Live from ASH 2022 | Ascentage Pharma Delivers Oral Presentations on Chinese Studies of Olverembatinib (HQP1351) at the ASH Annual Meeting for the Fifth Year, with Data Further Validating the Drug's Long-Term Efficacy and Safety

SUZHOU, China and ROCKVILLE, Md., Dec. 11, 2022 /PRNewswire/ -- Ascentage Pharma (6855.HK), a global biopharmaceutical company engaged in developing novel therapies for cancers, chronic hepatitis B (CHB), and age-related diseases, today announced that it has delivered two Oral Presentations on Chinese studies of the company's novel drug candidate olverembatinib (HQP1351) at the American Society of Hematology (ASH) 64th Annual Meeting and Exposition (New Orleans, LA). These two Oral Presentations featured Phase II results and 5-year follow-up data of olverembatinib. Prof. Xiaojun Huang and Prof. Qian Jiang from the Hematology Department of Peking University People's Hospital are the principal investigators of these studies. This year, the clinical results of olverembatinib have been selected for a total of three Oral Presentations.

The ASH Annual Meeting is one of the largest gatherings of the international hematology field, featuring world-class advances on cutting-edge scientific and clinical research in hematology. As a leading member of the Chinese hematology and oncology research community that has been increasingly active on the global stage, Ascentage Pharma will have results from 5 of its clinical trials selected for 4 Oral Presentations at this year's ASH Annual Meeting. In total, Ascentage Pharma will have 8 presentations at ASH 2022, with 4 Oral and 4 Poster Presentations (with 3 poster presentations submitted independently by investigators based on real-world evidence).

Those two Oral Presentations on Chinese studies of olverembatinibat this year's ASH Annual Meeting featured updated results from a Phase II pivotal trial of olverembatinib in patients with drug-resistant chronic myeloid leukemia (CML) harboring the T315I mutation and 5-year follow-up data from a Phase I study.

In the Chinese pivotal Phase II trials, olverembatinib showed positive long-term safety and efficacy in patients with T315I mutant CML chronic-phase (CML-CP) or CML accelerated-phase (CML-AP). In patients with T315I mutant CML-CP, (median treatment duration was 38 months), major cytogenetic response (MCyR) and major molecular response (MMR) rates were approximately 83% and 59%, respectively; and more than 80% of these patients continued to show durable responses at the time of this presentation. In patients with T315I mutant CML-AP (median treatment duration was 20 months), MCyR and MMR rates were 52% and 48%, respectively. The favorable long-term safety profile, including an incidence of occlusive events of 3%, is consistent with results of the Phase I study.

Also termed the "gatekeeper", the BCR-ABL1^T315I mutation is a major treatment challenge in patients with CML. In addition to showing favorable efficacy and safety in patients with T315I mutant CML, the Oral Presentation featuring the 5-year follow-up data of olverembatinib in Chinese patients with CML also showed deep and durable responses and a manageable safety profile in patients with CML-AP or CML-CP resistant to first- and/or second-generation TKIs. On multivariate analysis in the study, compound mutations at baseline did not impact responses to olverembatinib.

As the first approved third-generation BCR-ABL inhibitor in China and the second anywhere globally, olverembatinib was well-tolerated by patients who were on chronic treatment, with incidences of most treatment-related adverse events (TRAEs), including hematologic TRAEs, decreased as treatment proceeded. In particular, the risk of occlusive events, which are commonly elevated with treatment using the current only approved third-generation TKI in the US, was greatly reduced: the 50-month cumulative incidence of occlusive events with olverembatinib was about 7%, far lower than the 35%-40% commonly reported with the other agent from the same class. In addition, incidences of severe hepatotoxicity and pancreatitis were also very low with olverembatinib.

Developed by Ascentage Pharma, olverembatinib is a novel therapeutic with potent activity against BCR-ABL mutants, including the T315I mutation. Olverembatinib has been approved in China for the treatment of adult patients with TKI-resistant chronic-phase CML-CP or CML-AP. As a novel drug candidate with best-in-class potential, olverembatinib's clinical results have been selected for Oral Presentations at the ASH Annual Meeting for 5 consecutive years. To date, olverembatinib has been granted one Fast Track designation and three Orphan Drug designations by the US Food and Drug Administration (FDA), and one Orphan Drug designation by the European Medicines Agency (EMA). Furthermore, Ascentage Pharma and Tanner Pharma Group have jointly launched an innovative Named Patient Program (NPP) to allow access to olverembatinib on a named patient basis in more than 140 countries and regions where the drug is not yet commercially accessible.

