SBIR TOPIC 255

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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.