BioMarin’s Gene Therapy, Found to Reduce Bleeding Events in Hemophilia A, Submitted for U.S. Approval

BioMarin Pharmaceuticals’ investigational gene therapy valoctocogene roxaparvovec safely and significantly reduced bleeding events — including in target joints — and the use of prophylactic clotting factor VIII in adults with severe hemophilia A, data from a Phase 1/2 study show.

These results, along with an interim analysis of the ongoing GENEr8-1 Phase 3 trial (NCT03370913), supported BioMarin’s recent submission of a biologics license application (BLA) to the U.S. Food and Drug Administration (FDA). BioMarin is seeking FDA approval of valoctocogene roxaparvovec for the treatment of adults with hemophilia A.

The Phase 1/2 trial’s three-year data were reported in a study, “Multiyear Follow-up of AAV5-hFVIII-SQ Gene Therapy for Hemophilia A,” recently published in the New England Journal of Medicine.

“With each passing year, we come to appreciate further the transformation in patient lives that may be possible with gene therapy,” Hank Fuchs, MD, BioMarin’s president of worldwide research and development, said in a press release.

A similar marketing authorization application was submitted to the European Medicines Agency (EMA) in November 2019. The dual submissions make valoctocogene roxaparvovec the first gene therapy for hemophilia whose applications are being reviewed by health authorities for potential approval in the U.S. and in Europe.

BioMarin anticipates that the health authorities will start reviewing its applications between January and February, and it will provide an update at that time.

“We are grateful for the high level of interest from the health authorities in this investigational treatment,” Fuchs said in another press release. “Our hope is one day very soon to deliver a transformative treatment that has the potential to change the way hemophilia A is treated.”

Valoctocogene roxaparvovec, formerly known as BMN 270, is an investigational gene therapy that uses a modified and harmless version of an adeno-associated virus (AAV)  to deliver a functional copy of the clotting factor VIII gene. This gene is mutated in hemophilia A patients, promoting the production of the missing clotting factor.

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

One patient received a single infusion of a 6e12 vg/kg (vector genomes per kilogram) dose of valoctocogene roxaparvovec; another received a 2e13 vg/kg dose; six patients were given a 4e13 vg/kg dose; and seven received a 6e13 vg/kg dose.

The two men in the lower dose groups continued to have reduced levels of factor VIII and are still being monitored. Three-year data from these patients — along with a four-year update on the study — are expected to be presented at an upcoming scientific meeting by mid-2020, according to Fuchs.

Data on the remaining 13 study participants showed “effective control of bleeding,” the researchers said. Within the most recent year of follow-up, the men had factor VIII levels within the non-hemophilic range (one patient), the mild hemophilic range (11 participants), and the moderate hemophilic range (one patient). In addition, all of the men remained off factor VIII prophylaxis (preventive treatment).

A single administration of the therapy at the higher dose led to a 96% reduction in both the mean annualized bleed rate (ABR) and the mean factor VIII usage after three years, as previously reported. At that time, a total of six men (86%) were free from bleeding events.

Two years after receiving the 4e13 vg/kg dose, patients showed a 92% reduction in ABR and 95% less use of factor VIII; four of them (67%) had no bleeding events.

In addition, among both groups, all but one man in the 4e13 vg/kg dose group had full resolution of bleeding in target joints by year 2. Target joints are major joints with three or more bleeding events within a six-month period; these are considered to be resolved if there are less than two bleeds over 12 months.

Valoctocogene roxaparvovec was generally well-tolerated, with no new safety events reported and no treatment discontinuations. None of the participants developed factor VIII inhibitors.

These findings showed that this approach “resulted in sustained, clinically relevant benefit, as measured by a substantial reduction in annualized rates of bleeding events and complete cessation of prophylactic factor VIII use in all participants who had received 4×10¹³ vg per kilogram or 6×10¹³ vg per kilogram of the gene therapy,” the researchers said.

In the published study, the researchers also provided data into the variability of the gene therapy’s effectiveness and into the persistence and durability mechanisms of the introduced DNA.

“These data are critical in helping the scientific and medical communities understand this pioneering technology. With three years of data, we know more about valoctocogene roxaparvovec than any other gene therapies in development for hemophilia A,” said John Pasi, PhD, the study’s lead author, the chief investigator of the Phase 1/2 trial, and a principal investigator of the GENEr8-1 Phase 3 study.

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