Venetoclax

北京 2025年8月27日 /美通社/ -- 近日，由 陆道培分子医学团队发起并主导 ，南昌大学第一附属医院、中山大学附属第一医院等 34家署名机构 ，共 71名专家 合作完成的一项研究成果，在国际血液学 知名期刊 《 Blood》 在线发表。该研究首次系统揭示了在人群中广泛携带的小细环病毒（TTMV）将其基因组片段整合至人基因组，导致病毒基因与人维甲酸受体（RARA）基因融合，引发急性早幼粒细胞白血病（APL）的病毒流行病学、临床特征和关键分子致病机制。 该研究成果标志着白血病病毒病因学领域的一项重要进展，扩展了我们对白血病致病机制的新认识， 对这一组新发现的白血病的正确诊断和治疗有直接的帮助 ，也为未来针对性的诊断技术和治疗方案的优化提供了新的方向。 APL通常由PML::RARA融合基因驱动。由于中国专家的卓越贡献，已经使经典型的PML::RARA-APL由最凶险的白血病成为首个可以通过无化疗（全反式维甲酸ATRA+砷剂）为主的治疗获得超过 90% 治愈率的白血病类型。然而，近年来研究发现，在人群中广泛携带的TTMV病毒，也可在特定情况下导致APL，即TTMV::RARA-APL，但其临床与生物学特性和发病机制一直未被揭示。 自TTMV::RARA-APL被报道以来，陆道培分子医学团队一直着力于这一种新发现的白血病的实验诊断、临床特征和分子机制研究，并发起和组织涵盖由30多家单位的70多名专家参与的多中心协作网络。 本次发表的研究成果共纳入了来自多中心的 29例TTMV::RARA-APL患者 ，结合陆道培医院的白血病队列数据，系统揭示了这一组疾病的：临床流行病学特征、实验室检查、临床表现和治疗反应特点；通过病毒序列和进化分析，初步揭示了具有致白血病风险的TTMV毒株的序列和流行病学特征；通过基因组分析和实验验证，解析了从病毒基因片段整合到融合蛋白致病的关键分子机制； 基于这些发现，首次绘制出 TTMV导致APL的 "分子致病机制模型" 。 （病毒流行病学特征及主要分子机制） 01临床流行病学和疾病特点 TTMV::RARA-APL患者的细胞形态、免疫表型均与经典型PML::RARA-APL相近。但TTMV::RARA-APL主要发生于儿童，并且是继 PML::RARA之后第二常见的 RAR 融合类型。临床主要特征：13.8%（4/29）的患者以髓系肉瘤发病，6.9%（2/29）的患者以髓系肉瘤+APL发病，有更高的骨髓坏死、CNSL和髓外病变发生率；部分患者可通过ATRA+ATO为主的治疗或化疗获得长期缓解，但总体早期复发率较高，易发生ATRA和化疗继发耐药。部分患者对维奈克拉联合方案显示出良好疗效（10/12），造血干细胞移植对部分患者有益，但整体预后仍需更多探索。76.9%的患者伴有表观遗传调控基因突变（如ARID1A/B、TRRAP、HIST1H1B/C等），32.0% 的患者有累及 17q10/TP53缺失的核型异常；24%的患者有 7q22 异常。 02病毒流行病学分析 通过对患者来源TTMV序列与全球数据库比对，发现：大部分APL相关的TTMV病毒株不属于已定义的38个TTMV种，属于尚未被定义的病毒种；儿童与成人患者的病毒株分布存在差异，提示可能存在复杂的病毒-宿主互作机制。 03病毒导致白血病的分子机制 本研究发现，TTMV的基因组片段以微同源重组机制整合到人基因组中，整合位点始终位于RARA基因内含子2。不同患者中整合的TTMV基因组片段长度不一，均未包括完整的TTMV基因组。本研究明确了TTMV的核心整合区域：包括病毒启动子区和ORF2的N端，约510 ~ 610 bp的连续序列。并进一步明确病毒启动子中通过RUNX1结合基序劫持髓系原始细胞优势表达的 RUNX1 来启动融合基因的表达，同时解释了致病毒株的髓系细胞的趋向性。TTMV::RARA融合蛋白最少需保留TTMV-ORF2的N端56个氨基酸，介导形成同源三聚体。TTMV::RARA融合蛋白可被ATRA部分降解，对ATRA有剂量依赖性响应，但其转录激活能力弱于野生型RARA。已在临床病例中观察到，这些患者虽然初诊时通常对ATRA和其他化疗有治疗反应，但易快速累积耐药突变。 04展望 TTMV::RARA-APL的发现提醒我们：对形态疑似APL但PML::RARA阴性患者，尤其是儿童，应筛查TTMV::RARA；由于常规融合基因的分析不包含分析病毒序列，导致该类融合基因的分析困难，因此很多病例未被正确诊断。这提示临床医生在面对疑似 APL 但未检测到常见融合基因的病例时，应提高警惕，进行进一步检测分析。 该研究不仅为TTMV::RARA-APL的临床管理提供依据，也为病毒介导的白血病发生机制研究提供了范例，未来有望推动针对病毒整合环节的干预策略或免疫治疗开发。 这项具有里程碑意义的研究由陆道培分子医学团队发起和主导，共有来自全国34个署名机构的71名专家参与。该研究体现了中国血液学专家的团队合作精神，也进一步加强了我国在精准血液病诊疗与病毒肿瘤学领域的国际影响力。 陆道培分子医学团队周晓苏博士、陈佳琦博士和中山大学附属第一医院唐燕来医师是论文的共同第一作者，陆道培医院陆佩华院长、陆道培血液病研究院刘红星院长是论文的共同通讯作者。 - 作者简介- 周晓苏 博士 北京陆道培血液病研究院精准医学中心，细胞生物学实验室负责人 中国医学科学院博士后；中国海洋大学博士博士后出站后加入陆道培分子医学团队，主要从事血液肿瘤和免疫治疗相关的免疫微环境研究及分子诊断技术的研发，后转入血液病研究院精准医学中心，负责单细胞测序及血液肿瘤基因功能和致病机制的研究。建立了支撑关键机制研究（包括融合基因功能解析、血液肿瘤细胞模型建立、药物敏感性测试等）的核心实验技术平台与细胞模型体系，为团队在 APL 发病机制和精准诊疗领域的持续创新奠定了坚实的技术基础。于 Blood 等学术期刊发表论文 30 余篇。 陈佳琦 博士 燕达陆道培医院分子医学室，北京陆道培血液病研究院 吉林大学药理学博士，2017年加入陆道培分子医学团队；主要负责药物基因组项目临床应用及相关研究；复发难治及不典型APL项目组主要成员之一，主持开展APL精准诊疗系列讲座；发表学术论文30余篇多次于ASH、JSH、KCA、ISLH等国际国内会议进行学术报告和交流。中国中西医结合学会医学检验专委会分子诊断专委会委员， 血液系统疾病实验诊断专委会委员；中华药理学会会员，中华药学会会员，中国抗癌协会会员；中国非公立医疗机构协会病理学专委会委员；北京卫生法学会医疗机构合规与法务专委会委员。 陆佩华 院长 北京陆道培血液病研究院院长；陆道培医院医疗院长 毕业于北京大学医学院，在美国内布拉斯加医学中心完成住院医，毕业于美国斯坦福大学血液及肿瘤专科，美国肿瘤以及血液病专科协会认证的血液及肿瘤专家，具有美国血液病专科医生，肿瘤专科医生执照以及中国行医执照。 首都医科大学肿瘤学系第四届系务委员会委员；中国非公医疗机构协会第一届常务理事；中国非公立医疗机构协会血液病专业委员会优秀主任委员；中国非公立医疗机构协会生物技术与细胞应用专业委员会常务委员；中国造血干细胞捐献者资料库专家委员会委员；中国临床肿瘤学会（CSCO）抗白血病联盟专家委员会常务委员；中国抗癌协会第一届血液病转化医学专业委员会常务委员；北京医学教育协会第七届理事会理事；医学界价值医疗泰山奖2021年度医疗管理奖获得者；荣获德医双馨"2021人民好医生年度人物"。 刘红星 院长 北京陆道培血液病研究院执行院长；陆道培医院病理和检验医学科主任 从事临床医师工作 3 年，血液病实验诊断和相关研究工作 22 年，以通讯/第一作者发表学术论文 160 余篇。在白血病新分子分型、经典型/不典型 APL 关键发病和耐药机制、FLT3长度突变发生机制和精准分型、家族性噬血细胞综合征基因突变、白血病融合基因图谱、融合基因家族分类和致病性判读等方面，有多项国际原创性新发现或国际领先的研究成果，对血液病的精准诊断和治疗改进有直接的帮助，影响和改写着血液病国际诊疗指南和专家共识。

