How Do TFPI Neutralizing Antibodies Work?

Tissue factor pathway inhibitor (TFPI) neutralizing antibodies are a class of investigational medications developed for treatment of patients with hemophilia. The first drug to be developed in this class is befovacimab, however, phase 2 clinical trial of the drug was terminated early due to safety concerns because of clot formation (thrombosis) in patients.

Coagulation factors are specialized proteins in the blood that interact with each other and regulate the blood clotting (coagulation) process. Some factors promote clotting and others prevent clot formation, in order to enable the blood to clot where and when required, for instance, in an injury, and flow freely in blood vessels without clotting.

A fine balance must remain between coagulant and anticoagulant factors for a stable state (homeostasis) of the blood. Absence of, or incorrect functioning of any of the factors can cause blood coagulation disorders, which can cause excessive bleeding, or blood clots blocks in blood vessels.

Hemophilia is a bleeding disorder caused by mutations in genes that code for certain coagulation factors. There are two types of hemophilia, A and B; hemophilia A is caused by the deficiency or absence of coagulation factor VIII, and hemophilia B is caused by deficiency in or lack of coagulation factor IX.

Hemophilia patients suffer from spontaneous bleeding episodes, most commonly in the joints and muscles. Minor injuries can cause severe and uncontrolled bleeding. The standard treatment for hemophilia is increasing the coagulation factor levels or replacement of missing factors, through intravenous infusions.

Tissue factor pathway inhibitor is an anticoagulant protein that inhibits the clotting response in its early stages. TFPI neutralizing antibodies are human monoclonal antibodies produced in the lab. TFPI neutralizing antibodies are specifically designed to bind to and act against the TFPI protein, and block its anticoagulant activity.

Treatment with TFPI neutralizing antibodies as a prophylaxis was found to help reduce spontaneous bleeding episodes in hemophilia patients, and the need for regular coagulation factor replacement. However, clinical trials of the newly developed TFPI neutralizing antibody, befovacimab, have been terminated in phase 2, because of serious thrombosis events in some patients.

TFPI neutralizing antibodies were developed for the prevention of bleeding episodes in patients with hemophilia A or B. In multiple-dose, dose-escalating phase 2 clinical trials, TFPI neutralizing antibodies were administered subcutaneously into the tissue under the skin, once a week for 2 to 47 weeks with 100 mg, 225 mg and 400 mg doses.

The clinical trial was terminated prematurely due to drug-related serious thrombosis events in 3 patients.

Common side effects of TFPI neutralizing antibodies include the following:

• Injection site reactions including:
• Itching (pruritus)
• Swelling
• Inflammation
• Redness (erythema)
• Nausea
• Skin erythema
• Low fibrinogen level in blood (hypofibrinogenemia)
• Increased fibrin D-dimer
• Retinal artery thrombosis
• Stroke from reduced blood flow to brain (ischemic stroke)
• Transverse sinus thrombosis, a rare form of stroke
• Headache
• Dizziness

Information contained herein is not intended to cover all possible side effects, precautions, warnings, drug interactions, allergic reactions, or adverse effects. Check with your doctor or pharmacist to make sure these drugs do not cause any harm when you take them along with other medicines. Never stop taking your medication and never change your dose or frequency without consulting your doctor.

Generic and brand names of TFPI neutralizing antibodies include:

• befovacimab