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John L Magnani - One of the best experts on this subject based on the ideXlab platform.

  • use of gmi 1271 an e Selectin Antagonist in healthy subjects and in 2 patients with calf vein thrombosis
    Research and practice in thrombosis and haemostasis, 2020
    Co-Authors: Sumana Devata, Dana E Angelini, Susan Blackburn, Angela E Hawley, Daniel D Myers, Jordan K Schaefer, Martina V Hemmer, John L Magnani, Helen M Thackray, Thomas W Wakefield
    Abstract:

    Background: There is an unmet need for antithrombotic treatments for venous thromboembolic disease that do not increase bleeding risk. Selectins are cell adhesion molecules that augment thrombosis by activating immune cells to initiate the coagulation cascade. GMI-1271, a potent small-molecule E-Selectin Antagonist, has been shown in mouse models to decrease thrombus burden with a low risk of bleeding. Methods: A first-in-human study of GMI-1271 was conducted to assess its safety, tolerability, and pharmacokinetic (PK) profile. As a secondary end point, biomarkers of coagulation, cell adhesion, and leukocyte/platelet activation were evaluated. Aims 1 and 2 were performed in healthy volunteers and evaluated single and multiple doses of the study drug, respectively. Aim 3 included 2 patients with isolated calf-level deep vein thrombosis (DVT). Results: GMI-1271 showed consistent PK parameters for doses ranging from 2 to 40 mg/kg. Plasma levels increased in a linear manner with respect to dose, while clearance, volume of distribution, and half-life were not dose dependent. No accumulation was seen with multiple consecutive doses. No serious adverse events (grade 3 or 4) were reported. Biomarker analysis demonstrated a trend in reduction of soluble E-Selectin (sEsel) levels with GMI-1271 exposure, while exposure did not impact laboratory testing of coagulation. Two patients with calf vein DVT were treated with GMI-1271 and demonstrated rapid improvement of symptoms after 48 hours, with repeat ultrasound showing signs of clot resolution. Conclusions: We demonstrate that GMI-1271 is safe in healthy volunteers and provide proof of concept that an E-Selectin Antagonist is a potential therapeutic approach to treat venous thrombosis.

  • A Novel and Potent Inhibitor of E-Selectin, GMI-1687, Attenuates Thrombus Formation and Augments Chemotherapeutic Intervention of AML in Preclinical Models Following Subcutaneous Administration
    Blood, 2018
    Co-Authors: John M. Peterson, Daniel D Myers, Theodore A.g. Smith, Myung-gi Baek, Silvia Locatelli-hoops, Lingquan Deng, David A. Stewart, William E. Fogler, John L Magnani
    Abstract:

    Uproleselan (GMI-1271), an E-Selectin Antagonist, has been shown in preclinical models to disrupt activation of cell survival pathways in acute myeloid leukemia (AML), enhance chemotherapy efficacy, and improve survival. Uproleselan received FDA breakthrough therapy designation for adult relapsed/refractory AML in 2017 and Phase III studies are ongoing. In the present studies we report on the in vitro and in vivo comparative activities of an innovative high potency E-Selectin Antagonist, GMI-1687, a potential subcutaneously administered follow-on drug candidate to Uproleselan. The binding constant, association and dissociation rates of GMI-1687 to immobilized recombinant human (rh) E-Selectin were determined by surface plasmon resonance (SPR) at 25oC. The KD of GMI-1687 was 2.4 nM, with Kon = 3 x 106 M-1s-1 and Koff = 1 x10-2 s-1. Under similar experimental conditions the KD of Uproleselan was 520 nM with Kon = 0.02 x 106 M-1s-1 and Koff = 1 x10-2 s-1. GMI-1687 was evaluated for its ability to inhibit binding of sialyl Lea to immobilized rh E-Selectin. The median IC50 (n=6 independent assays) of GMI-1687 and Uproleselan in this assay was 15 and 550 nM, respectively. The in vitro activity of GMI-1687 to release adherent KG1a AML cells from E-Selectin coated wells was also determined. GMI-1687 at 100 nM detached approximately 55% of adherent AML cells and was significantly different from Uproleselan at an identical concentration (38% detachment, P=0.0216). The percent bioavailability (%F) of GMI-1687 was evaluated in male Sprague-Dawley rats following intravenous (IV) and subcutaneous (SC) routes of administration at 5 mg/kg. The mean (+/- SD) SC %F for GMI-1687 was 126 +/- 3.8%. GMI-1687 also showed high bioavailability in CD-1 mice after SC administration of 0.58 mg/kg with %F = 132 +/-38. The in vivo therapeutic activity of GMI-1687 following SC administration was assessed in an acute model of inferior vena cava (IVC) thrombosis and a tumor model of AML.Immediately following the induction of a non-occlusive thrombosis via electrical stimulation (250 mAmp) of the IVC, cohorts of male C57BL/6J mice (n=5/group) were given a single SC injection of saline (0.1 mL); Uproleselan (40 mg/kg); or GMI-1687 (4 mg/kg, 0.4 mg/kg or 0.04 mg/kg), and twenty-four hrs post thrombus induction the IVC was harvested from all mice and thrombus weights were determined. Treatment with GMI-1687 decreased thrombus formation with significant inhibition at 0.04 mg/kg (92%, P 47.5 days, P=0.0153 compared to AraC+DNR alone). In summary, a highly potent innovative Antagonist of E-Selectin, GMI-1687, has been produced that demonstrates high bioavailability following SC administration. SC injection of GMI-1687 shows significant activity in preclinical models previously reported for parenteral administration of Uproleselan, but at approximately 250-fold lower dose. GMI-1687 is therefore well-positioned for potential use in outpatient treatment settings where an E-Selectin Antagonist has therapeutic relevance. IND-enabling studies with GMI-1687 are currently underway. Disclosures Peterson:GlycoMimetics: Employment, Equity Ownership. Baek:GlycoMimetics: Employment, Equity Ownership. Locatelli-Hoops:GlycoMimetics: Employment, Equity Ownership. Lee:GlycoMimetics: Employment, Equity Ownership. Deng:GlycoMimetics: Employment, Equity Ownership. Stewart:GlycoMimetics: Employment, Equity Ownership. Smith:GlycoMimetics: Employment, Equity Ownership. Fogler:GlycoMimetics: Employment, Equity Ownership. Magnani:GlycoMimetics: Employment, Equity Ownership, Membership on an entity9s Board of Directors or advisory committees.

  • uproleselan gmi 1271 an e Selectin Antagonist improves the efficacy and safety of chemotherapy in relapsed refractory r r and newly diagnosed older patients with acute myeloid leukemia final correlative and subgroup analyses
    Blood, 2018
    Co-Authors: Daniel J. Deangelo, Jane L. Liesveld, Brian A. Jonas, Dale L. Bixby, Michael Odwyer, Anjali S Advani, Paula Marlton, William E. Fogler, Curt Wolfgang, John L Magnani
    Abstract:

