Valoctocogene Roxaparvovec Continues to Improve Bleeding Outcomes in Patients with Hemophilia A

In three-year follow-up results from an ongoing phase I/II study of patients with hemophilia A, valoctocogene roxaparvovec gene therapy significantly reduced annual bleeding rates (ABRs) and increased factor VIII (FVIII) activity levels. Lead author John Pasi, MBChB, PhD, from Barts and the London School of Medicine and Dentistry, presented the findings at the 2019 Congress of the International Society on Thrombosis and Haemostasis, which updated initial results presented at the 2017 American Society of Hematology Annual Meeting.

Valoctocogene roxaparvovec is an adeno-associated virus serotype 5 (AAV5) vector containing the B-domain-deleted FVIII gene. It is designed to be delivered in a single dose, as opposed to standard treatments of hemophilia A, which entail frequent intravenous infusions of missing FVIII.

“For people who have had to inject themselves with FVIII every other day to prevent bleeding, this treatment has the potential to be transformational,” Dr. Pasi said.

He presented results from the open-label, dose-escalation BMN 270-701 study, which enrolled 13 men from multiple U.K. centers. Patients were included if they had severe hemophilia A and residual FVIII levels ≤1 IU/dL and were exposed to FVIII concentrates or cryoprecipitate for at least 150 days.

All participants received a single dose of valoctocogene roxaparvovec, at 6×1013 vg/kg (n=6) and 4×1013 vg/kg (n=6).

After three years of follow-up, patients in both dosage groups appeared to require fewer infusions of FVIII per year, with reductions of 96% in the 6×1013 vg/kg group and 97% in the 4×1013 vg/kg group, compared with usage before treatment with valoctocogene roxaparvovec (p values not reported).

FVIII expression plateaued at approximately 20% at year three, and the researchers noted that FVIII expression levels are expected to decline over time. “Accordant modeling projections conservatively estimate the persistence of bleeding control for at least eight years post-administration and longer if expression plateaus are maintained, as observed in prior AAV gene therapy studies,” they wrote.

The gene therapy also produced significant reductions in ABRs in both groups. In the year prior to study treatment, patients in the 6×1013 vg/kg group experienced a mean of 16.3 bleeding episodes; that number dropped to 0.9 episodes in the first year, 0.2 in the second year, and 0.7 in the third year, representing a 96% decline (p values not reported). Similar reductions were seen in the 4×1013 vg/kg group, from 12.2 episodes in the year prior to treatment, to 0.9 episodes in year one and 1.2 episodes in year two, for a 92% decline (p values not reported).

Dr. Pasi also reported that there were no major safety issues observed in this trial, “with no inhibitor development or alanine transaminase elevations beyond year one.”

“With three years of data, it’s clear that valoctocogene roxaparvovec has the potential to change the way we treat this debilitating disease, which can improve the quality of life for people with severe hemophilia A,” said Dr. Pasi. However, the implications of these findings are limited by the small patient number. Attendees at the meeting also raised concerns about the long-term expression of FVIII, which will need to be determined with further follow-up.

The authors report relationships with BioMarin Pharmaceutical, the manufacturers of valoctocogene roxaparvovec.


Pasi KJ, Rangarajan S, Mitchell N, et al. First-in-human evidence of durable therapeutic efficacy and safety of AAV gene therapy over three years with valoctocogene roxaparvovec for severe haemophilia A (BMN 270-201 study). Abstract LB 01.2. Presented at the International Society of Thrombosis and Haemostasis 2019 Congress, July 8, 2019; Melbourne, Australia.