Ponatinib Hydrochloride

ROCKVILLE, Md. and SUZHOU, China, Nov. 6, 2024 /PRNewswire/ -- Ascentage Pharma (6855.HK), a global biopharmaceutical company engaged in discovering, developing, and commercializing therapies to address global unmet medical needs primarily for malignancies, today announced that multiple studies of its novel investigational drug candidate, olverembatinib (HQP1351), have been selected for presentations, including an Oral Report, at the 66th American Society of Hematology (ASH) Annual Meeting. This is the seventh consecutive year in which clinical data on olverembatinib have been selected for Oral Reports at the meeting, an achievement reflecting the strong recognition of olverembatinib's safety and efficacy profile by the international hematology community. This year, results from multiple clinical and preclinical studies on four of the company's investigational drug candidates (olverembatinib, lisaftoclax, APG-2449, and APG-5918) have been selected for presentations, including two Oral Reports, at the ASH Annual Meeting. Developed by Ascentage Pharma, olverembatinib is the first China-approved third-generation BCR:ABL1 inhibitor, currently being jointly commercialized in China by Ascentage Pharma and Innovent Biologics. At this year's ASH Annual Meeting, Ascentage Pharma will present an Oral Report featuring the latest clinical data of olverembatinib in the second-line treatment of patients with chronic-phase chronic myeloid leukemia (CP-CML), from a study led by Prof. Weiming Li, the principal investigator from Wuhan Union Hospital. Furthermore, updated data from a global multicenter study of olverembatinib and an investigational clinical study of olverembatinib in combination lisaftoclax (APG-2575), another one of Ascentage Pharma's lead drug candidates in investigation, in children with relapsed/refractory Philadelphia chromosome–positive acute lymphoblastic leukemia (R/R Ph+ ALL) will also be released in Poster Presentations at the meeting. The ASH Annual Meeting is one of the largest gatherings of the international hematology community, aggregating the latest scientific research on the pathogenesis and clinical treatment of hematologic diseases. The 66th ASH Annual Meeting will take place on December 7-10, 2024, local time, both online and in-person in San Diego, CA (United States). "For seven years in a row, clinical data of olverembatinib have been selected by the ASH Annual Meeting, setting another record in the number of consecutive years the drug is featured in Oral Reports at the meeting," said Dr. Yifan Zhai, Chief Medical Officer of Ascentage Pharma. "This reflects the strong recognition of the drug's therapeutic potential by the international hematology community. Furthermore, multiple studies of four of our investigational drug candidates have been selected for presentations at the meeting this year, underscoring Ascentage Pharma's robust capabilities in global innovation and investigational clinical development. We are eager to share detailed data at the event. Moving forward, we will continue to accelerate our