ASH 2023 | For the Sixth Consecutive Year, Results from Multiple Clinical Studies of Olverembatinib Have Been Selected for Presentations, Including Two Oral Reports, at the 2023 ASH Annual Meeting

SUZHOU, China, and ROCKVILLE, Md., Nov. 3, 2023 /PRNewswire/ -- 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 results from multiple clinical studies of the company's novel drug candidate, olverembatinib, have been selected for presentations, including two Oral Reports, at the 65^th American Society of Hematology (ASH) Annual Meeting. Being selected for Oral Reports at the ASH Annual Meeting for the sixth consecutive year underscores the significant interest in the drug by the global hematology community. This year, results from multiple clinical studies on two of Ascentage Pharma's lead drug candidates (olverembatinib and lisaftoclax) have been selected for presentations at the ASH Annual Meeting.

As a potential best-in-class drug, olverembatinib has broad therapeutic potential for the treatment of multiple solid tumors and hematologic malignancies. Currently, olverembatinib is being jointly commercialized by Ascentage Pharma and Innovent Biologics. Through an Oral Report at this year's ASH Annual Meeting, Ascentage Pharma will present the latest results from a randomized, controlled registrational Phase II study in patients with first- and second-generation tyrosine kinase inhibitor (TKI)-resistant chronic myeloid leukemia in the chronic-phase (CML-CP), led by Prof. Xiaojun Huang and Prof. Qian Jiang, from the Institute of Hematology of the Peking University People's Hospital. These data show that, in patients with CML-CP who were resistant/intolerant to TKIs, olverembatinib demonstrated statistically significant and clinically meaningful improvement in event-free survival (EFS), compared with the best available therapy (BAT), meeting the primary endpoint of the study.

The other Oral Report featuring early results from a Phase II study of olverembatinib combined with venetoclax and reduced-intensity chemotherapy in treatment-naïve patients with Ph+ ALL, led by Prof. Xiaoyuan Gong of the Institute of Hematology and Blood Diseases Hospital, the Chinese Academy of Medical Sciences

Also at this year's ASH Annual Meeting, Ascentage Pharma will release updated results from a US study of olverembatinib in a Poster Presentation. These data demonstrate the favorable potential clinical benefit of olverembatinib monotherapy and combination regimens in patients with heavily pretreated CML or Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph⁺ ALL) and show the drug's therapeutic effect in patients who had failed prior treatment with ponatinib or asciminib, further demonstrating the drug's potential as a new treatment option to patients with CML or Ph⁺ ALL worldwide.

In addition, multiple studies of olverembatinib were also selected for Poster Presentations, including one featuring a case series study of liposome mitoxantrone combined with venetoclax, homoharringtonine, and olverembatinib (the MVHO regimen) in pediatric patients with refractory or recurrent acute myeloid leukemia (AML), carried out by a team of investigators including Wenting Hu and Prof. Shuhong Shen of the Department of Hematology & Oncology, Shanghai Children's Medical Center of Shanghai Jiao Tong University School of Medicine (see the table below for details).

The ASH Annual Meeting is one of the largest gatherings of the international hematology community, bringing together the latest and most cutting-edge scientific research in the pathogenesis and clinical treatment of hematologic diseases. The 65^th ASH Annual Meeting will take place on December 9-12, 2023, local time, both online and in-person in San Diego, CA (United States).

"This is the sixth consecutive year for the updated clinical data of olverembatinib to be accepted for presentation at the ASH Annual Meeting, a new record for the drug," said Dr. Yifan Zhai, Chief Medical Officer of Ascentage Pharma. "This year, results from multiple studies of olverembatinib have been selected for presentations, including two Oral Reports, at the meeting. This indicates the global hematology community's strong recognition of olverembatinib, a global best-in-class drug. The large body of clinical data we are bringing to this year's ASH Annual Meeting underscores our broad progress in new drug discovery and clinical development. Moving forward, we will continue to expeditiously advance our clinical development programs globally for the benefit of patients in China and around the world."

