On December 10, 2024 Ascentage Pharma (6855.HK), a global biopharmaceutical company engaged in discovering, developing, and commercializing therapies to address global unmet medical needs primarily for malignancies, reported that it has released the latest clinical data from a global study of its novel drug candidate, olverembatinib (HQP1351), in patients with heavily pretreated chronic myeloid leukemia (CML), in a Poster Presentation at the 66th American Society of Hematology (ASH) (Free ASH Whitepaper) Annual Meeting, taking place in San Diego, CA, the United States (Press release, Ascentage Pharma, DEC 10, 2024, View Source;1-5-year-follow-up-data-from-a-global-study-of-olverembatinib-reaffirms-potential-in-overcoming-resistanceintolerance-to-ponatinib-or-asciminib-302327550.html [SID1234649007]). Prof. Hagop Kantarjian, MD, and Prof. Elias Jabbour, MD, from the Department of Leukemia, The University of Texas MD Anderson Cancer Center, are the principal investigators of the study.

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The ASH (Free ASH Whitepaper) Annual Meeting is one of the largest gatherings of the international hematology community, bringing together the most cutting-edge scientific research and latest data of investigational therapies that represent leading scientific and clinical advances in the global hematology field. Garnering growing interest from the global research community, results from multiple clinical and preclinical studies on four of Ascentage Pharma’s drug candidates (olverembatinib, lisaftoclax, APG-2449, and APG-5918) have been selected for presentations, including two Oral Reports, at this year’s ASH (Free ASH Whitepaper) Annual Meeting. Furthermore, this is the seventh consecutive year for studies of olverembatinib to be selected for Oral Reports at the meeting.

After releasing the preliminary results from the global study of olverembatinib in an Oral Report at ASH (Free ASH Whitepaper) 2022 and the updated results from a larger patient sample at ASH (Free ASH Whitepaper) 2023, this year Ascentage Pharma presented the 1.5-year follow-up data in patients with heavily pretreated CML-CP. In the latest data, olverembatinib showed strong, durable and consistent antileukemic activity, the ability to overcome resistance/intolerance to the third-generation tyrosine kinase inhibitor (TKI) ponatinib or the allosteric STAMP inhibitor asciminib, as well as favorable tolerability in patients with heavily pretreated CML-CP.

As the first approved third-generation BCR-ABL inhibitor in China, olverembatinib has already been approved for the treatment of adult patients with tyrosine kinase inhibitor (TKI)-resistant CP-CML or accelerated-phase (AP-) CML harboring the T315I mutation; and adult patients with CP-CML resistant to and/or intolerant of first- and second-generation TKIs. In January 2024, olverembatinib was cleared by the US Food and Drug Administration (FDA) to enter a global registrational Phase III trial in previously treated adult patients with CML-CP.

Prof. Elias Jabbour commented, "Olverembatinib is a very promising next-generation TKI, and existing data demonstrate its therapeutic ability in patients with resistant/intolerant to ≥2 TKIs CP-CML and above. The high response rate that Olverembatinib has shown in Ponatinib or Asciminib failed patients is encouraging. We continue to recruit for the global Phase III trial examining this novel therapy."

Dr. Yifan Zhai, Chief Medical Officer of Ascentage Pharma, said, "The latest data from this global study further demonstrated olverembatinib’s therapeutic potential in patients with drug-resistant CML, including those who had failed prior treatment with ponatinib and asciminib, and once again underscored the drug candidate’s promise in addressing an unmet global clinical need in CML. At Present, a global registrational Phase III study of olverembatinib has been cleared by the US FDA and is already ongoing. We hope, in not too distant future, this innovative drug will become accessible to patients worldwide who are in desperate need of novel therapies. Fulfilling our founding mission of addressing unmet clinical needs in China and around the world, we will expedite the global clinical development of our key drug candidates such as olverembatinib to bring more safe and effective therapies to patients as soon as possible."

Highlights of the data this study reported at ASH (Free ASH Whitepaper) 2024 are as below:

Olverembatinib (HQP1351) Overcomes Resistance/Intolerance to Asciminib and Ponatinib in Patients (pts) with Heavily Pretreated Chronic-Phase Chronic Myeloid Leukemia (CP CML): A 1.5-Year Follow-up Update with Comprehensive Exposure-Response (E-R) Analyses

Format: Poster Presentation

Abstract#: 3151

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

Highlights:

Introduction: New treatment options are needed for patients with CP-CML resistant/intolerant to third-generation (3G) TKI ponatinib and/or asciminib, a specifically targeting the ABL myristoyl pocket (STAMP) inhibitor. Olverembatinib is a well-tolerated TKI with potential to overcome resistance. This update presents efficacy and safety data of olverembatinib in patients with heavily pretreated CP-CML.

Enrolled Patients and Study Methods:

Adults with CP-CML previously treated with ≥2 TKIs and/or a STAMP inhibitor, adequate organ function, and no major molecular response (MMR) were eligible.
As of July 28, 2024, 67 pts with CP-CML were enrolled; median (range) follow-up was 74.3 (0.1-217.1) weeks; median (range) age, 50 (21-80) years; and 38 (56.7%) patients were male.
Patients were randomly allocated to receive olverembatinib at doses of 30, 40, or 50 mg orally every other day (QOD) in 28-day cycles, with stratification based on T315I mutation status. Comprehensive E-R analyses were performed.
Efficacy Results:

No patient had efficacy at baseline. 35 of 60 (58.3%) evaluable patients achieved CCyR and 29/64 (45.3%) achieved MMR. At 12 months, the overall MMR rate was 61.4% (27/44). CCyR was achieved by 66.7% of patients with the T315I mutation vs 54.8% without it, and MMR was achieved by 50.0% vs 43.5%, respectively.
Of 28 cytogenetic response-evaluable patients with ponatinib-failed CP-CML, 15 (53.6%) achieved CCyR. The CCyR rates in patients with prior ponatinib resistance and intolerance were 52.2% (12/23) and 75.0% (3/4), respectively. In the 30 molecular response-evaluable patients who were previously treated with ponatinib, 12 (40.0%) achieved MMR, including 47.8% (11/23) of those with prior resistance and 16.7% (1/6) with intolerance. No patient above had efficacy at baseline.
In evaluable patients with asciminib treatment failure, 37.5% (6/16) achieved CCyR and 30% (6/20) achieved MMR, including a CCyR rate of 30.8% (4/13) and an MMR rate of 26.7% (4/15) in those with prior resistance, and a CCyR rate of 50.0% (1/2) and an MMR rate of 25.0% (1/4) in those with intolerance. No patient had efficacy at baseline.
Safety Results: Among 66 subjects receiving olverembatinib, a total of 62 (93.9%) reported treatment-emergent adverse events (TEAEs) of any grade, with 44 (66.7%) experiencing grade ≥ 3 TEAEs. In addition, 60 (90.9%) patients reported TRAEs of any grade. Common TRAEs (≥20%) were elevated creatine phosphokinase (37.9%), thrombocytopenia (24.2%), and increased alanine aminotransferase (22.7%).

Conclusions: Olverembatinib was well tolerated and showed strong and durable antileukemic activity in patients with heavily pretreated CP-CML. The registrational study is recruiting.