Benzinga | Jul 21, 2021 10:03AM EDT

Biomarin Pharmaceutical Announces Oral Presentation At International Society On Thrombosis And Haemostasis 2021 Virtual Congress

BioMarin Pharmaceutical Inc. (NASDAQ:BMRN) announced today new data for valoctocogene roxaparvovec, an investigational gene therapy treatment for adults with severe hemophilia A, from its open-label Phase 1/2 study during an oral presentation at the International Society on Thrombosis and Haemostasis (ISTH) 2021 Virtual Congress.

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.

Table 1: Factor VIII Activity Levels of 4e13 and 6e13 vg/kg dose cohorts for 4 and 5 Years respectively as measured by CS and OS assays

Chromogenic Substrate One-Stage Assay Assay Factor VIII Activity, IU/dL Mean (SD) Mean (SD) Median Median

4e13 vg/kg Dose Cohort at 5.6 (5.6) 9.5 (7.0) 4 Years (N=6) 4.8 7.5

6e13 vg/kg Dose Cohort at 11.6 (12.2) 18.7 (17.5) 5 Years (N=7) 8.2 15.7

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 GENEr8-1 study were presented at ISTH. The mean Factor VIII activity from a subset of the population that had been dosed at least two years prior to the data cut date (N=17) falls between Factor VIII activity of the 6e13 and 4e13 vg/kg dose cohorts in the Phase 1/2 study and is of help in understanding the potential future trajectory of Factor VIII activity in the GENEr8-1 study. In the subset of the GENEr8-1 study that had been dosed at least two years prior to the data cut date, Factor VIII expression declined from a mean of 42.2 (median 23.9) IU/dL at the end of year one to 24.4 (median 14.7) IU/dL at the end of year two with continued hemostatic efficacy as measured by the chromogenic substrate (CS) assay.

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 Michael Laffan, faculty of Medicine, Department of Immunology and Inflammation at Imperial College London, Director of the Hammersmith Hospital Haemophilia Centre, and Chief Investigator for the valoctocogene roxaparvovec Phase 1/2 study. "These data show that most of the study participants have not had a bleed or had to infuse Factor VIII in the last five years after one infusion of valoctocogene roxaparvovec, which has the potential to provide a treatment choice that addresses many of the unmet needs in hemophilia."

"We are optimistic that ABR may be maintained acceptably low through years three, four, and five after treatment with valoctocogene roxaparvovec in the GENEr8-1 study given the predictable, and not sudden or dramatic, change in Factor VIII expression in the later years following treatment in the Phase 1/2 study," said Hank Fuchs, M.D., President, Worldwide Research and Development at BioMarin. "The data show excellent hemostatic efficacy in the 6e13 and 4e13 vg/kg dose cohorts, which is maintained into year five and four, respectively. We look forward to sharing topline two-year data from all participants in the pivotal Phase 3 GENEr8-1 study in early 2022."