clinical development programs in efforts to bring more treatment options to patients as soon as possible." An overview of presentations featuring Ascentage Pharma's drug candidates at ASH 2024: Major study abstracts on olverembatinib selected for presentations at the 2024 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) Oral Presentation Olverembatinib as Second-Line (2L) Therapy in Patients (pts) with Chronic Phase-Chronic Myeloid Leukemia (CP-CML) Format: Oral Presentation Abstract#: 480 Session: 632. Chronic Myeloid Leukemia: Novel Molecules in Clinical Practice Time: Sunday, December 8, 2024; 9:30 AM - 11:00 AM First Author: Prof. Weiming Li, Department of Hematology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology Highlights: Background: Olverembatinib, a third-generation tyrosine kinase inhibitor (TKI), has demonstrated remarkable efficacy and a favorable safety profile in patients with CML resistant and/or intolerant to at least 2 TKIs or with the T315I mutation. The aim of this study was to assess the efficacy and safety of olverembatinib as a second-line treatment for patients with CP-CML without the T315I mutation. Introduction: This is a single-arm, multicenter, open-label study designed to evaluate the efficacy, safety, and patients' quality of life of orally administered olverembatinib (40 mg QOD) in patients with CP-CML who were resistant/intolerant to one prior line of TKIs (including imatinib, flumatinib, nilotinib, and dasatinib) without the T315I mutation. Enrolled Patients and Study Methods: As of July 29, 2024, the study enrolled a total of 42 patients with non–T315I-mutant CML-CP. These patients received orally administered olverembatinib 40 mg every other day (QOD) in 28-day cycles. Efficacy Results: As of July 29, 2024, 33 (78.6%) patients had at least one efficacy assessment, 28 (66.7%) had at least two, 23 (54.8%) had at least three. Three patients had not yet undergone their first efficacy assessment. At data cutoff, 75.0% (24/32) of patients achieved a complete cytogenetic response (CCyR) and 40.6% (13/32) achieved a major molecular response (MMR). The CCyR and MMR rates evaluated at the end of Cycles 6, 9, 12, and 18 were 53.4% and 28.6%, 64.8% and 32.5%, 69.1% and 32.5%, and 77.7% and 43.9%, respectively, suggesting that efficacy improved over time. In 32 efficacy-evaluable patients, 23 were pretreated with second-generation TKIs as first-line treatment, of whom 19 (82.68%) achieved CCyR, and 10 (43.5%) achieved MMR. In 9 patients who were pretreated with imatinib, 5 achieved CCyR (55.6%) and 3 achieved MMR (33.3%). Safety Results: The median (range) treatment duration was 16.0 (1-18) months. A total of 37 (88.1%) patients experienced any-grade treatment-related adverse events (TRAEs), of whom 19 (45.2%) had grade ≥ 3 treatment-related adverse events (TRAEs) and 5 (11.9%) had olverembatinib-related serious AEs (SAEs). Nonhematologic TRAEs included skin hyperpigmentation (38.1%), hyperuricemia (23.8%), and creatine phosphokinase increased (21.4%). Most of these TRAEs were grade 1 or 2. Grade ≥ 3 hematologic