GMI-1359 / GlycoMimetics - LARVOL DELTA

Co-Targeting E-Selectin/CXCR4 with GMI-1359 Facilitates AML Stem Cell Mobilization and Protects BM Niches from Anti-Leukemia Therapy (ASH 2021) - P1 | "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."

IO biomarker • Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Oncology • BCL2 • BCL2L1 • CASP3 • CD123 • CD31 • CDKN1A • CXCR4 • FLT3 • JAK2 • KIT • MYC • NOS3 • PTPRC

A Study to Determine Safety and Tolerability of GMI-1359 in Subjects With HR+ Metastatic Breast Cancer (clinicaltrials.gov) - P1b | N=4 | Terminated | Sponsor: 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.

Trial completion date • Trial primary completion date • Trial termination • Breast Cancer • Hormone Receptor Breast Cancer • Oncology • Solid Tumor • CD34 • CTCs

FLT3 Inhibitors Upregulate CXCR4 and E-Selectin Ligands and CD44 Via ERK Suppression in AML Cells, and Blockade of CXCR4 and E-Selectin Signaling with GMI-1359 Overcomes AML Resistance to Quizartinib in Vitro and In Vivo (ASH 2021) - "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..."

Preclinical • Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Oncology • CD44 • CXCL12 • FLT3 • NRAS • STAT5

Two GlycoMimetics Posters at 63rd ASH Annual Meeting Highlight Potential of GMI-1359, a Dual Antagonist of CXCR4 and E-selectin (Businesswire) - "The second poster (#3348), presented today contains data demonstrating that in a patient derived xenograft model, both uproleselan and GMI-1359 increased the efficacy and extended median survival time in engrafted mice treated with venetoclax/HMA from 74 days to 90 and 91 days, respectively. In these studies, the inclusion of uproleselan or GMI-1359 in combination with venetoclax/HMA further significantly decreased both the leukemic blast and leukemic stem cell burden beyond that obtained with venetoclax/HMA alone."

Preclinical • Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Oncology

Two GlycoMimetics Posters at 63rd ASH Annual Meeting Highlight Potential of GMI-1359, a Dual Antagonist of CXCR4 and E-selectin (Businesswire) - "The first poster (#1171) — presented December 11 — describes the unexpected activities of FLT-3 inhibitors such as quizartinib and sorafenib in upregulating the expression of E-selectin ligands (sialyl Lex) and CXCR4, thereby increasing adhesion to protective niches in the bone marrow microenvironment and inducing chemoresistance. Using cells from a relapsed patient treated with a FLT-3 inhibitor in a murine model, the addition of GMI-1359, a dual antagonist of E-selectin and CXCR4, to quizartinib broke chemoresistance, led to a dramatic reduction in leukemic burden and a doubling of median survival time from 79 to 158 days (p<0.0001)."

Preclinical • Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Multiple Myeloma • Oncology

GlycoMimetics GMI-1359 Data Selected for Presentation at 63rd American Society of Hematology (ASH) Annual Meeting and Exposition (Businesswire) - "The first poster (#1171) describes the unexpected activities of FLT-3 inhibitors such as quizartinib and sorafenib to upregulate the expression of E-selectin ligands (sialyl Lex) and CXCR4 thereby increasing adhesion to protective niches in the bone marrow microenvironment and inducing chemoresistance. The addition of GMI-1359 to quizartinib in a PDX mouse model from a relapsed patient broke this induced chemoresistance, leading to a dramatic reduction in leukemic burden and a near-doubling of survival time. The second (#3348) demonstrates that GMI-1359 reduced adhesion and stimulated mobility of leukemic stem cells within the bone marrow microenvironment."

Preclinical • Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Oncology

[VIRTUAL] Development of GMI-1359, a novel agent targeting tumor-microenvironment cross-talk in bone metastatic cancer (AACR 2021) - P1b | "We also observed a decrease in primary tumor M-MDSCs and lung metastasis-associated macrophages.In summary, our preliminary clinical data suggest that GMI-1359 is well-tolerated and elicits on-target effects expected from disruption of the host microenvironment. Ongoing clinical and preclinical work will define the efficacy of this strategy to enhance responses to chemo and immune therapies."

Biomarker • Tumor microenvironment • Breast Cancer • Oncology • Solid Tumor • CD34 • CD8 • CXCL12 • CXCR4

A Study to Determine Safety and Tolerability of GMI-1359 in Subjects With HR+ Metastatic Breast Cancer (clinicaltrials.gov) - P1b; N=6; Recruiting; Sponsor: GlycoMimetics Incorporated; Trial completion date: Aug 2020 ➔ Mar 2022; Trial primary completion date: Aug 2020 ➔ Dec 2021

Clinical • Trial completion date • Trial primary completion date • Breast Cancer • Hormone Receptor Breast Cancer • Oncology • Solid Tumor • CD34 • CTCs

