Kooperativer Bibliotheksverbund

In: Blood, American Society of Hematology, Vol. 120, No. 21 ( 2012-11-16), p. 3422-3422

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). 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) 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. Disclosures: Patton: GlycoMimetics: Employment. Magnani:GlycoMimetics: Employment, Equity Ownership.

Type of Medium: Online Resource

ISSN: 0006-4971 , 1528-0020

URL: Article

DOI: 10.1182/blood.V120.21.3422.3422

Language: English

Publisher: American Society of Hematology

Publication Date: 2012

detail.hit.zdb_id: 1468538-3

detail.hit.zdb_id: 80069-7

In: Blood, American Society of Hematology, Vol. 132, No. Supplement 1 ( 2018-11-29), p. 1119-1119

Abstract: Introduction: Hemophagocytic lymphohistiocytosis (HLH) is a devastating disorder with protean clinical manifestations caused by the overproduction of T-cell derived cytokines. Cytokine-dependent activation of the Janus family kinases (JAK) is a hallmark of the final common pathway in HLH pathogenesis. Therefore, we initiated a single center, open-label, investigator-initiated trial to assess the efficacy and safety of ruxolitinib in adult patients with secondary HLH. Methods: Adult patients (≥18 years) who fulfilled 5 of 8 diagnostic criteria were eligible. Patients with CNS involvement or an active malignancy were ineligible. Patients who had received any prior systemic therapy (excluding corticosteroids) within 7 days of treatment were ineligible. Patients with normal renal function received oral ruxolitinib 15 mg twice daily on a continuous, 28-day cycle. Dose reductions for renal insufficiency and toxicity are permitted. Treatment was continued indefinitely until disease progression, unacceptable toxicity, or any other conditions for treatment discontinuation were met. The first patient was enrolled in February, 2016 and enrollment is ongoing. The primary endpoint is overall survival at 2 months. Secondary endpoints include the response rate, duration of response, progression-free and overall survival. Adverse events were graded and attributed in accordance with the National Cancer Institute Guidelines for the Cancer Therapy Evaluation Program. Disease parameters evaluable for response included all quantifiable signs and laboratory abnormalities included in the diagnostic criteria for HLH. A complete response (CR) required normalization of all signs and laboratory abnormalities. At least 25% improvement in two or more signs/laboratory abnormalities was required for a partial response (PR). At least a 50% worsening in two or more signs/laboratory abnormalities was considered progressive disease (PD), while failure to fulfill any of these criteria was considered stable disease (SD). Results: A total of 4 patient have been enrolled, all of whom fulfilled at least 5 of 8 diagnostic criteria for HLH. Hemophagocytosis, a pathologic hallmark of HLH, was observed in every patient. At the time of treatment initiation, all patients were anemic [median hemoglobin 7.1 g/dL (range: 6.2-7.5 g/dL)] and thrombocytopenic [median platelet count 47 K/uL (range: 14-107 K/uL)] . Three patients were neutropenic [median ANC 0.95 K/uL (range: 0-1.9 K/uL)]. HLH was secondary to an autoimmune disorder (n=3), infection (n=1), and a homozygous mutation in the STXBP2 gene, recently identified as a causative defect in primary HLH, was observed in one patient. Cytopenias significantly improved within the first week of treatment in all patients. On day +7, the mean increase in hemoglobin was 1.88 g/dL (0.2-3 g/dL), in ANC was 1.53 K/uL (range 0.1-5.3 K/uL) and platelet count was 74 K/uL (range 17-116 K/uL). Neutropenia resolved by day +40 and thrombocytopenia resolved by day +47 in all patients. Three of four patients became transfusion independent within 2 days of treatment initiation. Three of four patients received corticosteroids prior to and after initiation of ruxolitinib. The mean corticosteroid (prednisone equivalent) dose prior to treatment initiation was 225 mg/day (range: 60-391 mg/day) and was 38 mg/day (range: 0-75 mg/day) on day +30. Within 47 days of treatment initiation, corticosteroids were discontinued in 2 patients, and were discontinued in all patients by day +54. Significant improvements in ferritin and sIL-2R were also observed with a median 92.6% decrease in ferritin by day +30 (range 86.4-92.6%) and 86% median decrease in sIL-2R by day +30 (range 66.6-92.7%). All patients achieved at least a PR, and 2 patients remain on treatment ( 〉 2 months, 〉 8 months). Two patients discontinued treatment, one for progressive disease (due to recurrent symptoms), and another for drug intolerance (neuropathic foot pain). No severe adverse events have been observed. In addition to the patients enrolled in this study, two additional patients who met eligibility criteria were similarly treated (off study) at another institution. Both of these patients achieved at least a PR and remain on treatment ( 〉 8 months, 〉 14 months). Conclusions: Ruxolitinib led to rapid and durable responses and was well tolerated in adult patients with secondary HLH. Disclosures Devata: Affimed: Research Funding. Phillips:Abbvie: Research Funding; Pharmacyclics: Consultancy, Research Funding; Genentech: Consultancy; Bayer: Consultancy; Seattle Genetics: Consultancy; Gilead: Consultancy. Sood:Bayer: Research Funding. Wilcox:Incyte, Corp: Research Funding.

