Gene Therapy for Hemophilia A 'Transforming and Liberating'

Neil Osterweil

March 16, 2022

A form of gene therapy has shown significant benefit in men with a severe form of the bleeding disorder hemophilia A.

Significant results were seen 1 year after receiving a single intravenous infusion of valoctocogene roxaparvovec (AAV5-hFVIII-SQ), investigators from the international GENEr8-1 trial reported today in The New England Journal of Medicine.

"Truly Transformative and Liberating"

"If approved, this first-generation gene therapy would offer a new choice for care that could be truly transformative and liberating for eligible men with hemophilia," writes Courtney D. Thornburg, MD, from the Hemophilia and Thrombosis Treatment Center at Rady Children's Hospital, San Diego, California, in an accompanying editorial.

Hemophilia A is an X-linked bleeding disorder caused by mutations in the gene encoding for coagulation factor VIII. It is rare (affecting about 12 per 100,000), but is the most common type (hemophilia B affects about 3.7 per 100,000).  

The current treatment for hemophilia A is prophylactic infusions of factor VIII, often given three times per week.

With the gene therapy, such a patient could avoid at least 150 intravenous infusions of prophylactic factor in the span of a year, and have zero bleeds, Thornburg noted.

Valoctocogene roxaparvovec is an adeno-associated virus 5-based gene therapy vector that expresses a human factor VIII coding sequence, and is designed to correct the central genetic defect in hemophilia A.

Results from the phase 3 open label trial show that it was associated with improved endogenous clotting factor production, and also a significant decrease in bleeding.

At 49-52 weeks of follow-up, 132 patients in a modified intention-to-treat analysis had a mean increase in factor VIII activity levels of 41.9 IU/dL (P < .001).

In a subgroup of 112 patients, the mean annualized factor concentrate use at 4 weeks decreased by 98.6%, and annualized rates of treated bleeding declined by 83.8% (P < .001 for both comparisons).

"Valoctocogene roxaparvovec gene transfer for severe hemophilia A provided significant increases in factor VIII activity, with reduced bleeding and factor VIII use for most participants over a period of up to 2 years," conclude the investigators, led by Margareth C. Ozelo, MD, PhD, from the University of Campinas in Campinas, Brazil.

"We are very enthusiastic about the results of this phase 3 clinical trial," Ozelo commented to Medscape Medical News.

"It is important to recognize the clinical benefit achieved so far with treatment. During the first year, 90% of study participants had either zero treated bleeds or fewer treated bleeds post-infusion than with factor VIII prophylaxis," she said. "In addition, most of the study participants, including those from the phase 1/2 clinical trial, in the 5-year follow-up, remain free of the use of additional prophylactic treatments."

One issue that remains unanswered is how long the effects may last.

Valoctocogene roxaparvovec is a one-time infusion, she explained. "At least for now, redosing with the same AAV vector is not an option due to the immune response induced."

"The durability of therapeutic response is one of the critical issues involving this new treatment for hemophilia. Currently, we cannot predict how long the transgene expression will last," she added.

In the study, Ozelo and colleagues noted that "expression of the transferred gene appears to decline over time; further study is needed to address whether repeat treatment will be necessary or possible."

Editorialist Thornburg touched on this point in an interview with Medscape Medical News.

Complete elimination of factor VIII replacement therapy is an ambitious goal, but gene therapy could obviate the need for prophylaxis in a substantial proportion of patients, she said. "Any increase of about 3%–5% in endogenous factor VIII production would eliminate the need for regular preventive treatments, either with regular factor or nonfactor replacements.

"How long that will be sustained is an open question," she added. "With hemophilia B [factor IX deficiency] we have longer-term data showing quite good sustainability of the treatment, but I think it's still an open question for hemophilia A."

Thornburg also noted that further studies are needed to find similar therapies to benefit women and children with hemophilia, as well as for patients with factor VIII inhibitors, those with immunity to adenoviral vectors, and patients with hemophilia and concomitant liver disease or HIV infection.

GENEr8-1 Study Details and Results

The trial was conducted in men 18 and older with severe congenital hemophilia A who had received prophylaxis with factor VIII concentrates for at least 1 year and were negative for factor VIII inhibitors.

The patient sample included 20 men enrolled directly, and 110 participants in a prospective non-interventional study of bleeding episodes, factor VIII infusions, and patient-reported outcomes in individuals with severe hemophilia A.

Participants received one infusion of valoctocogene roxaparvovec, at a dose of 6x1013 vector genomes per kilogram of body weight.

They remained on factor VIII prophylaxis for 4 weeks after the infusion of the gene therapy product, but after that factor VIII was used on an as-needed basis.

A total of 134 patients received an infusion and were included in the safety analysis. Two patients who were HIV-positive were excluded from the modified intention-to-treat efficacy analysis.

As noted above, the trial met its primary efficacy endpoint of change from baseline in factor VIII activity 49-52 weeks after infusion, and the secondary endpoints of change from baseline to after week 4 in annualized use of factor VIII concentrate and the annualized number of treated bleeding episodes.

The most common adverse event was an elevation in alanine aminotransferase (ALT) levels, the investigators noted.

These elevations in ALT levels, which have also been seen with gene therapy for hemophilia B, occurred in 85.8% of patients, and could be safely managed with immunosuppressants, the authors commented.

Other common adverse events were headache, nausea, and elevations in aspartate aminotransferase levels, each occurring in slightly more than one third of patients.

"Overall, the risk–benefit profile appears favorable," the team commented.

The study was supported by BioMarin Pharmaceutical. Ozelo disclosed grant support from the company. Thornburg disclosed serving as a consultant to BioMarin and others.

N Engl J Med Published online March 16, 2022. Abstract, Editorial

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