Clinical evaluation of moroctocog alfa (AF‐CC), a new generation of B‐domain deleted recombinant factor VIII (BDDrFVIII) for treatment of haemophilia A: demonstration of safety, efficacy, and pharmacokinetic equivalence to full‐length recombinant factor VIII

Abstract

BDDrFVIII is a B-domain deleted recombinant factor VIII (rFVIII) product for haemophilia A. Manufacture uniquely includes purification chromatography by synthetic-affinity ligand rather than murine-based monoclonal antibody, as well as an albumin-free cell culture process. BDDrFVIII was studied in 204 patients, including 62 subjects <16 years old, in two studies. A double-blind, randomized, pharmacokinetic (PK) crossover study, utilizing a central laboratory assay (one-stage (OS)) for both drug potency assignment and plasma FVIII-activity measurements, demonstrated that BDDrFVIII was PK-equivalent to a full-length rFVIII. Favourable efficacy and safety were observed: during defined routine prophylaxis in a patient population significant for preexisting target joints, nearly half (45.7%) of patients had no bleeding, and a low-annualized bleed rate (ABR) was achieved (median 1.9); 92.5% of haemorrhages (n = 187) required < or =2 infusions. Three subjects (1.5%, across both studies) developed de novo inhibitors (low-titre, transient), and the primary safety endpoint, based on a prospective Bayesian analysis, demonstrated the absence of neoantigenicity for BDDrFVIII. The PK-equivalence, based on central testing to align test and reference articles, and the novel Bayesian analysis of inhibitor safety in these investigations reflect robust experimental designs with relevance to future studies. This extensive dataset demonstrates the safety and efficacy of BDDrFVIII for haemophilia A.

Incidence of factor VIII inhibitors throughout life in severe hemophilia A in the United Kingdom

“…Although such trials are traditionally conducted in patients thought to be inhibitor free, 2% to 8% of such patients are found to have an unsuspected, pre-existing, low-titer inhibitor at study entry. [7][8][9][10][11] Inhibitors first observed during the course of a clinical trial may have arisen by chance or may have been present but undetected before trial entry and so may be etiologically unrelated to the test product.…”

Efficacy and safety of rVIII-SingleChain: results of a phase 1/3 multicenter clinical trial in severe hemophilia A

“…With 1 or 2 injections, efmoroctocog alfa controlled 97.7% of bleeding episodes, moroctocog alfa (Refacto) controlled 88% (of 677 bleeding events across 2 studies), and rurioctacog alfa pegol (Adynovate) controlled 95.9% of bleeding episodes. 6,7,19 Of the patients on prophylaxis with rVIII-SingleChain, 43% achieved a zero bleed rate during the study. This is comparable to individualized prophylaxis with efmoroctocog alfa (45%) and twice-weekly prophylaxis with rurioctacog alfa pegol (39.6%).…”

“…These are not increased relative to patients who received rVIII-SingleChain 3 times week, in whom the observed median ABR was 1.93 (Q1, Q3: 0.0, 4.9) and the observed mean 6 SD ABR was 3.34 6 4.26. The ABR with prophylaxis was highly significantly (P , .0001) reduced compared with the ABR in the on-demand group (median ABR, 19 A total of 848 bleeding events were treated with rVIII-SingleChain in the study, 835 of which were assessed by the investigator. Of the 848 bleeding events, 590 occurred in the 27 patients on on-demand therapy and 258 occurred in the 146 patients on prophylaxis.…”

Production and characterization of polyclonal antibodies to human recombinant domain B-free antihemophilic factor VIII

“…It is manufactured by an albumin-free cell culture process using Chinese hamster ovary (CHO) cells grown in a chemically defined serum-free cell culture medium that contains no materials derived from human or animal sources. It is noteworthy that, in terms of immunogenicity, BDDrFVIII and plasma-derived native FVIII have very similar posttranslational modification, including sites of glycosylation (Recht et al, 2009).…”