) were 41.7%,90.9%,and 37.5% for Arms A,respectively.

In Arm A,patients with wild-typeCXCR4 (n =7) had better overall response to lisaftoclax than the CXCR4mut group (n = 3).

In Arms B and C,no significant differences between patients with/without CXCR4mut were observed.

Safety results:

In Arm B,1 dose-limiting toxicity (DLT,grade 3 clinical TLS),attributed to pre-existing renal impairment,occurred at 1,200 mg; and 1 grade 3 laboratory TLS,primarily attributed to dehydration and concomitant symptomatic therapies,000 mg. Abnormal electrolytes was resolved without recurrence after 1 day of drug interruption.

Grade ≥ 3lisaftoclax-related adverse events (AEs) included neutropenia (15.2%),thrombocytopenia (4.3%),decreased leukocytes (4.3%),TLS (4.3%),anemia (2.2%),weight loss (2.2%),and septic shock (2.2%).

Ventricular arrhythmia was not observed.

One patient required dose reduction because ofneutropenia.

The maximum-tolerated dose (MTD) was not reached.

Lisaftoclax combined with ibrutinib showed a PK exposure comparable to lisaftoclax or ibrutinib alone,indicating no potential drug-drug interactions (DDIs).

Conclusions: Lisaftoclax alone and combined with ibrutinib or rituximab was well tolerated and demonstrated measurable effects in patients with treatment-naïve or BTKi-treatment-failed WM.

APG-2449

Updated study results of novel FAK/ALK/ROS1 inhibitor APG-2449 in patients (pts) with non-small-cell lung cancer (NSCLC) resistant to second-generation ALK inhibitors.

Abstract#:3124

Session Title: Developmental Therapeutics—Molecularly Targeted Agents and Tumor Biology

Date and Time:June 1,Saturday,9:00 AM – 12:00 PM (Central Time)

First Author:Yuxiang Ma,China.

Highlights:

Background: ALK inhibitors increase FAK pathway gene expression in ALK+ NSCLC cell lines,with the highest induced expression in drug-tolerant persister cells. This suggests that FAK pathway activation is involved in the mechanism that leads to ALK TKI resistance in ALK+ NSCLC. APG-2449 is an orally active FAK inhibitor and a third-generation ALK/ROS1 TKI that has shown potent antitumor activity in preclinical models and clinical studies. This poster reports further safety and efficacy data of APG-2449.

Patient enrollment and methods:

This study comprises a dose-escalation portion and a dose-expansion portion. 1,200 mg daily (QD) was determined as the RP2D. There are two cohorts in the dose-expansion portion: Cohort 1 included patients with NSCLC who were resistant to second-generation ALK TKIs; Cohort 2 included patients with NSCLC who were ALK or ROS1 TKI naïve.

As of December 9,a total of 144 patients withNSCLC,mesothelioma,or ovarian cancer were treated with APG-2449 at doses ranging from 150 – 1,500 mg. The median (range) age of patients was 53 (21-78) years and 53.5% were female.

Efficacy results:

TheORRs of APG-2449 in patients with ROS1 and ALK TKI-naïve NSCLC (n=36) were 68.2% (15/22) and 78.6% (11/14),respectively. Of the 22 patients with NSCLC resistant to second-generation ALK inhibitors and without targetable bypass gene mutations (e.g.,KRAS G12C,BRAF V600E),9 achieved PRs (9/22; 40.9%). Among the patients treated with RP2D,12 had brain metastasis at baseline,9 of whom achieved intracranial PR,resulting in an intracranial ORR of 75.0%.

Biomarker analysis found that in patients withNSCLC that was resistant to second-generation ALK TKIs,PFS was correlated with phosphorylated FAK (pFAK) levels in the tumor tissue,suggesting that patients with higher pFAK levels were more likely to benefit from APG-2449.

Safety results: A total of 129 (89.6%) patients had treatment‑related adverse events (TRAEs),the most frequent of which were elevated serum creatinine (49.3%),increase in alanine aminotransferase (42.4%),increase in aspartate aminotransferase (36.1%); nausea (28.5%); vomiting (23.6%); diarrhea (22.9%); and decreased leukocyte count (22.2%). In all,20 (13.9%) TRAEs were grade ≥ 3.

Conclusions: APG-2449 demonstrated preliminary efficacy in patients with NSCLC whose disease was TKI naïve and resistant to second-generation ALK inhibitors,especially in brain metastases. Biomarker analysis showed that high pFAK expression levels in baseline tumor tissue correlated with improved APG-2449 treatment responses in patients with NSCLC resistant to second-generation ALK TKIs.

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

*Lisaftoclax and APG-2449 are investigational drugs that have not been approved in any country and region.

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,including 5 global registrational phase III studies,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 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 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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