Ascentage Pharma Announces Phase I/II Data of Olverembatinib (HQP1351) Published in the Journal of Hematology & Oncology, Further Validating the Drug's Best-in-Class Potential

SUZHOU,China and ROCKVILLE,Md.,Sept. 21,2022 --Ascentage Pharma (6855.HK),a global biopharmaceutical company engaged in developing novel therapies for cancers,chronic hepatitis B (CHB),and age-related diseases,announced that the results from a Phase I and Phase II study of olverembatinib (HQP1351) for the treatment of chronic myeloid leukemia (CML) have recently been published in the renowned oncology journal,the Journal of Hematology & Oncology (JHO),further demonstrating the durable efficacy and safety of olverembatinib in patients with CML.

Asajournal highly regarded by global hematology and oncology communities,JHO publishes the most cutting-edge studies covering every aspect of the hematology and oncology research and is rated with an Impact Factor (IF) of 23.1681. It is the official journal of the Chinese American Hematologist and Oncologist Network (CAHON).

Results from these studies of olverembatinib were published in a paper titled "Olverembatinib (HQP1351),a well-tolerated and effective tyrosine kinase inhibitor for patients with T315I-mutated chronic myeloid leukemia: results of an open-label,multicenter phase 1/2 trial" 2. The corresponding author of this paper is Prof. Xiaojun Huang,Director of the Institute of Hematology,Peking University,Director of the Hematology Department at Peking University People's Hospital,and the principal investigator of olverembatinib in China; the first author is Prof. Qian Jiang,Deputy Director of the Hematology Department at Peking University People's Hospital,and a co-principal investigator of olverembatinib in China.

The published results are based on 165 Chinese patients with CML heavily pretreated with multiple prior lines of treatment with tyrosine kinase inhibitors (TKIs). The patients also included those harboring the T315I mutation,and were followed up for a median of about 3 years.

In patients with CML in the chronic phase (CML-CP),the cumulative 3-year incidences of major cytogenetic response (MCyR) and major molecular response (MMR) were 79% and 56%,respectively; while in those with CML in the accelerated phase (CML-AP),the cumulative 3-year incidences of MCyR and MMR were 47% and 45%,respectively. Importantly,cytogenetic and molecular responses increased over time.In terms of safety,common non-hematologic AEs mainly included hyperpigmentation and hypertriglyceridemia,and most of these AEs were of Grade 1/2. Hematologic AEs were resolved after temporary treatment suspension or supportive care. Most AEs were controllable and tolerable,and the incidence of AEs such as thrombocytopenia fell steadily as the treatment went on.

Overall,olverembatinib demonstrated favorable tolerability and durable efficacy. Besides,olverembatinib was highly active against BCR-ABL1T315Imutants and had encouraging clinical activity against compound mutations for which no treatment option is available as of now.

CML is a hematologic malignancy of leukocytes,or white blood cells. The introduction of BCR-ABL1 TKIs significantly improved the clinical practice and management of CML. However,despite the clear clinical benefits brought by the first- and second-generation TKIs,resistance to TKIs remains a major challenge in the treatment of CML. BCR-ABL1 kinase domain mutations represent a key mechanism of drug resistance to TKIs.The T315I mutation is one of the most common mutations in drug-resistant CML,occurring in about 25% of all CML cases. Because patients with T315I-mutated CML are resistant to all first- and second-generation BCR-ABL1 inhibitors,there is an urgent unmet medical need for a safe and effective third-generation BCR-ABL1 inhibitor.

Olverembatinib,a potential best-in-class asset developed by Ascentage Pharma and a drug designated a National Major New Drug Development and Manufacturing Program,is the first and only approved third-generation BCR-ABL1 inhibitor in China,effectively ending the lack of treatment options for patients with T315I-mutated CML in the country. To date,olverembatinib has been included in the Chinese Society of Clinical Oncology (CSCO) Guidelines and the China Anti-Cancer Association's (CACA) 2022 Guidelines for the Holistic Integrative Management of Cancers,for the treatment of patients with TKI-resistant CML harboring the T315I mutation. (The CACA Guidelines also recommended olverembatinib for the treatment of patients with TKI-resistant/intolerant CML who have received at least two prior treatments.)

Althoughanother third-generation BCR-ABL1 inhibitor had been approved in other countries,substantial unmet medical needs remain in patients with drug-resistant CML because of limited accessibility and treatment-related adverse events,including cardiovascular disorders. Consequently,clinical progress with olverembatinib has garnered widespread interest from the global hemato-oncology research community in recent years. Since 2018,clinical results of olverembatinib have been selected for oral presentations at the American Society of Hematology (ASH) Annual Meetings for four consecutive years and was nominated for "Best of ASH" in 2019. To date,olverembatinib has been granted one Fast-Track designation and three Orphan Drug designations by the US Food and Drug Administration (FDA),and an Orphan designation by the European Medicines Agency (EMA) of the EU.

