How does Roctavian work?
Hemophilia A is a rare blood disorder, due to mutations in the F8 gene. This gene provides the instructions necessary for cells to make factor VIII, a protein that plays a crucial role in forming blood clots. Depending on the disease-causing mutation(s), cells makes too little factor VIII, or a factor that works poorly or is completely absent. The result for people with hemophilia A is slow or delayed clotting. They require regular infusions of either plasma-derived or recombinant factor VIII to prevent life-threatening bleeding episodes.
Roctavian uses a harmless virus, called AAV5, to carry a healthy copy of the F8 gene that is 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 virus delivers the recombinant F8 gene to the nuclei of the cells of several tissues, including the liver. However, only liver cells make factor VIII protein because of its liver-specific promoter. The liver then secretes the protein 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 Roctavian in 15 patients with severe hemophilia A.
Preliminary results from nine patients appeared in the New England Journal of Medicine in 2017. Factor VIII activity levels remained low in patients given a low or intermediate dose of Roctavian. However, six of seven patients who received a high dose of this therapy had sustained normalization of factor VIII activity levels over a period of one year. They also showed stabilization of hemostasis and a profoundly reduced need for replacement therapy. There were no severe side effects associated with the treatment.
The results of a multiyear follow-up of single-dose Roctavian therapy in 15 hemophilia A patients also appeared in the New England Journal of Medicine. 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 people given Roctavian at lower doses, three years after infusion. Six of these seven high-dose patients were free of spontaneous bleeds at a four-year trial update, as were five of six treated at a lower 4×1013 vg per kg dose.
While safety remained evident, the durability of factor VIII production was identified as a concern. Factor VIII activity levels dropped from a mean of 64.3 IU/dL (international units per deciliter) one year after high-dose treatment with Roctavian to a mean of 24.2 IU/dL at four years post-treatment, a 63% decline, a BioMarin update to the World Federation of Hemophilia 2020 summit showed.
The open-label and single-arm Phase 3 GENEr8-1 study (NCT03370913) is evaluating the safety and effectiveness of Roctavian in 134 people with severe hemophilia A (factor VIII levels of less than 1 IU/dL) and using prophylactic factor VIII infusions. The study is evaluating changes in median factor VIII activity for 52 weeks after a single 6×1013 vg/kg infusion of Roctavian, a dose identified as optimal in the Phase 1/2 trial. It is also looking at the number of bleeding episodes that require factor VIII replacement therapy. Full data collection is expected by late 2022, and the trial is set to conclude in September 2023.
Another Phase 3 clinical trial (NCT03392974) is evaluating the safety and effectiveness of Roctavian at 4×1013 vg/kg dose in severe hemophilia A patients being given 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. This study is due to end in March 2024.
A Phase 1/2 safety, tolerability, and effectiveness study (NCT03520712) of Roctavian at a 6×1013 vg/kg dose in 10 hemophilia A patients with residual factor VIII levels below 1 IU/dL and pre-existing antibodies against AAV5. This trial, enrolling by invitation only, aims to assess the number of treatment-related adverse events. Other goals are measures of Roctavian’s effectiveness, defined by factor VIII activity above 5 IU/dL at 26 weeks, and the number of bleeding episodes requiring replacement factor VIII therapy over five years. The study started in May 2018 and will end in June 2025. It is taking place in the U.K., France, and South Africa.
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.
In August 2020, the FDA issued a complete response letter to BioMarin requesting more trial data to support an approval decision.
Last updated: Aug. 25, 2020
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