Valoctocogene Roxaparvovec Efficacious in Treating Hemophilia A


Over 90% participants had an annualized bleeding rate of 0 or a lower bleed rate than baseline after week 4 after treatment.

Valoctocogene roxaparvovec showed efficacy in treating hemophilia A over baseline factor VIII prophylactic therapy in data from the phase 3 GENEr8-1 study announced by BioMarin.

These results, presented at the International Society on Thrombosis and Haemostasis (ISTH) 2021 Congress, showed that participants treated with valoctocogene roxaparvovec experienced a significant, 84% reduced mean annualized bleeding rate (ABR; P <.001) from baseline and a 99% reduced mean annualized Factor VIII utilization rate (P <.001) compared to baseline use.

"The demonstrated bleed control at 52 weeks and beyond in this pivotal study supports our thesis that gene therapy can play an important role in the treatment of severe hemophilia A and potentially creates the possibility for a new treatment paradigm," said lead principal investigator Margareth C. Ozelo, MD, PhD, director, INCT do Sangue Hemocentro UNICAMP, University of Campinas, in a statement. "It is encouraging to see meaningful endogenous Factor VIII expression and decreases in bleeding and Factor VIII infusions for people in this study. These pivotal results contribute to the growing body of data to increase understanding of the safety and efficacy of gene therapy treatment over time." 

The GENEr8-1 study is evaluating 134 participants with severe hemophilia A at baseline, defined as less than or equal to 1 IU/dL of Factor VIII activity. All participants received a single 6e13 vg/kg dose of valoctocogene roxaparvovec and had a minimum of 12 months of follow-up at the data cut off.

READ MORE: Phase 1/2 Study of SIG-001 for Hemophilia A on Hold Following Serious Adverse Event

New data showed that over 90% (N=134) of all participants had an ABR of 0 or a lower bleed rate than baseline after week 4 after treatment with valoctocogene roxaparvovec. In the rollover population of 112 participants, mean Factor VIII prophylaxis utilization decreased from 3961.2 IU/kg per year (median, 3754.4) at baseline to 56.9 IU/kg per year (median, 0) after week 4 of treatment (P <.001). Previously presented topline data demonstrated that the mean annualized Factor VIII infusion rate was reduced by 99% from 135.9 infusions (median, 128.6) to 2.0 infusions (median, 0.0) per year (P <0.001).

Investigators also found that, in 132 participants in the modified intent-to-treat population, there was a significant increase in mean endogenous Factor VIII expression level from an imputed baseline of 1 IU/dL to 42.9 IU/dL (median, 23.9; P <.001), as measured by the chromogenic substrate assay. In a subset of 17 participants dosed at least 2 years prior to the data cutoff, Factor VIII expression decreased from a mean of 42.2 IU/dL (median, 23.9) at the end of the first year to 24.4 IU/dL (median, 14.7) at the end of the second year with continued hemostatic efficacy.

"From the start of our valoctocogene roxaparvovec program, our goal remains to advance treatment options for people with severe hemophilia A in light of the unmet need in bleed control. Current prophylactic therapies for hemophilia A cannot maintain Factor VIII levels for sustained periods, leading to the need for frequent, regular infusions or injections while still having a risk of ongoing, unpredictable bleeds and unavoidable, irreversible joint damage even with standard of care treatment," added Hank Fuchs, MD, president, worldwide research and development, BioMarin, to the statement.

Valoctocogene roxaparvovec was overall well-tolerated by participants, with no discontinuations due to adverse events (AEs), although 1 participant was lost to follow-up. No participants developed inhibitors to Factor VIII or experienced thromboembolic events. AEs occurring within 48 hours post-infusion were categorized as infusion reactions. The most common infusion reactions were nausea (14.2%), fatigue (7.5%), and headache (6.0%). Four participants (3.0%) had an interrupted infusion due to infusion-related symptoms but were able to complete their infusion by slowing or pausing its and treating symptoms. Serious AEs (AEs) were reported by 22 (16.4%) participants that experienced a total of 43 SAEs.

The most common AE was aspartate transaminase (ALT) elevation and 79% of participants received corticosteroids as ALT treatment. Corticosteroid treatment lasted an average of 33 weeks and 72% of participants reported corticosteroid-related AEs such as acne, insomnia, cushingoid changes, and weight increases. Corticosteroid-related SAEs were reported by 3 participants. Some participants (29%) used other immunosuppressants due to contraindication, AEs, or poor response to corticosteroids. No Grade 4 ALT elevations occurred, and no participants met Hy's law criteria for drug-induced liver injury.

"These data build upon the foundation for a potential transformative treatment option that addresses the root cause of severe hemophilia A. Later at ISTH, we look forward to sharing 5 years of clinical data from the ongoing phase 1/2 study with the longest duration of clinical experience, which complements this pivotal phase 3 study, the largest study of a gene therapy in hemophilia A,” Fuchs added.

The FDA previously granted regenerative medicine advanced therapy designation to valoctocogene roxaparvovec in March 2021, breakthrough therapy designation in 2017, and orphan drug designation in 2016. 

BioMarin Announces Oral Presentation of Positive One-Year Results from Phase 3 Pivotal Trial with Valoctocogene Roxaparvovec Gene Therapy in Adults with Severe Hemophilia A at ISTH 2021 Virtual Congress. News release. BioMarin. July 19, 2021.
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