Studies of Ascentage Pharma's Drug Candidates to be presented at ASH 2023

Abtracts on olverembatinib presented at the 2023 ASH Annual Meeting are as follows (for details on the abstracts featuring lisaftoclax, please refer to a separate press release published at the same time):

Olverembatinib (HQP1351) Demonstrates Efficacy Vs. Best Available Therapy (BAT) in Patients (Pts) with Tyrosine Kinase Inhibitor (TKI)-Resistant Chronic Myeloid Leukemia Chronic-Phase (CML-CP) in a Registrational Randomized Phase 2 Study

Format: Oral Report
Abstract: #869
Session: 632. Chronic Myeloid Leukemia: Clinical and Epidemiological: Novel Therapeutic Approaches
Time: December 11, 2023, Monday, 3:45 PM (Pacific Time) / December 12, 2023, Tuesday, 7:45 AM (Beijing Time)

Highlights:

• This is a multicenter, randomized, registrational Phase II study designed to assess the efficacy and safety of olverembatinib compared with the BAT in patients with CML-CP.
• As of April 30, 2023, a total of 144 patients were enrolled, of whom 69.4% were male and 30.6% were female. The median (range) age of these patients was 49.0 (18-77) years. A total of 96 patients were treated with olverembatinib, and 48 patients were treated with BAT. The median (range) duration of follow-up for the olverembatinib and BAT arms were 12.67 (0.0-40.9) months and 2.94 (0.0-40.4) months, respectively. 66 (45.8%) patients had ≥1 BCR::ABL1 mutations, and 39 (27.1%) had the "gatekeeper" BCR::ABL1^T315I mutation, which confers resistance against all first- and second-generation tyrosine kinase inhibitors (TKIs). A total of 97 patients discontinued therapies (56 [58.3%] from the olverembatinib arm, 41 [85.4%] from the BAT arm) due to disease progression, treatment failure, adverse events (AEs), consent withdrawal, poor compliance, or death.
• Safety results: 82/96 (85.4%) patients receiving olverembatinib and 31/46 (67.4%) patients receiving BAT experienced grade≥3 AEs. AEs with an incidence >20% included thrombocytopenia; leukopenia; anemia; neutropenia; elevated creatine phosphokinase (CPK), alanine aminotransferase (ALT), and aspartate aminotransferase (AST); and hypertriglyceridemia. Serious AEs (SAEs) with an incidence >5% included thrombocytopenia. Common AEs (≥10%) that led to discontinuation, dose reduction, or treatment withdrawal were thrombocytopenia, neutropenia, and leukopenia.
• Efficacy results: Data showed that, in patients with CML-CP resistant/intolerant to prior treatment with TKIs, the olverembatinib arm, compared with the BAT arm, achieved statistically significant improvement in event-free survival (EFS), therefore meeting the primary endpoint of the study. The median (range) EFS was 21.22 (95% CI: 10.15 to not reached) months in the olverembatinib arm compared to 2.86 (95% CI 2.53-4.73) months in the BAT arm. Compared with the BAT control arm, olverembatinib reduced the risk of events by 65%. In the olverembatinib arm, the estimated EFS at 6, 12, and 24 months was 73% (95% CI, 62.5-81.0), 58.7% (95% CI, 47.5-68.2), and 46.9% (95% CI, 35.9-57.2), respectively. In the BAT group, it was 32.6% (95% CI,19.7-46.2), 26.1% (95% CI, 14.5-39.3), and 16.9% (95% CI, 7.7-29.2) at 6, 12 and 24 months, respectively. Neither the olverembatinib nor the BAT arm reached the median overall survival (OS). As of the data cutoff date, 34 (71%) patients in the BAT control arm were crossed-over to be treated with olverembatinib after reaching the EFS endpoint. The olverembatinib arm showed significantly better efficacy and higher response rates than the BAT control arm.
• Conclusions: Olverembatinib was observed to be better tolerated and more effective than BAT in patients with CML-CP resistant or intolerant to first- and second-generation TKIs.

