Efanesoctocog alfa for the prevention and treatment of bleeding in patients with hemophilia A

ABSTRACT

Introduction

Hemophilia A is an inherited bleeding disorder due to a deficiency of coagulation factor VIII (FVIII). Prevention and treatment of bleeding is traditionally through intravenous infusion of a FVIII concentrate. Modifications of recombinant FVIII (rFVIII) with an aim to prolong the half-life have been modest, thought because FVIII is dependent on plasma von Willebrand factor (VWF) for its half-life. Efanesoctocog alfa (ALTUVIIIO), approved by the Federal Drug Administration (FDA) in February 2023, was made independent of endogenous VWF by linking of the FVIII-binding D’D3 domain of VWF to B-domain deleted single chain FVIII.

Areas covered

This review will outline the development of efanesoctocog alfa and the pharmacokinetic and safety data from clinical trials, as well as efficacy data from the phase 3 trials. These data formed the basis for the FDA approval.

Expert opinion

Efanesoctocog alfa is a new type of FVIII replacement with an extended half-life allowing once weekly dosing to achieve hemostasis and FVIII trough levels of 13–15 IU/dL. This provides a highly effective option for treatment and prevention of bleeding in hemophilia A, where FVIII levels are easily measured. It also provides an option for treatment of bleeding and coverage for surgery with few infusions.

KEYWORDS:

• Hemophilia A
• Factor VIII
• Von Willebrand factor
• Prophylaxis
• Bleeding

Article highlights

• Hemophilia A is a bleeding disorder due to a deficiency of coagulation factor VIII (FVIII). The standard of care for more severely affected patients is prophylactic therapy to prevent bleeding.

• Greater than 95% of circulating FVIII is bound to von Willebrand factor (VWF) and this interaction is a major determinant of FVIII half-life. The extension of recombinant FVIII (rFVIII) half-life has been modest, thought due to the interaction of FVIII with endogenous VWF.

• Efanesoctocog alfa (ALTUVIIIO) is a novel rFVIII fusion protein that does not interact with endogenous plasma VWF resulting in an extended half-life. This was accomplished by addition of the VWF D’D3 domain, the region of VWF that binds and stabilizes FVIII, to single chain B-domain deleted rFVIII. In addition, the fusion protein includes the Fc domain of immunoglobulin and XTEN® polypeptides.

• In pharmacokinetic studies the half-life of efanesoctocog alfa in adults and adolescents was over 40 hours. This was an approximately four-fold prolongation of half-life and a 6–7-fold increase in the area under the FVIII activity over time curve (AUC) compared to that seen with unmodified rFVIII. When given prophylactically at 50 IU/kg intravenously weekly, FVIII activity levels increased to 100 − 120% and remained above 40% to day 4 and then were 13–15% at day 7 post infusion. Half-life and AUC increased as age increased in the study subjects. Following infusion in children <6 years of age, the time to 40 IU/dL was 59.2 hours and for the 6 to <12 year olds, 72.2 hours compared to 81.7 hours and 97 hours for the 12 to < 18 and ≥18 year olds, respectively.

• No significant safety concerns were identified, including no reports of anaphylaxis and no development of neutralizing antibodies (inhibitors) to FVIII. Clinical laboratory measurement of FVIII activity in patients on efanesoctocog alfa is best performed with a one-stage assay that uses a reagent other than Dade Actin FS. The latter results in a 2.5-fold overestimation of FVIII activity. Chromogenic substrate assays give similar overestimations of FVIII activity.

Declaration of interest

BA Konkle receives research funding paid to her institution from CSL Behring, Pfizer, Genentech/Roche, Sanofi, Spark and Takeda and has served as a paid consultant to BioMarin Pharmaceutical, Novo Nordisk, Regeneron, Pfizer, Sanofi and Takeda. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Scientific accuracy review

Sanofi provided a scientific accuracy review at the request of the journal editor.

Additional information

Funding

This paper was not funded.