GlycoMimetics is developing uproleselan, a specific E-selectin antagonist, 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 the circulation where they can be more readily killed by chemotherapy. In separate animal studies, uproleselan mobilized AML and multiple myeloma (MM) cancer cells out of the bone marrow, making them more sensitive to chemotherapy. In both AML and MM, 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 antagonism 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 December 2017, following completion of patient enrollment of our Phase 1/2 clinical trial earlier that year, 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 is designed to enroll 380 patients and is being 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.
At several key conferences and specifically at the ASH meeting in 2020, GLycoMimetics presented important new preclinical data pointing to an opportunity to combine uproleselan with venetoclax and a hypomethylating agent (HMA). In an oral presentation, this combination was shown to break chemoresistance by dramatically and significantly reducing tumor burden as detected by circulating human AML cells after three weeks of treatment, and by significantly increasing survival (p = 0.0009) in an animal model engrafted with AML from a patient with acquired resistance to venetoclax/HMA combination therapy. We believe these data support the need for further clinical investigation and are investigating such opportunities.
GlycoMimetics previously presented preclinical data showing that hypomethylating agents up-regulate the expression of E-selectin ligand on AML cells. The Company believes E-selectin upregulation increases the binding affinity of the blasts to the vascular endothelium, where E-selectin is expressed, and as a result, contributes to increased chemoresistance. By antagonizing E-selectin’s role in this cascade, GlycoMimetics believes uproleselan may be able to play a key role in deepening patient responses to or enhancing the duration of efficacy of venetoclax/HMA combinations.
In addition, GlycoMimetics scientists have rationally designed an innovative antagonist of E-selectin, GMI-1687, that we believe 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 product to broaden the clinical usefulness of an E-selectin antagonist to conditions where outpatient treatment is preferred or required, for example in treating vaso-occlusive crisis of sickle cell disease. We are currently conducting investigational new drug (IND)-enabling studies with GMI-1687.
If you have additional questions, please email clinicaltrials@glycomimetics.com
If you are interested in partnering for uproleselan, please email: bd@glycomimetics.com