Our belief is that drug combinations targeting both tumor-intrinsic and microenvironment-extrinsic pathways of acute myeloid leukemia (AML) will be essential for successful drug combination strategies. Intrinsic refers to mutations in the tumor cell that drive resistance such as BCL-2 expression and P-53 mutations. Extrinsic resistance is independent of molecular subtype and arises from interaction between leukemic cells and the bone marrow microenvironment, mediated by E-selectin. By disrupting the E-selectin/E-selectin ligand axis we believe uproleselan can eliminate extrinsic resistance in the bone marrow and can be transformative for AML patients.
This novel extrinsic approach with uproleselan was shown in our Phase 1/2 trial (published online September 16, 2021 in BLOOD) to result in following:
- A high remission rate compared to historical experience with salvage chemotherapy alone. In the relapsed/refractory population, 41% achieved a CR/CRi and, of note, 35% achieved CRs, which highlights the recovery of bone marrow in addition to anti-leukemic effect;
- A majority of evaluable patients achieved measurable residual disease (MRD) negativity at the end of induction, including a 69% (11/16) negative rate in the evaluable R/R AML population and a 56% (5/9) rate MRD negative rate in the evaluable de novo AML population; full CR with MRD negative status has been shown to be the strongest predictor for overall survival in AML;
- A high percentage of responding patients undergoing a subsequent transplant – 31% of patients (17/54) in the relapsed/refractory patients went on to allogeneic stem cell transplantation. This suggests that the addition of uproleselan to chemotherapy was associated not only with anti-leukemic effect but also with preserved performance status that allowed patients to undergo stem cell transplant while in remission, both critical factors for the success of transplantation;
- Prolonged survival, compared to historical experiences with chemotherapy alone.
Based on these encouraging results, the FDA granted Breakthrough Therapy Designation for uproleselan in adults with relapsed/refractory AML and GlycoMimetics initiated a Company-sponsored Phase 3 trial in this patient population (NCT03616470). Enrollment in this pivotal trial was completed in late 2021 with top line results anticipated after year-end 2022.
In addition, the National Cancer Institute (NCI) has initiated a Phase 2/3 registration trial, designed to evaluate the use of uproleselan in newly diagnosed older adults with AML who are fit for chemotherapy (NCT04964505). The Phase 2 component of this trial completed enrollment in late 2021, allowing for an interim analysis of Event-Free Survival.
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 Chinese Health authority has also designated uproleselan as a Breakthrough Therapy in Greater China. 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.
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