Prof. Xiaojun Huang,commented,"As a Chinese clinician with over 30 years of experience in hematologic research and a principal investigator of olverembatinib,I am pleased that clinical results on this innovative treatment have been published in the JHO,once again showing that olverembatinib brings a novel China-developed therapy to patients with CML around the world. I hope to see more domestically developed novel drugs that allow Chinese physicians the opportunity to lead more clinical trials. Our goal is to generate more China-based data and clinical experience and publish robust evidence-based prospective studies that can further elevate China's status in the global research community."

Prof. Qian Jiang added that,"At present,approximately 20-30% of all CML cases are TKI-resistant/intolerant,thus resulting in disease progression in many patients. Many of these patients fail to achieve desired treatment outcomes because of drug resistance or complications even after switching to a second or third TKIs. This is why TKI-resistant CML remains a major clinical challenge globally. Results published in the JHO demonstrate that olverembatinib can effectively target CML including patients with T315I mutation and has encouraging clinical activity even in patients with drug-resistant compound mutations within the BCR-ABL1 kinase domain,signifying the drug candidate's enormous potential as an effective treatment forCML."

Prof. Yifan Zhai,Chief Medical Officer of Ascentage Pharma said,"Olverembatinib is a novel drug candidate with best-in-class potential and is also a major component of Ascentage Pharma's global innovation strategy. The publication of the Phase I/II results in the JHO signals olverembatinib's therapeutic potential in drug-resistant CML as well as Ascentage Pharma's robust R&D capabilities. We hope that olverembatinib will bring an effective and safe treatment to patients with CML globally. We remain committed to our dual mission of addressing unmet clinical needs in China and around the world. We are accelerating our global clinical development programs to benefit more patients and have also launched a Global Named Patients Program in collaboration with Tanner Pharma to make olverembatinib available to the needy patients in approximately 140 countries where the drug is not commercially available."

Highlights of the results published in the Journal of Hematology & Oncology are as follows:

Olverembatinib (HQP1351),multicenter phase 1/2 trial

Methods:

This was a multicenter,open-label Phase I/II study.

The Phase I study comprised a dose-escalation and expansion adopting a standard "3+3" design,with 11 successive cohorts of patients with TKI-resistant CML receiving orally-administered olverembatinib at increasing alternate-day (QOD) doses of 1–60 mg in 28-day cycles. The primary endpoint of the Phase I study was the recommended Phase II dose (RP2D).

The Phase II study evaluated the efficacy and safety of olverembatinib at RP2D in patients with T315I-mutated CML-CP and CML-AP. The primary endpoints of the Phase II study were major cytogenetic response (MCyR) in patients with CML-CP and major hematologic response (MaHR) in those with CML-AP.

Patient characteristics:

Between October 26,2016,and October 8,2019,165 patients were enrolled: 127 with CML-CP and 38 with CML-AP. 66.7% (110) of those patients were men. The median age was 42 (range,20–74) years,and the median interval from CML diagnosis to first olverembatinib dose was 5.7 (range,0.3–23.2) years.

More than 80% of patients had received two prior TKIs: 90 (54.5%) with two and 45 (27.3%) with three or more.

Sanger sequencing identified 61.8% patients with a single T315I mutation,15.2% with T315I and additional mutations,and 8.5% with other mutations.

Phase I study

A total of 101 patients with TKI-resistant CML were enrolled in the Phase I study between October 26,and December 12,2018. Among them,86 had CML-CP and 15 had CML-AP.

Across 11 dose cohorts (1 to 60 mg QOD) in 28-day cycles,dose-limiting toxicity (DLT) was observed at 60 mg,and the maximum tolerated dose (MTD) was 50 mg. Based on preliminary safety and efficacy results,40 mg QOD was identified as the RP2D.

PhaseII study

After determining the RP2D,two pivotal studies were initiated across 10 sites in China that enrolled 41 patients with T315I-mutated CML-CP and 23 with T315I-mutated

CML-AP,of whom more than 60% had received second-line therapies.

As of September 30,2021,the median follow-up was 34.3 (range,4.8–58.6) months,and a total of 69.0% (114) of patients remained on the treatment with olverembatinib.

- Safety

The median treatment duration was 30.7 (range,1.2–58.6) months. Frequent nonhematologic treatment-related adverse events (TRAEs) included skin hyperpigmentation in 139 (84.2%) patients,followed by hypertriglyceridemia (57.6%),proteinuria (50.9%),hyperbilirubinemia (41.8%),hypocalcemia (38.8%),and elevated liver transaminases (35.8%).