Type of Medium: Online Resource

ISSN: 0006-4971 , 1528-0020

URL: Article

DOI: 10.1182/blood-2018-99-116854

Language: English

Publisher: American Society of Hematology

Publication Date: 2018

detail.hit.zdb_id: 1468538-3

detail.hit.zdb_id: 80069-7

In: Blood, American Society of Hematology, Vol. 126, No. 23 ( 2015-12-03), p. 1004-1004

Abstract: Background: GMI-1271 is a potent, specific E-selectin antagonist which targets interactions between cancer cells and the bone marrow niche thereby increasing tumor sensitivity to chemotherapy; avoids HSC mobilization; and inhibits thrombosis without increasing bleeding risk. Delayed inflammatory cell recruitment into the vein wall post thrombus induction indicates a possible decrease in leukocyte activation, which may be crucial in treating both acute and cancer associated thrombosis. Here we report first-in-human evaluation of GMI-1271 for safety (including bleeding), PK, and biomarker data for effects on adhesion and mobilization. Methods: Two Phase I single dose escalation DBRCT in healthy subjects evaluated 2, 5, 10, and 20 mg/kg IV doses of GMI-1271. Study 1 is complete and unblinded (GMI-1271 vs placebo). Study 2 is ongoing, remains blinded (GMI-1271 vs placebo) with open-label positive control (Lovenox), and is reported in aggregate. In both studies, assessments included safety (adverse events [AEs], clinical labs, bleeding time, PT/PTT, vitals, and exam); PK (drug levels in plasma and urine); and biomarkers (plasma soluble E-selectin [sEsel] , sPsel, sICAM-1 levels; and blood CD34+ counts). Only sEsel and CD34+ are reported for Study 1; sEsel, sPsel, sICAM-1 for Study 2. Comparisons to baseline were made by ANOVA and paired t-test models; PK analyses were for total clearance (CL), volume of distribution (Vz), elimination half-life (t½), fraction excreted (Fe), and renal clearance (CLr). Results: Forty-six subjects enrolled; 30 received GMI-1271 (10 each at 2 and 5 mg/kg; 6 at 10 mg/kg; and 4 at 20 mg/kg) and 16 received control (13 placebo, 3 Lovenox). Safety: All subjects completed the studies; labs, vitals, and exam were unremarkable. Bleeding times and PT/PTT were unaffected by E-selectin inhibition. No serious AEs were seen. For Study 1, AEs were seen in 12/18 (66.7%) of those on GMI-1271 and 5/10 (50%) on placebo. AEs were mostly mild events at the infusion site (i.e. tenderness or erythema), and occurred in both groups. One moderate AE occurred (vasovagal reaction) in the 2 mg/kg GMI-1271 cohort. Three AEs were possibly related to drug: 2 in the 2 mg/kg cohort (infusion site bruise, lightheaded), and 1 in the 5 mg/kg cohort (metallic taste). For Study 2, AEs were seen in 12/15 (80%) of those on GMI-1271/placebo and 3/3 (100%) on Lovenox. All AEs were mild. In GMI-1271/placebo group, all AEs were considered unrelated to study drug; 3 were infusion site bruise (1 per dose level). In the Lovenox group, AEs were bruise at injection site (related) and blood in urine (possibly related). PK: Plasma levels, Cmax, and AUC increased in a consistent dose-related manner in both studies (figure). CL, Vz, and t½ were not dose dependent; the latter averaged ~2.3 hours. ~66% of the dose was excreted unchanged in the urine independent of dose level, and CLr averaged 86 mL/min, less than estimated CrCl, suggesting tubular reabsorption is one component of CLr. Biomarkers: In Study 1, the absolute CD34+ and %CD34+ cell counts were normal across all cohorts. There was no dose-response for changes in peripheral CD34+ counts after administration of GMI-1271 (doses 2-10 mg/kg). Plasma concentrations of sEsel were relatively constant in the placebo and GMI-1271 2 mg/kg cohorts, with significant reduction (vs baseline, p=0.012) at 48hrs post-2mg/kg dose only. In the 5 and 10 mg/kg cohorts sEsel decreased significantly post-dose (p 〈 0.0001) and returned to baseline by 24 to 48 hours respectively; reductions were greater at high dose. In Study 2, significant reduction in sEsel was similarly seen after treatment vs baseline (p=0.05), and in sP-sel with treatment vs baseline (p = 0.04), or vs day 2 (p 〈 0.01). sICAM-1 was also lower after treatment vs baseline (p=0.05). Conclusion: First-in-human experience with the potent E-selectin antagonist GMI-1271 demonstrated favorable safety and PK at single doses up to 20 mg/kg. These findings are consistent with the glycomimetic class for safety at anticipated therapeutic levels. Biomarkers of physiologic effect demonstrated clear reductions in sEsel/sPsel; decreased leukocyte adhesion with lower sICAM-1 levels; and no CD34+ rise indicating no mobilization of HSCs. Studies of GMI-1271 are ongoing to evaluate activity in hematologic malignancies and thrombosis. Figure 1. Plasma concentrations and Cmax are consistent for GMI-1271 between Phase 1 studies. Figure 1. Plasma concentrations and Cmax are consistent for GMI-1271 between Phase 1 studies. Disclosures Sood: Bayer: Research Funding. Hemmer:GlycoMimetics: Employment, Equity Ownership. Flanner:GlycoMimetics: Employment, Equity Ownership. Kramer:GlycoMimetics: Consultancy. Nietubicz:GlycoMimetics: Employment, Equity Ownership. Myers:GlycoMimetics: Research Funding. Wakefield:GlycoMimetics: Research Funding. Magnani:GlycoMimetics: Employment, Equity Ownership, Membership on an entity's Board of Directors or advisory committees. Thackray:GlycoMimetics: Employment, Equity Ownership.