toxicities included platelet count decreased (38.1%), neutropenia (21.4%), and anemia (7.1%). Possibly olverembatinib-related any-grade cardiovascular events included hypertension (4.8%) and atrial tachycardia (2.4%), all of which were grade 1 or 2. Olverembatinib-related SAEs included platelet count decreased (7.1%), anemia, myelosuppression, and pyrexia (2.4% each). No deaths were reported. Conclusions: Olverembatinib may provide an effective and safe second-line treatment option for patients with CP-CML, especially those who have failed on second-generation TKIs in the first-line setting. Poster Presentations 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 Time: Sunday, December 8, 2024; 6:00 PM - 8:00 PM First Author: Dr. Elias Jabbour, Department of Leukemia, The University of Texas MD Anderson Cancer Center 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. CCyR and MMR rates in patients previously treated with both ponatinib and asciminib were 30% and 25%, respectively. 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. Safety and Efficacy of Olverembatinib (HQP1351) Combined with Lisaftoclax (APG-2575) in Children and Adolescents with Relapsed/Refractory Philadelphia Chromosome–Positive Acute Lymphoblastic Leukemia (R/R Ph+ ALL): First Report from a Phase 1 Study Format: Poster Presentation Abstract#: 1443 Session: 613. Acute Lymphoblastic Leukemias: Therapies Excluding Allogeneic Transplantation: Poster I Time: Saturday, December 7, 2024; 5:30 PM - 7:30 PM First Author: Prof. Jingliao Zhang, Institute of Hematology and Blood Diseases Hospital, Chinese Academy of Medical Sciences Highlights ： Background: Olverembatinib, a novel third-generation TKI, is well tolerated and exerts strong and durable antileukemic activity in patients with heavily pretreated CP-CML with or without the T315I mutation. Investigational lisaftoclax, a novel Bcl-2 inhibitor, has shown clinical antitumor benefits in patients with multiple hematologic malignancies. Currently, there are no effective treatment options available for pediatric patients with R/R Ph+ ALL. This study was designed to explore the safety, efficacy, and pharmacokinetic (PK) profile of olverembatinib alone or combined with lisaftoclax in children and adolescents with R/R Ph+ ALL. Methods: This was an open-label, Phase Ib study that enrolled children and adolescents aged < 18 years with R/R Ph+ ALL resistant or intolerant to at least 1 TKI (prior use of TKIs was not considered if patients had T315I mutation). Patients were required to have adequate Karnofsky/Lansky performance status score and organ function. Patients with symptomatic central nervous system disorders or significant bleeding, which were unrelated to Ph+ ALL, were excluded. Olverembatinib was administered orally at 40 mg adult equivalent dose (AED) every other day for 2 weeks (Days [D] 1-14), followed by the same dose of olverembatinib in combination with lisaftoclax at an assigned dose of 200/400/600 mg (AED) daily (QD) on D13-42 (a 3-day dose ramp-up from D13-15 was needed). Dexamethasone at 6 mg/m2/day was administered orally