    Background Binding of E-Selectin (E-sel) to sialyl Lex on the leukemic cell surface activates cell survival pathways and promotes chemotherapy resistance in AML. Expression of the E-sel ligand (E-sel-L) is associated with increased relapse and poor survival. Uproleselan (GMI-1271), a novel E-sel Antagonist, disrupts cell survival pathway activation, enhances chemotherapy response and protects from toxicity with improved survival in vivo. We added uproleselan to mitoxantrone, etoposide, cytarabine (MEC) chemotherapy for R/R AML patients (pts) and to cytarabine and idarubicin (7+3) induction for older, treatment naive (TN) AML pts. Here we report on final outcomes and correlative studies. Methods A Phase (Ph) 1/2 trial evaluated safety and efficacy of escalating doses of upro (5-20 mg/kg) combined with MEC in pts with R/R AML. The recommended Ph 2 dose (RP2D) was 10 mg/kg. Ph 2 added pts ≥60 yrs with TN AML treated with upro and 7+3. Uproleselan was given 24 hrs prior, every 12 hrs during and 48 hrs post chemotherapy. Responders could receive consolidation therapy (1 cycle MEC or 1-3 cycles IDAC) with uproleselan. Baseline E-sel-L expression on AML blasts (CD45+,SSC) and leukemic stem cells (LSC, CD34+CD38-CD123+) in blood and bone marrow (BM) was assessed by flow cytometry, for percentage of blasts binding to E-sel-Fc chimeric protein and HECA452 (antibody to sialyl Lex). Post-induction measurable residual disease (MRD-/MRD+) was assessed locally. Results 91 pts were enrolled (Ph 1 R/R=19; Ph 2 R/R=47. TN=25). Median age in R/R pts was 59 yrs (26-84) with 22/66 (33%) primary refractory, 22 (33%) CR1 Median age in TN pts was 67 yrs (60-79). 48% had adverse risk (ELN) and 52% secondary AML (sAML). Uproleselan was well tolerated, with no increase in adverse events, no Grade 3/4 mucositis, and mortality 8% (30d) and 12% (60d). CR/CRi was 72% (all), and 69% (sAML). 5/9 (56%) evaluable pts were MRD-. 19/25 (76%) proceeded to further anti-leukemic therapy; 11 (44%) proceeded to SCT. Median (95% CI) EFS, OS, and remission duration were 9.2 m (3.0-12.6), 12.6 m (9.9-NR), and 10.4 m (7.1-17.8) respectively; 1-year OS was 52%. For sAML, median (95% CI) EFS and OS were 7.7 m (1.1-9.5) and 10.5m (4.4-NR), respectively. For TN/MRD-, 1-year OS was 60%. E-sel-L was detectable on BM blasts in all 24 evaluable pts: median expression 31% (2-92) of blasts. In a subset of MRD evaluable pts (N=8), E-sel-L expression was higher in those who were MRD+ (35% vs 8%). In BM blasts (Figure N=24), LSC expression of E-sel-L correlated with blast E-sel-L (R2=0.87, p Conclusion The addition of uproleselan to chemotherapy was well tolerated, with low oral mucositis rates, high remission rates, high MRD- and transplant rates, and promising survival outcomes in pts with R/R and TN AML. High E-sel-L expression is associated with improved remission and survival with uproleselan treatment in R/R AML. Phase III studies in pts with R/R and (older) TN AML are underway. Disclosures DeAngelo:Shire: Honoraria; Amgen: Consultancy; BMS: Consultancy; ARIAD: Consultancy, Research Funding; Blueprint Medicines: Honoraria, Research Funding; Takeda: Honoraria; Glycomimetics: Research Funding; Novartis Pharmaceuticals Corporation: Consultancy, Honoraria; Amgen: Consultancy; Novartis Pharmaceuticals Corporation: Consultancy, Honoraria; Incyte: Consultancy, Honoraria; Glycomimetics: Research Funding; Blueprint Medicines: Honoraria, Research Funding; Pfizer Inc: Consultancy, Honoraria; Shire: Honoraria; BMS: Consultancy; Takeda: Honoraria; Incyte: Consultancy, Honoraria; Pfizer Inc: Consultancy, Honoraria; ARIAD: Consultancy, Research Funding. Jonas:Glycomimetics: Research Funding; Genentech/Roche: Research Funding; Celgene: Consultancy, Research Funding; Accelerated Medical Diagnostics: Research Funding; Daiichi Sankyo: Research Funding; Incyte: Research Funding; Esanex: Research Funding; Tolero: Consultancy; Kalobios: Research Funding; LP Therapeutics: Research Funding; Amgen: Consultancy; Pharmacyclics: Research Funding; Forma: Research Funding; AbbVie: Consultancy, Research Funding. Liesveld:Onconova: Other: DSMB; Abbvie: Honoraria. Bixby:GlycoMimetics: Research Funding. Advani:Glycomimetics: Consultancy; Novartis: Consultancy; Amgen: Research Funding; Pfizer: Honoraria, Research Funding. Marlton:GlycoMimetics: Research Funding; Novartis: Honoraria, Membership on an entity9s Board of Directors or advisory committees; Roche: Honoraria, Membership on an entity9s Board of Directors or advisory committees; Janssen: Honoraria, Membership on an entity9s Board of Directors or advisory committees; AbbVie: Honoraria, Membership on an entity9s Board of Directors or advisory committees; Astellas: Honoraria, Membership on an entity9s Board of Directors or advisory committees; Celgene: Membership on an entity9s Board of Directors or advisory committees; Pfizer: Membership on an entity9s Board of Directors or advisory committees. O9Dwyer:Janssen: Membership on an entity9s Board of Directors or advisory committees, Research Funding; BMS: Research Funding; Onkimmune: Equity Ownership, Membership on an entity9s Board of Directors or advisory committees, Research Funding; Celgene: Research Funding; Glycomimetics: Research Funding; Abbvie: Membership on an entity9s Board of Directors or advisory committees. Fogler:GlycoMimetics: Employment, Equity Ownership. Wolfgang:GlycoMimetics: Employment, Equity Ownership. Magnani:GlycoMimetics: Employment, Equity Ownership, Membership on an entity9s Board of Directors or advisory committees. Thackray:GlycoMimetics: Employment, Equity Ownership. Becker:GlycoMimetics: Research Funding.

  • gmi 1271 a novel e Selectin Antagonist in combination with chemotherapy in relapsed refractory aml
    Journal of Clinical Oncology, 2017
    Co-Authors: Daniel J. Deangelo, John L Magnani, Helen M Thackray, Jane L. Liesveld, Brian A. Jonas, Dale L. Bixby, Michael Odwyer, Anjali S Advani, Paula Marlton, Pamela S. Becker
    Abstract:

    2520Background: GMI-1271 is a novel Antagonist of E-Selectin (E-sel) that down-regulates cell survival pathways and enhances chemotherapy response. We assessed GMI-1271 plus salvage chemotherapy with mitoxantrone, etoposide, and cytarabine (MEC) for the treatment of patients (pts) with relapsed/refractory (R/R) AML. Methods: A phase (Ph) 1trial in pts with R/R AML escalated GMI-1271 across pharmacologically active doses from 5-20 mg/kg combined with MEC. Safety, tolerability and anti-leukemia activity were assessed. GMI-1271 was given 24 hrs prior, then every 12 hrs during and for 48 hrs post induction/consolidation. Eligible pts had an ECOG score 0-2, received ≤2 prior inductions, WBC < 20K ( < 40K after 2 dose levels), no active CNS disease, and adequate renal/hepatic function. E-sel expression was assessed. After confirming safety and tolerability, a Ph 2 study of GMI-1271 at 10 mg/kg plus MEC was initiated. Results: To date, 47 pts have enrolled (Ph 1 = 19; Ph 2 = 28 of planned 47). The recommended Ph...

  • gmi 1271 a novel e Selectin Antagonist combined with induction chemotherapy in elderly patients with untreated aml
    Journal of Clinical Oncology, 2017
    Co-Authors: Daniel J. Deangelo, John L Magnani, Helen M Thackray, Brian A. Jonas, Pamela S. Becker, Michael Odwyer, Anjali S Advani, Paula Marlton, Jane L. Liesveld
    Abstract:

    2560Background: The outcomes for elderly patients (pts) with acute myeloid leukemia (AML) remain poor, therefore newer and less toxic therapies are urgently needed. The binding of E-Selectin (E-sel), an adhesion molecule expressed in the bone marrow, to the leukemic cell surface activates survival pathways and promotes chemotherapy resistance. GMI-1271, a novel E-sel Antagonist, enhances chemotherapy responses and protects from common toxicities in preclinical models (Becker ASH 2013; Winkler ASH 2013 and 2014). We report interim Phase 2 data for GMI-1271 plus chemotherapy in elderly untreated pts with AML. Methods: Pts ≥ 60 yrs with untreated AML, ECOG 0-2, and adequate renal and hepatic function were eligible. Prior treatment of MDS was allowed. GMI-1271 (10 mg/kg) was given 24 hrs prior, during and 48 hrs post induction with infusional cytarabine and idarubicin (7+3). Safety, tolerability, and anti-leukemia activity were assessed. Two cycles of induction were allowed and responders could receive consol...

John T. Patton - One of the best experts on this subject based on the ideXlab platform.