Positive Findings From Phase 1b Trial of GlycoMimetics’ GMI-1359 To Be Presented at AACR 2021 Meeting (Businesswire) - P1b, N=6; NCT04197999; Sponsor: GlycoMimetics Incorporated; "GlycoMimetics, Inc...announces that a Phase 1b trial of GMI-1359, being conducted at Duke University Cancer Center, showed evidence of on-target effects, immune-activation and cell mobilization in the initial two patients treated with the Company’s dual antagonist of E-selectin and CXCR4...In the two patients who completed treatment, evaluations of peripheral blood showed a consistent mobilization of CD34+ hematopoietic stem and progenitor cells at doses beginning at 5 mg/kg and a reduction of plasma levels of soluble E-selectin....The data in the poster from a mouse metastatic breast carcinoma model demonstrated a reduction in the immune suppressive monocytic MDSCs at the primary tumor site and a significant increase in the CD8/Treg ratio in both the primary tumor and at the bone metastatic sites. "

P1 data • Preclinical • Breast Cancer • Oncology

A Study to Determine Safety and Tolerability of GMI-1359 in Subjects With HR+ Metastatic Breast Cancer (clinicaltrials.gov) - P1b; N=6; Recruiting; Sponsor: GlycoMimetics Incorporated

Clinical • New P1 trial • Breast Cancer • Hormone Receptor Breast Cancer • Oncology • Solid Tumor • CD34 • CTCs

[VIRTUAL] Glycomimetic drugs: From rational design to clinical trials (ACS-Sp 2021) - P3 | "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."

Clinical • Breast Cancer • Genetic Disorders • Hematological Disorders • Oncology • Pain • Sickle Cell Disease • Solid Tumor • CXCR4

GlycoMimetics to Share GMI-1359 and Galectin-3 Antagonist Program Data at AACR 2021 Meeting (Businesswire) - "GlycoMimetics...announces that an abstract presenting the interim analysis of a Phase 1b proof-of-concept study of GMI-1359, the Company’s dual antagonist of E-selectin and CXCR4, has been accepted for presentation at the American Association of Cancer Research (AACR) 2021 Annual Meeting, to be held virtually on April 10-15 and May 17-21....A second abstract also accepted for presentation highlights, for the first time, preclinical data in pancreatic cancer for the Company’s novel dual antagonist of galectin-3 and E-selectin, GMI-1757."

P1 data • Preclinical • Breast Cancer • Oncology • Pancreatic Cancer

Mobilization of tumor-primed, marrow-infiltrating lymphocytes into peripheral blood with inhibitors of E-selectin or E-selectin and CXCR4 (AACR 2018) - "GMI-1271 and GMI-1359 are potent, small-molecule glycomimetic antagonists of E-selectin and E-selectin/CXCR4, respectively. Collectively these results demonstrate the mobilization or redistribution of marrow-infiltrating tumor-specific CD8+ T cells into peripheral blood as a consequence of E-selectin and/or E-selectin and CXCR4 antagonism. Once in the periphery, these MILs could (1) be collected for adoptive immunotherapy approaches or (2) serve as a systemic augmentation of T cells for combination with immune stimulants as a foundation to boost active immunotherapy."

IO Biomarker • Colorectal Cancer • Leukemia

[VIRTUAL] Combined Blockage of E-Selectin and CXCR4 (GMI-1359) Enhances Anti-Leukemia Effect of FLT3 Inhibition (Sorafenib) and Protects Hematopoiesis in Pre-Clinical AML Models (ASH 2020) - "Further, GMI-1359 combined with cytarabine/daunorubicin provided a profound survival benefit in mice with FLT3-mutated leukemia (Zhang et al., Blood suppl 2015). Co-inhibition of E-selectin/CXCR4 enhances the anti-leukemia efficacy of FLT3 inhibition and preserves hematopoiesis in the BM in a PDX model of AML."

Acute Myelogenous Leukemia • Hematological Disorders • Hematological Malignancies • Leukemia • Oncology • CXCL12 • CXCR4 • FLT3

[VIRTUAL] Dual CXCR4 and E-Selectin Inhibition (GMI-1359) Rapidly Increases AML Cellular Motility Prior to Intravasation and Vascular Niche Depletion Observed By Intravital Bone Marrow Two-Photon Microscopy (ASH 2020) - "In a previous study, GMI-1359 markedly reduced leukemia cell adhesion to endothelial cells, leukemia cellularity in BM (Zhang et al., 2016) and it enhanced the survival of cytarabine/daunorubicin therapy in a FLT3-mutated AML model (Zhang et al., 2015). Our observations reveal an unexpected mechanism of action by a dual E-selectin/CXCR4 inhibitor involving cellular migratory motility enhancement in BM stroma prior to AML cell intravasation. We envisage that, besides the designed blocking of E-selectin and CXCR4 molecules from binding their corresponding ligands, the dual moiety GMI-1359 agent has a capacity to generate motility-enhancing signals in AML cells that single inhibitors do not seem to trigger. Among several mechanisms possible, this action could involve E-selectin and CXCR4 crosslinking by a dual moiety molecular structure or binding avidity enhancement, requiring further investigation."

Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Oncology • Transplantation • CXCL12 • CXCR4 • FLT3 • MLL

GlycoMimetics Program Data to be Highlighted Via Three Oral Presentations and Two Posters at 62nd American Society of Hematology Annual Meeting and Exposition (Businesswire) - "GlycoMimetics...announced that three abstracts including data from the Company’s clinical and research portfolio have been accepted for oral presentations and two abstracts have been accepted for poster presentations at the 62nd American Society of Hematology (ASH) Annual Meeting and Exposition, to be held virtually December 5-8, 2020...A third presentation discloses how targeting E-selectin with uproleselan may help patients with AML overcome resistance to venetoclax combined with hypomethylating agent (HMA) based therapy. Poster presentations convey how GMI-1359...enhances sorafenib’s anti-leukemia effect in pre-clinical AML models..."

Preclinical • Acute Myelogenous Leukemia • Hematological Malignancies • Oncology

Dual CXCR4 and E-Selectin Inhibitor, GMI-1359, Shows Anti-Bone Metastatic Effects and Synergizes with Docetaxel in Prostate Cancer Cell Intraosseous Growth. (PubMed, Cells) - "Metastatic castration resistant prostate cancer (mCRPC) relapses due to acquired resistance to docetaxel-based chemotherapy and remains a major threat to patient survival. Single agent CXCR4 (CTCE-9908) and E-selectin (GMI-1271) antagonists resulted in lower sensitizing effects compared to GMI-1359. These data provide a biologic rationale for the use of a dual E-selectin/CXCR4 inhibitor as an adjuvant to taxane-based chemotherapy in men with mCRPC to prevent and reduce bone metastases."

Journal • Genito-urinary Cancer • Oncology • Prostate Cancer • Solid Tumor

[VIRTUAL] Combined targeting of E-selectin/CXCR4 and FLT3 by GMI-1359 and sorafenib effectively reduces leukemia cell burden and protects normal hematopoiesis in a patient-derived AML xenograft model (AACR-II 2020) - "Further, GMI-1359 combined with cytarabine/daunorubicin provided a profound survival benefit in FLT3-mutated leukemia cell MV4-11-bearing mice (Zhang et al., 2015). The underlying mechanism(s) for this effect is under investigation. Our findings suggest that co-targeting E-selectin/CXCR4/FLT3 exerts remarkable protection of normal hematopoiesis in addition to more efficiently reducing leukemia cells."

Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Oncology • CXCR4 • FLT3

Inhibition of E-Selectin (GMI-1271) or E-selectin together with CXCR4 (GMI-1359) re-sensitizes multiple myeloma to therapy. (PubMed, Blood Cancer J) - No abstract available

Journal • Hematological Disorders • Hematological Malignancies • Multiple Myeloma • Oncology

GlycoMimetics to present new preclinical data highlighting biomarkers and potential expanded pipeline opportunities at Virtual AACR Annual Meeting 2020 (Businesswire) - "Important findings from the preclinical research include: Co-targeting and inhibition of E-selectin/CXCR4/FLT3 with GMI-1359 in combination with sorafenib exerts protection of normal hematopoiesis (blood cell formation) and more efficiently reduces leukemic burden compared to sorafenib alone, resulting in extended overall survival, in a patient-derived FLT3 resistant AML model; Inhibition of E-selectin with uproleselan during pre-transplant conditioning results in increased survival of mice in a hematopoietic stem cell transplantation and reconstitution model."

Preclinical • Acute Myelogenous Leukemia • Hematological Malignancies • Oncology

"$GLYC to Present New Preclinical Data for GMI-1271 and GMI-1359 at #AACR18 https://t.co/pjrIS7AAQ1" (@odibro)

Preclinical • Biosimilar • Oncology

Dual E-selectin and CXCR4 inhibition reduces tumor growth and metastatic progression in an orthotopic model of osteosarcoma (AACR 2018) - "These results indicate that the E-selectin and CXCR4 axes are important for the progression of osteosarcoma, and further, that inhibition of these two pro-tumor growth components by GMI-1359 has a therapeutic advantage over chemotherapy alone. Furthermore, studies in the adjuvant setting can provide proof of concept of utility of targeting CXCR4 and E- selectin ligands in the metastatic niche as a therapeutic strategy to limit metastatic progression in high risk patients."

Oncology • Sarcoma • Solid Tumor

Rational design of glycomimetic drugs in clinical trials for acute myelogenous leukemia and breast cancer (ACS-Sp 2020) - "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."

Clinical • CXCR4

"#GlycoMimetics Advances #GMI1359 Program With #Patent Issuance and #FDA Designations $GLYC https://t.co/Rl5zCLcF4R" (@1stOncology)

GlycoMimetics advances GMI-1359 program with patent issuance and FDA designations (Businesswire) - "GlycoMimetics...said that the United States Patent and Trademark Office has issued a patent for GMI-1359, covering composition of matter as well as pharmaceutical formulations, and will provide protection through 2035, excluding any patent term adjustments or extensions...GlycoMimetics....announced that the FDA has granted Orphan Drug Designation and Rare Pediatric Disease Designation to GMI-1359 for the treatment of osteosarcoma, a rare cancer affecting about 900 adolescents a year in the United States."

FDA event • Orphan drug • Patent