314 Reversal of Betrixaban-Induced Anticoagulation in Healthy Volunteers by Andexanet Alfa

Neurosurgery ◽  
2017 ◽  
Vol 64 (CN_suppl_1) ◽  
pp. 267-267 ◽  
Author(s):  
Mark Crowther ◽  
Genmin Lu ◽  
Janet Leeds ◽  
Joyce Lin ◽  
Alex Gold ◽  
...  
Keyword(s):  
Healthy Subjects ◽  
Anticoagulant Activity ◽  
Safety Information ◽  
Factor Xa ◽  
Double Blind Study ◽  
Double Blind ◽  
Matching Placebo ◽  
Medically Ill ◽  
Fxa Inhibitor ◽  
Andexanet Alfa

Abstract INTRODUCTION Andexanet alfa (andexanet) is a modified, recombinant human factor Xa (FXa) that acts as a decoy to bind and sequester FXa inhibitors, thus reversing their anticoagulation effects. Here, we report the efficacy of andexanet in reversing the anticoagulant activity of betrixaban, a direct FXa inhibitor which has recently completed a large Phase 3 clinical trial in acute medically ill patients (APEX). METHODS In this Phase 2, randomized, double-blind study, healthy subjects were dosed with 80 mg qd po betrixaban to steady state (7 days). In Cohort 1, subjects (n = 6) received 800-mg andexanet bolus 3 hours after the last dose of betrixaban, or matching placebo (n = 3). In Cohort 2, subjects (n = 6) received 800-mg andexanet bolus 4 hours after the last betrixaban dose, followed immediately by a 2-hour andexanet infusion (8 mg/min), or matching placebo (n = 3). Study endpoints included assessments of safety and pharmacodynamic markers of anticoagulation reversal. RESULTS >Following dosing with betrixaban, andexanet rapidly (2 minutes after the bolus) decreased anti-FXa activity by ∼80% in both cohorts (P < 0.001 vs. placebo) and decreased unbound betrixaban plasma concentration by 73% and 83% in Cohorts 1 and 2, respectively (P < 0.001 vs. placebo). The effects were maintained during the 2-hour infusion of andexanet. Thrombin generation was restored in 11/12 (91.7%) subjects administered andexanet vs. 2/6 (33.3%) placebo subjects. Andexanet was well-tolerated; there were no thrombotic events or other serious/severe adverse events. CONCLUSION Andexanet was well-tolerated and rapidly reversed anticoagulation effects of betrixaban in healthy subjects. The results of this and previous studies in healthy subjects indicate the potential of andexanet as a universal antidote for FXa inhibitors. An ongoing Phase 3b/4 study (ANNEXA-4) in patients receiving a FXa inhibitor who present with acute major bleeding and require urgent reversal of anticoagulation will provide efficacy and safety information on andexanet in this target patient population.

Abstract 212: Andexanet Alfa, a Universal Antidote for Reversal of Anticoagulation of Factor Xa Inhibitors in Healthy Human Volunteers

Stroke ◽  
2016 ◽  
Vol 47 (suppl_1) ◽  
Author(s):  
Mark Crowther ◽  
Alexander M Gold ◽  
Genmin Lu ◽  
Janet M Leeds ◽  
Brian L Wiens ◽  
...  
Keyword(s):  
Healthy Subjects ◽  
Statistical Significance ◽  
Factor Xa ◽  
Clinical Results ◽  
Phase 2 ◽  
Healthy Human ◽  
Serious Adverse Events ◽  
Double Blind ◽  
Secondary Endpoints ◽  
Andexanet Alfa