"The data reported in the two Oral Presentations further validated olverembatinib's favorable efficacy in patients with T315I mutant CML. Furthermore, olverembatinib also showed potent antitumor activity in patients who had failed multiple lines of prior therapies or harbored complex/compound mutations and these responses were durable," according to Prof. Qian Jiang, Deputy Chief of the Hematology Department of Peking University People's Hospital.

"It is also worth pointing out that olverembatinib has shown a favorable safety profile, as the incidence of most TRAEs decreased with longer treatment duration. In terms of occlusive events, severe hepatotoxicity, and pancreatitis, olverembatinib showed notably lower incidences that are preferrable over another third-generation TKI approved in the United States."

"Having the Chinese studies of olverembatinib selected for Oral Presentations at the ASH Annual Meeting for 5 consecutive years is an achievement we are very proud of, as it signifies the global hematology community's growing recognition for this novel molecule. Data released at this year's meeting further validated the deep and durable efficacy and favorable long-term safety of olverembatinib. We are confident that this drug candidate will continue to demonstrate its enormous potential for the treatment of patients with CML, including those with resistance or intolerance to other TKIs," said Dr. Yifan Zhai, Chief Medical Officer of Ascentage Pharma.

"Driven by our commitment to the mission of addressing unmet clinical needs in China and around the world, we will continue to accelerate our clinical development programs and strive to further explore the clinical potential and broaden the therapeutic window of olverembatinib. Hopefully our efforts will lead to more safe and effective therapeutics for patients in need," Dr. Zhai noted.

Data from the China studies of olverembatinib reported in Oral Presentations at this year's ASH Annual Meeting are as follows (for detailed results from the study of lisaftoclax and the US study of olverembatinib, please refer to other two press releases to be published during ASH 2022):

 Updated Results of Pivotal Phase 2 Trials of Olverembatinib (HQP1351) in Patients (Pts) with Tyrosine Kinase Inhibitor (TKI)-Resistant Chronic- and Accelerated-Phase Chronic Myeloid Leukemia (CML-CP and CML-AP) with T315I Mutation

• Format: Oral Presentation
• Abstract ID: # 170698
• Session: 632. Chronic Myeloid Leukemia: Clinical and Epidemiological: Novel Therapies
• Time: Saturday, December 10, 2022, 10:30 AM, Eastern Time / Saturday, December 10, 2022, 11:30 PM, Beijing Time
• Highlights:

•  
• The T315I mutation can confer a high degree of resistance to many first- and second-generation TKIs. Olverembatinib is a novel, orally active, third-generation BCR-ABL1 TKI. These Phase II pivotal trials, HQP1351-CC-201 and HQP1351-CC-202, conducted based on favorable Phase I trial results, showed that olverembatinib was efficacious and well tolerated in patients with TKI-resistant CML-CP and CML-AP with the BCR-ABL1^T315I genotype.
  
  
• The HQP1351-CC-201 Study (in patients with CML-CP)
  As of the cutoff date of September 30, 2022, 41 patients were enrolled, of whom 21 (51%) were male, with a median age of 47 (range, 22-70) years. The median interval from CML diagnosis to first olverembatinib dose was 5.3 (range, 0.6-23.2) years, and 32 (78%) patients had received ≥ 2 prior TKIs. The median treatment duration was 38 (range, 3-41) months, and Sanger sequencing detected 37 (90%) patients with the T315I mutation alone and 4 (10%) with T315I and compound mutations.
  
