Last updated Sept. 8, 2022 by Marisa Wexler, MS
✅ Fact-checked by Joana Carvalho, PhD
What is Roctavian for Hemophilia?
The European Commission granted Roctavian conditional approval in 2022 as a treatment for people with severe hemophilia A who don’t have inhibitors nor detectable antibodies against adeno-associated virus serotype 5 (AAV5).
BioMarin is planning to submit an application to the U.S. Food and Drug Administration (FDA) requesting Roctavian’s approval in the U.S. The company first applied for approval in the U.S. and EU in 2020, but regulators rejected the initial applications, citing a need for more data on the therapy’s effectiveness and safety.
Roctavian has been named an orphan drug in both the U.S. and EU for treating hemophilia A. It’s also been granted the designations of breakthrough therapy and regenerative medicine advanced therapy (RMAT) in the U.S., and given priority medicines (PRIME) designation in the EU for the same indication.
How does Roctavian Work?
Hemophilia A is caused by mutations in the F8 gene, which provides instructions for making a clotting protein called factor VIII (FVIII). Due to these mutations, the FVIII protein either does not function correctly or not enough is produced, ultimately resulting in slow or delayed blood clotting.
Roctavian uses a harmless adeno-associated virus virus, called AAV5, to carry and deliver a shorter but functional copy of the F8 gene to cells in the liver — the main producers of clotting factors in the body. By doing so, the one-time therapy is expected to restore functional FVIII production, thereby lowering the risk of bleeds, while reducing or potentially eliminating the need for routine preventive treatments.
How will Roctavian be administered?
In the Phase 3 GENEr8-1 trial, which supported Roctavian’s conditional approval in Europe, Roctavian was administered via a single infusion into the bloodstream, at a dosage of 6×10e13 vector genomes per kilogram of body weight (vg/kg).
Roctavian in clinical trials
Phase 1/2 trial
A multi-center, dose-escalation Phase 1/2 study (NCT02576795) is evaluating the safety, tolerability, and effectiveness of Roctavian in 15 male patients with hemophilia A. At the trial’s start, all participants had FVIII activity of 1% or lower (compared to normative values), consistent with severe hemophilia A.
All 15 were treated with a single infusion of Roctavian, at one of four doses:
- one patient was given a 6e12 vg/kg dose
- one participant received a 2e13 vg/kg dose
- six patients were given a 4e13 vg/kg dose
- seven participants received a 6e13 vg/kg dose
After three years, the two participants given the lowest doses of Roctavian continued to have FVIII activity below 1%, consistent with severe hemophilia A. However, the remaining 13 participants given higher doses of the therapy saw an increase in FVIII activity, together with a decrease in bleeding rates, and lower usage of replacement therapies.
These patients are still being followed in the trial that is still underway. Latest data showed these benefits were maintained for up to six years. At the latest follow-up, the average annual bleeding rate was 0.7 bleeds per year in both dose groups — representing a more than 90% decrease from rates seen before treatment. FVIII activity levels decreased over time, but remained within a range expected to provide therapeutic benefit, and no unexpected long-term safety issues were reported.
The Phase 3 GENEr8-1 clinical trial (NCT03370913) enrolled 134 men with severe hemophilia A who were on standard prophylactic (preventive) replacement therapy. All received a single infusion of Roctavian, at a dose of 6e13 vg/kg, and were followed for at least 49 weeks. The study’s main goals were to assess the effect of treatment on FVIII activity, as well as bleeding rates, and use of replacement therapy.
Results showed that after one year, 37.9% of participants had FVIII activity of 40% or higher — generally considered non-hemophilia levels. Among the remaining participants, 50% had FVIII activity levels ranging between 5–40% — usually indicating mild hemophilia — while 12.1% had levels lower than 5%. Available data suggested that FVIII activity generally declined over time after treatment.
Consistent with the increase in FVIII activity, bleeding rates decreased by more than 80%: from 4.8 bleeds per year before treatment to 0.8 bleeds per year after treatment with Roctavian. Most participants were bleed-free starting five weeks after treatment with Roctavian, and nearly all were off of prophylactic replacement therapy after two years. The ongoing study is continuing to collect long-term efficacy and safety data.
Other ongoing trials
A Phase 3b study called GENEr8-3 (NCT04323098) that enrolled 20 men with severe hemophilia A is also underway. In this study, participants will be given a single infusion of Roctavian alongside a regimen of anti-inflammatory corticosteroids, designed to dampen an immune response against the therapy’s viral vector that may lower its effectiveness. The study’s main goals are to assess the effect of treatment on FVIII activity, as well as bleeding rates, and use of replacement therapy. GENEr8-3 completed enrollment in early 2022, and initial results are expected in 2023.
A Phase 1/2 trial (NCT03520712) plans to test Roctavian in about 10 adult male patients with severe hemophilia A who have pre-existing antibodies against the AAV5 viral vector. All participants will receive a single infusion of Roctavian, with the main goal of assessing safety after over five years of follow-up.
Another Phase 1/2 study (NCT04684940) aims to enroll 20 men with severe hemophilia who have active or prior inhibitors — neutralizing antibodies against the FVIII protein, which can reduce the effectiveness of replacement therapies. The study’s main goal is to assess treatment’s safety over five years.
Common side effects of Roctavian
In the GENEr8-1, the most common side effects associated with Roctavian included:
- infusion-related reactions
- high levels of liver enzymes
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