Median Overall Survival (OS) of 15 months for subjects with complete remission (n=8) Median OS of 2nd Line efficacy evaluable population of 12 months (n=9) Median OS of Intent to Treat population (1L-7L) of 9 months (n=22) OS demonstrated by Annamycin in the MB-106 trial is significantly above industry expectations for relapsed AML (4-6 months) Clinical study report anticipated in Q1 2026 Company continues to execute Part A of the pivotal MIRACLE Phase 3 trial HOUSTON, Aug. 27, 2025 (GLOBE NEWSWIRE) — Moleculin Biotech, Inc., (Nasdaq: MBRX) (“Moleculin” or the “Company”), a late-stage pharmaceutical company with a broad portfolio of drug candidates targeting hard-to-treat cancers and viral infections, today announced the completion of its Phase 1B/2 (MB-106) clinical trial evaluating Annamycin in combination with Cytarabine (also known as “Ara-C” and for which the combination of Annamycin and Ara-C is referred to as AnnAraC) for the treatment of subjects with acute myeloid leukemia (AML). Database lock for the trial is expected by the end of September, with the final clinical study report (CSR) projected to be published in early Q1 2026. In total, 22 subjects were enrolled in the trial, with all subjects (1L-7L) who received AnnAraC per protocol having completed their efficacy evaluations (n=20). The updated overall survival (OS) data reveal the following: Median OS for Complete Remissions (CR): 15 months (n=8) with 4 subjects alive at study close Median OS for the intent to treat (ITT) Population (1L-7L): 9 months (n=22; 13 subjects experienced an event, 9 subjects censored) Median OS for 2L Efficacy Evaluable Population: 12 months (n=9) “Industry publications1 note that the typical OS for relapsed AML patients is roughly 4-6 months, these results highlight a remarkable improvement, exceeding expectations by 30% or more,” said Walter Klemp, Chairman and CEO of Moleculin Biotech. As previously reported, 8 subjects in the ITT population of 22 (36%) achieved a complete remission (CR) following treatment with AnnAraC. Among the subjects treated in the second line (2L) setting (n=10), the CR rate (the same primary efficacy endpoint as in the ongoing Phase 2B/3 pivotal MIRACLE trial), was 50%. Median durability for the 8 subjects achieving a CR was 10 months and continuing at the end of the study. CR durability ranged from 2 months to 22 months. CRs were achieved in subjects with a variety of prior treatments, including traditional 7+3 and venetoclax regimens. “We are glad to finally be in a position to close out our last Phase 2 AML trial, MB-106 by having completed follow-up on all subjects – some with durable CRs continuing – with database lock expected by the end of next month. While still technically preliminary, we are extremely pleased with the results of the MB-106 trial and look forward to the final CSR. These 2L data formed the basis for the design of the Phase 2B/3 pivotal MIRACLE trial with which we aim to gain eventual approval of Annamycin to serve the unmet need in 2L AML,” added Walter Klemp, Chairman and CEO of Moleculin. “We continue to see meaningful, positive trends across all data points, particularly in overall survival and durability. Of note, an 80+ yr old subject who achieved a CR with one cycle of Annamycin and then received two maintenance cycles of Annamycin finally relapsed after 600+ days. He then received a fourth round of Annamycin under compassionate use and is now back in remission. These data are very exciting and continue to give us hope that Annamycin has the potential to address the significant unmet need for safe and effective therapies for R/R AML. We also need to reemphasize that we have not seen any cardiotoxicity in any of the subjects to date, a key aspect of Annamycin.” “We can now also report that 50% of subjects achieving CR moved on to a curative bone marrow transplant, which is the most sought-after goal of