BioMarin Pharmaceutical Inc. announced positive topline results from its ongoing global Phase 3 GENEr8-1 study of valoctocogene roxaparvovec, an investigational gene therapy for the treatment of adults with severe hemophilia A. This is the largest global Phase 3 study to date for any gene therapy in any indication, with 134 participants. All participants in the study received a single dose of valoctocogene roxaparvovec and completed a year or more of follow-up. Data from the GENEr8-1 Phase 3 study with a mean follow-up of 71.6 weeks showed that in the pre-specified primary analysis for Annualized Bleeding Rate (ABR) a single dose of valoctocogene roxaparvovec significantly reduced ABR by 84% from a prospectively collected 4.8 (median 2.8) at baseline to 0.8 (median 0.0) bleeding episodes per year (p-value <0.0001), among a pre-specified group of prior participants in a non-interventional baseline observational study (rollover population; N=112). 80% of participants were bleed-free starting at week five after treatment. Valoctocogene roxaparvovec also significantly reduced the mean annualized Factor VIII in the rollover population by 99% from 135.9 (median 128.6) to 2.0 (median 0.0) infusions per year (p-value <0.0001). At the end of the first year post-infusion with valoctocogene roxaparvovec, participants in the modified intent-to-treat (mITT) population (N=132) had a mean endogenous Factor VIII expression level of 42.9 (SD 45.5, median 23.9) IU/dL, as measured by the chromogenic substrate (CS) assay, supporting the marked clinical benefits observed with abrogation of bleeding episodes and Factor VIII infusion rate. Factor VIII expression declined at a slower rate compared to the Phase 1/2 study, and remained in a range to provide hemostatic efficacy. In a subset of the mITT population that had been dosed at least two years prior to the data cut date (N=17), Factor VIII expression declined from a mean of 42.2 (SD 50.9, median 23.9) IU/dL at the end of year one to a mean of 24.4 (SD 29.2, median 14.7) IU/dL at the end of year two with continued hemostatic efficacy demonstrated by a mean ABR of 0.9 (median 0.0) bleeding episodes per year. Valoctocogene Roxaparvovec Safety: Overall, in the Phase 3 study, valoctocogene roxaparvovec has been well tolerated by the 134 participants who received a single 6e13 vg/kg dose. No participants developed inhibitors to Factor VIII, or thromboembolic events. One participant was lost to follow-up. Infusion-related reactions were effectively mitigated by managing infusion rates. Alanine aminotransferase (ALT) elevation (115 participants, 86%), a laboratory test of liver function, remained the most common adverse event (AE). Other common adverse events were headache (51 participants, 38%), nausea (50 participants, 37%), aspartate aminotransferase (AST) elevation (47 participants, 35%), arthralgia (38 participants, 28%) and fatigue (37 participants, 27%). Twenty-two (16.4%) participants experienced a total of 43 serious adverse events (SAEs), and all SAEs resolved. Common, steroid-related side effects can occur with temporary use of corticosteroid (or alternative immunosuppressants) to manage ALT elevation. These side effects have generally been grade 1/2 in intensity, manageable and reversible. Isolated grade 3 steroid-related sides effects (e.g., diabetes, hypertension, weight gain, bone fractures) were observed with longer-term higher dose corticosteroid administration. Corticosteroid-related grade 3 SAEs emerged as a safety issue with extended use of corticosteroids which were reversible with only one event of weight gain ongoing. Overall, in the Phase 1/2 study, the safety profile of valoctocogene roxaparvovec remains consistent with previously reported data with no delayed-onset, treatment-related events. 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 and included transient 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. GENEr8-1 Study Description: The global Phase 3 GENEr8-1 study evaluates superiority of valoctocogene roxaparvovec at the 6e13 vg/kg dose compared to the current standard of care, FVIII prophylactic therapy. All study participants had severe hemophilia A at baseline, defined as less than or equal to 1 IU/dL of Factor VIII activity. The study included 134 total participants, all of whom had a minimum of 12 months of follow-up at the time of the datacut. The first 22 participants were directly enrolled into the Phase 3 study, 17 of whom were HIV-negative and dosed at least 2 years prior to the datacut date (referred to as the subset). The remaining 112 participants (rollover population) completed at least six months in a separate non-interventional study to prospectively assess bleeding episodes, Factor VIII use, and health-related quality of life while receiving Factor VIII prophylaxis prior to rolling over to receive a single infusion of valoctocogene roxaparvovec in the GENEr8-1 study. Regulatory Status: BioMarin is working with the U.S. Food and Drug Administration (FDA) to align on steps forward to obtain marketing approval for valoctocogene roxaparvovec gene therapy for severe hemophilia A. The FDA recommended that the Company complete the Phase 3 study and submit two-year follow-up safety and efficacy data on all study participants. Additionally, the European Medicines Agency (EMA) requested one-year results from the full Phase 3 study to inform their benefit-risk assessment. To facilitate this submission within the EMA regulatory framework, BioMarin withdrew the MAA and plans to resubmit the MAA with these data to the EMA in the second quarter of 2021 following discussions with the Agency. The FDA has granted valoctocogene roxaparvovec Breakthrough Therapy Designation. BioMarin's valoctocogene roxaparvovec has received orphan drug designation from the FDA and EMA for the treatment of severe hemophilia A. The Orphan Drug Designation program is intended to advance the evaluation and development of products that demonstrate promise for the diagnosis and/or treatment of rare diseases or conditions. Phase 1/2 Dose Escalation Study Description: The Phase 1/2 dose escalation study is ongoing and continues to monitor participants long-term. In the study, a total of 15 patients with severe hemophilia A and Factor VIII activity levels less than or equal to 1 IU/dL received a single dose of BMN 270, seven of whom were treated at a dose of 6e13 vg/kg and six of whom were treated at a lower dose of 4e13 vg/kg. The other two participants were treated at lower doses as part of dose escalation in the study and did not achieve therapeutic efficacy.