QD from D15-42. The primary endpoints included safety assessments, overall response rate (ORR), measurable residual disease (MRD) negativity rate, and pharmacokinetic (PK) characteristics of olverembatinib alone or in combination with lisaftoclax. Patient Enrollment: From September 2022 to June 2024, a total of 10 patients were enrolled. The median (range) age was 13.0 (11-15) years, and 6 patients were male. The median (range) body weight was 49.85 (35.9-86.0) kg. Nine (90.0%) patients expressed the p190 transcript, and 1 patient (10.0%) expressed the p210 transcript. Three patients harbored BCR::ABL1 mutations [2, T315I; 1, F317L (c.951C>A)] at baseline. After 1 patient discontinued from the trial because of seizure on D1 of Course 1 (C1D1), 9 eligible patients were included in the 3+3 dose escalation model (n = 6, R/R; n = 3, intolerant): 3 patients in each Arm (A, B, and C) at assigned lisaftoclax dose levels of 200, 400, and 600 mg (AED), respectively. These patients completed 42 days of treatment and were assessed for the primary endpoints. Efficacy Results: Among 6 patients evaluable for morphologic responses, 2 patients achieved complete responses with incomplete count recovery (CRis), 2 achieved partial responses (PRs) at the end of olverembatinib monotherapy (EOM), resulting in an overall response rate (ORR) of 66.7%; and 5 (83.3%) patients achieved CRis at the end of olverembatinib and lisaftoclax combination course (EOC). In the 7 patients who were evaluable for molecular responses, 5 (71.4%) achieved MRD negativity, of which 1 was at EOM and 4 at EOC. Safety Results: 6 of 10 patients experienced grade ≥ 3 hematologic TEAEs, including anemia (3/10), neutropenia (7/10), and thrombocytopenia (3/10); 1 patient had grade 3 alanine aminotransferase increase leading to treatment discontinuation, and 1 patient discontinued the trial after experiencing a seizure at C1D1. PK Analyses: Preliminary PK analyses revealed similar PK characteristics and comparable exposure between pediatric and adult populations for olverembatinib and lisaftoclax. There was no significant accumulation after multiple doses, and no drug-drug interactions were observed between olverembatinib and lisaftoclax. Conclusions: These preliminary data showed that olverembatinib in combination with lisaftoclax appears to be a safe and effective regimen in pediatric patients with R/R Ph+ ALL. This regimen resulted in a promising CR rate of 83.3% and MRD negativity rate of 71.4% without intensive chemotherapy or immunotherapy. The study is currently in the dose-expansion phase. * Olverembatinib is an investigational drug that has not been approved for any indication outside China; lisaftoclax (APG-2575), APG-2449 and APG-5918 are investigational drugs that have not been approved in any country and region. About Ascentage Pharma Ascentage Pharma (6855.HK) is a global, integrated biopharmaceutical company engaged in discovering, developing, and commercializing therapies to address global unmet medical needs primarily in malignancies. 