Introduction: Andexanet alfa (AnXa) is a recombinant modified fXa molecule that acts as a specific antidote for fXa inhibitors. We report clinical results in healthy subjects anticoagulated with apixaban (apix), rivaroxaban (riva), edoxaban (edox), or enoxaparin (enox), demonstrating rapid and sustained reversal of anticoagulation following administration of AnXa. Methods: These were Phase 2/3 randomized, double-blind, placebo-controlled studies in healthy subjects. In Phase 2, about153 subjects age18 - 45 were given one of the fXa inhibitors (apix 5 mg BID, riva 20 mg QD, edox 60 mg QD or enox 40 mg QD) for 6 days. AnXa or placebo (3:1 randomization) was given IV on Day 6, 3hrs after the last inhibitor dose (∼inhibitor Cmax). Safety was followed through Day 48. A range of AnXa doses (bolus or bolus+infusion) was evaluated by correction of biomarkers (anti-fXa activity, free inhibitor concentrations and thrombin generation (TG)). In Phase 3 (ANNEXA™), older subjects age 50 to 75 were dosed with apix (5 mg BID) or riva (20 mg QD) for 4 days. ANNEXA™-A had 63 subjects treated with apix. AnXa (400 mg bolus; 400 mg bolus plus 4 mg/min x 2hr infusion) or placebo (3:1 randomization) was given on Day 4, 3 hrs after the last apix dose. ANNEXA™-R had 82 subjects treated with riva. AnXa (800 mg bolus; 800 mg bolus plus 8 mg/min x 2hr infusion) or placebo (2:1) was given on Day 4, 4 hrs after the last riva dose. Safety was followed through Day 43. Results: About 298 healthy subjects were enrolled in the studies. AnXa demonstrated rapid and sustained reversal of both direct and indirect fXa inhibitors as measured by correction of biomarkers. The ANNEXA™ studies confirmed findings from Phase 2, and met all primary (reversal of anti-fXa) and secondary endpoints (reduction of free inhibitor concentration and restoration of TG) with high statistical significance. AnXa was well-tolerated with no serious adverse events, thrombotic events, or antibodies to fX or fXa reported. Conclusion: AnXa treatment results in rapid and sustained reversal of anticoagulation of fXa inhibitors. A Phase 3b/4 confirmatory study (ANNEXA-4) in patients with acute major bleeds is ongoing.

Bombesin Reduces Food Intake after a Preload in Man by a Cholecystokinin-Independent Mechanism

1993 ◽  
Vol 85 (3) ◽  
pp. 277-280 ◽  
Author(s):  
R. J. Lieverse ◽  
J. B. M. J. Jansen ◽  
A. A. M. Masclee ◽  
C. B. H. W. Lamers
Keyword(s):  
Food Intake ◽  
Receptor Antagonist ◽  
Healthy Subjects ◽  
Saline Infusion ◽  
Blind Study ◽  
Double Blind Study ◽  
Double Blind ◽  
Cholecystokinin Receptor ◽  
Independent Mechanism

1. A double-blind study was undertaken to determine whether the infusion of bombesin inhibits the intake of a carbohydrate-rich meal, consumed 15 min after a 300 ml banana shake, in nine lean healthy subjects and whether the possible inhibition of food intake by bombesin is mediated by cholecystokinin. 2. The amount of food eaten during infusion of bombesin (267 ±60 g) and bombesin combined with the cholecystokinin-receptor antagonist loxiglumide (269±39g) was slightly (P = 0.09) less than during saline infusion (384 ± 40 g). In addition, preprandial feelings of hunger were significantly less during infusion of both bombesin and bombesin combined with loxiglumide. 3. In conclusion, infusion of bombesin tends to inhibit the intake of a carbohydrate-rich meal after a preload by a cholecystokinin-independent mechanism.

scholarly journals Reversal of Factor Xa Inhibitors by Andexanet Alfa May Increase Thrombogenesis Compared to Pretreatment Values

2019 ◽  
Vol 25 ◽  
pp. 107602961986349 ◽  
Author(s):  
Fakiha Siddiqui ◽  
Alfonso Tafur ◽  
Lorenzo Storino Ramacciotti ◽  
Walter Jeske ◽  
Debra Hoppensteadt ◽  
...  
Keyword(s):  
Thrombin Generation ◽  
Area Under The Curve ◽  
Factor Xa ◽  
Coagulation Factor ◽  
Inhibitory Effects ◽  
Clotting Time ◽  
Reversal Effect ◽  
Normal Human ◽  
Fxa Inhibitor ◽  
Andexanet Alfa

