Preclinical safety and efficacy of andexanet alfa in animal models

Lu, Genmin; Hollenbach, Stanley J.; Baker, Dale C.; Tan, S.; Hutchaleelaha, Athiwat; Curnutte, John T.; Conley, Pamela B.

doi:10.1111/jth.13768

Cited by 34 publications

(25 citation statements)

References 19 publications

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“…26 These observations suggest that the elevations in these markers may reflect the hemostasis of endogenous coagulation and fibrinolytic activities and may not necessarily be associated with the development of thrombotic events. In support of the hypothesis that binding of andexanet to TFPI does not present a major safety concern, there was no evidence of thrombotic events attributed to andexanet in the preclinical toxicology studies in monkeys 18 or in clinical phase 3 studies in healthy volunteers. 19 The design and results of the phase 2 study reported here informed the design of the phase 3 studies that evaluated the ability of andexanet to reverse apixaban and rivaroxaban anticoagulation in older healthy subjects.…”

Section: Discussionmentioning

confidence: 61%

“…17 In animals treated with rivaroxaban, andexanet reversed its effects on plasma anti-FXa activity and reduced unbound rivaroxaban concentrations. 18 Furthermore, andexanet dose-dependently reduced bleeding in animals treated with enoxaparin or fondaparinux. 17 Here, we report original data from the phase 1 and 2 studies of andexanet administered to healthy volunteers, with or without apixaban anticoagulation.…”

Section: Introductionmentioning

confidence: 94%

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Safety, pharmacokinetics, and reversal of apixaban anticoagulation with andexanet alfa

Siegal

Leeds

et al. 2017

Blood Advances

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Direct factor Xa (FXa) inhibitors lack a specific reversal agent for emergencies such as major bleeding or urgent surgery. Andexanet alfa, a modified, catalytically inactive, recombinant human FXa derivative, reverses anticoagulant effect by binding and sequestering FXa inhibitors. This original report of safety and dose-finding, phase 1 and 2 randomized, double-blind, placebo-controlled studies, investigated various doses of andexanet in healthy volunteers. Phase 1 evaluated the safety and pharmacokinetics of andexanet (n = 24) or placebo (n = 8). In phase 2, andexanet (n = 36) or placebo (n = 18) was administered following steady-state apixaban dosing (5 mg twice daily for 6 days); safety, pharmacokinetics, and pharmacodynamics were assessed. Andexanet plasma concentration increased proportionally with dose, with rapid elimination (terminal elimination half-life, 4.35-7.5 hours). Following apixaban treatment, andexanet rapidly (≤2 minutes) and dose dependently reduced unbound apixaban concentration vs placebo (51% to 89% vs 5% reduction; all < .05), decreased anti-FXa activity (67.8% to 95.0% vs 7.1% reduction; all < .05), and restored thrombin generation in 67% to 100% vs 6% of subjects (all < .01), maintaining these effects during continuous 45- and 120-minute infusions. Andexanet was well tolerated. Nine subjects had mild/moderate infusion reactions not associated with hemodynamic changes or respiratory compromise that generally resolved without intervention or dose reduction. There were no thrombotic events or other serious safety issues. In conclusion, andexanet reversed apixaban-mediated effects on pharmacodynamic markers of anticoagulation in healthy volunteers within minutes after administration and for the duration of infusion. This trial was registered at www.clinicaltrials.gov as #NCT01758432.

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Section: Discussionmentioning

confidence: 61%

Section: Introductionmentioning

confidence: 94%

Safety, pharmacokinetics, and reversal of apixaban anticoagulation with andexanet alfa

Siegal

Leeds

et al. 2017

Blood Advances

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“…In monkeys, they found neither significant safety concerns or unexpected outcomes. All observations were transient or reversible and included transient hypoactivity, labored respiration, vomiting, and anaphylactic reaction (Lu et al, 2017). Similarly to other antidotes, we tested the toxicity of HBC administered without heparin.…”

Section: Discussionmentioning

confidence: 99%

Heparin-Binding Copolymer as a Complete Antidote for Low-Molecular-Weight Heparins in Rats

Kałaska

Mikłosz

Kamiński

et al. 2020

J Pharmacol Exp Ther

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Bleeding resulting from the application of low-molecular-weight heparins (LMWHs) may be treated with protamine sulfate but lacks efficiency; its action against anti-factor Xa activity is limited to ~60%. Moreover, protamine sulfate can cause life-threatening hypersensitivity reactions. We developed diblock heparin-binding copolymer (HBC) that can neutralize the anticoagulant activity of parenteral anticoagulants. In the present study, we explored the safety profile of HBC and its potential to reverse enoxaparin, nadroparin, dalteparin, and tinzaparin in human plasma and at in vivo conditions. HBC-LMWHs complexes were characterized using zeta potential, isothermal titration calorimetry, and dynamic light scattering. The rat cardiomyocytes and human endothelial cells were used for the assessment of in vitro toxicity. Male Wistar rats were observed for up to 4 days after HBC administration for clinical evaluation, gross necropsy, and biochemistry and histopathological analysis. Rats were treated with LMWHs alone or followed by short-time intravenous infusion of HBC, and bleeding time and anti-factor Xa activity were measured. HBC completely reversed anti-factor Xa activity prolonged in vitro by all LMWHs with an optimal weight ratio of 2.5:1. The complexes of HBC-LMWHs were below 5 µm. We observed no effects on the viability of cardiovascular cells treated with HBC at concentrations up to 0.05 mg/mL. Single doses up to 20 mg/kg of HBC were well-tolerated by rats. HBC completely reversed the effects of LMWHs on bleeding time and anti-factor Xa activity in vivo after 20 minutes, and retained ~80% and ~60% of reversal activity after 1 hour and 2 hours, respectively. Well-documented efficacy and safety of HBC both in vitro and in vivo make this polymer a promising candidate for LMWHs reversal.

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“…The development programs for both drugs had extensive preclinical programs in animals and cohorts of nonbleeding human beings. [2][3][4][5] The approval pathways were discussed with the Food and Drug Administration and thought leaders at the White Oak campus at the same meeting in 2014, the results of which were published. 6 Both trials, ReverseAD and ANNEXA-4, were launched shortly thereafter.…”

Section: Andexanet Responsementioning

confidence: 99%

“…"Structural violence is one way of describing social arrangements that put individuals and populations in harm's way," said Paul Farmer. 3 I suggest that we are dealing with a "structural" problem in drug development.…”

Section: Andexanet Responsementioning

confidence: 99%