  • novel e Selectin Antagonist gmi 1271 decreases venous thrombosis without increased bleeding potential in a mouse model
    Blood, 2012
    Co-Authors: Daniel D Myers, Angela E Hawley, Thomas W Wakefield, John T. Patton, Suman L Sood, Peter K Henke, Jose A Diaz, Dorian Laird Culmer, Robert E Sigler, John L Magnani
    Abstract:

    Abstract 3422 Introduction: Selectins function in venous thrombosis presumably by binding and activating immune cells to initiate the coagulation cascade. E-Selectin (CD62E) is known to bind and activate both monocytes and neutrophils. GMI-1271 is a small molecule Antagonist that specifically inhibits E-Selectin and is rationally designed to mimic the bioactive conformation of the sialyl-Lex carbohydrate ligand. Here we determine whether specific inhibition of E-Selectin is sufficient to inhibit acute venous thrombosis and associated inflammatory events in both prophylactic and treatment protocols without causing the broader effects of increased bleeding time. Methods: Male C57BL/6J mice underwent our electrolytic inferior vena cava (IVC) model to produce a non-occlusive thrombosis via electrical stimulation (250 μAmp). Animals were divided into prophylactic or treatment groups. Both groups included the following: non-thrombosed animals (TC, no surgery or drug), 2 Day sham (needle inside the IVC and no current or drug), 2 Day CTR (current and no drug), 2 Day GMI-1271 (10mg/kg IP BID), and LMWH (Lovenox®, 6mg/kg SQ QD). Animals were divided into prophylactic or treatment groups. Mice in the prophylactic group were dosed one day pre-thrombus induction through day 1. Animals in the treatment groups received the first dose of the drug following thrombus induction on day 1. Mice were euthanized 2 days post-thrombosis for tissue harvest and blood collection for the following evaluations: thrombus weight; vein wall inflammatory cell counts per high power field; vein wall-thrombus histology; and intra-thrombus polymorphonuclear cell (PMN) counts. A separate group of mice received IV administration of compounds for tail bleeding time evaluation (seconds). Results: GMI-1271 Significantly Decreases Venous Thrombus Weight ([Figure 1][1]). Treatment with GMI-1271 decreased venous thrombus formation in a dose-dependent manner with significant inhibition at 10mg/kg (P=0.0271). Treatment with LMWH significantly decreased thrombus formation 2 day post induction at 6mg/kg (P=0.0203). All mice pre-treated prophylactically with GMI-1271 or LMWH followed the same pattern of decreasing thrombus weight 2 days post injury (P<0.05). E-Selectin Inhibition with GMI-1271 Does Not Increase Bleeding Potential ([Figure 2][2]) LMWH at 6 mg/kg dose significantly elevated tail bleeding times in mice versus controls (341±27, 491±60 vs. 82±6 seconds, P<0.01). GMI-1271 (10mg/kg, IV) had significantly lower tail bleeding times compared to an IV dose of LMWH (6mg/kg, P<0.01). Vein Wall Morphometrics and Histology Treatment: Only treatment with GMI-1271 significantly decreased vein wall monocyte extravasation compared to controls (P<0.05). Prophylaxis: GMI-1271 and LMWH prophylaxis significantly decreased vein wall PMN extravasation 2 days post thrombosis (P=0.027 and P=0.007 respectively). The same pattern held true for prophylaxis with GMI-1271 and LMWH on vein wall monocyte extravasation at the same time point (P<0.01). Intra-Thrombus PMN Counts: GMI-1271 prophylactic therapy significantly decreases intra-thrombus cell counts versus control animal (14.5±3.7 vs. 37.4±4.7 PMNs/HPF, P=0.009), and these animals had decreased venous thrombus burden. Of interest, only mice receiving GMI-1271 therapy visually have more intra-thrombus vascular channels compared to control animals and mice receiving LMWH therapy. Conclusion: GMI 1271 inhibits venous thrombosis and significantly decreases thrombus weight. GMI 1271 proposes a much lower risk of patients having bleeding complications. Vascular channels exclusively present in thrombi from mice receiving GMI-1271 therapy may aide in thrombus resolution which is currently under investigation. Delayed inflammatory cell recruitment of all cell types into the vein wall post thrombus induction indicates a possible decrease in leukocyte activation. This data suggest that inhibition of E-Selectin is sufficient to inhibit venous thrombosis without an increased bleeding risk and the small molecule E-Selectin specific Antagonist GMI-1271 is a viable therapeutic candidate for venous thrombosis treatment and prophylaxis. ![Figure 1.][3] Figure 1. Inhibition of venous thrombsis. ![Figure 2.][3] Figure 2. Effects of treatments on tail bleeding times. Disclosures: Patton: GlycoMimetics: Employment. Magnani: GlycoMimetics: Employment, Equity Ownership. [1]: #F1 [2]: #F2 [3]: pending:yes

  • pan Selectin Antagonist gmi 1070 affects biomarkers of adhesion activation and the coagulation cascade in sickle cell adults at steady state
    Blood, 2012
    Co-Authors: John L Magnani, John T. Patton, Frans A Kuypers, Sandra Larkin, Lori Styles, Laura Decastro, Marilyn J Telen, Helen M Thackray
    Abstract:

    Abstract 87 Introduction: Engagement of Selectins by their ligands leads to cellular activation and adhesion and plays a role in thrombus formation. In sickle cell disease (SCD), the Selectins underlie vaso-occlusion, which results in vaso-occlusive crisis (VOC). In SCD patients high levels of soluble E-Selectin (sEsel) are associated with increased mortality (Kato, BJH 2005). In addition, SCD patients exhibit chronic activation of the coagulation cascade and of leukocytes. Previously, we showed in animal models of SCD VOC that pan-Selectin Antagonist GMI-1070 reduced arrested RBC/WBC aggregates and improved blood flow and survival. In a Phase 1 study of SCD adults at steady state (not in VOC), GMI-1070 inhibited neutrophil activation and platelet/neutrophil aggregate formation and increased circulating neutrophils. Herein we report on the effect of GMI-1070 on biomarkers of monocyte, endothelial cell, and coagulation cascade activation; and on the effect of hydroxycarbamide (hydroxyurea or HU) on these biomarkers for patients on this trial. Methods: SCD adults at steady state (n=15) received an IV loading dose of GMI-1070 (20 mg/kg) and a second dose ten hours later (10 mg/kg). Safety and PK were reported elsewhere. HU use was noted. Biomarker blood samples were drawn prior to treatment, and at 4, 8, 24 and 48 hrs after the loading dose. Analytes measured included: soluble adhesion molecules sEsel, soluble P-Selectin (sPsel) and intracellular adhesion molecule-1 (ICAM-1) by multiplex ELISA; tissue factor and thrombin-antithrombin complexes (TF and TAT) by ELISA; and, surface expression of monocyte b2 integrins MAC-1 & LFA-1; and platelet-monocyte aggregates (PMA) by flow cytometry. Expression levels were compared against pre-treatment, and stratified by HU use. Analysis was by ANOVA F-test from mixed effects model. Data are reported for 11 subjects (biomarkers) and 15 subjects (neutrophils). Results: Soluble adhesion markers were reduced after 8 hrs (sEsel), or 4 and 8 hrs (sPsel; ICAM-1). Tissue factor (TF) was reduced at 4 and 8 hrs. Thrombin-antithrombin complex (TAT) levels and expression of MAC-1 and LFA-1 were reduced at all time points. The percentage of PMA was reduced at 8 hrs. (Table) When HU use was considered (HU–No; HU–Yes), the levels of sEsel, sPsel, ICAM-1, TF, TAT, MAC-1, and neutrophil counts were higher and more variable at baseline in the HU-No group, significantly so for ICAM-1 (p=0.048) and MAC-1 (p=0.001). After GMI-1070, significant reduction from baseline was seen in both groups: in the HU-No group for ICAM-1, TF, PMA, LFA-1, and in the HU-Yes group for sEsel, MAC-1, TF, TAT. Neutrophil counts increased at 24 hours in the HU-No group only (p=0.001). Conclusion: In this small sample of adults with SCD at steady state, Selectin inhibition by treatment with GMI-1070 resulted in reduction in soluble adhesion markers, leukocyte activation, PMA, and markers of coagulation activation. This suggests that Selectin inhibition affects downstream processes in vivo, continuing after plasma clearance of >97% of the drug. This may represent interference in the processes that lead to VOC in SCD. A phase 2 study is underway to further explore the effect of this experimental drug on these markers and in the treatment of VOC. Disclosures: Magnani:GlycoMimetics: Employment, Equity Ownership. Kuypers:GlycoMimetics: Research Funding. Patton:GlycoMimetics: Employment. Larkin:GlycoMimetics: Research Funding. Styles:GlycoMimetics: Research Funding. DeCastro:GlycoMimetics: Research Funding. Telen:GlycoMimetics: Research Funding. Wun:GlycoMimetics: Research Funding. Thackray:GlycoMimetics: Employment, Equity Ownership.

