On October 17, 2023 Ascentage Pharma (6855.HK), a global biopharmaceutical company engaged in developing novel therapies for cancer, chronic hepatitis B (CHB), and age-related diseases, reported that the registrational Phase III study (HQP1351AG301, NCT06051409) of olverembatinib, Ascentage Pharma’s lead drug candidate, combined with chemotherapy, versus imatinib combined with chemotherapy in treatment-naïve patients with Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL) has dosed its first patient (Press release, Ascentage Pharma, OCT 17, 2023, View Source [SID1234636083]). As a global best-in-class drug, olverembatinib holds the promise of becoming the first tyrosine kinase inhibitor (TKI) approved in China for the first-line treatment of Ph+ ALL.
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This global multi-center, randomized-controlled, open-label, registrational Phase III study (HQP1351AG301) is designed to evaluate the efficacy and safety of olverembatinib combined with chemotherapy versus imatinib combined with chemotherapy in newly-diagnosed patients with Ph+ ALL.
Accounting for 20%-30% of all ALL cases in adults, Ph+ ALL is commonly associated with a high relapse rate, short progression-free survival, and poor prognosis. Prior to the introduction of TKIs, a class of targeted small molecule compounds, allogeneic hematopoietic stem cell transplantation (allo-HSCT) after achieving complete responses (CRs) from chemotherapy was widely adopted as a first-line treatment for patients with Ph+ ALL. However, the five-year overall survival (OS) was only less than 30% and more than 70% patients relapsed before the transplantation or simply lacked access to the surgical treatment[1].
The clinical adoption of TKIs has resulted in a new clinical paradigm for patients with Ph+ ALL. However, first and second-generation TKIs have known clinical limitations, including high relapse rates and disappointing long-term survival with a three to five-year OS rate of just about 50%[2]. These limitations are primarily caused by low complete molecular responses (CMRs) and T315I kinase domain mutations, thus leaving substantial room for improvement in the treatment of Ph+ ALL. Currently, no TKI has been approved for the first-line treatment of Ph+ ALL in China and third-generation TKIs with more potent efficacy can potentially provide better prognosis to patients with Ph+ ALL by inducing a higher rate of CMRs and inhibiting the T315I mutation.
Ascentage Pharma’s novel drug candidate, olverembatinib, is an orally-administered third-generation TKI and the first and only China-approved third-generation BCR-ABL inhibitor. Currently, olverembatinib is being jointly commercialized by Ascentage Pharma and Innovent Biologics. In November 2021, Olverembatinib was approved by the Center for Drug Evaluation (CDE) of the China National Medical Products Administration (NMPA) 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. Previously, olverembatinib received a recommendation from the Chinese Society of Clinical Oncology (CSCO) Guidelines for the Diagnosis and Treatment Hematologic Malignancies as a treatment option for patients with Ph+ ALL.
(Olverembatinib is an investigational drug that has not been approved for any indication outside the Chinese mainland)
Prof. Weili Zhao, Vice President of Shanghai Jiaotong University School of Medicine Affiliated Ruijin Hospital and Director of Shanghai Institute of Hematology, commented, "Ph+ ALL used to be the most high-risk and difficult-to-treat subtype of leukemia and the introduction of TKIs has resulted in improved prognosis to patients with this condition. However, clinicians face the pressing question of which TKI offers the best efficacy and safety. We hope HQP1351AG301, a clinical study evaluating olverembatinib, a China-developed next-generation TKI, can provide an answer to those important questions."
Prof. Suning Chen, Deputy Director of the Hematology Department, the First Affiliated Hospital of Soochow University and Deputy Director of Jiangsu Institute of Hematology, noted, "Since its launch, olverembatinib showed excellent efficacy in patients with Ph+ ALL. We are very hopeful for the results from the HQP1351AG301 trial, as it is the first registrational clinical study for the first-line treatment of patients with Ph+ ALL."
Prof. Yang Shen, Deputy Director of the Hematology Department at Shanghai Jiaotong University School of Medicine Affiliated Ruijin Hospital, commented, "Olverembatinib has already been approved for the treatment of chronic myeloid leukemia in China. The HQP1351AG301 trial evaluates olverembatinib in Ph+ ALL, a potential additional indication in which olverembatinib has already showed promising therapeutic utility according to existing real-world data. We hope olverembatinib will offer a new treatment option to patients with Ph+ ALL."
Dr. Yifan Zhai, Chief Medical Officer of Ascentage Pharma, said, "At present, the long-term survival rate of patients with Ph+ ALL remains disappointing, thus leaving considerable room for improvement. Multiple studies have shown that more potent third-generation TKIs can offer durable responses and a higher survival rate to patients with Ph+ ALL, yet no TKIs have been approved for the first-line setting in China. We are glad that this registrational Phase III study of olverembatinib, a TKI that could potentially become the first one approved in China for the first-line treatment of Ph+ ALL, has successfully enrolled and dosed its first patient. Moving forward, we will actively advance this clinical program and try to bring this drug to market as soon as possible for the benefit of more patients."