Type of Medium: Online Resource

ISSN: 0006-4971 , 1528-0020

URL: Article

DOI: 10.1182/blood.V126.23.1004.1004

Language: English

Publisher: American Society of Hematology

Publication Date: 2015

detail.hit.zdb_id: 1468538-3

detail.hit.zdb_id: 80069-7

In: Blood, American Society of Hematology, Vol. 132, No. Supplement 1 ( 2018-11-29), p. 2479-2479

Abstract: Introduction: Over a three-year period, U.S. men with hemophilia were found to be 50 times more likely to die from renal disease than the general population (SMR 50; 95% CI 26.8-92.8) (Soucie et al., Blood 2000). Despite this finding, data regarding chronic kidney disease (CKD) and its risk factors in patients with hemophilia remain limited. The objective of this study is to determine the prevalence of CKD and CKD risk factors among older men with moderate and severe hemophilia. Methods: This CKD cohort study is an extension of a U.S. national study sponsored by the American Thrombosis and Hemostasis Network (ATHN). The study, entitled ATHN 1: A Cross-Sectional Analysis of Cardiovascular Disease (CVD) in the Hemophilia Population, began enrollment in 10/2012. Inclusion criteria are men with moderate or severe congenital hemophilia A or B (FVIII or IX level ≤ 5%), age 54-73. Men with an additional bleeding disorder (besides liver dysfunction) were excluded. In this extension study, CKD risk factors, historical creatinine levels, and history of renal events were obtained from patient interview and chart review after obtaining informed consent. Glomerular filtration rate (GFR) values were calculated using the CKD-EPI equation and compared to values in the general population using the NHANES dataset (Coresh et al., JAMA 2007). CKD is defined as the presence of either kidney damage or decreased kidney function with GFR 〈 60 ml/min/1.73 m2 for ≥ 3 months, irrespective of cause. Results: As of 6/30/2018, 134/200 planned subjects have been enrolled and interim analysis on 134 subjects from 18 U.S. hemophilia treatment centers (HTCs) is presented here. The majority were white (119; 88.8%) or African-American (13; 9.7%). Mean age was 64 years (SD: 5; range: 56-77). Most used factor on demand, with only 38.8% (52/134) on prophylaxis, defined as ≥2 doses of FVIII or ≥ 1 dose FIX/week. Four (3.0%) had a current inhibitor. Viral infection was common; 28.4% currently had hepatitis C, and 19.4% HIV. Hypertension (HTN) was reported in 51.5% of subjects, 14.9% diabetes mellitus (DM); and average BMI was 28.2 kg/m2 (36.6% obese). 11.6% (16/134) were found to have CVD (defined as angina, MI, TIA, or ischemic or embolic stroke). Acute kidney injury was common. Fasting blood work showed an abnormally elevated creatinine in 26.9% subjects (mean 1.1 mg/dl, SD 0.4). Mean historical maximum creatinine reported in the cohort was 1.0 (range 0.5-4.8), with mean GFR 67 (range 11-126). 11.4% (13/114) met the definition of CKD. Stages of CKD by GFR in the hemophilia cohort were similar to the NHANES general population (p=0.561). See Table 1 for subject reported history of renal events, and Table 2 for specific diagnoses of renal disease. In our cohort, hemophilia subjects with CKD tended to have a diagnosis of intrinsic kidney disease (60.0% vs 11.6%, p=0.02), and non-significantly tended to have DM (23.1% vs 12.8%), age ≥65 years (21.1% vs 9.4%), and HTN (18.0% vs 9.8%) compared to subjects without CKD. No other significant trends were identified, including no association with CVD, HCV, HIV, BMI, or hematuria. Conclusions: In this interim analysis of an ongoing national prospective cohort study, older men with moderate to severe hemophilia commonly report risk factors for CKD, including HTN (51.5%), DM, viral infection, and potential renal damaging medication use. Only 11.6% had CVD. Urological symptoms were also common, including hematuria and obstructive symptoms with