  • Novel E-Selectin Antagonist GMI-1271 Decreases Venous Thrombosis without Increased Bleeding Potential in a Mouse Model
    Blood, 2012
    Co-Authors: Daniel D Myers, Angela E Hawley, John T. Patton, Suman L Sood, Peter K Henke, Jose A Diaz, Dorian Laird Culmer, Robert E Sigler, Andrea T., Thomas W Wakefield
    Abstract:

    Abstract 3422 Introduction: Selectins function in venous thrombosis presumably by binding and activating immune cells to initiate the coagulation cascade. E-Selectin (CD62E) is known to bind and activate both monocytes and neutrophils. GMI-1271 is a small molecule Antagonist that specifically inhibits E-Selectin and is rationally designed to mimic the bioactive conformation of the sialyl-Lex carbohydrate ligand. Here we determine whether specific inhibition of E-Selectin is sufficient to inhibit acute venous thrombosis and associated inflammatory events in both prophylactic and treatment protocols without causing the broader effects of increased bleeding time. Methods: Male C57BL/6J mice underwent our electrolytic inferior vena cava (IVC) model to produce a non-occlusive thrombosis via electrical stimulation (250 μAmp). Animals were divided into prophylactic or treatment groups. Both groups included the following: non-thrombosed animals (TC, no surgery or drug), 2 Day sham (needle inside the IVC and no current or drug), 2 Day CTR (current and no drug), 2 Day GMI-1271 (10mg/kg IP BID), and LMWH (Lovenox®, 6mg/kg SQ QD). Animals were divided into prophylactic or treatment groups. Mice in the prophylactic group were dosed one day pre-thrombus induction through day 1. Animals in the treatment groups received the first dose of the drug following thrombus induction on day 1. Mice were euthanized 2 days post-thrombosis for tissue harvest and blood collection for the following evaluations: thrombus weight; vein wall inflammatory cell counts per high power field; vein wall-thrombus histology; and intra-thrombus polymorphonuclear cell (PMN) counts. A separate group of mice received IV administration of compounds for tail bleeding time evaluation (seconds). Results: GMI-1271 Significantly Decreases Venous Thrombus Weight ([Figure 1][1]). Treatment with GMI-1271 decreased venous thrombus formation in a dose-dependent manner with significant inhibition at 10mg/kg (P=0.0271). Treatment with LMWH significantly decreased thrombus formation 2 day post induction at 6mg/kg (P=0.0203). All mice pre-treated prophylactically with GMI-1271 or LMWH followed the same pattern of decreasing thrombus weight 2 days post injury (P

  • Vascular niche E-Selectin regulates hematopoietic stem cell dormancy, self renewal and chemoresistance
    Nature Medicine, 2012
    Co-Authors: Ingrid G Winkler, John L Magnani, John T. Patton, Valerie Barbier, Bianca Nowlan, Rebecca N Jacobsen, Catherine E Forristal, Jeanpierre Levesque
    Abstract:

    The self renewal of hematopoietic stem cells is regulated by the bone marrow microenvironment. Whereas previous studies have focused on the role of osteoblasts, Ingrid Winkler et al . now show that bone marrow endothelial cells in the so-called 'vascular niche' contribute to this regulation by directly inducing HSC proliferation. In mice, deficiency or antagonism of the endothelial-specific adhesion protein E-Selectin promotes HSC quiescence and self renewal. These findings may point to a new treatment strategy for preserving HSC function in patients undergoing chemotherapy. The microenvironment, or niche, surrounding a stem cell largely governs its cellular fate. Two anatomical niches for hematopoietic stem cells (HSCs) have been reported in the bone marrow, but a distinct function for each of these niches remains unclear. Here we report a new role for the adhesion molecule E-Selectin expressed exclusively by bone marrow endothelial cells in the vascular HSC niche. HSC quiescence was enhanced and self-renewal potential was increased in E-Selectin knockout ( Sele ^−/−) mice or after administration of an E-Selectin Antagonist, demonstrating that E-Selectin promotes HSC proliferation and is a crucial component of the vascular niche. These effects are not mediated by canonical E-Selectin ligands. Deletion or blockade of E-Selectin enhances HSC survival threefold to sixfold after treatment of mice with chemotherapeutic agents or irradiation and accelerates blood neutrophil recovery. As bone marrow suppression is a severe side effect of high-dose chemotherapy, transient blockade of E-Selectin is potentially a promising treatment for the protection of HSCs during chemotherapy or irradiation.

  • pan Selectin Antagonist gmi 1070 decreases venous thrombosis in a mouse model
    Blood, 2011
    Co-Authors: Daniel D Myers, Angela E Hawley, Thomas W Wakefield, John T. Patton, Shirley K. Wrobleski, Peter K Henke, Jose A Diaz, Dallas Slack, John L Magnani
    Abstract:

    Abstract 3273 Introduction: E- and P-Selectin have structural similarities and both facilitate white blood cell tethering on vascular endothelium. The beneficial effect of combined E- and P-Selectin inhibition in decreasing venous thrombosis (VT) by gene deletion in a mouse model of VT has been demonstrated. GMI-1070 is a pan-Selectin inhibitor designed to mimic the bioactive conformation of the sialyl-Le x carbohydrate binding domain of E-Selectin and the sulfate interactions of P- and L-Selectins. GMI-1070 has primary activity against E-Selectin, with second and tertiary activity against P- and L-Selectin. It has passed Phase I clinical trials showing no serious adverse events, and has a serum half-life in humans of 7 to 8 hours. In this study, the effect of pan-Selectin inhibition by GMI-1070 on reducing VT was evaluated. Methods: Male C57BL/6J mice (20-25grams) underwent our electrolytic IVC model (EIM) to produce a non-occlusive thrombosis via electrical free radical stimulation (250 μAmp) for 15 minutes. Experimental groups included the following: GMI-1070 delivered continuously by mini osmotic pump (300 mg/ml), and mice administered saline via the same protocol served as controls (SAL CTR). Continuous delivery of GMI-1070, or saline, began one day pre-thrombus induction. Mice were euthanized 2 and 6 days post-thrombosis for tissue harvest and blood collection for the following evaluations: thrombus weight (grams); plasma soluble E- and P-Selectin (ng/mg total protein); vein wall E- and P-Selectin protein by ELISA (pg/mg total protein); and vein wall inflammatory cell counts per high powered field. Results: Continuous GMI-1070 administration significantly decreased venous thrombus weight (WT) two days post thrombosis (78±8 vs. 216±97 ×10 −4 grams, P −4 grams, P≤0.05) [Figure 1]. Circulating E-Selectin protein was decreased significantly at both day 2 (21700±2014 vs. 56360±4284 pg/mg total protein, P Conclusions: GMI-1070 therapy significantly decreased venous thrombus formation. This pan-Selectin inhibitor modulated circulating E- and P-Selectin and vein wall E- Selectin levels thus decreasing systemic and local inflammatory effects of both adhesion molecules. GMI-1070 therapy significantly increased vein wall monocytes and these mice had the greatest VT resolution. GMI-1070 has a high therapeutic potential for decreasing thrombosis and Selectin related events. Disclosures: Patton: GlycoMimetics, Inc.: Employment, Equity Ownership. Magnani: GlycoMimetics, Inc.: Employment, Equity Ownership.

Helen M Thackray - One of the best experts on this subject based on the ideXlab platform.

