BioMarin announces positive phase III GENEr8-1 study results of valoctocogene roxaparvovec gene therapy in adults with severe hemophilia A.

BioMarin Pharmaceutical Inc. announced positive topline results from its ongoing global Phase III 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 III 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 III 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 ii 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. "this is the first statistical evidence demonstrating abr superiority in a gene therapy trial . these data give confidence in this groundbreaking alternative to existing therapies and bring us one step closer to a potential new treatment choice to fulfill an unmet medical need for people with hemophilia a," said steven w. pipe, md, professor of pediatrics and pathology, coagulation director, special coagulation laboratory laurence a. boxer, md research professor of pediatrics and communicable diseases department of pathology michigan medicine at the university of michigan and investigator in the phase iii study. "this data set adds to the growing body of scientific and clinical data around valoctocogene roxaparvovec gene therapy for hemophilia a and creates the possibility for a new treatment paradigm." "although factor replacement therapy has been shown to be a safe and effective treatment modality in hemophilia, it suffers both from incomplete prevention of joint disease and having a high treatment burden with recurring needs for intravenous infusions, which can limit important daily activities out of fear of bleeds," said guy young, m.d., director, hemostasis and thrombosis program at children's hospital los angeles and professor of pediatrics (clinical scholar), keck school of medicine of university of southern california. "novel therapeutic approaches such as gene therapy offer the prospect for both complete prevention of bleeds and subsequent joint damage and eliminating the burden associated with current treatments resulting in an improved quality of life." safety:overall, in the phase iii 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 ii 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. regulatory status: biomarin is working with the 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 iii 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 iii 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.>