Recombinant coagulation factor Xa (FXa), inactivated Zh-zo, also known as andexanet alfa (AA), is a modified version of human FXa that has been developed to neutralize FXa inhibitors. We studied the reversal effect of AA for these inhibitors in various anticoagulant and thrombin generation (TG) assays. Individual aliquots of normal human plasma containing 1 µg/mL of apixaban, betrixaban, edoxaban, and rivaroxaban, were supplemented with saline or AA at a concentration of 100 µg/mL. Clotting profiles include prothrombinase-induced clotting time, activated partial thromboplastin time, and prothrombin time. Factor Xa activity was measured using an amidolytic method. Thrombin generation was measured using a calibrated automated thrombogram. Differential neutralization of all 4 anticoagulants was noted in the activated clotting time and other clotting tests. The FXa activity reversal profile varied with an observed decrease in apixaban (22%), betrixaban (56%), edoxaban (28%), and rivaroxaban (49%). Andexanet alfa also led to an increased TG in comparison to saline. The peak thrombin was higher (40%), area under the curve (AUC) increased (15%), whereas the lag time (LT) decreased (17%). Andexanet alfa added at 100 µg/mL to various FXa supplemented systems resulted in reversal of the inhibitory effects, restoring the TG profile; AUC, LT, and peak thrombin levels were comparable to those of unsupplemented samples. Andexanet alfa is capable of reversing anti-Xa activity of different oral FXa inhibitors but overshoots thrombogenesis in both the saline and FXa inhibitor supplemented systems. The degree of neutralization of Xa inhibitor is specific to each agent.

scholarly journals Pharmacokinetics (PK) and Safety of Intravenous (IV) Brincidofovir (BCV) in Healthy Adult Subjects

2017 ◽  
Vol 4 (suppl_1) ◽  
pp. S311-S311 ◽  
Author(s):  
Mary Beth Wire ◽  
Marion Morrison ◽  
Maggie Anderson ◽  
Thangam Arumugham ◽  
John Dunn ◽  
...  
Keyword(s):  
Healthy Subjects ◽  
Geometric Mean ◽  
Compartmental Analysis ◽  
Repeat Dose ◽  
Double Blind Study ◽  
Double Blind ◽  
Dose Administration ◽  
To Receive ◽  
Male Subjects ◽  
Support Evaluation

Abstract Background BCV is a lipid conjugate nucleotide that has shown rapid viral clearance in patients with adenovirus infection and improved survival in animal models of smallpox. In preclinical studies in rats, IV BCV dosed twice weekly for up to 29 days was not associated with gastrointestinal (GI), hematopoietic, hepatic, or renal toxicity. This study evaluated the safety and PK of IV BCV in healthy subjects. Methods In this double-blind study, subjects were randomized 3:1 to receive IV BCV or placebo in sequential single ascending dose cohorts (Table 1). Plasma PK samples were collected over 7 days and assayed by HPLC-MS. Plasma BCV PK parameters were determined by non-compartmental analysis and dose proportionality was assessed. Safety assessments were collected over 14 days. Results Forty healthy male subjects (18–46 years, 83% White) were enrolled and completed the study. Plasma BCV Cmax and AUC∞ increased in proportion to dose (Table 1). AEs and alanine aminotransferase (ALT) elevations were dose- and infusion duration-related (Table 1). GI AEs were mild. All AEs and ALT elevations were transient and no serious AEs occurred. Conclusion Single doses of BCV 10–50 mg administered as a 2h IV infusion were well tolerated and not associated with significant clinical or laboratory abnormalities. BCV IV 10 mg and BCV IV 50 mg achieved geometric mean plasma BCV AUC∞ similar to and 4.5-fold, respectively, values achieved with BCV oral 100 mg tablets (Cmax = 251 ng/mL and AUC∞ = 1394 ng hours/mL). These data support evaluation of repeat dose administration in healthy subjects and virally-infected patients. Disclosures M. B. Wire, Chimerix: Employee and Shareholder, Salary. M. Morrison, Chimerix: Employee and Shareholder, Salary.M. Anderson, Chimerix: Employee and Shareholder, Salary. T. Arumugham, Chimerix: Employee and Shareholder, Salary. J. Dunn, Chimerix: Employee and Shareholder, Salary. O. Naderer, Chimerix: Employee and Shareholder, Salary.