  Preliminary efficacy: 100% of patients with CML-CP achieved complete hematologic response (CHR) (31/31, 10 others had CHR at baseline), 83% (34/41) patients had a MCyR, 73% (30/41) had a complete cytogenetic response (CCyR), 59% (24/41) had a MMR, and 54% (22/41) had a molecular response 4.0 (MR^4.0). The 36-month cumulative rates of MCyR, CCyR, MMR, MR^4.0, and MR^4.5 were 80% (64%, 90%), 71% (54%, 83%), 59% (42%, 72%), 51% (35%, 66%), and 51% (35%, 66%), respectively. The rates of continued MCyR, CCyR, and MMR at 36 months were 80% (61%, 91%), 81% (60%, 92%), and 85% (61%, 95%), respectively. The progression-free survival (PFS) rate at 36 months was 92% (77%, 97%) and the overall survival (OS) rate was 95% (82%, 99%). A total of 2 patients withdrew because of progressive disease (PD), 3 failed treatments, 4 had intolerances, 3 withdrew consent, and 2 discontinued for other reasons.
  
  Safety: Frequent hematologic TRAEs (all grades; grade 3/4; SAEs) included thrombocytopenia (71%; 49%; 7%), anemia (71%; 32%; 2%), leukopenia (51%; 15%; 0), and neutropenia (41%; 22%; 0). Common nonhematologic TRAEs (all grades; grade 3/4) included skin pigmentation (56%; 0%) and elevations in creatine kinase (56%; 20%), alanine transaminase (ALT, 44%; 2%) and aspartate aminotransferase (AST, 37%; 0) levels.
  
  
• The HQP-1351-CC-202 Study (in patients with CML-AP)
  As of the cutoff date of September 30, 2022, 23 patients were enrolled, of whom 18 (78%) were male, with a median age of 41 (range, 21-74) years. The median interval from CML diagnosis to first olverembatinib dose was 5.0 (range, 0.4-10.2) years, and 19 (83%) patients had received ≥ 2 prior TKIs. The median treatment duration was 20 (range, 1-41) months. The Sanger sequencing detected 19 (83%) patients with the T315I mutation alone and 4 (17%) with T315I and compound mutations.
  
  Preliminary efficacy: 74% (17/23) of patients with CML-AP achieved CHR. The 36-month cumulative rates of MCyR, CCyR, MMR, MR^4.0, and MR^4.5 were 52% (30%, 71%), 52% (29%, 71%), 48% (25%, 68%), 35% (16%, 55%), and 35% (16%, 55%), respectively. The rates of continued MCyR, CCyR, and MMR at 36 months were 81% (44%, 95%), 66% (32%, 86%), and 22% (4%, 50%), respectively. The PFS rate at 36 months was 62% (38%, 79%) and the OS rate was 70% (47%, 84%). A total of 5 patients withdrew because of PDs, 2 failed treatments, 4 experienced intolerances, 1 died, and 1 other discontinued for other reasons.
  
  Safety: Common hematologic TRAEs (all grades; grade 3/4; SAEs) included thrombocytopenia (78%; 57%; 17%), anemia (70%; 35%; 13%), leukopenia (57%; 30%; 0), and neutropenia (26%; 26%; 0). Common nonhematologic AEs included skin pigmentation (70%), hypocalcemia (52%), proteinuria (57%), hypertriglyceridemia (61%), hyperphosphatemia (48%), hyperuricemia (26%), and arthralgia (35%), of which most were grade 1/2.
  
  
• Conclusions: Olverembatinib was efficacious and well tolerated in patients with TKI-resistant CML-CP and CML-AP with the BCR-ABL1^T315I genotype. These results are consistent with the safety and efficacy profiles observed in the T315I mutant cohort in the Phase I study. Based on the results of these pivotal trials, the Center for Drug Evaluation (CDE) of the China National Medical Products Administration (NMPA) granted conditional approval for olverembatinib in November 2021.

A Five-Year Follow-up on Safety and Efficacy of Olverembatinib (HQP1351), a Novel Third-Generation BCR-ABL Tyrosine Kinase Inhibitor (TKI) in Patients with TKI-Resistant Chronic Myeloid Leukemia (CML) in China

• Format: Oral Presentation
• Abstract ID: #170868
• Session: 632. Chronic Myeloid Leukemia: Clinical and Epidemiological: Novel Therapies
• Time: Saturday, December 10, 2022, 10:00 AM, Eastern Time / Saturday, December 10, 2022, 11:00 PM, Beijing Time
• Highlights

