Gene Therapy for Hemophilia A Becomes a Reality

A form of gene therapy showed substantial benefit in men with a severe form of the inherited bleeding disorder hemophilia A. Notable results were observed 1 year after a single intravenous infusion of valoctocogene roxaparvovec (AAV5-h5VIII-SQ). The international study (GENEr8-1) was published on 17 March 2022 in The New England Journal of Medicine.

Dr Courtney D. Thornburg of the Hemophilia and Thrombosis Treatment Center at Rady Children's Hospital in San Diego, California, said, “If approved, this first-generation gene therapy will offer a treatment option that could be truly transforming and liberating for eligible men with hemophilia”.

What Is Hemophilia A?

Caused by a mutation in the gene encoding clotting factor VIII, hemophilia A is an X-linked inherited bleeding disorder. Although rare, it is the most common type of hemophilia. Hemophilia A affects approximately 12 in every 100 thousand people, whereas hemophilia B affects approximately 3.7. Of patients with hemophilia A, 87% are male.

Current treatment for hemophilia A involves prophylactic (disease-preventing) infusions of factor VIII, usually 3 times a week.

Dr Thronburg said that, with gene therapy, such a patient would no longer need at least 150 prophylactic factor administrations per year and would have no bleeding.

How Does Valoctocogene Roxaparvovec Work?

Valoctocogene roxaparvovec is an adenovirus-5-based gene therapy vector expressing the factor VIII sequence, designed to correct the central genetic defect in hemophilia A. In other words, genetic material that will produce factor VIII is loaded into a carrier virus.

Results from the open-ended phase 3 study showed that this was associated with improved production of endogenous clotting factor and a substantial reduction in bleeding.

An analysis at 49-52 weeks of follow-up found that factor VIII activity levels in 132 patients reached 41.9 IU/dL. In a subgroup of 112 patients, mean annual factor use at 4 weeks fell by 98.6% and annual rates of treated bleeding fell by 83.8%.

Researchers led by Margareth C. Ozelo of the University of Campinas in Brazil concluded that “valoctocogene roxaparvovec gene transfer for severe hemophilia A produced substantial increases in factor VIII activity, with reduced bleeding and factor VIII use for most participants over a period of 2 years”. Ozelo said they were very excited about the results of this phase 3 clinical trial.

"We should not forget the success achieved with treatment so far. During the first year, among study participants, 90% had either no bleeding or less bleeding after infusion than with factor VIII prophylaxis. In addition, most participants, including individuals from the phase 1/2 trial, did not receive additional prophylactic treatment during 5 years of follow-up."

The one unanswered question is how long the effect of this treatment will last.

Ozole explained that valoctocogene roxaparvovec is a one-time infusion. “At least for now, repeat administration of the same adenovirus-5 (AVV) vector is not an option because of the induced immune response. The durability of response to this new treatment for hemophilia is one of the critical issues. We cannot currently predict how long transgene expression will last.”

In this study, Ozelo and colleagues noted that “expression of the transferred gene declined over time; further studies are needed to understand whether retreatment will be necessary”.

Dr Thornburg also addressed this issue, saying that completely replacing factor VIII therapy is an ambitious goal, but gene therapy could eliminate the need for prophylaxis in a substantial proportion of patients.

“Any increase of approximately 3-5% in endogenous factor VIII production could replace regular preventive treatment with either factor or nonfactor agents and remove the need for it. There is no answer yet as to how long this will last. We have longer-term data showing fairly good durability with treatment for hemophilia B (factor IX deficiency), but this remains an unanswered question for hemophilia A.”

Thornburg also emphasized the need for further research to find a similar treatment that would benefit women and children, people immune to adenoviral vectors, and patients with hemophilia who also have liver disease or HIV infection.

Details and Results of the GENEr8-1 Study

The study was conducted in men aged 18 and older with congenital severe hemophilia A who had received factor VIII prophylaxis for at least 1 year and were negative for factor VIII inhibitors. Participants received valoctocogene roxaparvovec at a weight-based dose of 60 trillion vector genomes per kilogram. Patients did not receive factor VIII prophylaxis during the 4 weeks after infusion of the gene therapy product, but factor VIII was subsequently used as needed. A safety analysis was performed in the total study population of 134 patients. Two HIV-positive patients were excluded from the treatment efficacy analysis.

In summary;

• There was a significant increase in factor VIII activity from baseline at 49-52 weeks after infusion, meeting the study's primary endpoint,
• Changes in factor VIII use and the annual number of treated bleeding episodes met the secondary endpoint.
  • A reduction of 83.8% in bleeding episodes and
  • a reduction of 98.6% in the need for factor VIII infusions were reported.

The researchers reported that the most common adverse effect was an increase in alanine aminotransferase (ALT). These ALT elevations, also observed with gene therapy for hemophilia B, occurred in 85.8% of patients and were safely managed with immunosuppressants. Other common adverse effects included headache, nausea and increases in aspartate aminotransferase (AST). Each was mild and observed in fewer than one-third of patients.