urination. In our cohort, 11.4% met the definition of CKD, defined as the presence of either kidney damage or GFR 〈 60 ml/min/1.73 m2 for ≥ 3 months. The distribution of GFR values appeared similar to the general population. As with risk factors associated with CKD in the general population, diagnosis of intrinsic kidney disease was significantly associated with CKD in hemophilia subjects, with non-significant trend for increased DM, older age, and HTN compared to subjects without CKD. It is reassuring that the prevalence of CKD does not appear to be increased in men with hemophilia compared to the general population, despite a known and unexplained high incidence of HTN in the hemophilia population. We plan to formally compare the prevalence of CKD and CKD risk factors with similarly aged men in the ARIC database once enrollment is complete, as understanding the risk factors that contribute to CKD is essential to halt its progression. Disclosures Sood: Bayer: Research Funding. Shapiro:BioMarin: Research Funding; Shire: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Novo Nordisk: Membership on an entity's Board of Directors or advisory committees, Research Funding; Prometic Life Sciences: Consultancy, Research Funding; Kedrion Biopharma: Consultancy, Research Funding; Sangamo Biosciences: Consultancy; Octapharma: Research Funding; OPKO: Research Funding; Daiichi Sankyo: Research Funding; Bayer Healthcare: Other: International Network of Pediatric Hemophilia; Bio Products Laboratory: Consultancy; Genetech: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Bioverativ, a Sanofi Company: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding. Kessler:Biomarin: Research Funding; Dimension Advisory boards: Membership on an entity's Board of Directors or advisory committees; DSMB: Membership on an entity's Board of Directors or advisory committees; Sangamo: Research Funding; Novo Nordisk: Honoraria, Research Funding; Octapharma: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Genentech: Research Funding; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees; Bayer: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Key:UniQure BV: Research Funding. Quon:Bioverativ, a Sanofi Company: Speakers Bureau; NovoNordisk: Consultancy, Speakers Bureau; Bayer: Consultancy; Shire: Speakers Bureau; Genetech: Consultancy, Speakers Bureau; Octapharma: Consultancy. Manco-Johnson:Novo Nordisk: Honoraria; CSL Behring: Honoraria; Bayer AG: Honoraria, Research Funding; Biogentek: Honoraria; Baxalta, now part of Shire: Honoraria. Cuker:Kedrion: Membership on an entity's Board of Directors or advisory committees; Genzyme: Consultancy; Spark Therapeutics: Research Funding; Synergy: Consultancy. Ragni:Novo Nordisk: Research Funding; Shire: Research Funding; MOGAM: Membership on an entity's Board of Directors or advisory committees; Sangamo: Research Funding; Alnylam: Membership on an entity's Board of Directors or advisory committees, Research Funding; Sangamo: Research Funding; SPARK: Consultancy, Research Funding; CSL Behring: Research Funding; Biomarin: Membership on an entity's Board of Directors or advisory committees, Research Funding; Bioverativ: Consultancy, Research Funding; SPARK: Consultancy, Research Funding. von Drygalski:UniQure BV, Bayer, Bioverativ/Sanofi, Pfizer, Novo Nordisk, Biomarin, Shire, CSL Behring: Consultancy. Kouides:UniQure: Other: DSMB; Octapharma: Research Funding. Escobar:Bayer, CSL Behring, Genentech, Hemabiologics, Kedrion, Novo Nordisk, Octapharma, Pfizer and Shire: Consultancy; Pfizer: Research Funding. Wang:Daiichi Sankyo: Consultancy, Other: Travel. Konkle:Shire: Research Funding; Genentech: Consultancy; Bioverativ: Research Funding; BioMarin: Consultancy; Pfizer: Research Funding; Gilead: Consultancy; Spark: Consultancy, Research Funding; CSL Behring: Consultancy; Sangamo: Research Funding.