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. The company has built a rich pipeline of innovative drug candidates that includes 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 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 has conducted more than 40 clinical trials in the US, Australia, Europe, and China, including 13 registrational studies (completed/ ongoing/planned). Olverembatinib, the company's first lead asset developed for the treatment of drug-resistant chronic myeloid leukemia (CML) and the company's first approved product in China, 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 National Reimbursement Drug List (NRDL). Furthermore, olverembatinib has been granted Orphan Drug Designations (ODDs) 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 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 and other relationships with numerous leading biotechnology and pharmaceutical companies such as Takeda, AstraZeneca, Merck, Pfizer and Innovent; and research and development relationships with leading research institutions such as Dana-Farber Cancer Institute, Mayo Clinic, MD Anderson Cancer Center, National Cancer Institute and the University of Michigan. The company has built a talented team with a wealth of global experience in the discovery and development of innovative drugs and fully functional 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. Forward-Looking Statements The forward-looking statements made in this article relate only to the events or information as of the date on which the statements are made in this article. Except as required by law, Ascentage Pharma undertakes no obligation to update or revise publicly any forward-looking statements, whether as a result of new information, future events, or otherwise, after the date on which the statements are made or to reflect the occurrence of unanticipated events. You should read this article completely and with the understanding that our actual future results or performance may be materially different from what we expect. In this article, statements of, or references to, our intentions and expectations or those of any of our Directors or our Company are made as of the date of this article. Any of these intentions and expectations may alter in light of future development. 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亚盛医药（6855.HK）今日宣布，公司原创1类新药奥雷巴替尼（商品名：耐立克®）有多项临床进展获选第66届美国血液学会（American Society of Hematology，ASH）年会，其中1项获口头报告。这是该品种的临床进展连续第7年入选ASH年会口头报告，充分体现国际血液学界对其疗效和安全性的认可。值得一提的是，今年，公司四个品种（耐立克®、APG-2575、APG-2449、APG-5918）有多项临床和临床前进展入选ASH年会展示及报告，并获两项口头报告。 耐立克®是亚盛医药自主研发的全球层面best-in-class潜力药物，为中国首个获批上市的第三代BCR:ABL抑制剂，该品种在中国的商业化推广由亚盛医药和信达生物共同负责。公司将在此次ASH年会上，口头报告其用于慢性期慢性髓细胞白血病（CP-CML）患者二线治疗的研究最新进展，该研究主要研究者为武汉协和医院黎纬明教授。此外，耐立克®海外临床研究的最新进展、以及该品种联合公司另一重磅品种Bcl-2抑制剂APG-2575（lisaftoclax）治疗复发/难治性（R/R）费城染色体阳性急性淋巴细胞白血病（Ph+ ALL）儿童患者的研究数据也将以壁报展示形式公布。 一年一度的ASH年会是全球血液学领域规模最大的国际学术盛会之一，全面涵盖了血液疾病的病因研究和治疗研究。第66届ASH年会将于当地时间2024年12月7日至10日间在美国圣地亚哥以线下结合线上的形式举行。 翟一帆博士 亚盛医药首席医学官 “今年将是耐立克®连续第7年在ASH年会上展示最新临床进展，又一次刷新其口头报告连续入选记录，体现了国际血液学界对耐立克®这一全球层面best-in-class潜力药物的巨大认可。此外，今年，公司四个重点品种有多项进展入选ASH年会展示及报告，充分显现了公司的全球创新和开发实力。