•  
• This open-label, multicenter Phase I study assessed a 5-year follow-up on the safety and efficacy of olverembatinib in adult patients with CML-CP or CML-AP resistant or intolerant to first- or second-generation TKIs. Patients evaluated in the study were orally administered olverembatinib every other day (QOD) in 28-day cycles in 11 dose cohorts ranging from 1 to 60 mg. From October 26, 2016, to September 30, 2022 (data cutoff date), 101 patients with CML-CP (n = 86) and CML-AP (n = 15) were enrolled and treated with olverembatinib. The median treatment duration was 50 months. A total of 71 (70%) patients were male, with a median age of 40 (range, 20-64) years and a median interval from diagnosis to initial olverembatinib treatment of 6.0 (range, 0.3-15) years. A total of 84 (83%) patients received ≥ 2 lines of TKI therapy, and 63 (62%) had T315I mutations. At baseline, compound mutations were detected in 12 (12%) patients, of whom 8 (67%) had the BCR-ABL1^T315I genotype. A total of 20 (20%) patients had 2 (n = 13) or ≥ 3 (n = 7) mutations. As of the data cutoff date, 71 (70%) of the 101 patients continued treatment and 30 (23 with CML-CP and 7 with CML-AP) discontinued because of PD, intolerance, or other reasons.
  
  
• Long-term efficacy: In efficacy-evaluable patients with CML-CP (≥ 30 mg dose cohort), the cumulative rate of MCyR, CCyR, MMR, MR^4.0, and MR^4.5 at 48 months were 80% (69%, 87%), 71% (60%, 80%), 55% (44%, 65%), 45% (34%, 55%), and 39% (28%, 49%), respectively; and  rates of continued MCyR, CCyR, and MMR at 48 months were 75% (63%, 84%), 66% (52%, 77%), and 75% (60%, 86%), respectively. At 48 months, the PFS rate was 88.6 (79.2%, 93.9%).
  
  In efficacy-evaluable patients with CML-AP (≥ 30mg dose cohort), cumulative rates of MCyR, CCyR, MMR, MR^4.0, and MR^4.5 at 48 months were each 40% (15%, 64%); and the rates of continued MCyR, CCyR, and MMR at 48 months were each 83% (27%, 98%). At 48 months, the PFS rate was 50% (22.9%, 72.2%).
  
  Olverembatinib showed potent activity in patients with CML who harbored compound mutations. In efficacy-evaluable patients with CML-CP with compound mutations, cumulative rates of MCyR, CCyR, MMR, MR^4.0, and MR^4.5 at 48 months were 64%, 55%, 58%, 33%, and 25%, respectively; while in the efficacy-evaluable patients with CML-AP who harbored compound mutations, cumulative rates of MCyR, CCyR, MMR, MR^4.0, and MR^4.5 at 48 months were each 60% (all in patients receiving ≥ 30 mg).
  
  
• Safety data from the 5-year follow-up: the incidence of hematologic TRAEs such as thrombocytopenia, leukopenia, and anemia, decreased as treatment proceeded over time. The incidence of grade 3/4 thrombocytopenia was associated with BCR-ABL1 mutation status and the interval from CML diagnosis to the first olverembatinib dose. The incidence of nonhematologic TRAEs such as skin pigmentation, hypertriglyceridemia, and proteinuria remained relatively unchanged with longer durations of treatment. Incidences of grade 3/4 cardiovascular events (CVEs) such as hypertension (4%), pulmonary arterial hypertension (1%), tricuspid valve insufficiency (1%), acute coronary syndrome (1%), arrhythmia (1%), coronary arteriosclerosis (1%), atrial fibrillation (1%), cerebral infarction (1%), lacunar infarction (1%), and myocardial damage (1%) did not notably increase as the treatment proceeded over time.
  
  
• Conclusions: The 5-year follow-up results of this first-in-human trial show that the response to olverembatinib in patients with TKI-resistant CML-CP and CML-AP improved with longer duration of treatment. The safety of olverembatinib was largely consistent with previously reported results, and the incidences of most TRAEs decreased over time.

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 1/2 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), 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. A New Drug Application (NDA) for HQP1351 has been submitted and subsequently granted Priority Review status and a Breakthrough Therapy Designation (BTD) by the Center for Drug Evaluation (CDE) in China. 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 four 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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