Type of Medium: Online Resource

ISSN: 0006-4971 , 1528-0020

URL: Article

DOI: 10.1182/blood-2018-99-119637

Language: English

Publisher: American Society of Hematology

Publication Date: 2018

detail.hit.zdb_id: 1468538-3

detail.hit.zdb_id: 80069-7

In: Blood, American Society of Hematology, Vol. 124, No. 21 ( 2014-12-06), p. 2836-2836

Abstract: Introduction: Cardiovascular disease (CVD) is a disease of aging. While men with hemophilia were initially thought to be protected from CVD, it is now clear that atherothrombotic events do occur. The objective of this study is to determine the prevalence of CVD and CV risk factors among older men with moderate and severe hemophilia. Methods: A U.S. national cross-sectional study began enrollment in 10/2012. Inclusion criteria are men with moderate or severe congenital hemophilia A or B (FVIII or IX level ≤ 5%), age 54-73. Men with an additional bleeding disorder (besides liver dysfunction) were excluded. After obtaining informed consent, CV risk factors, medications, and history of thrombotic events were obtained from patient interview and chart review. A fasting blood sample was assayed centrally. Results: As of 8/1/2014, 160/200 planned subjects were recruited and interim analysis on 126 subjects from 18 U.S. Hemophilia Treatment Centers is presented here. The majority were white (109; 86.9%) or African American (15; 11.5%). Mean age was 62 years (SD: 5; range: 54-74). Most used factor on demand, with only 34.1% (43/126) on prophylaxis, defined as ≥2 doses of FVIII or ≥ 1 dose FIX/week. Five (4.0%) had a current inhibitor. Viral infection was common; 68.3% currently had hepatitis C, and 25% HIV. Hypertension (HTN) was reported in 65.6% of subjects, 37.3% dyslipidemia and 24.6% diabetes (DM); 44.5% had ever smoked, 56.3% denied engaging in at least moderate physical activity and 43.7% had a family history of CVD. Average BMI was 28 kg/m2 (29.4% obese) and waist circumference 97 cm. Fasting blood work showed an abnormally elevated: creatinine in 27.6% subjects (mean 1.09 mg/dl, SD 0.5), CRP in 6.3% (4.15 mg/L, 10.6), total cholesterol in 18.1% (169.49 mg/dl, 35.8), triglycerides in 25.2% (122.10 mg/dl, 58.2), LDL in 19.7% (102.27 mg/dl, 32.3); and low HDL in 45.7% (42.80 mg/dl, 12.2). Ten subjects (7.9%) reported prior angina; 7 (5.6%) atrial fibrillation/flutter; 3 (2.4%) leg deep venous thrombosis; 2 (1.6%) myocardial infarction (MI), transient ischemic event (TIA), or pulmonary emboli; and 1 (0.8%) coronary artery angioplasty, stent placement, CABG, or peripheral arterial angioplasty. In total, 11 subjects had CVD (defined as angina, MI, TIA, or ischemic or embolic stroke), a prevalence rate of 8.7%. This is significantly lower than the reported prevalence of 23% CVD in similar aged men without hemophilia in the longitudinal ARIC cohort (p-value 〈 0.001). The qualifying diagnoses in our cohort included angina, MI and TIA. None of the men with CVD were on antiplatelet or anticoagulant medications. Due to the small number of events, individual CV risk factors thus far did not achieve statistical significance in predicting CVD. Compared to never smokers, ever smokers had an odds ratio (OR) of 3.7 (95% CI: 0.9-14.8) of CVD. For HTN, dyslipidemia, and DM, the OR (95% CI) of CVD were 2.5 (0.5-12.1), 2.2 (0.6-7.5), and 1.9 (0.5-6.8), respectively. Positive family history (OR 2.4 (0.7-8.8)) and low-level of physical activity (1.4 (0.4-5.0)) also suggested some association with increased CVD risk. Obese BMI and large waist circumference were not significant. Men using prophylaxis appeared less likely to have CVD (1/43, 2.3%) than men not on prophylaxis (10/83, 12.1%), OR 0.2 (0.02-1.4), although the difference was not statistically significant. HIV+ men (1/32, 3.1%) were also less likely to have CVD compared to non-HIV+ men (10/92, 10.9%), OR 0.3 (0.2-10.9), but not significantly so. Lastly we investigated the role of anti-HTN (used in 36.5% of all subjects), cholesterol lowering (16.7%), and DM medications (10.3%) in reducing CVD. Not taking anti-HTN, cholesterol or DM medications non-significantly increased CVD risk with an OR in all subjects of 1.5, 3.3, or 3.9 respectively. Conclusions: In this interim analysis of an ongoing national cross-sectional study, older men with moderate to severe hemophilia commonly report risk factors for CVD, including HTN (65.6%), dyslipidemia (37.3%) and renal insufficiency (27.6%). Despite this, the prevalence of reported CVD is low at 8.7%, suggesting that men with hemophilia may be protected from forming pathogenic thrombi. More data is needed to determine if the approach to prophylaxis or other therapies should be altered in this population. We plan to formally compare the prevalence of CVD and CV risk factors with similarly aged men in the ARIC database once enrollment is complete. Disclosures Sood: Bayer: Research Funding. Shapiro:Baxter: Consultancy, Global Steering Committee Other, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Novo Nordisk: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Bayer: Consultancy, Global Steering Committee, Global Steering Committee Other, Research Funding; CSL Behring: Research Funding; Biogen Idec: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Kedrion: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding. Kempton:Baxter Healthcare, Inc: Membership on an entity's Board of Directors or advisory committees; CSL Behring: Membership on an entity's Board of Directors or advisory committees; Kedrion Biopharma: Membership on an entity's Board of Directors or advisory committees; NovoNordisk, Inc: Research Funding. Fogarty:Amgen Inc: Consultancy; Bayer HealthCare Pharmaceuticals: Consultancy; Baxter: Consultancy; Biogen Idec Inc.: Consultancy; Chugai Pharma USA: Consultancy; Pfizer Inc: Consultancy; Baxter: Research Funding; Biogen Idec Inc.: Research Funding; CSL Behring: Research Funding; Pfizer Inc: Research Funding; Medscape LLC: Honoraria; VindicoMed: Honoraria. Ragni:Biogen Idec: Consultancy, Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding; GlaxoSmithKline: Consultancy, Research Funding; Tacere Benitec: Consultancy, Drug Safety Monitoring Board, Drug Safety Monitoring Board Other; Baxter: Research Funding; Bayer: Research Funding; CSL Behring: Research Funding; Merck: Research Funding; Novartis: Research Funding; Novo Nordisk: Research Funding; Pfizer: Research Funding; Spark Therapeutics: Research Funding; Vascular Medicine Institute, PIttsburgh, PA: Research Funding. Neff:Baxter: Membership on an entity's Board of Directors or advisory committees. Konkle:CDC: Research Funding, This work was supported by CDC grant 1U01DD000761-01 Other.

