GlycoMimetics is developing uproleselan, a specific E-selectin inhibitor, to be used in combination with chemotherapy to treat patients with acute myeloid leukemia (AML) and potentially other hematologic cancers.
E-selectin plays a critical role in binding cancer cells within vascular niches in the bone marrow, which prevents the cells from entering circulation where they can be more readily killed by chemotherapy. In separate animal studies, uproleselan mobilized AML and MM cancer cells out of the bone marrow, making them more sensitive to chemotherapy. In both the AML and MM studies, tumor burden was significantly reduced in animals treated with a combination of chemotherapy and uproleselan as compared to animals treated with chemotherapy alone. In addition, the combination of uproleselan with chemotherapy resulted in improved survival rates for the treated animals, compared to chemotherapy alone. In other animal studies, uproleselan appeared to reduce some of the side effects of chemotherapy, such as bone marrow toxicity resulting in neutropenia, which is an abnormally low number of the white blood cells that serve as the primary defense against infection; and mucositis, which is the inflammation and sloughing of the mucous membranes lining the digestive tract. We believe that treatment with uproleselan results in lower bone marrow toxicity due to its inhibition of E-selectin, which makes stem cells in the bone marrow divide less frequently, thereby protecting them from chemotherapy agents that target rapidly dividing cells.
In 2017 we completed participant enrollment and in December 2017, at the annual meeting of the American Society of Hematology (ASH), we presented clinical data from our Phase 1/2 clinical trials in defined populations of patients with AML. The data showed high remission rates, improved overall survival and improved duration of survival, as compared to historical controls. In addition, the data suggested a favorable safety, pharmacokinetic, or PK, and biomarker profile for uproleselan. Full details regarding the Phase 1/2 results presented at ASH 2017 may be found here: DeAngelo-GMI-1271-201-ASH-2017-Abstract-894.pdf. Based on these positive results, we have initiated a Phase 3 trial (NCT03616470) in adults with relapsed/refractory AML who are considered to be medically eligible to receive intensive chemotherapy. This pivotal trial will enroll 380 patients and be conducted at US and international sites.
The FDA has granted Breakthrough Therapy Designation for uproleselan in adults with relapsed or refractory AML. Additionally, uproleselan has received Fast Track designation from the FDA, which may lead to faster delivery to people living with AML if the treatment is found to be effective. The European Union granted Orphan Drug Designation for uproleselan in AML, a designation the FDA granted the drug candidate in 2015. Uproleselan has not been approved for use by any worldwide health authority.
In addition, GlycoMimetics scientists have rationally designed an innovative antagonist of E-selectin, GMI-1687, that is suitable for subcutaneous (SC) administration. When given by SC injection, GMI-1687 has been observed to have equivalent activity to uproleselan in preclinical models, but at an approximately 250-fold lower dose. We believe that GMI-1687 could be developed as a potential life-cycle expansion to broaden the clinical usefulness of an E-selectin antagonist to conditions where outpatient treatment is preferred or required. We are currently conducting investigational new drug (IND)-enabling studies with GMI-1687.
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