Efanesoctocog alfa, formerly known as BIVV001 and rFVIIIFc-VWF-XTEN, is an investigational factor VIII (FVIII) replacement therapy for people with hemophilia A.
Bioverativ developed the therapy to extend protection from bleeds in hemophilia A patients, with preventive (prophylaxis) dosing at weekly, or longer, intervals. Sanofi acquired Bioverativ in 2018 and is continuing to develop the treatment, along with Sobi.
The U.S. Food and Drug Administration (FDA) accepted the company’s investigational new drug application for efanesoctocog alfa in June 2017. This was based on encouraging results from preclinical studies.
How does efanesoctocog alfa work?
Efanesoctocog alfa is based on Fc fusion technology, and is made by adding a region of a blood-clotting protein called von Willebrand factor (VWF) and a polypeptide called XTEN to a recombinant, or man-made, FVIII-Fc fusion protein. The goal is to potentially extend its lifetime in circulation. It is the first molecule of its kind to fuse together four different proteins: FVIII, VWF, XTEN, and Fc.
Efanesoctocog alfa in preclinical studies
In preclinical studies, the pharmacological properties of efanesoctocog alfa were similar to those of recombinant FVIII (rFVIII). The experimental therapy also extended the half-life of FVIII in mouse models of hemophilia A to four times beyond that achieved with conventional FVIII. The half-life of intravenously (into-the-vein) administered efanesoctocog alfa was about 37 hours.
In addition, animals that received a low dose — 25 international units per kg of body weight (IU/kg) — of efanesoctocog alfa retained 5% of normal FVIII activity after 120 hours. This suggested the potential for full protection from spontaneous bleeding in this animal model.
When the treatment was delivered under the skin, the bioavailability (availability in the plasma) of efanesoctocog alfa was 20%. This was a significant increase compared with the less than 1% seen with conventional FVIII. After 24 hours of under-the-skin administration of efanesoctocog alfa, FVIII levels in the blood were equal to or greater than those attained with conventional FVIII delivered intravenously, or into the vein, at the same dose.
Efanesoctocog alfa in clinical trials
An open-label, dose-escalation Phase 1/2a study, called EXTEN-A (NCT03205163), investigated the safety, tolerability, and pharmacokinetics (movement of a substance into, through, and out of the body) of a single dose of efanesoctocog alfa.
The therapy was injected into the bloodstream of men with severe hemophilia type A, whose FVIII activity levels were less than 1% of normal. Participants received a single dose of Advate, a man-made FVIII replacement therapy, at a dose of 25 IU/kg or 65 IU/kg. After three days, patients received the same dose of efanesoctocog alfa.
Efanesoctocog alfa lasted three to four times longer in the body compared with Advate, according to results from the study published in The New England Journal of Medicine.
A single dose of efanesoctocog alfa was also able to safely and effectively increase FVIII activity levels in the patients. The treatment was generally well-tolerated, with no allergic reactions or clinically significant treatment-related adverse events observed during the study.
A Phase 3, open-label, non-randomized clinical trial (NCT04161495), called XTEND-1, is currently recruiting up to 150 patients, 12 and older, who have previously received treatment for hemophilia A, to assess the safety and efficacy of efanesoctocog alfa.
In the trial, being conducted at sites in California, Nevada, and Washington, researchers are placing participants into two different treatment groups. One group of patients will receive a weekly prophylactic dose of efanesoctocog alfa (50 IU/kg) for 52 weeks, while the second will receive on-demand injections of the therapy at the same dose for 26 weeks. Patients in the second group will then switch to weekly prophylaxis for another 26 weeks.
The study’s main goal is to assess the effects of prophylactic treatment on the annualized bleeding rate, or on the number of bleeds patients experience within a year. It will also assess the treatment’s safety and pharmacological properties. The study is expected to conclude in January 2022.
Another open-label trial, called XTEND-Kids (NCT04759131), is evaluating the development of inhibitors — neutralizing antibodies against FVIII — over the course of 52 weeks in boys, 12 and younger, with severe hemophilia A and receiving efanesoctocog alfa.
The study will also evaluate the treatment’s safety and efficacy at reducing the number of spontaneous and traumatic bleeding episodes, as well as the therapy’s pharmacological properties.
The trial, which is currently recruiting, seeks to enroll about 65 children who have previously been treated with other FVIII therapies. During the study, patients will receive an injection of the investigational therapy, once weekly, for one year. The first patient has already been dosed. After completing the trial, participants will have the option to enter an extension phase to continue the treatment.
The FDA granted efanesoctocog alfa orphan drug designation in August 2017, and the European Commission followed suit in June 2019. The therapy was also granted fast track designation by the FDA in February 2021. This designation is given to speed up the development and review of therapies that treat severe or life-threatening disorders for which there are clear unmet clinical needs.
Last updated: June 1, 2021
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