Type of Medium: Online Resource

ISSN: 0006-4971 , 1528-0020

URL: Article

DOI: 10.1182/blood.V124.21.2836.2836

Language: English

Publisher: American Society of Hematology

Publication Date: 2014

detail.hit.zdb_id: 1468538-3

detail.hit.zdb_id: 80069-7

In: Blood, American Society of Hematology, Vol. 128, No. 22 ( 2016-12-02), p. 3826-3826

Abstract: Background : Selectins, among other adhesion-mediated functions, facilitate and augment thrombosis; standard anticoagulants address thrombosis but also increase bleeding risk. Previous work in animal models showed inhibiting E-selectin decreases venous thrombosis (VTE) and vein wall inflammation without adverse bleeding events, making E-selectin inhibition a favorable therapeutic candidate for VTE. GMI-1271 is a potent, specific E-selectin antagonist. Here we report final analysis of safety, PK, biomarker and bleeding risk profile for GMI-1271 in 2 phase 1 studies of healthy subjects. Methods: The first study was a blinded single ascending dose (SAD) evaluation of 2, 5, 20, or 40mg/kg of GMI-1271 (n=4/cohort), vs placebo control saline (n=4) or active control Lovenox 1mg/kg (n=4). The second was an open-label multiple ascending dose (MAD) study of 10 (n=3) or 20mg/kg (n=3) of GMI-1271 QD d 1-5 vs Lovenox 1mg/kg (n=2) d 1-5. Assessments included safety (adverse events [AEs], clinical labs, bleeding time, PT/PTT, vitals, exam); PK (plasma and urine); and biomarkers. Biomarkers included ELISAs (CRP, D-dimer, IL-10, MPO, Prothrombin fragment 1.2, soluble E-selectin (sEsel), soluble P-selectin (sPsel), sICAM, Thrombin-antithrombin complex (TAT), Tissue Factor (TF), TNFα, VWF activity, and sCD40L); PicoGreen Assay for circulating DNA; flow cytometry (Platelet Monocyte Aggregates (PMA), Mac-1, LFA-1, and CD44) and Thromboelastography (TEG). See Table 1 for functional description. SAD remains blinded to GMI-1271 or placebo (GMI-1271/p). In SAD, we measured biomarker values at baseline, 8 and 24 h after dosing. Analysis was performed of biomarkers at each dose level and then pooled by GMI-1271/p vs Lovenox. In MAD, we measured biomarker values at baseline and day 4. Comparisons were made using unpaired t-test. Results: In total, 32 subjects enrolled and received GMI-1271/placebo (GMI-1271/p; 20), GMI-1271 (6) or Lovenox (L; 6). Safety: All subjects completed dosing uneventfully. Safety findings for GMI-1271/p were unremarkable. No moderate or serious AE were seen. AE overall were as expected in healthy volunteers. In SAD, only 1/20 GMI-1271/p subjects experienced an AE possibly related to study drug (mild transient headache); 0/6 in MAD. In the L group we saw expected mild transaminitis and injection site bruising. In all studies, GMI-1271 had no effect on bleeding time, PT, or PTT. PK: Plasma levels, Cmax, and AUC increased in a linear manner. Cl, Vz, and t ½ were not dose dependent; no accumulation was seen with multiple dosing (Fig 1 and 2). TEG: In SAD, there was a tendency to increase R, K, and decrease A and MA with no change in % lysis in L vs GMI-1271/p. In MAD, we saw a similar trend as SAD except for an increase in % lysis in L. In the pooled SAD analysis, there was a statistically significant difference between GMI-1271/p and L (higher values) for R (p 〈 0.001) and K (p 〈 0.001); MA was statistically higher in GMI-1271/p vs L (p 〈 0.05). sEsel: In SAD, there was a trend for sEsel to decrease with treatment in all cohorts (combined GMI-1271/p vs L p= 0.017). In MAD, there was non-significant trend for sEsel to decrease between Day 0 and Day 4 in GMI-1271; sEsel levels trended upward with L in comparison. MPO: In SAD, there was a trend for increased values in L vs GMI-1271/p, except for the 40mg/kg cohort. When pooled, there was a significant difference between GMI-1271/p vs L (higher levels) p 〈 0.01. In MAD, there was a non-significant trend for higher levels in L vs GMI-1271. MAC-1 In SAD, there was no change. In MAD, there was a significant decrease in MAC-1 at the 10mg/kg dose (p 〈 0.01). No other notable trend was seen in the other biomarkers measured. Conclusion: We report a favorable safety, biomarker and bleeding profile for the E-selectin antagonist GMI-1271 in healthy subjects. There is no signal to suggest GMI-1271 increases bleeding potential based on adverse events, PT, PTT, bleeding time, and TEG values, unlike traditional anticoagulants. An additional unblinded analysis of the biomarkers will be presented at ASH. We note a trend for sE-sel to decrease with GMI-1271 treatment even in this healthy volunteer population, consistent with previous experience and as expected based on mechanism of action. A phase 1 study of GMI-1271 is currently ongoing to evaluate the safety and efficacy of E-selectin antagonism for the treatment of patients with calf vein DVT. PK Figures: Figure 1: SAD; Figure 2: MAD. Figure 1 Figure 1. Figure 2 Figure 2. Disclosures Hemmer: GlycoMimetics, Inc.: Employment, Equity Ownership. Flanner:GlycoMimetics, Inc.: Employment. Parker:GlycoMimetics, Inc.: Employment. Li:GlycoMimetics, Inc.: Employment, Equity Ownership. Froehlich:Novartis: Consultancy; Janssen: Consultancy; Pfizer: Membership on an entity's Board of Directors or advisory committees; Boehringer-Ingelheim: Membership on an entity's Board of Directors or advisory committees; Fibromuscular Disease Society of America: Research Funding; Blue Cross/Blue Shield of Michigan: Research Funding; Merck: Consultancy. Magnani:GlycoMimetics: Employment, Equity Ownership, Membership on an entity's Board of Directors or advisory committees. Thackray:GlycoMimetics: Employment, Equity Ownership. Sood:Bayer: Research Funding.