我们期待在后续会议期间与大家分享相关研究的详实数据。未来，亚盛医药将进一步加速推进临床开发，早日为患者带来更多治疗选择。” ASH 2024亚盛医药产品相关研究一览： 耐立克®入选2024 ASH年会的主要研究摘要如下：（APG-2575入选ASH年会的摘要详细信息参见同期发布的另一篇新闻稿） 口头报告 Olverembatinib as Second-Line (2L) Therapy in Patients (pts) with Chronic Phase-Chronic Myeloid Leukemia (CP-CML) 奥雷巴替尼用于慢性期慢性髓细胞白血病（CP-CML）患者的二线治疗 展示形式：口头报告 摘要编号：480 分会场：632. 慢性髓细胞白血病：新型药物的临床应用 报告时间： 2024年12月8日，星期日，上午9:30 - 11:00（美国西部时间） 2024年12月9日，星期一，凌晨1:30 – 3:30（北京时间） 第一作者：武汉协和医院 黎纬明教授 核心要点： 研究背景：奥雷巴替尼是第三代酪氨酸激酶抑制剂（TKI），在耐药和（或）不耐受至少2种TKI或伴有T315I突变的CML患者中显示出突出的疗效和良好的安全性。本研究旨在评估奥雷巴替尼二线治疗无T315I突变的CP-CML患者的疗效和安全性。 研究介绍：这是一项针对既往使用过一种TKI治疗后耐药或不耐受（包括伊马替尼、氟马替尼、尼洛替尼及达沙替尼等）的CML-CP患者的开放性、单臂、多中心临床研究，旨在评估隔日口服40mg奥雷巴替尼在一种TKI治疗耐药/不耐受的非T315I 突变CML-CP患者中的疗效、安全性及患者生活质量。 入组患者和研究方法：截至2024年7月29日，共入组非T315I 突变的CML-CP 患者42例。奥雷巴替尼采用隔日给药（QOD）的方式，28天为一个周期。 疗效数据： 截至2024年7月29日，33例（78.6%）患者接受了至少1次疗效评估，28例（66.7%）接受了至少2次疗效评估，23例（54.8%）接受了至少3次疗效评估。3例患者尚未进行首次疗效评估。 至截止日期，75.0%（24/32）的患者获完全细胞遗传学反应（CCyR），40.6%（13/32）获主要分子学反应（MMR）。第6、9、12、18个周期评估的CCyR率和MMR率分别为53.4%和28.6%、64.8%和32.5%、69.1%和32.5%、77.7%和43.9%，提示疗效随用药时间延长而改善。 在32例疗效可评估的患者中，有23例曾以第二代TKI作为一线治疗，其中19例（82.68%）获CCyR，10例（43.5%）获MMR；在既往接受伊马替尼治疗的9例患者中，5例获CCyR（55.6%)，3例获MMR（33.3%）。 安全性数据：中位（区间）治疗时间16.0（1 ~ 18）个月。共有37例（88.1%）患者发生了任何级别的治疗相关不良事件（TRAEs），其中19例（45.2%）发生了≥3级TRAEs，5例（11.9%）发生了与奥雷巴替尼相关的严重不良事件（SAEs）。非血液学TRAEs包括皮肤色素沉着（38.1%）、高尿酸血症（23.8%）和肌酸磷酸激酶升高（21.4%）。TRAE多为1 ~ 2级。≥3级血液学不良反应包括血小板减少（38.1%）、中性粒细胞减少（21.4%）和贫血（7.1%）。与奥雷巴替尼可能相关的任何级别心血管事件包括高血压（4.8%）和房性心动过速（2.4%），所有这些事件均为1级或2级。奥雷巴替尼相关SAEs包括血小板计数减少（7.1%）、贫血、骨髓抑制和发热（各2.4%）。无死亡报告。 结论：奥雷巴替尼可能为二线CP-CML患者提供一种安全有效的治疗选择，尤其是对于一线使用二代 TKIs治疗失败的患者。 壁报展示 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 奥雷巴替尼（HQP1351）可克服经深度治疗的慢性期慢性髓细胞白血病（CP CML）患者对Asciminib和Ponatinib的耐药/不耐受：来自1.5年随访的最新数据及综合暴露-反应（E-R）分析 展示形式：壁报展示 摘要编号：3151 分会场：632. 慢性髓细胞白血病：临床及流行病学研究：壁报展示II 报告时间： 2024年12月8日，星期日，下午6:00 - 8:00（美国西部时间） 2024年12月9日，星期一，上午10:00 - 12:00（北京时间） 第一作者：MD安德森癌症中心（MD Anderson Cancer Center） Elias Jabbour教授 核心要点： 研究介绍：对第三代（3G）TKI Ponatinib和/或Asciminib（一种特异性靶向ABL 肉豆蔻酰 （STAMP）的抑制剂）耐药/不耐受的CP-CML患者亟需新的治疗选择。奥雷巴替尼是一种耐受性良好的TKI，具有克服其他TKI耐药的潜力，本次更新介绍了奥雷巴替尼在反复经治的CP-CML患者中的疗效和安全性数据。 入组患者和研究方法： 入组条件为既往接受过≥2种TKIs和/或一种STAMP抑制剂治疗、入组时器官功能良好、且既往治疗未达到MMR的成人CP-CML患者。 截至2024年7月28日，共有67例CP-CML患者入组，中位（范围）随访时间为74.3（0.1-217.1）周；中位（范围）年龄为50（21-80）岁；其中38 （56.7%）例患者为男性。 这些患者被随机分配到奥雷巴替尼治疗组，隔天口服一次(QOD)，28天为一个周期，剂量为30,40或50mg。同时根据T315I突变状态进行分层，并进行全面的E-R分析。 疗效数据： 共60例患者疗效可评估，所有患者均为基线时无疗效。其中35例（58.3%）患者入组治疗后达到CCyR，29/64（45.3%）例达到MMR。12个月时，整体MMR率为61.4%（27/44），其中T315I突变患者的CCyR率为66.7%，而没有T315I突变患者的CCyR率为54.8%，MMR率分别为50.0%和43.5%。 在28例Ponatinib治疗失败的细胞遗传学反应可评估的CP-CML患者中，有15例（53.6%）达到CCyR，23例既往Ponatinib耐药患者的CCyR率为52.2%（12/23），4例既往Ponatinib不耐受患者的CCyR率为75.0%（3/4）。30例先前接受过Ponatinib治疗的分子学缓解可评估患者中，共有40.0%（12/30）达到MMR，其中23例既往Ponatinib耐药患者的MMR率为47.8%（11/23），既往6例Ponatinib不耐受患者的MMR率为16.7%（1/6）, 所有患者均为基线时无疗效。 在Asciminib治疗失败的可评估患者中，37.5%（6/16）达到CCyR，30%（6/20）达到MMR，其中既往Asciminib耐药的患者的CCyR率为30.8%（4/13）、MMR率为26.7%（4/15）；既往Asciminib不耐受患者的CCyR率为50.0%（1/2 )，MMR率为25.0%（1/4) ，所有患者均为基线时无疗效。 先前同时接受过Ponatinib和Asciminib治疗患者的CCyR率和MMR率分别为30%和25%，所有患者均为基线时无疗效。 安全性数据：在66例患者中，62（93.9%）例报告了任何级别的治疗期间出现的不良事件（TEAEs），其中44（66.7%）例经历了≥3级的TEAEs。