Update of Olverembatinib (HQP1351) Overcoming Ponatinib and/or Asciminib Resistance in Patients (Pts) with Heavily Pretreated/Refractory Chronic Myeloid Leukemia (CML) and Philadelphia Chromosome-Positive Acute Lymphoblastic Leukemia (Ph⁺ ALL)

Format: Poster Presentation

Abstract: #1798

Session: 632. Chronic Myeloid Leukemia: Clinical and Epidemiological: Poster I

Time: December 9, 2023, Saturday, 5:30 PM - 7:30 PM (Pacific Time) / December 10, 2023, Sunday, 9:30 AM – 11:30 AM (Beijing Time)

Highlights

• Olverembatinib, a novel, potent BCR::ABL1 tyrosine kinase inhibitor (TKI), has shown strong antitumor activity in patients with CML and Ph⁺ ALL. This abstract reports on the safety, efficacy, and pharmacokinetics (PK) of olverembatinib in patients with CML and Ph⁺ ALL outside China, particularly in patients previously treated with third-generation TKI ponatinib and/or allosteric STAMP inhibitor asciminib.
• Methods: Olverembatinib was administered orally once every other day (QOD) in 28-day cycles. In the monotherapy cohort, patients were enrolled after treatment failures on at least 2 prior TKIs and randomized to receive olverembatinib QOD at 30, 40, or 50 mg. In the combination cohort, patients with Ph⁺ B-cell precursor ALL (BCP ALL) or lymphoid CML-BP (CML-LBP) resistant to at least 1 TKI were enrolled and administered olverembatinib (30 or 40 mg) QOD in combination with blinatumomab.
• As of June 30, 2023, 76 patients were enrolled, including 57 with CML-CP and 19 with advanced Ph⁺ leukemia. The median (range) age was 54.5 (21-80) years and 56.6% of patients were male.11 (14.5%), 23 (30.3%) and 39 (51.3%) patients had received 2, 3, and ≥4 TKIs, respectively. A total of 52.6% of patients were previously treated with ponatinib, of whom 67.5% were resistant and 25.0% were intolerant to the drug, and 7.5% of patients failed for other reasons. A total of 27.6% of patients were previously treated with asciminib, of whom 71.4% were resistant and 19.1% were intolerant to the agent, and 9.5% failed for other reasons. At baseline, 32% of patients had T315I mutations, 38% had hypertension, and 17.1% had other cardiovascular comorbidities.
• The median (range) duration of treatment was 24.1 (0-134) weeks. PK analysis showed that western patients had a PK profile similar to historical data on Chinese patients.
• Safety results: 12 patients with CML-CP and 7 with advanced Ph⁺ leukemia discontinued treatment for reasons including AEs (n=4), disease progression (n=7), and other reasons (n=8). A total of 54 (83.1%) patients experienced treatment-related AEs (TRAEs) of any grade after receiving olverembatinib. Grade ≥3 AEs occurring in ≥3 patients (≥ 4.6% incidence) included thrombocytopenia (17%), neutropenia (13.8%), elevated blood creatine phosphokinase (13.8%), leukopenia (7.7%), anemia (4.6%), and elevated lipase (4.6%). 10 (15.4%) patients experienced olverembatinib treatment-related serious AEs (SAEs). 2 (3.1%) patients discontinued the study due to TRAEs, and no TRAE-related deaths were reported.
• Efficacy results:
  Among 50 efficacy-evaluable patients with CML-CP, 57% (25/44) achieved a complete cytogenetic response (CCyR), 43% (21/49) achieved a major molecular response (MMR), and efficacy continued to improve over time. The rate of MMR in patients with CML-CP treated for 6 months and 12 months was 66% and 88%, respectively. At 24 months, the rate of progression-free survival (PFS) was 75% (95% CI: 56.1-86.7) and the OS was 97.6% (95% CI: 90.8-99.4). Among patients whose disease failed ≥4 prior TKIs, CCyR and MMR rates were 57% (13/23) and 42% (11/26), respectively; In patients with CML-CP harboring the T315I mutation, CCyR and MMR rates were 60% (9/15) and 44% (7/16), respectively; In patients without the T315I mutation, CCyR and MMR rates were 55% (16/29) and 42% (14/33), respectively; In patients who had failed treatment with ponatinib, CCyR and MMR rates were 53% (8/15) and 38% (6/16), respectively; In patients who had failed treatment with asciminib, CCyR and MMR rates were 43% (3/7) and 38% (3/8), respectively. Among the 8 patients who were resistant/intolerant to both ponatinib and asciminib, 2 achieved MMR.
  