Type of Medium: Online Resource

ISSN: 0006-4971 , 1528-0020

URL: Article

DOI: 10.1182/blood.V128.22.3826.3826

Language: English

Publisher: American Society of Hematology

Publication Date: 2016

detail.hit.zdb_id: 1468538-3

detail.hit.zdb_id: 80069-7

In: Blood, American Society of Hematology, Vol. 114, No. 22 ( 2009-11-20), p. 3499-3499

Abstract: Abstract 3499 Poster Board III-436 Acquired hemophilia A (AH) is a rare disorder marked by the development of auto-antibodies to factor VIII. Patients present with a prolonged aPTT that does not correct with mixing and clinically evident bleeding. The Hemophilia and Thrombosis Research Society (HTRS) registry is maintained to study treatment strategies for hemophilia and related disorders in the US. Prior analysis of data resulted in the identification of 25 patients with 29 acute bleeds recorded. An expanded and updated analysis is now presented of treatment patterns for acute bleeds in patients with AH. In total, 90 patients were identified in HTRS, 51 of whom had 138 reported bleeding episodes. Of these, 71 bleeds (51%) were treated with recombinant Factor VIIa (rFVIIa), including 49 bleeds treated with rFVIIa alone and 22 with rFVIIa plus other agents or blood products. In addition, 51 (37%) bleeds were treated with other agents including aPCC (Autoplex T: 19 bleeds, FEIBA: 13 bleeds), aPCC and blood products (7 bleeds), blood products alone (8 bleeds), and FVIII (2 bleeds). 14 episodes did not require treatment for acute bleeds, and 2 had no treatment data recorded. Of patients with bleeds, there were 28 males and 22 females; 36 were Caucasian and 13 African-American. Mean (median) age at time of bleed was 69 (76) years. For those treated with rFVIIa, median (range) initial dose was 91.2 (22-270) mcg/kg, median dose per infusion was 91.0 (22-270), and total treatment dose per bleeding episode was 536.1 (22-18,000)) mcg/kg. Total number of rFVIIa doses was 4 (1-240) for a median of 1 (1-60) day and total treatment duration of 1 (1-60) day for the entire bleeding episode. Dosing data is not available for aPCC. Efficacy was rated by the physician at 72 hours. In patients using rFVIIa, effectiveness was rated as the bleeding stopped in 53/71 episodes (75%); bleeding slowed in 13/71 episodes (no other agents given for 8 episodes, no bleed stop date identified in 3 and the bleed stopped with other agents in 2), bleeding stopped but a re-bleed occurred in 48 hours for 1 episode (no other agents given), no improvement in 3 episodes (no bleed stop date identified in 2, and switched to other agent in 1). Overall rFVIIa efficacy including complete and partial response was 93%. rFVIIa was used as first line therapy in 63 episodes, and as second line therapy in 8. rFVIIa treatment failure, in which the bleed responded to an alternative agent, was 3/71 (4.2%) episodes. Treatment results were not documented for 1 episode. In patients using aPCC, the bleeding stopped in 28/38 episodes (74%); bleeding slowed in 5/38 episodes (no other agents given), and there was no improvement in 5 episodes (no other agents given). Overall aPCC efficacy including complete and partial response was 87%. aPCC treatment failure was 2/45 (4.4%). Of note, 15% of rFVIIa and 50% of bleeds treated with aPCC occurred in 1 patient. Reported adverse events with rFVIIa were rare. One 31-year-old patient with pre-eclampsia and bleeding after a Caesarean section experienced transient neurologic symptoms after receiving rFVIIa 90 mcg/kg q2h for 113 consecutive doses; a cerebral MRI showed multifocal ischemia. No thrombotic complications were reported in 3 individuals treated with higher dose rFVIIa (160,180, 270 mcg/kg). AE data for other agents is not available. While registry data can only demonstrate the treatment captured in selected bleeds reported, this significantly expanded HTRS registry now represents the 2nd largest data set reporting factor use in AH. Treatment of AH has also been documented in recent registries outside the US (e.g. EACH2, SACHA). The current analysis demonstrates rFVIIa and aPCC effectiveness consistent with prior reports. The registry suggests that failures to conventional dosing may respond to very high dosing for rFVIIa without sacrificing safety. As this registry was originally intended in part to track the safety of rFVIIa, these derived data may be somewhat biased and selective. Nevertheless, they are certainly indicative that rapid and safe hemostasis can be achieved in an aging adult population where thrombogenicity of hemostatic agents is of major concern. This registry will continue to collect data on AH patients to determine whether treatment and dosing trends change as experience with rFVIIa expands. In addition, these expanded data support HTRS as a suitable platform to assess other critical management issues (e.g. immune tolerance) within the AH population in the future. Disclosures: Off Label Use: Treatment of acquired hemophilia with aPCC and FVIII concentrates. Konkle:CSL Behring: Membership on an entity's Board of Directors or advisory committees; Bayer: Membership on an entity's Board of Directors or advisory committees; Novo Nordisk: Membership on an entity's Board of Directors or advisory committees; Baxter: Consultancy, Research Funding. Kessler:Bayer: Consultancy, Honoraria, Research Funding; Baxter: Consultancy, Honoraria, Research Funding; Novo Nordisk: Consultancy, Honoraria, Research Funding; Octapharma: Consultancy, Honoraria, Research Funding. Ma:CSL Behring: Membership on an entity's Board of Directors or advisory committees; Novo Nordisk: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Cooper:Novo Nordisk: Employment.

