Val-Rox BLA for Hemophilia A Delayed Again


BioMarin now expects to file in September 2022 instead of June.

The FDA has made additional requests for data for the Biologics License Application (BLA) of BioMarin’s hemophilia A gene therapy program, valoctocogene roxaparvovec (val-rox; Roctavian), delaying the therapy’s filing yet again.1

The FDA has requested additional data relating to val-rox's durability and safety profile. BioMarin is working to collect this data from ongoing trials, including GENEr8-1 (NCT03370913), GENEr8-3 (NCT04323098), and the non-clinical study GENEr8, and plans to resubmit the BLA by the end of September 2022 instead of June.

The FDA previously rejected BioMarin’s BLA for val-rox in August 2020, issuing a complete response letter that cited the need for additional durability data.2 At the time, the FDA requested 2-year follow-up data to confirm the durability of the treatment. The EMA continues to assess val-rox'sMarketing Authorization Application with a Committee for Medicinal Products for Human Use decision expected this year.1

BioMarin previously, in March 2022, announced the publication of results from the GENEr8-1 study in the New England Journal of Medicine which showed that val-rox restored endogenous factor VIII production and significantly reduced bleeding and use of enzyme replacement therapy in patients with hemophilia A.3

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“...Further investigation is needed to inform best practices for the prevention and treatment of elevations in alanine aminotransferase levels to optimize transgene expression and minimize the need for immunosuppressants. Moreover, follow-up is critical to assess long-term safety,” Courtney D. Thornburg, MD, medical director, Hemophilia and Thrombosis Treatment Center, and director, Hemostasis and Thrombosis Research Program, Rady Children's Hospital-San Diego, and director, Hemostasis and Thrombosis Fellowship Program, and professor, clinical pediatrics, UC San Diego School of Medicine, wrote in a related editorial, reflecting the FDA’s concerns.4

Investigators infused 134 participants that completed at least 51 weeks of follow-up.3 In 132 human immunodeficiency virus–negative participants, mean chromogenic substrate factor VIII activity levels during weeks 49 through 52 were 42.9 IU per deciliter (standard deviation [SD], 45.5) and median chromogenic substrate factor VIII activity levels were 23.9 IU per deciliter (interquartile range [IQR], 11.9-62.3). The mean change in factor VIII activity from baseline was 41.9 IU per deciliter (95% CI, 34.1-49.7; P <.001) and median change was 22.9 IU per deciliter (IQR, 10.9-61.3).

All participants experienced at least 1 mild adverse event (AE), which included headache (38.1%), nausea (37.3%), and elevations in aspartate aminotransferase levels (35.1%). Serious AEs were reported by 22 (16.4%) patients and 5 of these AEs were treatment-related. Alanine aminotransferase elevations occurred in 115 participants (85.8%) and were managed with immune suppressants. No participants developed factor VIII inhibitors or thrombosis.

“If approved, this first-generation gene therapy would offer a new choice for care that could be truly transformative and liberating for eligible men with hemophilia. More investigation is needed for children and women with hemophilia and for persons currently excluded because of preexisting AAV immunity, factor VIII inhibitors, liver disease, or HIV infection. Ultimately, highly anticipated gene therapies such as valoctocogeneroxaparvovec and others in the therapeutic pipeline will improve the health and well-being of many persons with hemophilia. Health care systems, policymakers, insurers, clinicians, and community partners must prepare the way,” Thornburg wrote.4

1. BioMarin delays hemophilia a therapy valoctocogeneroxaparvovec filing as FDA calls for more data. News release. BioMarin. May 31, 2022.
2. FDA turns down BioMarin's hemophilia A gene therapy. News release. BioMarin. August 19, 2020. Accessed July 27, 2021.
3. Ozelo MC, Mahlangu J, Pasi J, et al. Valoctocogeneroxaparvovec gene therapy for hemophilia A. New Eng J Med. 2022; 386: 1013-1025. doi: 10.1056/NEJMoa2113708
4. Thornburg CD. Prepare the way for hemophilia A gene therapy. New Eng J Med. 2022; 386: 1081-1082.doi: 10.1056/NEJMe2200878
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