On April 30, 2020 GlycoMimetics, Inc. (Nasdaq: GLYC) reported that important new preclinical data on the mechanism of action for its late-stage clinical candidate, uproleselan, are published in the April 27, 2020, issue of Nature Communications (Press release, GlycoMimetics, APR 30, 2020, View Source [SID1234556810]). The paper outlines how uproleselan, an investigational, first-in-class, targeted inhibitor of E-selectin, can reduce chemoresistance in acute myeloid leukemia (AML) through the key mechanism of targeted E-selectin inhibition.1
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"This paper offers compelling data on the mechanism of action of uproleselan," said John Magnani, Ph.D., GlycoMimetics Senior Vice President and Chief Scientific Officer. "AML cells that bind E-selectin become chemoresistant in protective niches in the bone marrow, eventually causing relapsed disease. This data demonstrates that, as a potent antagonist of E-selectin, uproleselan breaks this chemoresistance."
Barbier et.al. explain in the manuscript how AML blasts release inflammatory cytokines that further enhance the expression of E-selectin. AML blasts that strongly express the E-selectin ligand (sialyl Lex), in particular, are 12 times more likely to survive chemotherapy, and this is a major cause of relapsed disease. By selectively inhibiting E-selectin, uproleselan disrupts this pro-survival pathway and prolongs survival when paired with chemotherapy in an animal model of AML.
The journal article can be accessed here.
1 Barbier et.al. Nature Communications (April 27) doi.org/10.1038/s41467-020-15817-5
About Uproleselan
Discovered and developed by GlycoMimetics, uproleselan and GMI-1687 are investigational, first-in-class, targeted inhibitors of E-selectin. Uproleselan (yoo’ pro le’ sel an), currently in a comprehensive Phase 3 development program in AML, has received Breakthrough Therapy Designation from the U.S. FDA for the treatment of adult AML patients with relapsed or refractory disease. Uproleselan is designed to block E-selectin (an adhesion molecule on cells in the bone marrow) from binding with blood cancer cells as a targeted approach to disrupting well-established mechanisms of leukemic cell resistance within the bone marrow microenvironment. In a Phase 1/2 clinical trial, uproleselan was evaluated in both newly diagnosed elderly and relapsed or refractory patients with AML. In both populations, patients treated with uproleselan together with standard chemotherapy achieved better-than-expected remission rates and overall survival compared to historical controls, which have been derived from results from third-party clinical trials evaluating standard chemotherapy, as well as lower-than-expected induction-related mortality rates. Treatment in these patient populations was generally well-tolerated, with fewer than expected adverse effects.