A Phase 2 Randomized, Double-Blind, Placebo-Controlled Trial Demonstrating Reversal Of Rivaroxaban-Induced Anticoagulation In Healthy Subjects By Andexanet Alfa (PRT064445), An Antidote For Fxa Inhibitors

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 3636-3636 ◽  
Author(s):  
Crowther Mark ◽  
Mathur Vandana ◽  
Kitt Michael ◽  
Lu Genmin ◽  
Pamela B. Conley ◽  
...  
Keyword(s):  
Adverse Events ◽  
Healthy Subjects ◽  
Controlled Study ◽  
Pharmacokinetic Data ◽  
Phase 2 ◽  
Employment Equity ◽  
Double Blind ◽  
Double Blind Placebo ◽  
Equity Ownership ◽  
Andexanet Alfa

Abstract Background Direct factor Xa inhibitors have demonstrated compelling anticoagulant efficacy and/or safety profiles across multiple diverse patient populations. A specific antidote to reverse anticoagulation during episodes of serious uncontrolled bleeding or before urgent/emergent surgery is lacking. Andexanet alfa (proposed INN)(AnXa, PRT064445) is a modified, recombinant human fXa molecule that is catalytically inactive but retains high-affinity binding to direct fXa inhibitors. It thus acts as a decoy to reverse fXa inhibitor-mediated anticoagulation in preclinical and early clinical studies. Methods This ongoing Phase 2, double-blind, placebo-controlled study is examining the reversal by AnXa of the anticoagulant activity of rivaroxaban (riva), as well as the pharmacokinetics and safety in healthy subjects. Reversal of riva anticoagulation will be studied with up to 6 different dose cohorts/ regimens of AnXa or placebo in a 6:3 ratio (i.e., 9 subjects per cohort). Riva is administered at an oral dose of 20 mg qd for 6 days and AnXa administered intravenously on Day 6, 3 hours after the last riva dose – the approximate time of maximum riva concentration (mean ± SD: 0.64 ± 0.22 mM, n=18). Pharmacodynamic and safety data are collected through Day 48 with pharmacokinetic data through Day 10. Results We report here available data from the first 2 AnXa dose cohorts (210 mg and 420 mg, n =18). Immediately after completion of the 210 mg and 420 mg doses, anti-fXa activity decreased dose-dependently by 20% and 53%, respectively, from the pre-AnXa level and returned to placebo levels by approximately 2 hours after treatment (Figure). In parallel, the plasma concentrations of unbound riva were decreased by 32% and 51%, respectively, relative to pre-AnXa values. In addition, riva-induced inhibition of thrombin generation and prolongation of both prothrombin time and activated clotting time were also rapidly partially reversed by AnXa in a dose-dependent manner. At 2 minutes after AnXa administration, the molar ratio of AnXa to total plasma riva was 0.8 for the 210 mg dose (1.2 µM/1.6 µM, respectively) and 1.2 for the 420 mg dose (2.6 µM/2.1 µM, respectively). AnXa infusion was not associated with increases in prothrombin fragments F1+2, thrombin-antithrombin, or D-dimer (all values were within normal ranges). As expected, tissue factor pathway inhibitor activity decreased due to its binding to AnXa. AnXa was well tolerated and there were no thrombotic events, serious, or severe adverse events. Adverse events occurring in 1 or more AnXa or placebo recipients included infusion-related reactions (n = 3, all mild in severity) and post-procedural hematoma, headache, or postural dizziness (n = 2 each). Summary/Conclusions Results from this ongoing clinical trial demonstrate that AnXa is able to dose-dependently partially reverse the anticoagulant effects of rivaroxaban, as assessed by pharmacodynamic markers, in healthy subjects. These data are consistent with previously reported results with apixaban in that AnXa sequesters rivaroxaban and apixaban in a similar stoichiometric manner. Additional data with higher doses of AnXa will also be presented. AnXa is well-tolerated and a potentially promising, universal antidote for fXa inhibitors. Disclosures: Mark: Portola Pharmaceuticals: Consultancy. Off Label Use: The use of PRT064445 as an antidote for reversal of anticoagulation from direct and indirect fXa inhibitors is investigational. Vandana:Portola Pharmaceuticals: Consultancy. Michael:Portola Pharmaceuticals: Employment, Equity Ownership. Genmin:Portola Pharmaceuticals: Employment, Equity Ownership. Conley:Portola Pharmaceuticals: Employment, Equity Ownership. Stanley:Portola Pharmaceuticals: Employment, Equity Ownership. Castillo:Portola Pharmaceuticals: Employment, Equity Ownership. Hutchaleelaha:Portola Pharmaceuticals: Consultancy. Karbarz:Portola Pharmaceuticals: Employment. Lin:Portola Pharmaceuticals: Employment. Barron:Portola Pharmaceuticals: Employment. Russell:Portola Pharmaceuticals: Employment. Levy:Portola Pharmaceuticals: Employment. Connolly:Portola Pharmaceuticals: Consultancy. Curnutte:Portola Pharmaceuticals: Employment, Equity Ownership.

