GMI-1359

P1b, N=4, Terminated, GlycoMimetics Incorporated | Trial completion date: Mar 2022 --> Aug 2021 | Recruiting --> Terminated | Trial primary completion date: Dec 2021 --> Aug 2021; After demonstrating the on target effect of GMI-1359 via pharmacodynamic markers (CXCR4 and E-selectin), Sponsor terminated the trial due to COVID-related slow enrollment.

We previously demonstrated (Chang et al., ASH 2020) that E-selectin blockade by the pharmacological antagonist, GMI-1271 (uproleselan; GlycoMimetics, Inc) sensitized therapy-resistant LSC to Bcl-2 targeted therapy...Hence, we hypothesized that co-targeting E-selectin/CXCR4 more efficiently mobilizes AML cells from BM niches and synergizes with the anti-leukemia activity of venetoclax/hypomethylating agent (Ven/HMA)...We also observed upregulated pro-survival signaling pathways such as phosphorylation of AKT-MAPK-ERK along with increased Bcl-xL, Bcl-2, and Idu expression in MSC from the GMI-1359 + Ven/HMA treated PDX mice compared to Ven/HMA single treatment cohorts. Collectively, our results provide strong evidence that co-targeting E-selectin/CXCR4 with GMI-1359 profoundly reduces BM retention of LSC as well as protects BM niche component cells from apoptosis induced by targeted therapy, resulting in improving the anti-leukemia activity of Ven/HMA therapy in AML.

Unexpectedly, 72-h suppression of MEK/ERK signaling with selumetinib or pimasertib also upregulated CXCR4 in MOLM14 cells. No effects in this regard were observed by suppressing AKT/mTOR or Stat5 with AZD8055 or STAT5-IN-1, respectively. Additionally, in Dox-inducible NRAS (G12D)-mutated MOLM13 AML cells which also harbor FLT3 ITD mutations, ERK activation by doxycycline downregulated CXCR4 levels implying the MEK/ERK signaling pathway was associated with the suppression of CXCR4. Furthermore, under BM microenvironment-mimicking, co-culture using human MSCs/ECs and MOLM14 cells, blockade of CXCR4 and/or E-selectin signaling using the CXCR4 antagonist plerixafor, the E-selectin antagonist GMI-1271, or the CXCR4 and E-selectin dual inhibitor GMI-1359 showed that GMI-1359 markedly abrogated BM protection and sensitized MOLM14 cells to quizartinib-induced apoptosis. We further validated the effect of GMI-1359 in a PDX model of AML which were from a patient who relapsed from sorafenib+E6201+DAC in clinic and showed resistant to quizartinib ex vivo...GMI-1359 sensitized AML cells to quizartinib-induced apoptosis in vitro and statistically significantly extended AML PDX mouse survival in vivo . These findings provide a pre-clinical rational for using GMI-1359 to prevent or overcome FLT3i resistance when treating FLT3-mutant AML patients.

P1b, N=6, Recruiting, GlycoMimetics Incorporated | Trial completion date: Aug 2020 --> Mar 2022 | Trial primary completion date: Aug 2020 --> Dec 2021

GMI-1070 (rivipansel) was designed to inhibit E, P, and L-selectins by incorporating a mimic of sialyl Lex together with that of the tri-sulfated domain of PSGL-1...In animal models of VOC, GMI-1687 blocked occlusion and normalized blood flow at 0.04 mg/kg BID...Based on positive phase 2 data, the FDA granted uproleselan “Breakthrough Therapy Designation”...Animal models of bone metastasis treated with GMI-1359 and chemotherapy show reduction of tumor volume and significant improvement in survival. GMI-1359 is now being studied in breast cancer patients at Duke University.

GMI-1271 (uproleselan) is a specific and potent (KD = 450nM) E-selectin antagonist now in phase 3 clinical trials for the treatment of acute myelogenous leukemia (AML). Animal models of bone metastasis treated with GMI-1359 show significant improvement in survival, reduction of tumor volume and well as improved integrity of the bone. GMI-1359 is now in phase 2 clinical trial for treatment of breast cancer.