Hemophilia A Gene Therapy Offers Sustained Clinical Benefit

In men with severe hemophilia A, treatment with an adeno-associated virus serotype 5 (AAV5) vector containing a B-domain-deleted factor VIII (FVIII) gene, known as AAV5-hFVIII-SQ or valoctocogene roxaparvovec, led to significant reductions in bleeding events and gradually reduced the need for prophylactic FVIII use, according to 3-year follow-up from a phase I/II study led by K. John Pasi, MBChB, PhD, from the Royal London Hospital. These findings, which were published in the New England Journal of Medicine, “show multiyear FVIII expression [after a single infusion] and effective control of bleeding, [leading to] sustained clinical benefit,” particularly in patients who received the highest doses of AAV5-hFVIII-SQ, the authors wrote.

This dose-escalation study enrolled 15 men with severe hemophilia A, defined as FVIII level ≤1 IU/dL. Per study protocol, patients who were using prophylactic FVIII replacement therapy discontinued infusions prior to enrollment, but participants were allowed to self-administer FVIII therapy if a bleeding event occurred during the study. Glucocorticoids also were permitted if a patient’s post-infusion alanine aminotransferase level reached 1.5 times the baseline value.

Patients received a single infusion of AAV5-hFVIII-SQ at the following doses:

  • cohort 1 (n=1): 6×1012 vector genome (vg)/kg
  • cohort 2 (n=1): 2×1013 vg/kg
  • cohort 3 (n=7): 6×1013 vg/kg
  • cohort 4 (n=6): 4×1013 vg/kg

Participants were hospitalized and observed for 24 hours following infusion.

During follow-up, all participants experienced at least one adverse event, including 11 who experienced elevations of their alanine aminotransferase levels. However, no new safety signals were noted, and no development of FVIII inhibitors or other FVIII antibodies was detected.

Over the first 20 to 28 weeks after infusion, circulating FVIII levels gradually increased across the cohorts. These levels quickly peaked and slowly decreased thereafter. By 3 years after infusion, the 2 participants in cohorts 1 and 2 had FVIII expression levels <1 IU/dL, with monitoring ongoing and recurrence of need for regular FVIII infusions.

However, the 7 participants in cohort 3 who received higher doses of AAV5-hFVIII-SQ had a median FVIII expression of 20 IU/dL at 3-year follow-up. This group also experienced a substantial reduction in their mean annualized bleeding rate (ABR), from 16.3±15.7 events per year at baseline to 0.7±1.6 events at 3 years – representing a 96% decrease in their mean ABR. At 3 years, the mean annualized number of exogenous FVIII infusions per participant also decreased by 96% in this cohort. (See TABLE for changes in median values per year of follow-up). All patients in cohort 3 also experienced resolution of bleeding in target joints (defined as major joints where ≥3 bleeding events occurred within 6 months).

In cohort 4, where patients received an AAV5-hFVIII-SQ infusion of 4×1013 vg/kg, patients had median FVIII expression levels of 13 IU/dL at the end of year 2 of follow-up. There also was a 92% reduction in participants’ mean ABR and a 95% decrease in the mean annualized number of FVIII infusions at the end of year 2. Overall, 5 of 6 patients in this cohort experienced resolution of bleeding in target joints.

Although these findings suggest that the gene therapy led to durable improvements in FVIII levels and reductions in bleeding, the study’s small sample size limits investigators’ ability to identify specific variables that may have contributed to variability in individual FVIII levels. The authors noted that participants are being continually monitored, and an expanded phase III study examining the efficacy and safety of AAV5-hFVIII-SQ is ongoing.

The authors report relationships with BioMarin Pharmaceutical, which funded this study.


Pasi KJ, Rangarajan S, Mitchell N, et al. Multiyear follow-up of AAV5-hFVIII-SQ gene therapy for hemophilia A. N Engl J Med. 2020;382:29-40.