any induction therapy in AML,” Mr. Klemp continued. “The results we have seen in 2L patients are better than any drug ever approved for second line AML and more than double the average for the last five drugs approved for 2L use.” “Looking ahead, we are focused on driving Part A of our Phase 3 MIRACLE trial forward and remain on track recruit the first 45 enrolled patients before the end of this year on which safety and efficacy will be unblinded. The final data from MB-106, coupled with the expected data from the MIRACLE trial will be invaluable as we continue to unlock the full potential of Annamycin for the treatment of AML,” concluded Mr. Klemp. The median age of subjects in MB-106 is 68 years. A total of 18 subjects had relapsed/refractory AML and 4 subjects were first line treatment. Two subjects discontinued early due to allergic reactions. All subjects who completed treatment had undergone post therapy disease response assessments (bone marrow assessment and/or peripheral blood evaluation) (Day 15 or later). No clinically significant signs of cardiotoxicity were noted during or after treatment in any of the subjects enrolled. The combination was well tolerated with myelosuppression and infections being the main adverse events (AEs). All data from MB-106 is preliminary and subject to change. Annamycin, also known by its non-proprietary name of naxtarubicin, currently has Fast Track Status and Orphan Drug Designation from the FDA for the treatment of relapsed or refractory acute myeloid leukemia, in addition to Orphan Drug Designation for the treatment of soft tissue sarcoma. Furthermore, Annamycin has Orphan Drug Designation for the treatment of relapsed or refractory acute myeloid leukemia from the EMA. The Company is currently evaluating Annamycin in combination with Cytarabine (also known as “Ara-C” and for which the combination of Annamycin and Ara-C is referred to as “AnnAraC”) in a Phase 3 pivotal trial for the treatment of AML patients who are refractory to or relapsed after induction therapy (R/R AML). This global Phase 3 “MIRACLE” trial (derived from Moleculin R/R AML AnnAraC Clinical Evaluation) includes sites in the US, Europe and the Middle East. For more information about the MIRACLE trial, visit clinicaltrials.gov and reference identifier NCT06788756. Additionally, the clinical trial in the EU is on euclinicaltrials.eu and the reference identifier there is 2024-518359-47-00. 1 – Bruno C. Medeiros, Is there a standard of care for relapsed AML?, Best Practice & Research Clinical, Haematology, Volume 31, Issue 4, 2018, Pages 384-386, ISSN 1521-6926; Roboz GJ, Sanz G, et al. Guadecitabine vs TC in relapsed/refractory AML after intensive chemotherapy: a randomized phase 3 ASTRAL-2 trial. Blood Adv. 2024 Apr 23;8(8):2020-2029. doi: 10.1182/bloodadvances.2023012062. PMID: 38231126; PMCID: PMC11103175.; Faderl S, Wetzler M, et al. Clofarabine plus cytarabine compared with cytarabine alone in older patients with relapsed or refractory acute myelogenous leukemia: results from the CLASSIC I Trial. J Clin Oncol. 2012 Jul 10;30(20):2492-9. doi: 10.1200/JCO.2011.37.9743. Epub 2012 May 14. PMID: 22585697; PMCID: PMC4874149. About Moleculin Biotech, Inc. Moleculin Biotech, Inc. is a Phase 3 clinical stage pharmaceutical company advancing a pipeline of therapeutic candidates addressing hard-to-treat tumors and viruses. The Company’s lead program, Annamycin, is a next-generation highly efficacious and well tolerated anthracycline designed to avoid multidrug resistance mechanisms and to lack the cardiotoxicity common with currently prescribed anthracyclines. Annamycin is currently in