Investigational Gene Therapy Results in Huge Drop in Bleeding Rates and Factor VIII Usage, Updated Data Show

Valoctocogene roxaparvovec, BioMarin Pharmaceutical‘s investigational gene therapy, results in a more than 90% drop in annual bleeding rates and the use of clotting factor VIII (FVIII) in men with severe hemophilia A, updated data from a Phase 1/2 clinical trial show. It also precluded the need for prophylactic therapy.

The findings, covering data up to four years after treatment, were presented recently at the World Federation of Hemophilia (WFH) Virtual Summit by John Pasi, PhD, the trial’s chief investigator and a professor at Barts and the London School of Medicine and Dentistry.

“With four years of data, this study represents the longest duration of clinical experience for any gene therapy in hemophilia A. It is exciting to observe that all study participants remain off factor VIII prophylaxis therapy, while also experiencing a greater than 90 percent reduction in bleeding episodes from a single administration of valoctocogene roxaparvovec,” Pasi said in a press release.

“These data demonstrate the very real potential of a paradigm shift in the treatment of hemophilia A and that ongoing research into gene therapies could represent an entirely new way to approach meeting the high unmet need in patients,” he said.

Formerly known as BMN 270, the therapy uses a modified and harmless adeno-associated virus (AAV) to deliver a functional copy of the F8 gene, which is mutated in people with hemophilia A and impairs FVIII production.

The ongoing Phase 1/2 trial (NCT02576795) is assessing the five-year safety and effectiveness of four different doses of valoctocogene roxaparvovec, given through a single infusion directly into the bloodstream, in 15 men with severe hemophilia A.

Results at three years of treatment showed that the two higher doses — 4e13 and 6e13 vector genomes (vg)/kg — resulted in clinically meaningful increases in FVIII levels.

The newly presented findings — cutoff date April 8 — comprised a four-year update for the 6e13 vg/kg dose group (seven men) and a three-year update for the 4e13 vg/kg dose group, which includes six men.

Results submitted to the WFH summit showed that the gene therapy was safe and effectively lowered the mean annualized bleed rates (ABR) in both groups. In addition, all men remained free from factor VIII prophylaxis (preventive) treatment.

The presented data revealed that the therapy resulted in substantial and sustained drops in bleedings requiring factor VIII infusions.

The cumulative mean ABR remained less than one in both groups, reflecting a 95% reduction from study start in the 6e13 vg/kg (high) group and a 93% drop in the 4e13 vg/kg (low) dose group.

Also, mean factor VIII usage reduced by 96% from more than 130 infusions to about five per year in both groups.

Notably, in the past year, six men (86%) treated with the high dose and four (67%) with the low dose remained free of bleeding events. Five men (83%) in the low dose group had no spontaneous bleeds.

Consistent with the observed benefits, the mean activity levels of factor VIII in these participants remained in the therapeutic range.

While before treatment FVIII activity was 1 international unit (IU)/dL or less, indicative of severe hemophilia A, updated levels were between 24.2 and 35.4 IU/dL — depending on the method used — in the high dose group and between 9.9 and 14.9 IU/dL in the low dose group.

“BioMarin is committed to the bleeding disorders community with the most robust and advanced clinical development program for a potential first gene therapy in severe hemophilia A,” said Hank Fuchs, MD, BioMarin’s president of global research and development.

“Demonstrating a 96% reduction in exogenous factor VIII usage as patients are now producing their own endogenous factor VIII is a potential benefit that we hope to be able to offer as we work closely with regulators to seek approval and work to reduce the burden of hemophilia,” Fuchs said.

Valoctocogene roxaparvovec is currently under priority review by the U.S. Food and Drug Administration (FDA) and accelerated assessment by the European Medicines Agency (EMA) for treating 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 — an EMA branch whose recommendations are usually followed by the agency — by the end of this year or early 2021.

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). The company expects to announce GENEr8-1’s one-year data by the end of the year or the first quarter of 2021.