SBIR TOPIC 255

急性髓性白血病（AML）是一种起源于骨髓的侵袭性造血癌。AML是成人白血病最常见的形式；老年人目前的最佳治疗反应率为6-8%。长期目标是推进mrx102的开发，用于AML的临床治疗，这是一个尚未满足的医疗需求。MRx102是天然产物雷公藤甲素的创新衍生物，通过抑制关键的细胞内信号通路，对AML母细胞和细胞系具有细胞毒性。雷公藤甲素在中国的一项临床研究中诱导40%的急性白血病完全应答。初步的大鼠毒理学结果表明，mrx102可能具有改善的毒性特征。在这些拟议的研究中，mrx102剂量反应关系将在裸鼠人类AML异种移植模型中进行评估，并扩展到另外两个AML细胞系。mrx02的最佳给药途径将通过比较血浆生物利用度来确定，并评估备用化合物的活性。根据初步结果和申请人在其他雷公藤甲素衍生物方面的经验，MRx102有望在AML异种移植模型中表现出优异的疗效和良好的效力，足以在II期合同中进行进一步的临床前开发，从而进行IND的药理学和GLP毒理学研究、IND申请和临床评估。

Acute Myeloid Leukemia (AML) is an aggressive hematopoietic cancer originating in the bone marrow. AML is the most common form of adult leukemia; older adults have a 6-8% best current therapy response rate. The long-term objective is advancing the development of MRxl02 to clinical treatment of AML, an unmet medical need. MRx102 is an innovative derivative of the natural product triptolide, which is cytotoxic for AML blasts and cell lines by inhibiting critical intracellular signaling pathways. Triptolide induced 40% complete acute leukemia responses in a Chinese clinical study. Preliminary rat toxicology results suggest MRxl02 may have an improved toxicity profile. In these proposed studies, the MRxl02 dose response relationship will be assessed in the nude mouse human AML xenograft model, and extended with two additional AML cell lines. The optimal route of administration for MRxl02 will be determined by comparison of plasma bioavailability, and backup compounds will be evaluated for activity. Based on preliminary results and applicant experience with other triptolide derivatives, MRx102 is expected to show excellent efficacy with good potency in the AML xenograft models sufficient to enable further preclinical development in the Phase II contract leading to IND-enabling pharmacology and GLP toxicology studies, IND filing and clinical evaluation.