Study: Hemophilia A Gene Therapy Offers Clinical Benefit


Additionally, this treatment gradually reduced the need for prophylactic FVII use, suggesting an effective control of bleeding that leads to a sustained clinical benefit in patients who received the highest doses of AAV5-hFVIII-SQ.

Treatment with an adeno-associated virus serotype 5 (AAV5) vector containing a B-domain-deleted factor VIII gene, also known as AAV5-hFVIII-SQ or valoctogene roxaparvovec, led to significant reductions in bleeding events in men with severe hemophilia A, according to a study published in the New England Journal of Medicine. Additionally, this treatment gradually reduced the need for prophylactic FVII use, suggesting an effective control of bleeding that leads to a sustained clinical benefit in patients who received the highest doses of AAV5-hFVIII-SQ, according to the study.

Fifteen men with severe hemophilia A were enrolled in the dose-escalation study, defined as FVIII level ≤1 IU/dL. 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. Further, glucocorticoids 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

Patients were then hospitalized and observed for 24 hours following infusion. All participants experienced at least 1 adverse event during follow-up, including 11 who experienced elevations of their alanine aminotransferase levels. No new safety signals were noted and no development of FVIII inhibitors or other FVIII antibodies was detected, according to the study authors.

In the first 20 to 28 weeks after infusion, circulating FVIII levels gradually increased across the cohorts in the participants. 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.

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. In addition, this group 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, according to the study authors.

The mean annualized number of exogenous FVIII infusions per participant at 3 years also decreased by 96% in this cohort.

Patients received an AAV5-hFVIII-SQ infusion of 4×1013 vg/kg in cohort 4, and patients had a median FVIII expression levels of 13 IU/dL at the end of the second year of follow-up. There 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. Five out of 6 patients in this cohort experienced resolution of bleeding in target joints, according to the study authors.

There were limitations to the study, including a small sample size, which limited the researchers’ ability to identify specific variables that may have contributed to variability in individual FVIII levels. The study authors noted that participants are still being monitored, as they plan to expand the phase 3 study examining the efficacy and safety of AAv5-hFVIII-SQ.


Hemophilia A gene therapy offers sustained clinical benefit. ASH Clinical News. Published April 1, 2020. Accessed April 14, 2020.

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