  • use of gmi 1271 an e Selectin Antagonist in healthy subjects and in 2 patients with calf vein thrombosis
    Research and practice in thrombosis and haemostasis, 2020
    Co-Authors: Sumana Devata, Dana E Angelini, Susan Blackburn, Angela E Hawley, Daniel D Myers, Jordan K Schaefer, Martina V Hemmer, John L Magnani, Helen M Thackray, Thomas W Wakefield
    Abstract:

    Background: There is an unmet need for antithrombotic treatments for venous thromboembolic disease that do not increase bleeding risk. Selectins are cell adhesion molecules that augment thrombosis by activating immune cells to initiate the coagulation cascade. GMI-1271, a potent small-molecule E-Selectin Antagonist, has been shown in mouse models to decrease thrombus burden with a low risk of bleeding. Methods: A first-in-human study of GMI-1271 was conducted to assess its safety, tolerability, and pharmacokinetic (PK) profile. As a secondary end point, biomarkers of coagulation, cell adhesion, and leukocyte/platelet activation were evaluated. Aims 1 and 2 were performed in healthy volunteers and evaluated single and multiple doses of the study drug, respectively. Aim 3 included 2 patients with isolated calf-level deep vein thrombosis (DVT). Results: GMI-1271 showed consistent PK parameters for doses ranging from 2 to 40 mg/kg. Plasma levels increased in a linear manner with respect to dose, while clearance, volume of distribution, and half-life were not dose dependent. No accumulation was seen with multiple consecutive doses. No serious adverse events (grade 3 or 4) were reported. Biomarker analysis demonstrated a trend in reduction of soluble E-Selectin (sEsel) levels with GMI-1271 exposure, while exposure did not impact laboratory testing of coagulation. Two patients with calf vein DVT were treated with GMI-1271 and demonstrated rapid improvement of symptoms after 48 hours, with repeat ultrasound showing signs of clot resolution. Conclusions: We demonstrate that GMI-1271 is safe in healthy volunteers and provide proof of concept that an E-Selectin Antagonist is a potential therapeutic approach to treat venous thrombosis.

  • gmi 1271 a novel e Selectin Antagonist in combination with chemotherapy in relapsed refractory aml
    Journal of Clinical Oncology, 2017
    Co-Authors: Daniel J. Deangelo, John L Magnani, Helen M Thackray, Jane L. Liesveld, Brian A. Jonas, Dale L. Bixby, Michael Odwyer, Anjali S Advani, Paula Marlton, Pamela S. Becker
    Abstract:

    2520Background: GMI-1271 is a novel Antagonist of E-Selectin (E-sel) that down-regulates cell survival pathways and enhances chemotherapy response. We assessed GMI-1271 plus salvage chemotherapy with mitoxantrone, etoposide, and cytarabine (MEC) for the treatment of patients (pts) with relapsed/refractory (R/R) AML. Methods: A phase (Ph) 1trial in pts with R/R AML escalated GMI-1271 across pharmacologically active doses from 5-20 mg/kg combined with MEC. Safety, tolerability and anti-leukemia activity were assessed. GMI-1271 was given 24 hrs prior, then every 12 hrs during and for 48 hrs post induction/consolidation. Eligible pts had an ECOG score 0-2, received ≤2 prior inductions, WBC < 20K ( < 40K after 2 dose levels), no active CNS disease, and adequate renal/hepatic function. E-sel expression was assessed. After confirming safety and tolerability, a Ph 2 study of GMI-1271 at 10 mg/kg plus MEC was initiated. Results: To date, 47 pts have enrolled (Ph 1 = 19; Ph 2 = 28 of planned 47). The recommended Ph...

  • gmi 1271 a novel e Selectin Antagonist combined with induction chemotherapy in elderly patients with untreated aml
    Journal of Clinical Oncology, 2017
    Co-Authors: Daniel J. Deangelo, John L Magnani, Helen M Thackray, Brian A. Jonas, Pamela S. Becker, Michael Odwyer, Anjali S Advani, Paula Marlton, Jane L. Liesveld
    Abstract:

    2560Background: The outcomes for elderly patients (pts) with acute myeloid leukemia (AML) remain poor, therefore newer and less toxic therapies are urgently needed. The binding of E-Selectin (E-sel), an adhesion molecule expressed in the bone marrow, to the leukemic cell surface activates survival pathways and promotes chemotherapy resistance. GMI-1271, a novel E-sel Antagonist, enhances chemotherapy responses and protects from common toxicities in preclinical models (Becker ASH 2013; Winkler ASH 2013 and 2014). We report interim Phase 2 data for GMI-1271 plus chemotherapy in elderly untreated pts with AML. Methods: Pts ≥ 60 yrs with untreated AML, ECOG 0-2, and adequate renal and hepatic function were eligible. Prior treatment of MDS was allowed. GMI-1271 (10 mg/kg) was given 24 hrs prior, during and 48 hrs post induction with infusional cytarabine and idarubicin (7+3). Safety, tolerability, and anti-leukemia activity were assessed. Two cycles of induction were allowed and responders could receive consol...

  • GMI-1271, a novel E-Selectin Antagonist, in combination with chemotherapy in relapsed/refractory AML.
    Journal of Clinical Oncology, 2017
    Co-Authors: Daniel J. Deangelo, John L Magnani, Helen M Thackray, Jane L. Liesveld, Brian A. Jonas, Michael O'dwyer, Dale L. Bixby, Anjali S Advani, Paula Marlton, Pamela S. Becker
    Abstract:

    2520Background: GMI-1271 is a novel Antagonist of E-Selectin (E-sel) that down-regulates cell survival pathways and enhances chemotherapy response. We assessed GMI-1271 plus salvage chemotherapy with mitoxantrone, etoposide, and cytarabine (MEC) for the treatment of patients (pts) with relapsed/refractory (R/R) AML. Methods: A phase (Ph) 1trial in pts with R/R AML escalated GMI-1271 across pharmacologically active doses from 5-20 mg/kg combined with MEC. Safety, tolerability and anti-leukemia activity were assessed. GMI-1271 was given 24 hrs prior, then every 12 hrs during and for 48 hrs post induction/consolidation. Eligible pts had an ECOG score 0-2, received ≤2 prior inductions, WBC < 20K ( < 40K after 2 dose levels), no active CNS disease, and adequate renal/hepatic function. E-sel expression was assessed. After confirming safety and tolerability, a Ph 2 study of GMI-1271 at 10 mg/kg plus MEC was initiated. Results: To date, 47 pts have enrolled (Ph 1 = 19; Ph 2 = 28 of planned 47). The recommended Ph...

  • A Phase I/II Study of GMI-1271, a Novel E-Selectin Antagonist, in Combination with Induction Chemotherapy in Relapsed/Refractory and Elderly Previously Untreated Acute Myeloid Leukemia; Results to Date
    Blood, 2016
    Co-Authors: Daniel J. Deangelo, John L Magnani, Helen M Thackray, Jane L. Liesveld, Brian A. Jonas, Michael O'dwyer, Dale L. Bixby, Pamela S. Becker
    Abstract:

