BioMarin’s Gene Therapy for Hemophilia A Continues to Prevent Bleeds After Four Years, Trial Shows

BioMarin Pharmaceuticals’ investigational gene therapy valoctocogene roxaparvovec continues to safely and effectively prevent bleeding episodes and the need for prophylactic clotting factor VIII in adults with severe hemophilia A, four-year data from a Phase 1/2 clinical trial show.

The results were submitted for presentation at the World Federation of Hemophilia (WFH) Virtual Summit, to be held June 14–19.

“This additional data is an important step toward a potential first treatment of its kind for this devastating disease,” John Pasi, PhD, the trial’s chief investigator and a professor at Barts and the London School of Medicine and Dentistry, said in a press release.

The gene therapy is currently under priority review by the U.S. Food and Drug Administration (FDA) and accelerated assessment by the European Medicines Agency (EMA) for the treatment of adults with severe hemophilia A. If approved, it will be marketed under the brand name Roctavian.

The FDA’s decision is expected by Aug. 21, while BioMarin anticipates an opinion from the Committee for Medicinal Products for Human Use (CHMP) — an EMA branch whose regulatory recommendations are usually followed by the agency — by the end of the year or early 2021.

“We continue to move forward with health authorities to make this treatment available for people with severe hemophilia A,” said Hank Fuchs, MD, BioMarin president of worldwide research and development.

The gene therapy, formerly known as BMN 270, uses a modified and harmless version of an adeno-associated virus (AAV)  to deliver a functional copy of the F8 gene, which provides instructions for making the clotting factor VIII and is mutated in people with hemophilia A. It is given through a single infusion directly into the bloodstream.

The ongoing Phase 1/2 trial (NCT02576795) is evaluating the five-year safety and effectiveness of four different doses of valoctocogene roxaparvovec in 15 adult men with severe hemophilia A.

Previous three-year data showed that the two men in the lower dose groups — 6e12 and 2e13 vg/kg (vector genomes per kilogram) — continued to have low levels of factor VIII and were still being monitored.

In contrast, the remaining 13 men — six given a 4e13 vg/kg dose and seven a 6e13 vg/kg dose — showed a clinically meaningful increase in factor VIII levels, a profound drop in the mean annualized bleed rate (ABR), and no need for factor VIII prophylaxis (preventive treatment).

The newly released data comprised a four-year update for the 6e13 vg/kg (high) dose group and a three-year update for the 4e13 vg/kg (low) dose group.

Results showed that all men have remained off prophylactic treatment and that their mean ABR continued to be low — 1.3 for the high dose group and 0.5 for the low dose group — and below pre-treatment rates.

In the past year, six men (86%) treated with the high dose and five (83%) in the low dose group remained free of bleeding events. The activity levels of factor VIII in these participants dropped proportionally with the years and continues to be in a therapeutic range.

The therapy’s safety profile was consistent with that previously reported, with no new adverse events and no withdrawals from the study. None of the participants developed factor VIII inhibitors or thrombotic events (those associated with the formation of blood clots that obstruct the blood flow).

The most common treatment-associated adverse events occurred early after treatment and included temporary infusion-associated reactions, and transient, asymptomatic, and mild-to-moderate increases in the levels of certain liver proteins.

“Each year of data increases our knowledge of safety and efficacy and contributes to the growing body of scientific data on gene therapies in general and hemophilia A in particular,” Pasi said.

“In just over four years since starting clinical trials in patients, we’ve submitted applications for marketing authorizations globally, and we continue to contribute to the growing body of scientific data in gene therapy for hemophilia A with five studies underway,” Fuchs said.

Valoctocogene roxaparvovec previously received breakthrough therapy designation from the FDA, as well as priority medicines, or PRIME,  designation from the EMA. It also was granted orphan drug designation by both regulatory agencies.

Both U.S. and European Union applications were based on the Phase 1/2 trial’s three-year data and on an early analysis of the ongoing Phase 3 GENEr8-1 trial (NCT03370913). BioMarin expects to announce GENEr8-1’s one-year data in the first quarter of 2021.