Presentation Highlights

An important clinical question in the management of patients with severe hemophilia A (HA) is whether the successful transfer of the F8 gene (BMN 270) could significantly benefit these patients. However, the size of the gene and other factors have limited the success of this approach–until now. In a Late-Breaking Session on Tuesday, John Pasi, Ph.D., F.R.C.P., F.R.C.Path. revealed results of the first successful gene transfer in humans for the treatment of severe HA. Data available on patients followed for up to 52 weeks post–gene transfer of the 6x1013 VG/kg dose were presented.

  • FVIII activity plateaued by 20 weeks, with median levels within the normal range after week 20.
  • The median annualized bleeding rate for subjects previously on prophylactic therapy declined pre-dosing through the last follow-up visit.
  • Mild, transient ALT elevations were noted in all patients.

Hemophilia A, a monogenetic X-linked disorder of factor VIII (FVIII), is an ideal candidate for gene therapy. Until very recently, successful gene transfer in HA patients has been challenged by the F8 gene size, protein synthesis constraints, and vector biology. Results of his ongoing phase 1/2, dose-escalation study of AAV5-FVIII gene transfer in patients with severe HA were presented by Pasi at this ISTH session.

In this study,15 subjects received a single intravenous dose of an AAV5 vector containing the B-domain deleted F8 gene at 1 of 4 doses: 6x1012 VG/kg (n = 1), 2x1013 VG/kg (n = 1), 4x1013 VG/kg (n = 6), or 6x1013 VG/kg (n = 7); safety, efficacy, immunogenicity, and other endpoints were assessed. The data up to 52 weeks post–gene transfer in subjects who received the 6x1013 VG/kg dose were presented.

Pasi found that FVIII activity plateaued by 20 weeks, with median levels within the normal range (89-122 IU/dL) after week 20. Individual FVIII levels ranged from 19 to 164 IU/dL. The median annualized bleeding rate for subjects previously on prophylactic therapy (n = 6) declined from 17 (range: 0-40) before gene transfer to 0 (0-7) 2 weeks post-infusion through last follow-up visit; 5 subjects experienced no bleeds. Median annualized FVIII infusions declined from 139 (105-159) to 0 (0-16), 2 weeks post-infusion through the last follow-up visit. Mild, grade 1, asymptomatic alanine aminotransferase (ALT) increases were reported in all 7 subjects. Peak ALT levels ranged from 59 to 95 U/L (upper limit of normal (ULN): 43 U/L); 6 subjects had normal ALT levels. All subjects in the 6x1013 VG/kg cohort were able to discontinue protocol-mandated corticosteroids. For subjects in the lower dose 4x1013 VG/kg cohort with at least 12 weeks of data (n = 3), FVIII activity levels have increased to between 31 to 42 IU/dL.

This study represents a landmark study of the first successful gene transfer in humans for the treatment of severe HA resulting in sustained, clinically relevant FVIII activity that profoundly reduces bleeding and exogenous FVIII replacement. BMN 270 was well tolerated with only mild, transient ALT elevations.

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