Roctavian, Hem A Gene Therapy, Sustains Drop in Bleeding Rates, Phase 3 Data Show

Roctavian, an investigational gene therapy, significantly reduced bleeding rates and the need for other treatments in men with severe hemophilia A over at least one year, top-line data from a Phase 3 clinical trial show.

The therapy’s durability in sustaining factor VIII production at levels necessary to control bleeding was also evident at one year after the single infusion, a key point as dropping factor VIII expression levels were noted in an earlier Phase 1/2 study.

Among a subgroup of 17 patients treated at least two years ago, a slower decline in durability from that earlier trial was evident, BioMarin Pharmaceutical, Roctavian’s developer, said in a press release.

Both the U.S. Food and Drug Administration (FDA) and the European Medicines Agency (EMA) last year delayed regulatory decisions on this therapy until more trial data were available. The FDA specifically requested full results covering two years of treatment, while the EMA asked for one year of data.

BioMarin plans to re-submit an application to the EMA before the close of June with this top-line data, showing the study’s primary and secondary goals were met. It is also continuing to work with the FDA on a path to regulatory approval.

The Phase 3 GENEr8-1 trial (NCT03370913) is evaluating Roctavian in 134 adult males with hemophilia A — reported to be the largest global Phase 3 study to date for any gene therapy in any indication.

All enrolled received a single 6e13 vector genomes/kg dose of the investigational therapy, and have completed at least one year of follow-up — mean follow-up time is 71.6 weeks, just under a year and a half. The data cutoff date was November 2020.

Prior to the trial, the mean annualized bleeding rate (ABR) was 4.8 bleeds per year among the 112 patients treated at least one year ago.  Their mean ABR had decreased significantly to 0.8 bleeds per year at one year post-treatment. A majority, 80%, were bleed-free beginning at five weeks after treatment.

Roctavian’s use also reduced the need for replacement therapy by 99% — from 135.9 to two infusions per year.

Across all 134 trial patients, a mean FVIII level of 42.9 international units per deciliter (IU/dL; normal range is 50 to 150 IU/dL) was recorded at one year, “supporting the marked clinical benefits observed with abrogation of bleeding episodes and Factor VIII infusion rates,” the release stated.

All Phase 3 trial participants had initial FVIII levels of 1 IU/dL or less, meaning severe hemophilia A. Those enrolled in the Phase 1/2 trial (NCT02576795), which took place in the U.K., also had severe disease.

In the 17 men treated over two years ago, mean FVIII levels fell from 42.2 IU/dL at one year post-treatment to 24.4 IU/dL at two years. The mean ABR in these Phase 3 patients was 0.9 bleeds per year.

Durability is a legitimate concern, Guy Young, MD, director of the Hemostasis and Thrombosis Program at the Children’s Hospital of Los Angeles, said in an interview with Hemophilia News Today hours after the FDA’s August delay was announced.

Data reaching five to 10 years post-treatment is likely needed to consider durability, Young said. More important, he thought, were the declines in annualized bleeding rates and factor replacement therapy reported in earlier Phase 3 and updated Phase 1/2 data.

“There’s not a single report of a major safety issue” years out, Young said. And “if we look at factor usage and bleeds, they’re down to close to 100% — 96%, 97%.”

No new safety concerns were identified in the Phase 3 study. The most common adverse event, reported in 115 (86%) participants, was elevated levels of a liver enzyme called alanine aminotransferase.

Other common adverse events included headache, nausea, joint pain, fatigue, and elevated levels of another liver enzyme, aspartate aminotransferase. A total of 22 participants reported 43 serious adverse events, all of which resolved.

No clotting-related adverse events were found, and no patients developed inhibitors to FVIII (antibodies that bind to the clotting factor and prevent it from working).

“This is the first statistical evidence demonstrating ABR superiority in a gene therapy trial. These data give us confidence in this groundbreaking alternative to existing therapies,” said Steven W. Pipe, MD, a trial investigator and professor at the University of Michigan.

These data add “to the growing body of scientific and clinical data around valoctocogene roxaparvovec [Roctavian] gene therapy for hemophilia A and creates the possibility for a new treatment paradigm,” Pipe said.

Hemophilia A is caused by mutations in the gene F8, which codes for factor VIII (FVIII), a clotting protein. Roctavian, as a gene therapy, aims to deliver a non-mutated version of this gene to the body’s cells (specifically to cells in the liver), allowing production of functional FVIII.

To deliver the gene, Roctavian uses a modified and harmless version of a virus called AAV5.

“Over the past seven years, we have conducted rigorous scientific research and clinical programs to address the unmet medical needs of people with severe hemophilia A,” said  Hank Fuchs, MD, president of worldwide research and development at BioMarin.

“We are very encouraged by these data and look forward to working with regulatory authorities, treating physicians, and people with hemophilia A to further understand the potential of this gene therapy,” he added.