Effect of a Nitroglycerin Patch on Perfusion to the Foot in Healthy Subjects

2006 ◽  
Vol 96 (4) ◽  
pp. 318-322 ◽  
Author(s):  
Paul Jeong Kim ◽  
L. Clay Ballinger ◽  
Donald Kushner
Keyword(s):  
Nitric Oxide ◽  
Healthy Subjects ◽  
Healing Process ◽  
Experimental Period ◽  
Drug Group ◽  
Wound Healing Process ◽  
Double Blind Study ◽  
Double Blind ◽  
Adhesive Patch ◽  
The Subject

Nitric oxide is an endogenous gas released by endothelial cells that induces vasodilatation and plays other important roles in the wound-healing process. Nitroglycerin preparations are liberators of nitric oxide. Podiatric physicians have used nitroglycerin paste and patches on patients in an attempt to increase perfusion to the foot. However, the drug’s efficacy seems to be largely anecdotal. A prospective, randomized, placebo-controlled, double-blind study was conducted to investigate the efficacy of a nitroglycerin patch in locally increasing perfusion to the foot. Twenty-two healthy subjects were randomly assigned to either a drug group (nitroglycerin patch, 0.2 mg/h) or a placebo group (adhesive patch without active ingredient). The patch was applied to the plantar arch of the foot. Objective and subjective measures were then used to detect changes in perfusion to the foot after a 2-hour experimental period. The objective measures, cutaneous thermometry and photoplethysmography, found no significant measurable difference in perfusion to the foot between the drug and placebo groups (P &gt; .05). A subjective questionnaire used to assess changes in temperature or sensation detected by the subject yielded similar results. Thus a nitroglycerin patch dose of 0.2 mg/h showed no measurable ability to increase perfusion to the foot. Further research is needed to validate the indications for this therapy. (J Am Podiatr Med Assoc 96(4): 318–322, 2006)

scholarly journals Retrospective Comparison of Andexanet Alfa and 4-Factor Prothrombin Complex for Reversal of Factor Xa-Inhibitor Related Bleeding

2021 ◽  
Vol 27 ◽  
pp. 107602962110390
Author(s):  
Victoria M. Stevens ◽  
Toby C. Trujillo ◽  
Tyree H. Kiser ◽  
Robert MacLaren ◽  
Paul M. Reynolds ◽  
...  
Keyword(s):  
Factor Xa ◽  
Similar Rate ◽  
Thromboembolic Events ◽  
Equivalent Number ◽  
Retrospective Comparison ◽  
Number Of Patients ◽  
Mortality Incidence ◽  
Fxa Inhibitor ◽  
Baseline Characteristics ◽  
Andexanet Alfa