Type of Medium: Online Resource

ISSN: 0006-4971 , 1528-0020

URL: Article

DOI: 10.1182/blood.V114.22.3499.3499

Language: English

Publisher: American Society of Hematology

Publication Date: 2009

detail.hit.zdb_id: 1468538-3

detail.hit.zdb_id: 80069-7

In: Blood, American Society of Hematology, Vol. 124, No. 21 ( 2014-12-06), p. 593-593

Abstract: Background: Previous studies have shown that inhibition of E-selectin can decrease thrombus formation and associated inflammation. E-selectin (CD-62E) is a cell adhesion molecule that is expressed on activated endothelial cells and plays an important role in leukocyte recruitment to the site of vascular injury. GMI-1271 is designed to mimic the bioactive conformation of the sialyl-Lex carbohydrate binding domain of E-selectin and is a specific E-selectin inhibitor. There remains an unmet medical need for a translatable therapeutic that can treat VT in combination with lower, safer levels of low molecular weight heparin (LMWH) anticoagulation. We hypothesize that E-selectin inhibition combined with LMWH will permit lower doses of therapeutic LMWH for the treatment of VT without increasing adverse bleeding events. Methods: Male C57BL/6J mice, 10 weeks old (23-28 grams, n5), 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 non-treated controls (CTR-No Tx), animals given LMWH (3-6 mg/kg, SQ, once daily (qd), the E-selectin inhibitor GMI-1271 20/kg intraperitoneal (IP) twice daily (BID), and a combination of the agents. The dose range of LMWH that produced anti-Xa levels in the therapeutic range (0.5-1.0IU/mL) and significantly decreased thrombus weight in this mouse VT model was 5 and 6 mg/kg. Treated mouse groups received the first dose of experimental therapy immediately following thrombus induction and through day 2. Animals were euthanized 2 days post-thrombosis for tissue harvest and blood collection for the following evaluations: thrombus weight (grams), anti-Xa testing, and tail vein bleeding time (seconds). Results: GMI-1271 Works in Combination with LMWH to Decreases Venous Thrombosis : LMWH dosed at 6mg/kg and 5mg/kg alone, significantly decreased venous thrombus weight at 2 days, versus non-treated controls (73.0±7.5, 62.8±1.9 vs. 186.8±63.9 x10-4 grams, P 〈 0.01). Notably, the combination of GMI-1271 20 mg/kg + LMWH 4mg/kg (33% dose decrease from LMWH 6 mg/kg), and GMI-1271 20 mg/kg + LMWH 3mg/kg (50% dose decrease from LMWH 6 mg/kg dose), significantly decreased thrombus weight, versus non-treated controls (75.6±17.1, 73.0±14.8 vs. 186.8±63.9 x10-4 grams, P 〈 0.01), equivalent to the results of higher doses of LMWH alone (FIGURE 1 A). GMI-1271 Does not Increase Bleeding Potential: GMI-1271 administration did not significantly elevate tail bleeding times, versus non-treated control mice (67.00±44 vs. 53.8±7.5 seconds). LMWH dosed at 5mg/kg and 6 mg/kg, elevated tail bleeding times in mice with the 5 mg/kg LMWH group significant versus non-treated controls (87±25 vs. 53.8±7.5 seconds, P 〈 0.005). Both animal groups treated with GMI-1271, in combination with lower dose LMWH therapy, had tail bleeding times comparable to non-treated control animals (FIGURE 1 B). Conclusion: We report, for the first time, that GMI-1271 works in combination with LMWH to significantly reduce acute VT without increasing bleeding times and by inference, bleeding potential. These preliminary studies suggest that E-selectin inhibition with GMI-1271 may be used to treat VT alone, or in combination with lower and safer levels of LMWH anticoagulation. Figure 1 Figure 1. Disclosures Magnani: GlycoMimetics Inc.: Employment, Equity Ownership, Membership on an entity's Board of Directors or advisory committees.

Type of Medium: Online Resource

ISSN: 0006-4971 , 1528-0020

URL: Article

DOI: 10.1182/blood.V124.21.593.593

Language: English

Publisher: American Society of Hematology

Publication Date: 2014

detail.hit.zdb_id: 1468538-3

detail.hit.zdb_id: 80069-7

In: Research and Practice in Thrombosis and Haemostasis, Elsevier BV, Vol. 4, No. 2 ( 2020-02), p. 193-204

Type of Medium: Online Resource

ISSN: 2475-0379

URL: Article

DOI: 10.1002/rth2.12279

Language: English

Publisher: Elsevier BV

Publication Date: 2020

detail.hit.zdb_id: 2901840-7

In: JAMA Internal Medicine, American Medical Association (AMA), Vol. 179, No. 4 ( 2019-04-01), p. 533-

Type of Medium: Online Resource

ISSN: 2168-6106

DOI: 10.1001/jamainternmed.2018.7816

Language: English

Publisher: American Medical Association (AMA)

Publication Date: 2019