Durable Response Observed With Gene Therapy for Hemophilia A

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The phase 3 GENEr8-1 study evaluated valoctocogene roxaparvovec in adults with severe hemophilia and residual FVIII levels less than or equal to 1 IU/dL.

Positive 2-year data were announced from a phase 3 study evaluating valoctocogene roxaparvovec, an investigational adeno-associated virus (AAV) gene therapy, in adults with severe hemophilia A. 

The open-label, single-arm GENEr8-1 study (ClinicalTrials.gov Identifier: NCT03370913) is evaluating the efficacy and safety of valoctocogene roxaparvovec in 134 adults with severe hemophilia A with residual FVIII levels less than or equal to 1 IU/dL receiving prophylactic Factor VIII replacement therapy for at least 12 months. All patients received a single administration of valoctocogene roxaparvovec via intravenous infusion.

Results showed that treatment with valoctocogene roxaparvovec significantly reduced annualized bleeding rate (ABR) by 4.1 treated bleeds per year (P <.0001), or 85% from a baseline mean of 4.8. The mean ABR was 0.8 through the entire efficacy evaluation period, 0.9 during year 1, and 0.7 during year 2.

Additionally, mean annualized Factor VIII infusion rate was significantly reduced by 133 infusions per year (P <.0001) or 98% from baseline. The mean annualized infusion rate was 2.6 through the entire efficacy evaluation period, 1.5 during year 1, and 3.4 during year 2.

At year 2, patients in the modified intent-to-treat population (n=132) had a mean endogenous Factor VIII activity level of 23.0 (median 11.8) IU/dL, as measured by the chromogenic substrate assay, and 36.1 (median 21.6) IU/dL, as measured by the one-stage assay.

There were no new safety signals identified during year 2 and no treatment-related serious adverse events were reported. The most common adverse events included transient infusion associated reactions and mild to moderate elevations in alanine aminotransferase. Headache, arthralgia, nausea, aspartate aminotransferase elevation, and fatigue were also reported.

“These results show that valoctocogene roxaparvovec could profoundly change the way hemophilia A is treated,” said Hank Fuchs, MD, President of Worldwide Research and Development at BioMarin. “We are looking forward to continuing to work with health authorities to bring this therapy to patients with hemophilia A.”

In August 2020, BioMarin received a Complete Response Letter from the Food and Drug Administration requesting data demonstrating a durable effect with valoctocogene roxaparvovec using ABR as the primary endpoint. The Company plans to resubmit the Biologics License Application with the 2-year results from the GENEr8-1 study in the second quarter of 2022.


BioMarin announces stable and durable annualized bleed control in the largest phase 3 gene therapy study in adults with severe hemophilia A; 134-participant study met all primary and secondary efficacy endpoints at two year analysis. News release. BioMarin Pharmaceutical Inc. Accessed January 10, 2022. https://investors.biomarin.com/2022-01-09-BioMarin-Announces-Stable-and-Durable-Annualized-Bleed-Control-in-the-Largest-Phase-3-Gene-Therapy-Study-in-Adults-with-Severe-Hemophilia-A-134-Participant-Study-Met-All-Primary-and-Secondary-Efficacy-Endpoints-at-Two-Year-Analysis