Discovered and developed by GlycoMimetics, uproleselan is an investigational first-in-class, E-selectin antagonist. Uproleselan (yoo’ pro le’se lan), currently in a comprehensive Phase 3 development program in acute myeloid leukemia (AML), has received Fast Track and Breakthrough Therapy designations from the U.S. Food and Drug Administration (FDA) for the treatment of adult AML patients with relapsed or refractory disease. Uproleselan is also being evaluated in a Phase 2/3 trial by the National Cancer Institute (NCI) as a potential new treatment for newly diagnosed AML patients fit for chemotherapy.
Uproleselan is designed to bind to E-selection and block the normal processes controlled by E-selectin. E-selectin is expressed on the surface of blood vessels, and its binding to myeloid cells confers a pro-survival effect via NF-kB signaling. Uproleselan is designed to provide a novel approach to disrupting established mechanisms of leukemic cell resistance. It is believed that by binding to E-selectin, uproleselan pushes AML cells out of their protective niche, blocks cellular communication signals that promote survival, and sensitizes cancer cells to the toxic effects of chemotherapy.
Results of a Phase 1/2 trial of adults living with relapsed/refractory AML treated with uproleselan were published on September 16, 2021, in BLOOD. Findings included:
- A high remission rate compared to historical experience with salvage chemotherapy alone. In the relapsed/refractory (R/R) population, 41% achieved a Complete Response (CR)/Complete response incomplete hematologic recovery (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 R/R 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;
- The addition of uproleselan to chemotherapy was well tolerated, with high remission rates, low induction mortality, and low rates of mucositis, providing a strong rationale for phase 3 randomized confirmatory studies.
Regulatory Designations*
Breakthrough Therapy – U.S. FDA and Chinese Health Authority in adult relapsed/refractory AML
Fast Track – U.S. FDA in adult relapsed/refractory AML
Orphan Drug – U.S. FDA and European Union
*Uproleselan has not been approved for use by any worldwide health authority