Efanesoctocog alfa: the renaissance of Factor VIII replacement therapy

Abstract

Efanesoctocog alfa (Altuviiio,TM Sanofi-SOBI) is a B domain-deleted single-chain Factor VIII (FVIII) connected to D'D3 domain of von Willebrand Factor (vWF). Its ingenious design allows efanesoctocog alfa to operate independently of endogenous vWF and results in an outstanding 3-4 times longer half-life compared to standard and extended half-life (EHL) FVIII products. The prolonged half-life ensures sustained high levels of factor activity, maintaining normal to near-normal ranges for the majority of the week, facilitating the convenience of once-weekly administration. Efanesoctocog alfa received regulatory approval in 2023 for application in both adults and children with inherited hemophilia A in the United States and Japan. Its sanctioned use encompasses both prophylaxis and 'on demand' treatment for bleeding episodes. The European Medicines Agency (EMA) is currently undertaking a comprehensive review of Altuviiio. TM This comprehensive review focuses on the immunological profile of efanesoctocog alfa, a highly sophisticated new class of EHL FVIII molecule. The integration of the vWF D'D3 domain, XTEN polypeptides, and potential regulatory T-cell epitopes within various segments of efanesoctocog alfa collectively serves as a mitigating factor against the development of a neutralizing T-cell-mediated immune response. We hypothesize that such distinctive attribute may significantly reduce the risk of neutralizing antibodies, particularly in previously untreated patients. The discussion extends beyond regulatory approval to encompass the preclinical and clinical development of efanesoctocog alfa, including considerations for laboratory monitoring. The review also highlights areas that warrant further investigation to deepen our understanding of this groundbreaking therapeutic agent.

Figure 1.

Structure of efanesoctocog alfa. Efanesoctocog alfa (Efa) is a heterodimeric glycoprotein produced in HEK293 cells after transfection with 3 expression vectors. These vectors include a plasmid encoding a human BDD Factor VIII (FVIII)-XTEN²⁸⁸-crystallizable fragment (Fc) construct, a plasmid encoding von Willebrand Factor (vWF) D1D2D’D3^{C1099A/C1142A} domains-XTEN¹⁴⁴-Fc, and a plasmid allowing the expression of PACE/furin. The structure of Efa includes the parental recombinant Factor VIII Fc (rFVIIIFc) with a 288 aa-long XTEN (XTEN²⁸⁸) integrated between the FVIII A2 and a3 domains, and the vWF D’D3 domains fused to a 114 aa-long XTEN (XTEN144) and to a Fc fragment. The C1099A and C1142A mutations in D’D3 prevent dimerization of the domain. The D1D2 and D’D3 domains are separated by a furing cleavage site. The interaction between the FVIII- XTEN²⁸⁸-Fc and the D’D3-XTEN¹⁴⁴-Fc is maintained by the pairing of the 2 Fc fragments and the low affinity between D’D3 and the FVIII light chain. The heterodimers, thus, present with an avidity that exceeds the affinity of FVIII for endognous vWF in the patients’ blood, and the in vivo half-life of Efa is independent from that of the endogenous vWF.

Figure 2.

Immunological profile of efanesoctocog alfa. A classical immune response to a T-cell-dependent extracellular antigen, such as therapeutic Factor VIII (FVIII), involves: i) the uptake of the antigen by antigen-presenting cells; ii) the processing of the antigen and presentation of antigen-derived peptides on MHC class II molecules to antigen-specific naïve CD4⁺ T cells; iii) the activation of the T cells; iv) a cross-talk between the activated T cells and naïve B cells that express antigen-specific B-cell receptors; and v) the differentiation of the B cells into antibody-secreting cells. The figure depicts the proposed interactions of the different moieties of efanesoctocog alfa (Efa) (i.e., FVIII, crystallizable fragments [Fc], XTEN polypeptides, and von Willebrand Factor [vWF] D’D3 domains) with the different phases of the immune response. Green arrow symbols indicate a probable effect in mellowing down immunogenicity; orange arrows indicate a possible effect on immunogenicity. Thus, cellular uptake may be reduced by the virtue of the presence of the XTEN polypeptides and the vWF D’D3 domains. XTEN polypeptides are not presented on MHCII molecules to T cells. FVIII and Fc fragments contain Tregitopes that may reduce, at least in part, the immunogenicity of the molecule, particularly if D’D3 were found to also contain Tregitopes. The XTEN polypeptides and the D’D3 domains may also reduce the binding of FVIII to the B-cell receptor of FVIII-specific naïve and memory B cells, thus reducing the T/B-cell cross-talk. IgG: immunoglobulin G.