Clinical data have been published for a gene therapy for hemophilia A that is approaching the market — valoctocogene roxaparvovec (Roctavian), which is currently under review by the US Food and Drug Administration.

Hemophilia A (a deficiency of clotting Factor X) is the most common form of the disease, accounting for about 85% of patients.

The other type is hemophilia B (deficiency of clotting Factor VIII), and a gene therapy for this form of the disease has recently been launched — etranacogene dezaparvovec (Hemgenix), at the enormous price tag of $3.5 million.

Both products comprise of a one-off intravenous IV infusion that delivers a functional gene via an adeno-associated virus that instructs the body to make the missing clotting factor. The hope is that this one-off infusion will act as a ‘cure’ and that the individual will be freed from life-long prophylaxis and/or treatment.

The new clinical data on valoctocogene roxaparvovec, published online today in the New England Journal of Medicine, show that the beneficial effects from the gene are largely durable at 2 years, but they are anticipated to fade with time.

Two years after the one-time infusion, there remained “a significant reduction in the annualized bleeding rates” among 132 men who, at baseline, had severe hemophilia A requiring ongoing factor VIII prophylaxis, said the investigators, led by hematologist Johnny Mahlangu, MB BCh, MMed, of the University of the Witwatersrand in Johannesburg, South Africa.

However, the team predicted that median factor VIII activity would decrease below 10% of normal by year 3 or 5 depending on measurement technique, which would still translate to mild disease with an annualized bleeding rate of less than 1 episode per year.

“Although valoctocogene roxaparvovec may not eliminate bleeding, it potentially provides more consistent protection than factor VIII prophylaxis with less treatment burden,” the team said.

New Questions

Data from the study “will directly inform therapeutic decision making” in Europe, where valoctocogene roxaparvovec is already conditionally approved, and the United States, where it is awaiting approval by the FDA, says Lindsey George, MD, a hematologist and gene therapy specialist at Children’s Hospital of Philadelphia, in an accompanying editorial.

The study speaks to an ongoing concern about the durability of gene therapy for hemophilia, but also raises new questions, she said.

For instance, while some patients had normal Factor VIII production and activity at 2 years, activity had dropped substantially in others, including in six men who resumed prophylaxis. “The cause of the decrease in factor VIII expression is an unanswered question,” and despite an anticipated US price tag of around $2.5 million per treatment, “it is not possible” at the moment “to predict where an individual patient may fall within this range,” she writes.

Also, some subjects had elevations in liver aminotransferase levels that lasted for several months, including 2 years after infusion in 29% of subjects. Elevations in liver aminotransferase levels were treated with immune suppression for a median of 33 weeks.

“This is a unique finding with an undefined cause and long-term safety implications,” George said.

Getting to the bottom of such issues will be necessary for hemophilia gene therapy to fulfill its promise as “a one-time, lifelong, disease-ameliorating” fix for the condition, she asserts.

Study Details

The new report was a follow up of the initial trial in 134 men who were treated with a single infusion of 6 × 10¹³ vector genomes per kilogram of body weight.

Among the 132 subjects available for 2-year evaluation, median factor VIII activity was in the range of mild hemophilia (6%–49% of normal) with an 84.5% reduction in bleeding events from baseline. 

More than 80% of participants had no bleeding events requiring treatment, and there was a 98% reduction from baseline in mean use of exogenous factor VIII.  

Overall, at year 2, 4.5% of subjects had factor VIII activity consistent with severe hemophilia A; 9.1% had activity consistent with moderate disease; 59.8% had activity consistent with mild disease, and 26.5% had activity in the normal range above 40 IU/dL. The investigators estimated that the typical half-life of the transgene-derived factor VIII production system is 123 weeks.

Among the six men who resumed prophylaxis, most had fewer bleeding events than when they were on prophylaxis before the infusion, investigators noted.

All the subjects developed antibodies to the virus delivery vector, precluding retreatment.

The work was funded by valoctocogene roxaparvovec maker BioMarin Pharmaceuticals. Several investigators are employees. Others reported ties to BioMarin and other companies; Mahlangu, for instance, reported research grants from BioMarin, Roche, Novo Nordisk, Pfizer, and others. George reported a research grant from Asklepios Biopharmaceutical and having a patent licensed to the company. She is also an advisor for STRM.BIO. The full list of author disclosures can be found with the original article.

N Engl J Med. Published online February 22, 2023. Abstract, Editorial

M. Alexander Otto is a physician assistant with a master’s degree in medical science and a journalism degree from Newhouse. He is an award-winning medical journalist who worked for several major news outlets before joining Medscape. Alex is also an MIT Knight Science Journalism fellow. Email: [email protected]

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