Roctavian (valoctocogene roxaparvovec) is an investigational gene therapy being developed by BioMarin Pharmaceutical to treat severe hemophilia A with a single-dose intravenous injection.

The therapy was previously named Valrox (a name change was announced in May 2020), and earlier known as BMN 270. The U.S. Food and Drug Administration (FDA) is expected to decide whether to approve Roctavian on or before August 21, 2020. 

How does Roctavian work?

Hemophilia A is a rare blood disorder caused by mutations in the F8 gene that provides instructions for making factor VIII, a protein that plays a crucial role in forming blood clots. The mutation causes factor VIII to be reduced in amount, absent, or dysfunctional. Because factor VIII is necessary for normal blood clotting, hemophilia A patients have delayed clotting and require regular infusions of either plasma-derived or recombinant factor VIII to prevent life-threatening bleeding episodes.

Roctavian contains a harmless virus called AAV5 that carries a healthy copy of the factor VIII gene under the control of a liver-specific promoter. Promoters are regions in the DNA that dictate where a certain gene will be active. When Roctavian is infused into hemophilia A patients, the recombinant factor VIII gene is delivered into the nuclei of the cells of several tissues, including the liver. However, factor VIII protein is made only in the liver cells because of the liver-specific promoter. It then is secreted into the bloodstream.

Roctavian in clinical trials

Preliminary clinical studies indicated that a single optimal dose infusion of Roctavian could restore the normal blood-clotting pathway in hemophilia A patients.

A Phase 1/2 multi-center, dose-escalation study (NCT02576795) is underway to assess the safety, tolerability, and effectiveness of Valrox in 15 patients with severe hemophilia A.

Preliminary results from nine patients were published in the New England Journal of Medicine in 2017. While factor VIII activity levels remained low when patients were given a low or intermediate dose of Roctavian, six of seven patients who were given a high dose of treatment had sustained normalization of factor VIII activity levels over a period of one year, with stabilization of hemostasis, and profoundly reduced need for replacement therapy. There were no severe adverse side effects associated with the treatment.

The results of a multi-year follow-up of single-dose Roctavian gene therapy in 15 hemophilia A patients was reported in the New England Journal of Medicine in January 2020. Seven participants who received high-dose Roctavian (6×1013 viral genomes – vg per kg) had a median factor VIII expression of 20 IU per dL (international units per deciliter) compared with less than 1 IU per dL in the three patients who received lower doses of Roctavian, at three years after infusion. Patients who received 4×1013 vg per kg or 6×1013 vg per kg of Roctavian gene therapy showed a substantial reduction in the number of bleeding events in a year and complete cessation of prophylactic (preventive) factor VIII usage.

A Phase 3 open-label, single-arm clinical trial (NCT03370913) is evaluating the safety and effectiveness of Roctavian in hemophilia A patients who have factor VIII levels of less than 1 IU/dL and who have received prophylactic factor VIII infusions. The study will assess changes in median factor VIII activity for 52 weeks after a single infusion of Roctavian and the number of bleeding episodes that require factor VIII replacement therapy. The trial is ongoing, but no longer recruiting participants. It is expected to be completed by September 2023.

Another Phase 3 clinical trial (NCT03392974) is evaluating the safety and effectiveness of Roctavian in hemophilia A patients with factor VIII levels below 1 IU/dL and receiving prophylactic factor VIII replacement infusions. The trial is assessing changes in median factor VIII activity and the number of bleeding episodes requiring replacement factor VIII therapy for 52 weeks after a single infusion of Roctavian. The study began in March 2018 and is expected to be completed in March 2024.

A Phase 1/2 safety, tolerability, and effectiveness study (NCT03520712) of Roctavian in 10 hemophilia A patients with residual factor VIII levels below 1 IU/dL and pre-existing antibodies against AAV5 is enrolling participants by invitation only. It aims to assess the number of treatment-related adverse events, the effectiveness of Roctavian defined by factor VIII activity above 5 IU/dL at 26 weeks, and the number of bleeding episodes requiring replacement factor VIII therapy over a period of five years. The study started in April 2018 and is expected to be completed in June 2024. It is being conducted at two centers in the U.K. — the Royal Free Hospital in London and University Hospital Southampton.

Other details

The FDA granted Roctavian breakthrough therapy designation based on the results of the Phase 1/2 trial in October 2017. Roctavian also received orphan drug designation from both the FDA and the European Medicines Agency (EMA) in March 2016.

Last updated: Feb. 3, 2020


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