Four-year data show sustained reduction in bleeding with BioMarin's haemophilia A gene therapy

BioMarin on Wednesday reported updated results from an ongoing Phase I/II study of valoctocogene roxaparvovec, showing that Factor VIII activity levels after infusion with its experimental gene therapy continue to support the lower bleed rates and annualised Factor VIII usage seen in patients with severe haemophilia A. Chief investigator John Pasi, who presented the findings at the World Federation of Hemophilia (WFH) virtual summit, said that with up to four years of data, "study participants remain off Factor VIII prophylaxis therapy, while also experiencing a greater than 90% reduction in bleeding episodes from a single administration of valoctocogene roxaparvovec…These data demonstrate the very real potential of a paradigm shift in the treatment of haemophilia A."

Study results presented at WFH include four years of data for the 6e13 vg/kg cohort and three years of data for the 4e13 vg/kg cohort. BioMarin noted that all study participants had severe haemophilia A at baseline, defined as 1 IU/dL of Factor VIII activity or less.

Six patients in the 6e13 vg/kg cohort were previously on Factor VIII prophylaxis, and during the four years following treatment with valoctocogene roxaparvovec, the cumulative mean annualised bleed rate (ABR) fell 95% to 0.8, compared with the pre-infusion baseline. In the fourth year, the mean ABR was 1.3 bleeding episodes, while in the year prior to treatment, the mean ABR was 16.3 bleeds. There was also a 96% reduction in mean Factor VIII usage to 5.4 infusions per year cumulatively over four years, from a baseline of 135.6 infusions per year. BioMarin noted that among all seven study participants in the 6e13 vg/kg cohort, six out of the seven, were bleed-free after four years.

Gradual decline in clotting factor levels

The company also said that six of seven patients with evaluable samples continued to produce their own endogenous clotting factor, with the mean Factor VIII activity level of the 6e13 vg/kg cohort being 24.2 IU/dL, as measured by chromogenic substrate (CS) assay. However, this is continuing the gradual decline seen in previous post-infusion readings. At the end of the first, second and third years after treatment with valoctocogene roxaparvovec, mean Factor VIII activity levels were 64 U/dL, 36 U/dL and 33 IU/dL, respectively, in this dose cohort. 

Meanwhile, BioMarin said that in the six participants enrolled in the 4e13 vg/kg cohort, results also showed sustained reductions in bleeding requiring Factor VIII infusions. The cumulative mean ABR was reduced by 93% to 0.9, with continued absence of target joint bleeds in five of six subjects during the three years observed. In the third year of follow-up, the mean ABR was 0.5, compared with a mean 12.2 bleeding episodes pre-infusion, and four of six study participants were bleed-free. Moreover, there was a 96% reduction in mean Factor VIII usage to 5.7 infusions per year cumulatively over three years, from a baseline of 142.8 infusions per year. BioMarin said the mean Factor VIII activity level of this cohort was 9.9 IU/dL, as measured by the CS assay, at three years post-infusion.

The investigational AAV5-based gene therapy, also known as BMN 270, is currently being evaluated under a priority review by the FDA, with an action date of August 21. Meanwhile, BioMarin's marketing application has been validated by the European Medicines Agency (EMA), with the company anticipating an opinion from the EMA's Committee for Medicinal Products for Human Use in late 2020 or early next year. Valoctocogene roxaparvovec has also received orphan drug designations by both regulators for the treatment of severe haemophilia A.

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