Grade 3/4 hematologic TRAEs included thrombocytopenia (51.5%),anemia (23.0%),leukopenia (20.6%),and neutropenia (11.5%). Myelosuppression tended to occur early,and most TRAEs resolved after temporary treatment suspension or supportive care (including platelet or erythrocyte transfusion or dose adjustment).

Cardiovascular events (CVEs) possibly related to olverembatinib,such as hypertension (13.3%),pericardial effusion (8.5%),were observed in 53 (32.1%) patients. 11.5% of these CVEs were Grade 3/4,including a 5% incidence of arterial occlusive and venous thrombotic events,a value that is far lower than the 31% reported with the world's first approved third-generation BCR-ABL1 inhibitor.

Except for skin hyperpigmentation and proteinuria,incidences of TRAEs decreased over time during the follow-up period. Decreased renal function was not observed in patients with persistent proteinuria. Serious AEs (SAEs; in ≥ 1% of patients) included thrombocytopenia (9.0%),anemia (6.0%),and pneumonia (3.0%),as well as pyrexia or atrial fibrillation (in 2.0% each) followed by acute myocardial infarction,cholelithiasis,pericardial effusion,upper-respiratory-tract infection,and urinary-tract infection (in 1% each). Most SAEs resolved after temporary treatment suspension or dose reduction.

- Efficacy

The median follow-up period of 126 evaluable patients with CML-CP since the start of an effective dose (≥30 mg QOD) was 37 (range,7–58) months. 100% of patients achieved a complete hematologic response (CHR [not present at baseline]). MCyR and CCyR rates were 79.3% and 69.4%,respectively. 55.6% of patients experienced a major molecular response (MMR),44.4% had MR4.0,and 38.9% showed MR4.5. Cytogenetic and molecular response rates increased over time. The cumulative 3-year incidences of MCyR,CCyR,MMR,MR4.0,and MR4.5 were 78.6%,69.0%,55.9%,43.5%,and 38.6%,respectively. Probabilities of progression-free survival (PFS) and overall survival (OS) at 3 years were 92.0% and 94.0%,respectively.

In 38 evaluable patients with CML-AP,the median duration follow-up was 27 (range,5–56) months since the onset of an effective dose. 78.4% patients had a MaHR and 73% experienced a CHR. MCyR and CCyR rates were both 47.4%; 44.7% and 36.8% of patients achieved MMR and MR4.0,respectively,and 34.2% had MR4.5. Cytogenetic and molecular response rates increased over time. The 3-year cumulative incidences of achieving MCyR,and MR4.5 were 47.4%,47.4%,44.7%,39.3%,and 32.1%,respectively. Probabilities of PFS and OS at 3 years were 60.0% and 71.0%,respectively.

Conclusions

Olverembatinib was well tolerated and exhibited robust and durable activity in patients with TKI-resistantCML-CP and CML-AP. In particular,olverembatinib was highly active against BCR-ABL1T315I mutants and demonstrated encouraging clinical activity against compound mutations.

*This is a study of an investigational drug that has not been approved in the US.

References

1. 2-Year Impact Factor (2021) as released by ClarivateTM

2. Jiang Q,Li Z,Qin Y,et al. Olverembatinib (HQP1351),multicenter phase 1/2 trial. J Hematol Oncol. Aug 18 2022;15(1):113. doi:10.1186/s13045-022-01334-z

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,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 nine 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 50 Phase I/II clinical trials in the US,Australia,Europe,and China. Olverembatinib,the company's core drug candidate developed for the treatment of drug-resistant chronic myeloid leukemia (CML),was granted Priority Review status and a Breakthrough Therapy Designation (BTD) by the Center for Drug Evaluation (CDE) of the China National Medical Products Administration (NMPA) and is already approved for the indication. In addition,olverembatinib was also granted an Orphan Drug Designation (ODD) and a Fast Track Designation (FTD) by the US FDA,and an Orphan Designation by the EU. To date,Ascentage Pharma has obtained a total of 15 ODDs,2 FTDs,and 2 Rare Pediatric Disease (RPD) designations from the FDA and 1 ODD from the EU for four of the company's investigational drug candidates. Ascentage Pharma has been designated for multiple Major National R&D Projects,including 5 National Major New Drug Discovery and Manufacturing projects,1 New Drug Incubator status,4 Innovative Drug Programs,and 1 Major Project for the Prevention and Treatment of Infectious Diseases.

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,Merck,AstraZeneca,and Pfizer. The company has built a talented team with global experience in discovering,developing,launching,and commercializing innovative drugs and is setting up 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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