    Background The treatment of patients with relapsed acute myeloid leukemia (AML) remains a significant challenge with poor outcomes due to a low response rate. Although cytotoxic chemotherapy remains the standard approach for treatment, novel agents are needed to improve clinical outcomes. Binding of leukemic blasts to E-Selectin (E-sel), an adhesion molecule expressed constitutively in the bone marrow endothelium, activates leukemic cell survival pathways, thereby contributing to chemotherapy resistance. GMI-1271 is a novel Antagonist of E-sel, putatively disrupting leukemia cell survival pathways and enhancing chemotherapy response. We performed a phase 1/2 trial of GMI-1271 plus MEC (mitoxantrone, etoposide and cytarabine) for the treatment of relapsed/refractory (R/R) and a pilot study adding GMI-1271 to 7+3 for previously untreated elderly patients with AML. Methods A phase 1/2 open label trial of patients with R/R AML, with escalation of a single cycle of GMI-1271 across 3 dose levels combined with MEC, was conducted to assess safety, tolerability, pharmacokinetics (PK), pharmacodynamics (PD) and antileukemic activity. In addition, a pilot study was performed at the recommended phase 2 dose (RP2D) plus infusional cytarabine and idarubicin (7+3) in patients ≥60 years with untreated AML. Eligible patients (R/R AML) had an ECOG score of 0-2, received ≤2 prior induction regimens, WBC 1K) and 35 d (platelets >100K) in responders. AEs were typical for MEC. Ph1 CR/CRi rate was 47% (42% CR%) with no observable dose response; 26% proceeded to subsequent stem cell transplant. Six of 9 remain in CR at data cut-off. Median OS and PFS have not been reached. One subject >70yrs with refractory disease who achieved CR (negative by flow) was retreated with GMI-1271/MEC again off protocol and remains in CR (9mo). PK analysis showed linear kinetics; an average 50 y.o. had clearance 1.28 L/h with elimination t1/2>3h; Cl decreased 2%/yr of increased age, and was 28% lower than in healthy adults. No accumulation was seen. Time over IC50 for E-sel binding was >50% of the dosing interval for most patients at 10 mg/kg, and well in excess of effective preclinical exposure. PD analysis showed sE-sel on Day 8 decreased below baseline (p˂0.0013) with no dose response, suggesting on-target activity at all dose levels. Normal HSCs were not mobilized into the periphery after sentinel GMI-1271 dose. RP2D was determined to be 10 mg/kg BID based on drug exposure, time over IC50 for E-sel binding, lack of DLT, and similar on-target PD and clinical outcomes. To date, 10 patients enrolled on the Ph2 R/R AML arm; an additional 37 will be enrolled. In the previously untreated elderly AML arm, 3 patients enrolled in the safety run-in and no DLTs were observed, therefore an additional 22 patients will be enrolled. Updated response data will be presented at ASH. Conclusion We report on early clinical assessment of novel E-Selectin Antagonist GMI-1271 in R/R AML patients, with a high response rate (CR/CRi 47%) in this challenging group. No significant toxicities and no DLT were observed for GMI-1271. Ph2 dose expansion is ongoing. Disclosures DeAngelo: Celgene: Consultancy; Ariad: Consultancy; Baxter: Consultancy; Incyte: Consultancy; Amgen: Consultancy; Novartis: Consultancy; Pfizer: Consultancy. Liesveld: Onconova: Other: Data safety monitoring board; Astex: Honoraria; glycomimetics: Research Funding. O'Dwyer: Glycomimetics: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Honoraria, Research Funding; Janssen: Consultancy, Honoraria, Research Funding. Magnani: GlycoMimetics: Employment, Equity Ownership, Membership on an entity's Board of Directors or advisory committees. Thackray: GlycoMimetics: Employment, Equity Ownership. Becker: GlycoMimetics: Research Funding.

Paul S. Frenette - One of the best experts on this subject based on the ideXlab platform.

  • gmi 1070 a novel pan Selectin Antagonist reverses acute vascular occlusions in sickle cell mice
    Blood, 2010
    Co-Authors: Jungshan Chang, John L Magnani, John T. Patton, Beat Ernst, Arun K Sarkar, Paul S. Frenette
    Abstract:

    Leukocyte adhesion in the microvasculature influences blood rheology and plays a key role in vaso-occlusive manifestations of sickle cell disease. Notably, polymorphonuclear neutrophils (PMNs) can capture circulating sickle red blood cells (sRBCs) in inflamed venules, leading to critical reduction in blood flow and vaso-occlusion. Recent studies have suggested that E-Selectin expression by endothelial cells plays a key role by sending activating signals that lead to the activation of Mac-1 at the leading edge of PMNs, thereby allowing RBC capture. Thus, the inhibition of E-Selectin may represent a valuable target in this disease. Here, we have tested the biologic properties of a novel synthetic pan-Selectin inhibitor, GMI-1070, with in vitro assays and in a humanized model of sickle cell vaso-occlusion analyzed by intravital microscopy. We have found that GMI-1070 predominantly inhibited E-Selectin–mediated adhesion and dramatically inhibited sRBC-leukocyte interactions, leading to improved microcirculatory blood flow and improved survival. These results suggest that GMI-1070 may represent a valuable novel therapeutic intervention for acute sickle cell crises that should be further evaluated in a clinical trial.

  • Effects of Pan-Selectin Antagonist GMI-1070 on the Treatment of Vaso-Occlusion in Sickle Cell Mice
    Blood, 2008
    Co-Authors: Jungshan Chang, John T. Patton, Paul S. Frenette, John L Magnani
    Abstract:

    Acute vaso-occlusion (VOC) in patients with sickle cell disease (SCD) induces intense pain arising from organ damage and is the major cause of morbidity and mortality. Hypoxia and abnormal sickle red blood cells (RBC) induce inflammatory mediators and activation of the vascular endothelium leading to the recruitment of adherent leukocytes and sickle RBC followed by aggregates that eventually occlude blood flow. Previous studies have implicated the critical roles of cell adhesion molecules E- and P-Selectins by using intravital microscopy in SCD mice (Berkeley strain) with altered genetic backgrounds (SCD transplanted in recipients lacking E-and P-Selectins), or antibodies against endothelial Selectins, or small molecules directed against the Selectins. Here, we designed a treatment protocol for this SCD mouse model, in which a small molecule pan-Selectin Antagonist (GMI-1070) is administered to sickle cell mice late in the process of established vaso-occlusion in order to test the effects of GMI-1070 in a more clinically relevant model. GMI-1070 is a small molecule pan-Selectin Antagonist designed on the bioactive conformation of the carbohydrate ligand and inhibits leukocyte adhesion to activated endothelium in vitro with particularly strong activity against E-Selectin (IC50 = 3.4 μM). Berkeley SCD mice were generated by bone marrow transplantation into lethally irradiated C57BL/6 male mice and the fully engrafted (100% donor RBC chimerism) mice were used for intravital microscopy experiments. VOC events were induced by injection with TNF-α at time 0 and the formation of occlusions were allowed to proceed as long as possible just prior to the death of the control mice. GMI-1070 (20 mg/kg) or vehicle (PBS pH 7.4) were administered at t = 110 min. Post-capillary and collecting venules in the cremaster muscle were analyzed for effects on an established VOC event. Under these conditions, GMI-1070 significantly increased the microcirculatory blood flow to levels observed in non-sickle cell mice (vehicle: 237 ± 15 nL/sec; GMI-1070: 533 ± 58 nL/sec; p

  • effects of pan Selectin Antagonist gmi 1070 on the treatment of vaso occlusion in sickle cell mice
    Blood, 2008
    Co-Authors: Jungshan Chang, John T. Patton, Paul S. Frenette, John L Magnani
    Abstract:

    Acute vaso-occlusion (VOC) in patients with sickle cell disease (SCD) induces intense pain arising from organ damage and is the major cause of morbidity and mortality. Hypoxia and abnormal sickle red blood cells (RBC) induce inflammatory mediators and activation of the vascular endothelium leading to the recruitment of adherent leukocytes and sickle RBC followed by aggregates that eventually occlude blood flow. Previous studies have implicated the critical roles of cell adhesion molecules E- and P-Selectins by using intravital microscopy in SCD mice (Berkeley strain) with altered genetic backgrounds (SCD transplanted in recipients lacking E-and P-Selectins), or antibodies against endothelial Selectins, or small molecules directed against the Selectins. Here, we designed a treatment protocol for this SCD mouse model, in which a small molecule pan-Selectin Antagonist (GMI-1070) is administered to sickle cell mice late in the process of established vaso-occlusion in order to test the effects of GMI-1070 in a more clinically relevant model. GMI-1070 is a small molecule pan-Selectin Antagonist designed on the bioactive conformation of the carbohydrate ligand and inhibits leukocyte adhesion to activated endothelium in vitro with particularly strong activity against E-Selectin (IC50 = 3.4 μM). Berkeley SCD mice were generated by bone marrow transplantation into lethally irradiated C57BL/6 male mice and the fully engrafted (100% donor RBC chimerism) mice were used for intravital microscopy experiments. VOC events were induced by injection with TNF-α at time 0 and the formation of occlusions were allowed to proceed as long as possible just prior to the death of the control mice. GMI-1070 (20 mg/kg) or vehicle (PBS pH 7.4) were administered at t = 110 min. Post-capillary and collecting venules in the cremaster muscle were analyzed for effects on an established VOC event. Under these conditions, GMI-1070 significantly increased the microcirculatory blood flow to levels observed in non-sickle cell mice (vehicle: 237 ± 15 nL/sec; GMI-1070: 533 ± 58 nL/sec; p<0.0001). The recruitment of adherent leukocytes to the vascular endothelium was also significantly reduced (vehicle: 2235 ± 156; GMI-1070: 1270 ± 203 cells/mm2; p=0.0013), and there were significant and dramatic reductions in the capture of sickle red blood cells to adherent leukocytes (vehicle: 0.68 ± 0.27; GMI-1070: 0.03 ± 0.01 interactions/WBC, min, 100ml; p=0.0003). Mice began to succumb to VOC within 2.5 hours after injection of TNF-α and surgical trauma which continued until all of the control SCD mice died. Administration of GMI-1070 prevented the death of half of the treated mice within the timeframe of the experiment and extended the median survival of mice from 5 hours (control, vehicle-treated) to greater than 9 hours for the GMI-1070- treated SCD mice (p = 0.0067). These studies show that GMI-1070 can significantly and dramatically improve the condition and survival of the animals with a severe VOC even when dosed well after the initiating challenge. Thus these data strongly support the use of GMI-1070 for the treatment of patients in acute vaso-occlusive crisis. GMI-1070 is currently in a Phase I clinical trial.