共60（90.9%）例报告了任何级别的与治疗相关的不良事件（TRAEs），常见TRAEs（发生率≥20%）为肌酸激酶升高（37.9%）、血小板减少（24.2%）和谷丙转氨酶升高（22.7%）。 结论：奥雷巴替尼耐受性良好，在反复经治的CP-CML患者中显示出显著而持久的抗白血病活性。目前注册III期研究正在招募中。 Safety and Efficacy of Olverembatinib (HQP1351) Combined with Lisaftoclax (APG-2575) in Children and Adolescents with Relapsed/Refractory Philadelphia Chromosome–Positive Acute Lymphoblastic Leukemia (R/R Ph+ ALL): First Report from a Phase 1 Study 奥雷巴替尼（HQP1351）联合Lisaftoclax（APG-2575）治疗复发/难治性费城染色体阳性急性淋巴细胞白血病（R/R Ph+ ALL）儿童及青少年患者的安全性和疗效：一项I期临床研究的首次报告。 展示形式：壁报展示 摘要编号：1443 分会场：613. 急性淋巴细胞白血病：同种移植以外的疗法：壁报展示I 报告时间： 2024年12月7日，星期六，下午5:30 - 7:30（美国西部时间） 2024年12月8日，星期日，上午9:30 - 11:30（北京时间） 第一作者：中国医学科学院血液病医院 张婧嫽教授 核心要点： 研究背景：奥雷巴替尼是新型三代TKI，具有良好耐受性，并在已接受深度治疗的CP-CML患者中（无论是否有T315I突变）表现出强大且持久的抗白血病活性。Lisaftoclax是一种新型Bcl-2抑制剂，在多种血液恶性肿瘤中显示出抗肿瘤效果。目前，R/R Ph+ ALL儿童患者尚无有效治疗选择。本研究旨在探索奥雷巴替尼单药或联合Lisaftoclax在R/R Ph+ ALL儿童患者中的安全性、有效性及药代动力学（PK）特征。 研究方法： 这是一项开放标签的Ib期研究，入组的为年龄小于18岁的R/R Ph+ ALL儿童患者，这些患者对至少一种TKI耐药或不耐受（如果患者携带T315I突变，则不考虑既往TKI使用情况）。患者需具备足够的Karnofsky/Lansky功能状态评分和器官功能。患有与Ph+ ALL无关的症状性中枢神经系统疾病或显著出血的患者被排除在外。 奥雷巴替尼以成人等效剂量（AED）40 mg口服，隔日一次，持续2周（第1-14天）。然后同剂量的奥雷巴替尼联合Lisaftoclax，后者的指定剂量为200/400/600 mg（AED），每日一次（QD），第13-42天（第13-15天需3天剂量递增）。地塞米松以6 mg/m²/天的剂量从第15-42天每日口服一次。主要终点包括奥雷巴替尼单药/联合APG-2575的安全性评估、总反应率（ORR）、可测量的残留疾病（MRD）阴性率、以及PK特征。 入组情况：从2022年9月至2024年6月，共入组了10例患者。中位年龄（范围）为13.0（11-15）岁，其中6例为男性。中位体重（范围）为49.85（35.9-86.0）kg。9例（90.0%）患儿表达p190转录本；1例（10.0%）表达p210转录本。基线时，3例患儿携带BCR-ABL1突变，包括2例T315I突变和1例F317L突变。1例患儿因在第1疗程第1天（C1D1）发生癫痫而退出试验，9例患儿被纳入3+3剂量递增模型：每组（A、B和C组）各3例患儿，分别接受200、400和600 mg（AED）指定剂量的Lisaftoclax。这些患儿完成了42天的治疗，并接受了主要终点评估。 疗效数据：在6例形态学反应可评估的患儿中，在奥雷巴替尼单药治疗结束时（EOM），2例达到CR伴不完全血细胞恢复（CRi），2例达到部分缓解（PR），ORR为66.7%；在奥雷巴替尼和Lisaftoclax联合治疗结束时（EOC），5例（83.3%）达到完全缓解（CR）；在7例分子学可评估的患儿中，有5（71.4%）例达到了MRD阴性，其中1例在EOM达到，4例在EOC达到。 安全性数据：10例患儿中有6例经历了≥ 3级的血液学治疗期间出现的不良事件，包括贫血（3/10）、中性粒细胞减少（7/10）和血小板减少（3/10）；1例患儿因3级丙氨酸氨基转移酶升高而停止治疗，另1例患儿在第1疗程第1天（C1D1）发生癫痫并退出试验。 PK：初步PK分析显示，奥雷巴替尼和Lisaftoclax在儿童和成人中具有相似的PK特征和可比的药物暴露，经过多次给药后未见显著蓄积。且奥雷巴替尼和Lisaftoclax之间未观察到药物相互作用。 结论：初步数据表明，奥雷巴替尼联合Lisaftoclax为R/R Ph+ ALL患儿提供了一种安全且有效的治疗选择。该方案在无需强化疗或免疫治疗的情况下，实现了83.3%的CR率和71.4%的MRD转阴率。目前，该研究正处于剂量扩展阶段。 关于亚盛医药 亚盛医药是一家综合性的全球生物医药企业，致力于研发创新药，以解决肿瘤等领域全球患者尚未满足的临床需求。2019年10月28日，公司在香港联交所主板挂牌上市，股票代码：6855.HK。 亚盛医药已建立丰富的创新药产品管线，包括抑制Bcl-2、IAP 或 MDM2-p53 等细胞凋亡通路关键蛋白的抑制剂；新一代针对癌症治疗中出现的激酶突变体的抑制剂等，为全球唯一在细胞凋亡通路关键蛋白领域均有临床开发品种的创新公司。目前公司已在中国、美国、澳大利亚及欧洲开展40多项临床试验，其中包括13项注册临床研究（已完成/进行中/拟启动）。 用于治疗慢性髓细胞白血病的核心品种耐立克®曾获中国国家药品监督管理局新药审评中心（CDE）纳入优先审评和突破性治疗品种，并已在中国获批，是公司的首个上市品种。目前，耐立克®已被成功纳入《国家基本医疗保险、工伤保险和生育保险药品目录》。该品种还获得了美国FDA快速通道资格、孤儿药资格认定以及欧盟孤儿药资格认定。 截至目前，公司共有4个在研新药获得16项FDA和1项欧盟孤儿药资格认定，2项FDA快速通道资格以及2项FDA儿童罕见病资格认证。凭借强大的研发能力，亚盛医药已在全球范围内进行知识产权布局，并与武田、默沙东、阿斯利康、辉瑞、信达等领先的生物制药公司，以及MD安德森癌症中心（MD Anderson Cancer Center）、梅奥医学中心（Mayo Clinic）、丹娜法伯癌症研究院（Dana-Farber Cancer Institute）、美国国家癌症研究所（NCI）和密西根大学等学术机构达成全球合作关系。 亚盛医药已构建在原创新药研发与临床开发领域经验丰富的国际化人才团队，以及成熟的商业化生产与市场营销团队。亚盛医药将不断提高研发能力，加速推进公司产品管线的临床开发进度，真正践行"解决中国乃至全球患者尚未满足的临床需求"的使命，以造福更多患者。 前瞻性声明 本文所作出的前瞻性陈述仅与本文作出该陈述当日的事件或资料有关。除法律规定外，于作出前瞻性陈述当日之后，无论是否出现新资料、未来事件或其他情况，我们并无责任更新或公开修改任何前瞻性陈述及预料之外的事件。请细阅本文，并理解我们的实际未来业绩或表现可能与预期有重大差异。本文内所有陈述乃本文章刊发日期作出，可能因未来发展而出现变动。