Andexanet alfa, sold under the trade name Andexxa among others, is an

antidote An antidote is a substance that can counteract a form of poisoning. The term ultimately derives from the Greek term φάρμακον ἀντίδοτον ''(pharmakon) antidoton'', "(medicine) given as a remedy". Antidotes for anticoagulants are s ...

for the medications

rivaroxaban Rivaroxaban, sold under the brand name Xarelto among others, is an anticoagulant medication (blood thinner) used to treat and prevent blood clots. Specifically it is used to treat deep vein thrombosis and pulmonary emboli and prevent blood clo ...

and

apixaban Apixaban, sold under the brand name Eliquis, is an anticoagulant medication used to treat and prevent blood clots and to prevent stroke in people with nonvalvular atrial fibrillation through directly inhibiting factor Xa. Specifically it is ...

, when reversal of

anticoagulation Anticoagulants, commonly known as blood thinners, are chemical substances that prevent or reduce coagulation of blood, prolonging the clotting time. Some of them occur naturally in blood-eating animals such as leeches and mosquitoes, where the ...

is needed due to uncontrolled bleeding. It has not been found to be useful for other

factor Xa inhibitor Direct factor Xa inhibitors (xabans) are anticoagulants (blood thinning drugs), used to both treat and prevent blood clots in veins, and prevent stroke and embolism in people with atrial fibrillation (AF). Medical use Direct factor Xa inhibito ...

s. It is given by

injection into a vein Intravenous therapy (abbreviated as IV therapy) is a medical technique that administers fluids, medications and nutrients directly into a person's vein. The intravenous route of administration is commonly used for rehydration or to provide nutrie ...

. Common side effects include

pneumonia Pneumonia is an inflammatory condition of the lung primarily affecting the small air sacs known as alveoli. Symptoms typically include some combination of productive or dry cough, chest pain, fever, and difficulty breathing. The severit ...

and

urinary tract infection A urinary tract infection (UTI) is an infection that affects part of the urinary tract. When it affects the lower urinary tract it is known as a bladder infection (cystitis) and when it affects the upper urinary tract it is known as a kidne ...

s. Severe side effects may include

blood clots A thrombus (plural thrombi), colloquially called a blood clot, is the final product of the blood coagulation step in hemostasis. There are two components to a thrombus: aggregated platelets and red blood cells that form a plug, and a mesh of cr ...

heart attack A myocardial infarction (MI), commonly known as a heart attack, occurs when blood flow decreases or stops to the coronary artery of the heart, causing damage to the heart muscle. The most common symptom is chest pain or discomfort which ma ...

stroke A stroke is a disease, medical condition in which poor cerebral circulation, blood flow to the brain causes cell death. There are two main types of stroke: brain ischemia, ischemic, due to lack of blood flow, and intracranial hemorrhage, hemorr ...

s, or

cardiac arrest Cardiac arrest is when the heart suddenly and unexpectedly stops beating. It is a medical emergency that, without immediate medical intervention, will result in sudden cardiac death within minutes. Cardiopulmonary resuscitation (CPR) and possi ...

. It works by binding to rivaroxaban and apixaban. It was approved for medical use in the United States in May 2018. It was developed by Portola Pharmaceuticals.

Medical uses

Andexanet alfa is used to stop life-threatening or uncontrollable bleeding in people who are taking

. There are no randomised clinical trials as of 2019. Studies in healthy volunteers show that the molecule binds factor Xa inhibitors and counters their anti-Xa-activity. The only published clinical trial is a prospective, open label, single group study. This study reports results on 352 people and demonstrates a reduction of anti-Xa-activity while also showing an excellent or good hemostatic efficacy in 82%. While people who were expected to die in 30 days were excluded from the study, 14% of participants died. There was no relationship between hemostatic efficacy and reduced anti-Xa-activity. The FDA has demanded a randomised clinical trial: the first results are not expected before 2023.

Adverse effects

Common side effects include pneumonia and urinary tract infections. Severe side effects may include

. Andexanet alfa has a

boxed warning In the United States, a boxed warning (sometimes "black box warning", colloquially) is a type of warning that appears on the package insert for certain prescription drugs, so called because the U.S. Food and Drug Administration specifies that i ...

that it is associated with arterial and venous blood clots, ischemic events, cardiac arrest, and sudden deaths.

Pharmacology

Mechanism of action

Andexanet alfa is a biologic agent, a recombinant modified version of human activated

factor X Factor X, also known by the eponym Stuart–Prower factor, is an enzyme () of the coagulation cascade. It is a serine endopeptidase (protease group S1, PA clan). Factor X is synthesized in the liver and requires vitamin K for its synthesis. Fa ...

(FXa). Andexanet alfa differs from native FXa due to the removal of a 34 residue fragment that contains the

Gla domain Vitamin K-dependent carboxylation/gamma-carboxyglutamic (GLA) domain is a protein domain that contains post-translational modifications of many glutamate residues by vitamin K-dependent carboxylation to form γ-carboxyglutamate (Gla). Proteins wi ...

. This modification reduces andexanet alfa's procoagulant potential. Additionally, a serine to alanine (S419A) mutation in the active site eliminates its activity as a prothrombin to thrombin catalyst, but still allows the molecule to bind to FXa inhibitors. FXa inhibitors bind to andexanet alfa with the same affinity as to natural FXa. As a consequence in the presence of andexanet alfa natural FXa is partially freed, which can lead to effective

hemostasis In biology, hemostasis or haemostasis is a process to prevent and stop bleeding, meaning to keep blood within a damaged blood vessel (the opposite of hemostasis is hemorrhage). It is the first stage of wound healing. This involves coagulatio ...

. In other words, it acts as a decoy receptor. Andexanet alfa reverses effect of all anticoagulants that act directly through FXa or by binding

antithrombin III Antithrombin (AT) is a small glycoprotein that inactivates several enzymes of the coagulation system. It is a 432-amino-acid protein produced by the liver. It contains three disulfide bonds and a total of four possible glycosylation sites. α-Ant ...

. The drug is not effective against factor IIa inhibitor

dabigatran Dabigatran, sold under the brand name Pradaxa among others, is an anticoagulant used to treat and prevent blood clots and to prevent stroke in people with atrial fibrillation. Specifically it is used to prevent blood clots following hip or kn ...

. Its activity is measured using the anti-Xa test, which is utilized to determine the amount of available factor Xa for coagulation

History

It was approved in the United States in 2018 based on data from two phase III studies on reversing the anticoagulant activity of FXa inhibitors rivaroxaban and apixaban in healthy volunteers. As a condition of its accelerated approval there is a study being conducted comparing it to other currently used reversal agents ("usual care").

Society and culture

Economics

Initial pricing (AWP) is $58,000 per reversal (800 mg bolus + 960 mg infusion, $3,300 per 100 mg

vial A vial (also known as a phial or flacon) is a small glass or plastic vessel or bottle, often used to store medication as liquids, powders or capsules. They can also be used as scientific sample vessels; for instance, in autosampler devices i ...

) which is higher than reversal agents for other DOAC agents (

idarucizumab Idarucizumab, sold under the brand name Praxbind, is a monoclonal antibody used as a reversal agent for dabigatran. Idarucizumab was developed by Boehringer Ingelheim. One study sponsored by the manufacturer found that idarucizumab effectively ...

for use in

reversal is $4,200 per reversal).

References

External links

* * {{Portal bar , Medicine Antidotes AstraZeneca brands Recombinant proteins