  Among the 13 efficacy-evaluable patients with advanced Ph+ leukemia, 3 (23%) achieved MMR, of whom 1 patient harbored the T315I mutation and 2 were T315I mutation negative and resistant to ponatinib.
  
  In the combination cohort, 2 patients with Ph⁺ BCP ALL received olverembatinib 30 mg QOD in combination with blinatumomab. Both patients achieved CCyR and 1 achieved negative minimal residual disease (MRD) status after 1 treatment cycle.

• Conclusions: Olverembatinib alone or combined with blinatumomab was efficacious and well tolerated in heavily pretreated patients with CML or Ph+ ALL. The efficacy of olverembatinib was not affected by prior exposure to ponatinib or asciminib, and the status of the T315I mutation. Olverembatinib may provide an effective treatment option for patients with CML or Ph+ ALL who have failed 2 or more TKIs.

Olverembatinib Combined with Venetoclax and Reduced-Intensity Chemotherapy for Patients with Newly Diagnosed Philadelphia Chromosome-Positive Acute Lymphoblastic Leukemia: Early results from a phase II study

Format: Oral Report
Abstract: #827
Session: 614. Acute Lymphoblastic Leukemia: Therapies, Excluding Transplantation and Cellular Immunotherapies: Optimal Frontline Treatment for ALL
Time: December 11, 2023, Monday; 3:45 PM (Pacific Time) / December 12, 2023, Tuesday; 7:45 AM (Beijing Time)

Highlights:

• Background: The combination of olverembatinib (HQP1351), a novel third-generation tyrosine kinase inhibitors (TKIs), with venetoclax generated high response rates in patients with relapsed/refractory Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph ALL). However, the efficacy and safety of these two agents-based regimens as frontline treatment remains unknown.
• Methods: This is a single-arm phase II study (NCT05594784) that enrolled patients (pts) ≥ 14 years (yrs) of age with newly diagnosed Ph+ ALL. Pts were treated with a combination of venetoclax (100 mg d1, 200 mg d2, 400 mg d3-28), olverembatinib 40 mg once every continuously other day, vincristine 1.4 mg/m² (maximum dose 2 mg) on day 1, 8, 15, 22, and prednisone 60 mg/m² on day 1-14; 40 mg/m² on day 15-28 in cycle 1. In cycle 2-3, oral treatment with venetoclax 400 mg × 7 days, olverembatinib once every other day continuously and prednisone 60 mg/m × 7 days were administrated. Cycles were repeated every 28 days. During cycle 1, The dose of olverembatinib was reduced to 30 mg once every other day for pts achieving a complete molecular response (CMR). The primary endpoint of this study was the CMR rate at 3 months. CMR was defined as undetectable BCR:ABL1 transcripts by using the RT-PCR method with sensitivity of 0.001%. MMR was defined as more than 3-log reduction of BCR:ABL1 transcripts.
• From August 2022 to April 2023, a total of 31 pts were enrolled. All pts completed 3 cycles of treatment and could be assessed for the primary endpoint. The data cutoff date was July 25, 2023 with a median follow-up time of 5.8 months. The median age was 40 years (range, 20-66 years) and males accounted for 58.1%. Twenty-three pts (74.2%) expressed the p190 transcript and 8 pts (25.8%) expressed the p210 transcript. The median expression level of BCR:ABL1 was 96.33% (range, 70.79%-175.39%).
• Efficacy results: All patients achieved CR at the end of cycle 1 and no TLS or treatment-related deaths occurred. Molecular response at the end of cycle 1 was CMR in 17 patients (54.8%), and MMR in 8 (25.8%). Molecular response at 3 months was CMR in 19 patients (61.3%) and MMR in 10 (32.3%). No patients developed relapses or deaths at the last follow-up.
• Safety results: The regimen was well-tolerated and safe. Most side effects were grade 1-2. The demand for transfusion and the incidence of infections significantly decreased compared to our historic data. No patient discontinued olverembatinib or venetoclax due to toxicity.
• Conclusions: The combination of olverembatinib and venetoclax with reduced-intensity chemotherapy is a safe and effective regimen in patients with newly diagnosed Ph ALL. The regimen results in high rates of CMR in the absence of intensive chemotherapy or immunotherapy.

