Benefits of Roctavian, Hem A Gene Therapy, Holding for Up to 6 Years

Marta Figueiredo, PhD avatar

by Marta Figueiredo, PhD |

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A double helix DNA strand reclines on a couch in front of a therapist taking notes.

A single dose of the experimental gene therapy Roctavian (valoctocogene roxaparvovec) prevents bleeds and the need for preventive treatment, or prophylaxis, for up to six years in men with severe hemophilia A, according to updated data from a Phase 1/2 trial.

“With every year of observation in this study, we learn more about the impact of a single infusion of [Roctavian] on hemostatic [blood clotting] control and continue to see low levels of bleeds in the absence of prophylactic therapy,” Michael Laffan, the trial’s chief investigator and the director of the Hammersmith Hospital Hemophilia Center, in London, said in a press release.

“Six years of data represents the longest duration of clinical experience for a gene therapy in hemophilia A and provides unparalleled understanding of safety,” added Laffan, also a professor of hemostasis and thrombosis at Imperial College London.

The trial’s updated results will be shared in an oral presentation at the International Society on Thrombosis and Hemostasis 2022 Congress, to be held July 9–13 in London.

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“We are encouraged after six years of data in this Phase 1/2 study by the consistent and durable bleed control following a one-time treatment with [Roctavian],” said Hank Fuchs, MD, the president of worldwide research and development at BioMarin Pharmaceutical, Roctavian’s developer.

“These data demonstrate the potential to change the treatment paradigm by providing severe hemophilia A patients hope for longer intervals free from prophylactic therapy,” Fuchs added.

A regulatory application seeking Roctavian’s approval to treat severe hemophilia A is currently being reviewed in the European Union (EU), for the second time, with a decision expected soon.

BioMarin plans to resubmit a similar application to the U.S. Food and Drug Administration (FDA) by the end of September. That resubmission will include additional information and data analyses requested by the agency in recent meetings.

Roctavian’s initial regulatory applications — filed in 2020 and covering six-month, interim results from the ongoing Phase 3 GENEr8-1 trial (NCT03370913) — were rejected both in the EU and the U.S., with health authorities requesting follow-up data. Specifically, EU regulators sought one-year follow-up data, while two years’ worth were requested in the U.S.

“We continue to work with regulatory authorities to potentially make available the first gene therapy in severe hemophilia A as an important treatment option,” Fuchs said.

“The thorough feedback recently provided by the FDA increases our ability to support the FDA’s review of our application and hopefully makes Roctavian available as a choice for patients in the United States,” Fuchs added.

Roctavian received orphan drug, breakthrough therapy, and regenerative medicine advanced therapy designations in the U.S. for severe hemophilia A. In Europe, it was granted orphan drug and priority medicine status for the same indication. These designations are meant to speed the therapy’s clinical development and regulatory review.

Administered intravenously as a single infusion directly into the bloodstream, Roctavian uses a modified and harmless adeno-associated virus to deliver a working version of F8, the mutated gene in hemophilia A, to liver cells. The F8 gene contains the instructions for making the blood clotting factor VIII (FVIII); liver cells are the body’s main producers of clotting factors.

As such, this therapy is expected to restore FVIII production, thereby lowering or eliminating spontaneous bleeds and the need for preventive FVIII replacement therapies, a standard hemophilia treatment.

A Phase 1/2 trial (NCT02576795) now is evaluating the seven-year safety and effectiveness of ascending doses of Roctavian in 15 men with severe hemophilia A.

The newly announced data concerned 13 participants who received one of two doses of the gene therapy. Both doses successfully raised FVIII levels and controlled bleeds, and allowed patients to remain off prophylaxis.

Seven of these men were given the highest dose — 6e13 vector genomes per kilogram, or vg/kg — and were followed for six years. The remaining six received Roctavian at a dose of 4e13 vg/kg and were followed for five years.

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Consistent with previous four- and five-year findings for these men, updated results showed that the single infusion of Roctavian continued to effectively lower bleeding rates and the use of FVIII replacement therapies for up to six years.

Specifically, the mean annualized bleed rate (ABR) for the high-dose group was 0.7 bleeds in year six — corresponding to a 95% cumulative reduction relative to the period before treatment. Similarly, the mean cumulative ABR in the low-dose group dropped by 91% at five years, with a mean of 0.7 bleeds per year.

The use of replacement therapies also dropped substantially in both groups: by 96% at year six in the high-dose group, and by 93% at year five in the low-dose group. All men in both dose groups currently remain off prophylactic FVIII treatment.

Six months prior to the data cut-off date, one man treated with the 4e13 vg/kg dose temporarily resumed prophylaxis for one month, after which he was bleed-free through the last follow-up.

FVIII activity levels were reduced over time, but remained within an effective therapeutic range.

Roctavian’s safety profile remained consistent with previous data, with no reports of delayed treatment-related adverse events (side effects). None of the patients experienced adverse blood-clotting events, developed FVIII inhibitors (which can render the therapy useless), or left the study.

Since the first year, all men remained off corticosteroids, an immunosuppressive treatment commonly given prior to and after virus-based gene therapies to suppress potential immune reactions against the viral carrier.

The most common treatment-related adverse events occurred soon after dosing and included short-term infusion-associated reactions and temporary increases in liver proteins and enzymes that were not associated with symptoms or long-lasting sequelae. These raises in liver-related molecules, suggestive of liver damage, are a common adverse event of virus-based gene therapies.