Gene Therapy with BMN 270 Results in Therapeutic Levels of FVIII in Mice and Primates and Normalization of Bleeding in Hemophilic Mice

Abstract

Hemophilia A is an X-linked bleeding disorder caused by mutations in the gene encoding the factor VIII (FVIII) coagulation protein. Bleeding episodes in patients are reduced by prophylactic therapy or treated acutely using recombinant or plasma-derived FVIII. We have made an adeno-associated virus 5 vector containing a B domain-deleted (BDD) FVIII gene (BMN 270) with a liver-specific promoter. BMN 270 injected into hemophilic mice resulted in a dose-dependent expression of BDD FVIII protein and a corresponding correction of bleeding time and blood loss. At the highest dose tested, complete correction was achieved. Similar corrections in bleeding were observed at approximately the same plasma levels of FVIII protein produced either endogenously by BMN 270 or following exogenous administration of recombinant BDD FVIII. No evidence of liver dysfunction or hepatocyte endoplasmic reticulum stress was observed. Comparable doses in primates produced similar levels of circulating FVIII. These preclinical data support evaluation of BMN 270 in hemophilia A patients.

My Pathway to Adeno-Associated Virus and Adeno-Associated Virus Gene Therapy: A Personal Perspective

“…Development of the AAV-FVIII program proceeded rapidly, and with initial preclinical studies completed, 15 a Phase I trial began in the fall of 2014. The outcome of this trial 16 was highly encouraging, and pivotal trials were initiated in 2017.…”

Haemophilia gene therapy: From trailblazer to gamechanger

“…115 Seven of those patients were treated with the highest dose of 6 × 10 13 vg/kg after a dose escalation study. 115 Seven of those patients were treated with the highest dose of 6 × 10 13 vg/kg after a dose escalation study.…”

“…Recently, a phase I/II clinical trial was performed (BioMarin; NCT02576795), in which 9 patients were treated with an AAV5 vector expressing FVIIIΔB 114 based on encouraging results in primates and haemophilic mice. 115 Seven of those patients were treated with the highest dose of 6 × 10 13 vg/kg after a dose escalation study. Six of 7 patients treated with the highest dose of 6 × 10 13 vg/ kg showed a gradual increase in FVIII activity levels and reached more than 50% of normal FVIII activity levels after 20 weeks, when steady-state levels were attained.…”

Bioengineered molecules for the management of haemophilia: Promise and remaining challenges

“…These animal model results suggest the potential for BDD‐FVIII and its codon‐optimized variants, to induce UPR and cellular stress within the ongoing clinical trial programmes. Previously noted BMN 270 was investigated within mice and cynomolgus monkeys . BMN 270 produced therapeutic levels of FVIII activity within an immune‐incompetent double knockout mouse (FVIII and recombinant activating gene 2 knockouts).…”