  • gmi 1070 a small pan Selectin Antagonist that inhibits leukocyte adhesion and migration in multple disease models in vivo
    Blood, 2007
    Co-Authors: John L Magnani, Jungshan Chang, Paul S. Frenette, Beat Ernst, Arun K Sarkar, Yonhong Li, Scarlett Goon, Bea Wagner, John T. Patton
    Abstract:

    Rational design of glycomimetic inhibitors based on the bioactive conformation of functional carbohydrates provides new therapeutic opportunities for the development of small molecule drugs with improved activity, pharmacokinetics, and bioavailability relative to native ligands. In designing more active glycomimetic Selectin inhibitors, the low enthalpy (ΔH 0 ) of the reaction is compensated by pre-forming the bioactive conformation thereby improving the entropy (ΔS 0 ), known as S/H compensation. Modifications of the molecule that also stabilize the core structure, further improve ΔS 0 and binding activity. To improve ΔH 0 , second site interactions were explored. To address the requirements for P and L-Selectins, interactions were combined for both carbohydrate and sulfate-binding domains to produce heterobifunctional molecules. By stabilizing the bioactive core and exploring second site molecular interactions, we have produced a family of pan-Selectin Antagonists, one of which (GMI-1070) is now in development and scale-up synthesis as a lead compound. GMI-1070 is a potent inhibitor of E, P, and L-Selectins in vitro and inhibits E and P-Selectin-mediated leukocyte adhesion to endothelial monolayers under flow conditions. More importantly, GMI-1070 is active in several animal models of diseases requiring leukocyte adhesion and migration such as: a delayed-type hypersensitivity (DTH) response, cardiac ischemia/reperfusion injury, and vaso-occlusive crisis in sickle cell disease. GMI-1070 significantly inhibited infarct size in an ischemia/reperfusion cardiac injury model in rats. A single dose at 10mg/kg gave maximal inhibition. The effects of GMI-1070 on T-cell migration was studied in a DTH model. Mice were sensitized with oxazolone on the abdomen and then, 7 days later challenged on the ear. Donors T-cells from a different cohort of similarly sensitized mice were fluorescently labeled and injected into the test cohorts at the time of administration of GMI-1070. Three hours following injection, migration of fluorescent T-cells to the challenged area was determined. Selectin-dependent T-cell migration in the DTH response was completely eliminated with a dose of 10mg/kg of GMI-1070, suggesting the potential clinical application in diseases involving skin homing T-cells such as graft vs. host disease (GVHD) after bone marrow transplantation, and other inflammatory skin diseases. We have also shown that acute myelogenous leukemia (AML) cells adhere to endothelial cells under flow in a Selectin-dependent mechanism suggesting that graft vs. leukemia as well as graft vs. host may be affected by treatment with GMI-1070. GMI-1070 was also tested in a model of vaso-occlusive crisis in sickle cell disease using Berkeley sickle cell mice. Blood flow was restored to normal values and adhesion of sickle red blood cells to adherent leukocytes was essentially eliminated as determined intravital microscopy using a dose of 20mg/kg administered at the time of elicitation of the vaso-occlusive challenge (TNFα) and at the start of intravital microscopy (70 minutes later). Based on the encouraging results in disease models, we are advancing the clinical development of GMI-1070 into Phase 1 studies to support indications which include the treatment of sickle cell patients in vaso-occlusive crisis.

  • a novel Selectin Antagonist gmi 1070 prevents vaso occlusion in sickle cell mice by inhibiting leukocyte adhesion and activation
    Blood, 2007
    Co-Authors: Jungshan Chang, John L Magnani, John T. Patton, Arun K Sarkar, Paul S. Frenette
    Abstract:

    Previous studies using intravital microscopy in a sickle cell disease (SCD) mouse model (Berkeley) suggest that adherent leukocytes (WBCs) play a key role in vaso-occlusion by capturing circulating erythrocytes (RBCs) in venules. In addition, mice deficient in both P-and E-Selectins are protected from vaso-occlusion (VOC) induced by surgical trauma and TNF-α stimulation, suggesting that targeting Selectins or their ligands represents a potentially useful strategy. Selectins bind to specific sialylated and fucosylated carbohydrate structures presented by glycoprotein or glycolipid ligands. Here, we tested the effect of novel small glycomimetic Selectin inhibitors, GMI-1070 and GMI-1077, on leukocyte behavior and sickle cell VOC. Berkeley SCD mouse bone marrow was transplantated into lethally irradiated C57BL/6 animals to generate age- and gender-matched genetically identical cohorts of SCD mice. Fully engrafted male SCD mice were treated with TNF-α and prepared for intravital microscopy examination of the cremaster muscle 90 min later. GMI-1070, GMI-1077 (both 20 mg/kg) or vehicle (PBS) were administered immediately prior to cytokine stimulation (t=0 min), and an additional dose was given at t=70min. Another group of mice was injected with antibodies against P-and E-Selectins (PES, 1 mg/kg) as positive control. Several post-capillary and collecting venules were examined between t= 90min and t= 150min. Antibody blockade of endothelial Selectins completely ablated leukocyte rolling, whereas GMI-1070 and GMI-1077 significantly increased the rolling flux fractions (PBS: 5.0±1.2 GMI-1070: 10.6±1.3%%; GMI-1077: 9.9±1.0%; p P-Selectin. Since the hallmark of E-Selectin-mediated adhesion is the slow leukocyte rolling, we analyzed leukocyte rolling velocities in the various group and indeed found a 2-fold increase in rolling velocities in sickle mice treated with GMI-1070 compared to PBS control (PBS: 21±1 μm/s, GMI-1070: 38±1 μm/s, p<0.001). Consistent with these results, other studies using a parallel plate flow chamber (0.9 dynes/cm2) revealed that GMI-1070 was much more potent (1000-fold difference) in inhibiting the binding of human PMNs to TNF-α-stimulated (to induce E-Selectin) endothelial cells (HUVEC) than with IL-4 and histamine stimulated HUVECs (to induce P-Selectin). Further, competitive inhibition assays revealed that the IC50 of GMI-1070, relative to the standard glycyrrhizin, was much lower for E-Selectin than P-Selectin. These studies suggest that E-Selectin-mediated adhesion/signaling may play a more important role than previously appreciated in the pathophysiology of SCD, and suggest that GMI-1070 may be beneficial for the treatment of sickle cell vaso-occlusion.

Anne Kirsten - One of the best experts on this subject based on the ideXlab platform.

  • inhaled pan Selectin Antagonist bimosiamose attenuates airway inflammation in copd
    Pulmonary Pharmacology & Therapeutics, 2013
    Co-Authors: Henrik Watz, Daniel Bock, Michael T Meyer, Katrin Schierhorn, Karin Vollhardt, Christiane Woischwill, Frauke Pedersen, Anne Kirsten, K M Beeh, Wolfgang Meyersabellek
    Abstract:

    Selectins, a family of cell adhesion molecules, are involved in leukocyte extravasation to sites of inflammation. We investigated the safety and efficacy of the inhaled pan-Selectin Antagonist Bimosiamose in patients with chronic obstructive pulmonary disease (COPD). 77 COPD patients (mean forced expiratory volume in 1 s, 57% pred.) were enrolled in a cross-over, double-blind, randomized, Placebo-controlled, multi-center trial. Bimosiamose (10 mg) or Placebo was inhaled twice daily via the breath actuated nebulizer Akita2 Apixneb™ for 28 days on top of standard bronchodilator therapy. Efficacy was assessed by measurement of inflammatory parameters in induced sputum (differential cell count, interleukin-8, matrix-metalloproteinase-9, myeloperoxidase) and lung function at day 28 of both treatment periods. The total adverse event ratio of Bimosiamose compared to Placebo treatment was balanced. Compared to Placebo, treatment with Bimosiamose led to a decrease of the interleukin-8 concentration (-9.49 ng/mL, 95%CI -18.8 to -2.7 ng/mL, p = 0.008), for the neutrophil count a difference of -0.368 × 10(6) cells/mL (95%CI -1.256 to 0.407 × 10(6)/mL, p = 0.313) was found. The macrophage count decreased by -0.200 × 10(6) cells/mL (95%CI -0.365 to -0.044 × 10(6) cells/mL, p = 0.012). Most lung function parameters showed a small numeric increase. Inhalation of Bimosiamose for 28 days was safe and well tolerated in patients with COPD. It led to an attenuation of airway inflammation (EudraCT 2009-017257-35; NCT ID: NCT01108913).

