In patients with hemophilia A, treatment with the gene therapy valoctocogene roxaparvovec compared with emicizumab was associated with lower bleeding rates and an increased probability of no bleeds, according to data derived from several analyses and published in the journal Haemophilia.  

Patients with severe hemophilia A are known to experience spontaneous bleeding into joints that can result in disabling, painful arthropathy. Individuals with this condition exhibit a deficiency in the clotting protein factor VIII (FVIII). In those with severe hemophilia A, the standard of care has been regular prophylaxis with either standard half-life or extended half-life FVIII, or with the biospecific antibody emicizumab—with the latter mimicking the activity of FVIII protein.

Although the efficacy of emicizumab prophylactic therapy has been reported in the phase 3 HAVEN 3 trial, data on the effectiveness of the agent compared with FVIII products in a real-world setting are limited. It has been recognized that the use of gene therapy may offer a treatment option for individuals with severe hemophilia A by preventing bleeding for many years with a single infusion rather than the use of FVIII or emicizumab—both of which require multiple, more frequent infusions.

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The investigators sought to compare bleeding rates among participants with severe hemophilia A (ie, FVIII ≤1 IU/dL) by evaluating findings from the following trials:

  • Open-label, single-group, multicenter, phase 3 GENEr8-1 trial: valoctocogene roxaparvovec 6 × 1013 vg/kg
  • Open-label, multicenter, phase 3 HAVEN 3 trial: prophylactic emicizumab
  • Multicenter, noninterventional, prospective, longitudinal BMN 270-902 study: FVIII prophylaxis  

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Matching-adjusted indirect comparison (MAIC) methods were used to conduct cross-trial comparisons of valoctocogene roxaparvovec vs emicizumab and FVIII prophylaxis in an effort for account for differences between the study populations at baseline. Following MAIC weighting, annualized bleeding rates and percentages of patients without any bleeds were compared with respect to the following factors:

  • Treated bleeds
  • All bleeds
  • Treated joint bleeds
  • Treated spontaneous bleeds

Results of the study showed that by using MAIC weighting, the annualized bleeding rate for all bleeds was statistically significantly lower with valoctocogene roxaparvovec compared with emicizumab (rate ratio, 0.55; 95% CI, 0.33-0.93). In addition, although the annualized bleeding rates following MAIC for treated bleeds and treated joint bleeds were both lower among those treated with valoctocogene roxaparvovec vs emicizumab, the difference did not achieve statistical significance.

Regarding the percentage of participants with no bleeds following MAIC, significantly more individuals treated with valoctocogene roxaparvovec compared with emicizumab experienced no treated bleeds (odds ratio [OR], 3.25; 95% CI, 1.53-6.90), as well as no treated joint bleeds (OR, 2.75; 95% CI, 1.20-6.31).

Compared with the mainly standard half-life FVIII prophylaxis regimens used in the 270-902 study, mean annualized bleeding rates (other than all bleeds) were significantly lower, with significantly higher proportions of participants reporting no bleeds, for all outcomes with emicizumab.

“Valoctocogene roxaparvovec provided generally lower bleeding rates and higher probability of no bleeds, including treated joint bleeds, than emicizumab,” the researchers noted. “Emicizumab was more effective than the FVIII prophylaxis regimens used in 270-902,” they concluded.


Astermark J, Buckner TW, Frenzel L, et al. Matching-adjusted indirect comparison of bleeding outcomes in severe haemophilia A: comparing valoctocogene roxaparvovec gene therapy, emicizumab prophylaxis, and FVIII replacement prophylaxis. Haemophilia. Published online June 22, 2023. doi:10.1111/hae.14818