development for the treatment of relapsed or refractory acute myeloid leukemia (AML) and soft tissue sarcoma (STS) lung metastases. The Company has begun the MIRACLE (Moleculin R/R AML AnnAraC Clinical Evaluation) Trial (MB-108), a pivotal, adaptive design Phase 3 trial evaluating Annamycin in combination with cytarabine, together referred to as AnnAraC, for the treatment of relapsed or refractory acute myeloid leukemia. Following a successful Phase 1B/2 study (MB-106), with input from the FDA, the Company believes it has substantially de-risked the development pathway towards a potential approval for Annamycin for the treatment of AML. This study remains subject to appropriate future filings with potential additional feedback from the FDA and their foreign equivalents. Additionally, the Company is developing WP1066, an Immune/Transcription Modulator capable of inhibiting p-STAT3 and other oncogenic transcription factors while also stimulating a natural immune response, targeting brain tumors, pancreatic and other cancers. Moleculin is also engaged in the development of a portfolio of antimetabolites, including WP1122 for the potential treatment of pathogenic viruses, as well as certain cancer indications. For more information about the Company, please visit www.moleculin.com and connect on X, LinkedIn and Facebook. Forward-Looking Statements Some of the statements in this release are forward-looking statements within the meaning of Section 27A of the Securities Act of 1933, Section 21E of the Securities Exchange Act of 1934 and the Private Securities Litigation Reform Act of 1995, which involve risks and uncertainties. Forward-looking statements in this press release include, without limitation, the timing of the MB-106 database lock for the trial and the publication of the final CSR, the timing of the release of the initial data on the first 45 subjects in the MIRACLE trial, and the Company’s ability to reconcile the US and EU MIRACLE protocols with the FDA and EMA, respectively. Moleculin will require significant additional financing, for which the Company has no commitments, in order to conduct its clinical trials as described in this press release, and the milestones described in this press release assume the Company’s ability to secure such financing on a timely basis. Although Moleculin believes that the expectations reflected in such forward-looking statements are reasonable as of the date made, expectations may prove to have been materially different from the results expressed or implied by such forward-looking statements. Moleculin has attempted to identify forward-looking statements by terminology including ‘believes,’ ‘estimates,’ ‘anticipates,’ ‘expects,’ ‘plans,’ ‘projects,’ ‘intends,’ ‘potential,’ ‘may,’ ‘could,’ ‘might,’ ‘will,’ ‘should,’ ‘approximately’ or other words that convey uncertainty of future events or outcomes to identify these forward-looking statements. These statements are only predictions and involve known and unknown risks, uncertainties, and other factors, including those discussed under Item 1A. “Risk Factors” in our most recently filed Form 10-K filed with the Securities and Exchange Commission (SEC) and updated from time to time in our Form 10-Q filings and in our other public filings with the SEC. Any forward-looking statements contained in this release speak only as of its date. We undertake no obligation to update any forward-looking statements contained in this release to reflect events or circumstances occurring after its date or to reflect the occurrence of unanticipated events. Investor Contact:JTC Team, LLCJenene Thomas(908) 824-0775MBRX@jtcir.com