  • efficacy of the pan Selectin Antagonist bimosiamose on ozone induced airway inflammation in healthy subjects a double blind randomized placebo controlled cross over clinical trial
    Pulmonary Pharmacology & Therapeutics, 2011
    Co-Authors: Anne Kirsten, Henrik Watz, Daniel Bock, Frauke Pedersen, Wolfgang Meyersabellek, Gunther Kretschmar, H Magnussen
    Abstract:

    Abstract Selectins, a family of cell adhesion molecules, are involved in the activation and extravasation of leukocytes in inflammatory diseases. Inhalation of ozone induces an inflammation of the airways, which is dominated by neutrophils. We investigated the effect of repeated inhalations of the pan-Selectin Antagonist Bimosiamose on ozone-induced airway inflammation in healthy volunteers. In a double-blind, placebo-controlled, randomized, cross-over study Bimosiamose (10 mg bid) was inhaled via a breath actuated nebulizer (AKITA2 APIXNEB®) for 4 days. Treatment was followed by inhalation of ozone (250 ppb) for 3 h with intermittent exercise. Induced sputum was collected 3 h post ozone challenge for analysis of cellular and non-cellular composition. 18 subjects were randomized and completed the study. All treatments were safe and well tolerated. Compared to placebo Bimosiamose reduced the numbers of sputum neutrophils by 40% (p = 0.068) and concentrations of interleukin-8 and matrix-metalloproteinase-9 in sputum supernatant by 35% (p = 0.004) and 46% (p = 0.022), respectively. Inhalation of Bimosiamose showed favourable anti-inflammatory effects on ozone-induced airway inflammation in healthy volunteers. Further studies have to proof and translate this anti-inflammatory effect of Bimosiamose into a clinical benefit in patients with chronic obstructive pulmonary disease. (ClinTrialgov Ident: NCT01108913).

  • late breaking abstract inhaled pan Selectin Antagonist bimosiamose in copd a double blind randomized placebo controlled phase ii study
    European Respiratory Journal, 2011
    Co-Authors: Henrik Watz, Daniel Bock, Katrin Schierhorn, Karin Vollhardt, Christiane Woischwill, Frauke Pedersen, Anne Kirsten, K M Beeh, Michael Meyer, Wolfgang Meyersabellek
    Abstract:

    Background: Bimosiamose a pan-Selectin Antagonist, previously attenuated ozone-induced airway-inflammation in healthy volunteers. Here we investigated the safety and efficacy of Bimosiamose in a cross-over, double-blind, randomized, placebo-controlled, multi-center trial in patients with COPD. Methods: 77 moderate to severe COPD patients (GOLD II-III) were enrolled. Bimosiamose (10 mg) or placebo was inhaled by the breath actuated nebulizer Akita2 Apixneb™ for 28 days twice daily on top of standard bronchodilator therapy. Efficacy was assessed by cellular and non-cellular parameters in induced sputum at baseline and day 28 of both treatment periods. Lung function (FEV1, FVC, PEF, IC) was measured by standardized spirometry. Results: The total AE ratio of Bimosiamose compared to placebo treatment was balanced. In induced sputum, as compared to placebo, treatment with Bimosiamose led to a reduction of absolute numbers of non-squamous cells (-23%), neutrophils (-24%), lymphocytes (-44%), eosinophils (-34%) and macrophages (-49%), IL-8 (-27%), MMP-9 (-16%) and MPO (-7%). Treatment difference was statistically significant for IL-8 (p=0.009) and macrophages (p=0.012). Compared to baseline, Bimosiamose improved FEV1 by 50 mL (-15 to 115; 95%CI) and IC by 117 ml (11 to 222; 95%CI) at day 28. Treatment difference was statistically significant for FVC (p=0.036). Conclusions: Inhalation of Bimosiamose for 28 days was safe and well tolerated. It led to an attenuation of airway inflammation and trend towards lung function improvements. These findings support the potential of Bimosiamose as a new anti-inflammatory therapy for COPD.

  • Efficacy of the pan-Selectin Antagonist Bimosiamose on ozone-induced airway inflammation in healthy subjects – A double blind, randomized, placebo-controlled, cross-over clinical trial
    Pulmonary Pharmacology & Therapeutics, 2011
    Co-Authors: Anne Kirsten, Henrik Watz, Daniel Bock, Frauke Pedersen, Gunther Kretschmar, Wolfgang Meyer-sabellek, H Magnussen
    Abstract:

    Abstract Selectins, a family of cell adhesion molecules, are involved in the activation and extravasation of leukocytes in inflammatory diseases. Inhalation of ozone induces an inflammation of the airways, which is dominated by neutrophils. We investigated the effect of repeated inhalations of the pan-Selectin Antagonist Bimosiamose on ozone-induced airway inflammation in healthy volunteers. In a double-blind, placebo-controlled, randomized, cross-over study Bimosiamose (10 mg bid) was inhaled via a breath actuated nebulizer (AKITA2 APIXNEB®) for 4 days. Treatment was followed by inhalation of ozone (250 ppb) for 3 h with intermittent exercise. Induced sputum was collected 3 h post ozone challenge for analysis of cellular and non-cellular composition. 18 subjects were randomized and completed the study. All treatments were safe and well tolerated. Compared to placebo Bimosiamose reduced the numbers of sputum neutrophils by 40% (p = 0.068) and concentrations of interleukin-8 and matrix-metalloproteinase-9 in sputum supernatant by 35% (p = 0.004) and 46% (p = 0.022), respectively. Inhalation of Bimosiamose showed favourable anti-inflammatory effects on ozone-induced airway inflammation in healthy volunteers. Further studies have to proof and translate this anti-inflammatory effect of Bimosiamose into a clinical benefit in patients with chronic obstructive pulmonary disease. (ClinTrialgov Ident: NCT01108913).

  • p138 efficacy of inhaled pan Selectin Antagonist bimosiamose on ozone induced airway inflammation in healthy subjects
    Thorax, 2010
    Co-Authors: Anne Kirsten, Henrik Watz, Daniel Bock, Frauke Pedersen, Wolfgang Meyersabellek, Gunther Kretschmar, H Magnussen
    Abstract:

    Selectins, a family of adhesion molecules, play a key role in the activation and extravasation of leukocytes in inflammatory diseases, like COPD. We investigated the effect of repeated inhalations of the pan-Selectin Antagonist Bimosiamose on ozone-induced airway inflammation in healthy volunteers. In a double-blind, placebo-controlled, randomised, cross-over study the effect of a 4-days treatment with 10 mg of Bimosiamose bid inhaled by a breath actuated nebuliser (AKITA2 APIXNEB®) on cellular and non-cellular composition of induced sputum after inhalation of ozone (250 ppb) for three hours was evaluated. 18 subjects were randomised and completed the study. All treatments were safe and well tolerated. Bimosiamose, compared to placebo treatment, reduced numbers of sputum neutrophils by 40% (p=0.068) and lymphocytes by 65% (p=0.004). Sputum concentration of interleukin-8 and MMP-9 was diminished by 35% (p=0,004) and 46% (p=0,022), respectively. Inhalation of Bimosiamose showed a broad and favourable significant effect on ozone-induced airway inflammation in healthy subjects. Further studies have to proof and translate this anti-inflammatory effect of Bimosiamose into a clinical benefit in patients with COPD.