The aim of this retrospective study was to compare andexanet alfa and 4-factor prothrombin complex (4F-PCC) for reversal of factor Xa (FXa)-inhibitor bleeding. Patients that received andexanet alfa for reversal were included. An equivalent number of patients administered 4F-PCC for FXa-inhibitor bleeding were randomly selected as historical controls. The primary outcome was effective hemostasis achievement within 12 h, defined using ANNEXA-4 criteria. Thromboembolic events and mortality within 30 days were also evaluated. A total of 32 patients were included. Baseline characteristics were not statistically different between andexanet alfa (n = 16) and 4F-PCC (n = 16). Intracranial bleeding was the primary reversal indication in 43.8% versus 62.5% of patients, respectively. Effective hemostasis was reached in 75.0% of andexanet alfa patients compared to 62.5% of 4F-PCC patients ( P = .70). Thromboembolic events occurred in 4 (25.0%) patients and 3 (18.8%) patients, respectively ( P = .99). Mortality incidence was 12.5% and 31.3%, respectively ( P = .39). Andexanet alfa and 4F-PCC attained hemostasis in a majority of patients. A high, but a similar rate of thromboembolic events was seen with both treatments. Prospective studies are needed to elucidate comparative risks and benefits of the 2 agents.

Abstract 10: Randomized, Double-Blind, Placebo-Controlled Single Ascending Dose Pharmacokinetic and Pharmacodynamic Study of PRT064445, a Universal Antidote for Factor Xa Inhibitors

2013 ◽  
Vol 33 (suppl_1) ◽  
Author(s):  
Mark Crowther ◽  
Michael Kitt ◽  
Matthew McClure ◽  
Uma Sinha ◽  
Genmin Lu ◽  
...  
Keyword(s):  
Unplanned Pregnancy ◽  
Factor Xa ◽  
Factor Xa Inhibitors ◽  
Double Blind Study ◽  
Dependent Manner ◽  
Platelet Activity ◽  
Double Blind ◽  
Phase 2 Trial ◽  
Direct Factor Xa Inhibitors

Background Direct factor Xa inhibitors [fXaI] have superior anticoagulant efficacy and/or safety relative to warfarin and LMWH but are limited by lack of a specific antidote to reverse anticoagulation during episodes of serious bleeding or before surgery. PRT064445 [PRT] is a modified, human recombinant fXa that is catalytically inactive but retains high-affinity binding to direct fXaI and heparin- antithrombin III complexes. It competes with native fXa for fXaI drugs, thus reversing direct and indirect fXaI-mediated anticoagulation. Methods In this phase I, first-in-man double-blind study, 32 healthy volunteers were randomized (6:2) within dosing cohorts to a single IV bolus of PRT (30 mg, 90 mg, 300 mg, or 600 mg) or placebo and followed for 28 days. Anti-fXa activity was assayed in vitro by adding exogenous rivaroxaban (50 ng/mL) to subject plasma samples. Results The terminal t1/2 was ~6 hours. AUC and Cmax increased disproportionately relative to dose. In the presence of PRT, thrombin generation and anti-fXa activity of rivaroxaban ( Figure ) were reversed in a dose-dependent manner. There were no thrombotic AEs or deaths. There was 1 serious AE (pneumonia) and 3 non-serious infusion-related reactions without anaphylaxis [90 mg (2) and placebo (1)]. One unplanned pregnancy occurred ~10 days post-treatment, followed shortly by a spontaneous abortion. Prothrombin fragment 1 + 2, thrombin-antithrombin complex, and D-dimer transiently increased with dose; other coagulation parameters including PT, aPTT, ACT and platelet activity were unchanged. Conclusions PRT is a promising universal antidote for fXaI. A Phase 2 trial evaluating PRT reversal of several fXaI is ongoing.

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