Enrollment Complete for GENEr8-3 Trial of Roctavian Plus Steroids

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by Steve Bryson, PhD |

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BioMarin Pharmaceutical has completed enrollment in GENEr8-3, a Phase 3b study evaluating its investigational gene therapy Roctavian (valoctocogene roxaparvovec) in combination with corticosteroids in men with severe hemophilia A.

Top-line data from the 52-week (one year) study are expected to be released in early 2023, according to a company press release.

Administered by a single infusion directly into the bloodstream, Roctavian provides a healthy copy of the F8 gene, which carries instructions for making a blood-clotting protein called factor VIII (FVIII) that is defective or missing in people with hemophilia A.

Delivered to the liver by a harmless adeno-associated virus, called AAV5, the therapy is designed to restore the production of FVIII and lower the risk of spontaneous bleeds, while reducing or eliminating the need for preventive (prophylactic) FVIII replacement therapy, a standard hemophilia treatment.

GENEr8-3 (NCT04323098) enrolled men, ages 18 and older, at sites in the U.S., Brazil, Australia, and Taiwan. All participants have severe hemophilia A, with less than 1% of normal FVIII clotting activity).

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Roctavian will be given alongside a regular regimen of immunosuppressive corticosteroids to help prevent immune responses against the therapy’s carrier virus.

To enroll, participants were required to have received prophylactic FVIII replacement therapy for at least one year before entering the study, and have no evidence of FVIII inhibitors — neutralizing antibodies targeting the delivered FVIII.

The study’s primary goal is to assess changes in FVIII activity over the course of one year. Secondary goals include evaluating changes in the use of FVIII replacement therapy, the annual number of bleeding episodes, and the patients’ quality of life.

BioMarin also has completed enrollment in GENEr8-1 (NCT03370913), a Phase 3 study testing a single dose of Roctavian in 134 men with severe hemophilia A.

Data recently announced by the company showed the gene therapy lowered bleeding rates by about 85% after two years. Additionally, more than 80% of the patients remained bleed-free two years after infusion. Nearly all patients stopped their preventive replacement therapies.

The U.S. Food and Drug Administration (FDA) has delayed a decision on Roctavian’s approval until full two-year data from this trial was available. BioMarin is now planning to meet with the FDA to discuss the resubmission of a new approval request between April and June.

An ongoing Phase 1/2 dose-escalation study, called study 270–201 (NCT02576795), is evaluating the safety and efficacy of the gene therapy in 15 adult men with severe hemophilia A. Five-year results showed Roctavian led to a sustained reduction in bleeding frequency and the need for replacement therapies, while improving or maintaining patients’ quality of life.

Another Phase 1/2 trial (NCT04684940) is investigating a single dose of the therapy in up to 20 severe hemophilia A patients with active or prior FVIII inhibitors.

Lastly, the company is running a Phase 1/2 trial, called 270-203 (NCT03520712), evaluating a single dose of Roctavian in about 10 men, also ages 18 and older, with severe hemophilia A who carry pre-existing antibodies against the AAV5 viral vector.

Last year, BioMarin resubmitted a regulatory application seeking Roctavian’s approval in Europe. A decision on that application is expected by June.