Combination of Liposome Mitoxantrone, Venetoclax, Homoharringtonine, and Olverembatinib (HQP1351) (MVHO) in Pediatric Patients with Refractory or Recurrent Acute Myeloid Leukemia (AML): Case Series

Format: Poster Presentation
Abstract: #2840
Session: 613. Acute Myeloid Leukemias: Clinical and Epidemiological: Poster II
Time: December 10, 2023, Sunday, 6:00 PM - 8:00 PM (Pacific Time) / December 11, 2023, Monday, 10:00 AM – 12:00 PM (Beijing Time)

Highlights:

• Background: AML accounts for up to 25% of all pediatric acute leukemia cases. Although the OS in pediatric AML has increased to approximately 70% in recent years because of enhanced risk stratification and therapeutics, approximately 30% of patients experience relapse, and 5% to 10% die because of disease complications or untoward medication effects. Hence, pediatric AML continues to represent an unmet medical need. This study investigated the safety and efficacy of the MVHO therapy in pediatric patients with refractory or relapsed AML.
• Methods: The study enrolled patients with recurrent or newly diagnosed AML with poor prognosis secondary to related molecular abnormalities, including NUP98 rearrangements, FUS-ERG, CBFA2T3-GLIS2, and del(7/7q), who did not achieve complete remission (CR) after first-line induction therapy (i.e., DA, DAE, DAH, MAG, and CLAG). Patients were administered the MVHO regimen, which included 1 dose of liposome mitoxantrone at 8 mg/m²; venetoclax at 300 to 350 mg/m² once daily on days (D) 1 through 7 (with dose escalation if high tumor burden); homoharringtonine at 2 mg/m² once daily on D1 through 7; and olverembatinib at 20-30 mg/m² every other day on D1, 3, 5, and 7. The remission rate after 1 cycle (28-35 days, depending on hematopoietic recovery), overall response rate, recurrence rate, EFS, hematologic toxicity, and infection rate of the MVHO protocol were evaluated.
• A total of 18 patients were enrolled (9 boys and 9 girls), with a median (range) age of 7.3 (4 months-13 years) years, and underwent a total of 27 cycles of the MVHO therapy. Half of the patients underwent 1 cycle and the other half underwent 2 cycles. Per French-American-British (FAB) classification criteria, patients had myelodysplastic syndrome (n = 2); mixed-phenotype acute leukemia (n = 2); and AML subtypes M7 (n = 4), M2 (n = 4), M5 (n = 4), M4 (n = 1), and M0 (n = 1).
• Efficacy results: The median (range) follow-up time was 131 (26-256) days. The objective response rate (CR + complete remission with incomplete hematological recovery [Cri] + partial response) was 83.3%, and the remission rate (CR + Cri) after 1 cycle was 72.2%. A total of 8 patients were minimum residual disease negative. For the 6 patients with relapsed AML, the remission rate after 1 cycle was 66.7%. A total of 3 patients discontinued because of no response or disease progression, and 12 patients underwent hematopoietic stem cell transplantation, after which 1 patient relapsed. The rate of recurrence was 6.7% (1/15). The 8-month mean (± SD) EFS was 60.1% (± 19%) and the OS was 100%.
• Safety results: Among the 26 cycles of treatment evaluated for toxicity, there were no associated fatal infections or bleeding events. Prophylactic levofloxacin and posaconazole were administered orally (or intravenously administered anti-infection treatment in the case of infection) during myelosuppression in each cycle. No breakthrough infection was observed in 5 of 26 cycles of MVHO. There was 1 case of septic shock, and the incidence of grade ≥ 3 infection was 80.7%, which included pneumonia and bloodstream infections. Common grade 4 TRAEs were neutropenia, which was experienced by 100% of patients, and grade 4 thrombocytopenia, which was experienced by 46.1% of patients. Platelets did not decrease to below 100,000/μL after 5 of 26 cycles of MVHO treatment.
• Conclusions: MVHO therapy was effective and reasonably well tolerated in pediatric patients with refractory or recurrent AML, suggesting that it may comprise a suitable first-line treatment option for pediatric patients with AML.

* 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 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, 2 FTDs, and 2 Rare Pediatric Disease (RPD) Designations 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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