Five-year and four-year post-treatment follow-up of the 6e13 vg/kg and 4e13 vg/kg cohorts, respectively, shows a sustained treatment benefit of valoctocogene roxaparvovec. All participants in both cohorts remain off prophylactic Factor VIII treatment.
Annualized Bleed Rate
The 6e13 vg/kg dose cohort of the Phase 1/2 study (N=7), with a mean follow-up of 266.1 weeks (5.1 years), showed that a single dose of valoctocogene roxaparvovec after week 4 reduced mean ABR by 95% from 16.3 (median 16.5) at baseline to 0.8 (median 0.0) bleeding episodes per year among the 6 participants previously treated with FVIII prophylaxis. In year 5, 86% (6 of 7) of study participants in the 6e13 vg/kg dose cohort had no treated bleeds.
The 4e13 vg/kg dose cohort of the Phase 1/2 study (N=6), with a mean follow-up of 218.6 weeks (4.2 years) showed that a single dose of valoctocogene roxaparvovec reduced mean ABR by 92% from 12.2 (median 8.0) at baseline to 1.0 (median 0.5) bleeding episodes per year. In year 4, 50% (3/6) of study participants in the 4e13 vg/kg dose cohort had no treated bleeds.
Factor VIII Utilization
In the 6e13 vg/kg dose cohort after week 4, the mean annualized Factor VIII utilization was reduced by 96% from 135.6 (median 136.5) to 5.2 (median 0.1) infusions per year among the six participants previously treated with FVIII prophylaxis. (This excludes one study participant receiving on-demand Factor VIII prophylaxis at baseline.)
In the 4e13 vg/kg dose cohort after week 4, the mean annualized Factor VIII utilization was reduced by 95% from 142.8 (median 155.8) to 7.8 (median 1.4) infusions per year. During follow-up, in both cohorts, exogenous Factor VIII was used as treatment for bleeding, surgery or procedures, and as one-time prophylaxis.
Factor VIII Expression and Rate of Change Over Time Comparable in Phase 1/2 and Pivotal Phase 3 Studies
For the 6e13 vg/kg and 4e13 vg/kg cohorts, study participants continued to have clinically meaningful levels in endogenous Factor VIII expression (Table 1). Mean Factor VIII activity levels over five and four years, respectively, support the observed reductions in bleed rates and annualized Factor VIII usage.
Factor VIII activity levels for participants in the 6e13 and 4e13 vg/kg vg/kg dose cohorts, was highest in year 1, and the rate of Factor VIII decline in years 4 and 5 were commensurate with that observed in previous years. Earlier, results from the pivotal Phase 3
Individual Participant ABR, Factor VIII Infusion Rate, and Factor VIII Activity
In the 6e13 and 4e13 vg/kg dose cohorts, after week 4, all participants continued to experience a reduction in ABR compared to their baseline values, even participants with low Factor VIII activity. No participants chose to resume routine prophylaxis.
In the most recent year of observation in the 6e13 vg/kg dose cohort, six of the seven participants were in the mild to moderate hemophilia range, and one participant was below the lower limit of quantification as measured by the CS assay. Measuring with the one-stage (OS) assay, one participant was in the non-hemophilic range, four were in the mild range, and one was in the moderate range.
In the 4e13 vg/kg dose cohort, four of the six participants were in the mild to moderate hemophilia range, and two participants were below the lower limit of quantification as measured by the CS assay. Measuring with the OS assay, all six participants were in the mild to moderate range.
'The consistent and impressive bleed control in the majority of the study participants out to five years in this study, which is the longest duration of clinical experience for any gene therapy in hemophilia A, which increases our understanding of the interplay between Factor VIII expression, ABR, and Factor VIII infusion rate as it relates to hemostatic efficacy,' said Professor
'We are optimistic that ABR may be maintained acceptably low through years three, four, and five after treatment with valoctocogene roxaparvovec in the
Safety Summary
Overall, the safety profile of valoctocogene roxaparvovec in the Phase 1/2 study remains consistent with previously reported data with no delayed-onset treatment related adverse events. All participants continue to remain off corticosteroids since the first year. No participants developed inhibitors to Factor VIII, and no participants withdrew from the study. No participants have developed thrombotic events. The most common adverse events associated with valoctocogene roxaparvovec occurred early after a single infusion and included short-lived infusion-associated reactions and transient, asymptomatic, and mild to moderate rise in the levels of certain proteins and enzymes measured in liver function tests with no long-lasting clinical sequelae.
Regulatory Status
The
The MAA submission includes safety and efficacy data from the 134 subjects enrolled in the Phase 3
In
The FDA granted Regenerative Medicine Advanced Therapy (RMAT) designation to valoctocogene roxaparvovec in
In addition to the RMAT Designation and Breakthrough Therapy Designation,
Robust Clinical Program
About Hemophilia A
People living with hemophilia A lack sufficient functioning Factor VIII protein to help their blood clot and are at risk for painful and/or potentially life-threatening bleeds from even modest injuries. Additionally, people with the most severe form of hemophilia A (FVIII levels
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