Efmoroctocog Alfa: A Review in Haemophilia A

Abstract

Efmoroctocog alfa (Elocta ® , Eloctate ® , Eloctate™), an extended half-life (EHL) recombinant factor VIII (rFVIII)-Fc fusion protein, is approved for the treatment and prophylaxis of bleeding in patients with haemophilia A. The efficacy of efmoroctocog alfa in the prevention and treatment of bleeding in previously treated patients (PTPs) and previously untreated patients (PUPs) with severe haemophilia A has been demonstrated in phase III studies; this includes its use in the perioperative setting (in PTPs). Furthermore, the effectiveness of efmoroctocog alfa in clinical practice has been confirmed in numerous real-world studies; compared with conventional, standard half-life (SHL) FVIII products, prophylaxis with this EHL FVIII product achieved similar or reduced bleeding rates with fewer injections. Efmoroctocog alfa was generally well tolerated; inhibitors occurred in approximately one-third of PUPs in a phase III study. Efmoroctocog alfa is an established and effective EHL FVIII replacement therapy for the management of haemophilia A. Compared with SHL FVIII products, EHL FVIII products such as efmoroctocog alfa have the potential to optimise prophylactic outcomes by decreasing the burden of treatment or increasing the level of bleed protection. Plain Language SummaryCoagulation factor VIII (FVIII) replacement therapy is the mainstay of haemophilia A treatment; FVIII prophylaxis is the standard of care for severe disease. EHL rFVIII products have been developed to decrease the burden and/or increase the effectiveness of prophylaxis compared with conventional FVIII/rFVIII products which, due to their shorter half-lives, require more frequent injections. Efmoroctocog alfa (Elocta ® , Eloctate ® , Eloctate™), a first-in-class rFVIII-Fc fusion protein with a half-life ≈ 1.4−1.8 times longer than that of conventional FVIII/rFVIII preparations, is approved for the prophylaxis and treatment of bleeding in patients with haemophilia A in various countries worldwide. The efficacy of efmoroctocog alfa has been demonstrated in phase III trials in patients with severe haemophilia A, and its effectiveness, particularly as FVIII prophylaxis, has been confirmed in numerous studies in clinical practice. The rate of formation of neutralizing anti-FVIII antibodies (inhibitors) with efmoroctocog alfa is similar to that with other FVIII/rFVIII products. Based on a large body of clinical trial and real-world data, efmoroctocog alfa is an established and effective EHL FVIII replacement therapy for the management of haemophilia A.

rFVIII‐Fc in severe haemophilia A: The incentive switch in case of high risk of joint bleedings

“…It is a rFVIII-Fc fusion protein made of a recombinant, B-domain deleted FVIII molecule, linked to the Fc domain of a human immunoglobulin G1, thereby protecting it from the lysosomal degradation. 6 Therefore, the half-life of rFVIII-Fc is equivalent to 1.5 times that of the available SHL FVIII products. After consultation with their referring physician, patients could switch to rFVIII-Fc or stay with SHL clotting factors.…”

Pharmacokinetic parameters of simoctocog alfa in children with hemophilia A without inhibitors in real clinical practice

“…При сравнении собственных данных с GENA-03 (также детская популяция, Нувик) результаты почти идентичны -9,73 ± 2,69 ч [13]. Однако у взрослых пациентов на терапии симоктокогом альфа наблюдается более длительный период полувыведения -17,1 ч (GENA-01) [13], что сравнимо с пролонгированными концентратами фактора [14].…”

“…При сравнении фармакокинетических параметров пациентов, включенных в наше исследование, с данными детской популяции на терапии эфморок-токогом альфа (пролонгированный концентрат FVIII) отмечено следующее: период полувыведения FVIII на эфмороктокоге альфа у детей до 6 лет составил 12,3 ч, 6-11 лет -13,5 ч, 12-17 лет -16 ч и во взрослой группе старше 15 лет -19 ч. Таким образом, в группе пациентов, которая максимально приближена к нашей по медиане возраста, период полувыведения составил 13,5 ч, что сопоставимо с таковым у симоктокога альфа [14,17].…”

Ion Mobility-Mass Spectrometry and Collision-Induced Unfolding Rapidly Characterize the Structural Polydispersity and Stability of an Fc-Fusion Protein

“…Fc-fusion proteins constitute an emerging class of protein therapeutics that have demonstrated great efficacy across a broad range of pathologies due to their diverse compositions and mechanisms of action. − Such therapeutic modalities combine the pharmacological properties of a broad range of biomolecules with the distinctive biological functions of the fragment crystallizable (Fc) region of an immunoglobulin G (IgG). , The active components of Fc-fusion proteins can be peptides, , cytokine traps, recombinant enzymes, , or the extracellular domains (ECDs) of receptors, , where most are attached to both chains of the disulfide-linked, dimeric Fc domain. Most notably, Fc-fusion proteins possess increased serum half-life owing to their reduced renal clearance and neonatal Fc-receptor (FcRn)-mediated recycling from endosomes. , Apart from half-life extension, the Fc domain can also greatly improve the solubility and stability of hydrophobic biomolecules, increase expression and secretion rates during production, enable facile purification via affinity for Protein A, and elicit Fc-mediated effector functions. , Combined, these advantages have led to the approval of 13 Fc-fusion proteins by the FDA to date, and approximately 40 therapeutics are currently in clinical development. , …”

“…1−3 Such therapeutic modalities combine the pharmacological properties of a broad range of biomolecules with the distinctive biological functions of the fragment crystallizable (Fc) region of an immunoglobulin G (IgG). 4,5 The active components of Fc-fusion proteins can be peptides, 6,7 cytokine traps, 3 recombinant enzymes, 8,9 or the extracellular domains (ECDs) of receptors, 10,11 where most are attached to both chains of the disulfide-linked, dimeric Fc domain. Most notably, Fc-fusion proteins possess increased serum half-life owing to their reduced renal clearance and neonatal Fc-receptor (FcRn)-mediated recycling from endosomes.…”