'Pioneering' Single Gene Injection for Haemophilia A Patients

Liam Davenport

January 13, 2020

Haemophilia A patients could end their dependence on prophylactic factor VIII injections with just one injection of a novel gene therapy, suggests a preliminary study that showed an ongoing clinical benefit several years after receiving treatment.

The phase I/II trial, which was led by Professor John Pasi, Barts and the London School of Medicine and Dentistry, London, involved 15 men with severe Haemophilia A, who were given an infusion of valoctocogene roxaparvovec, an adenovirus-associated vector-mediated gene transfer of human factor VIII (AAV5-hFVIII-SQ, BioMarin Pharmaceutical).

After 3 years of follow-up, 13 patients had an annualised bleeding event rate of zero, and no patients required regular prophylactic factor VIII to prevent bleeding.

'Pioneering Technology'

The research, which was published in the January 2nd issue of the New England Journal of Medicine, follows previous 1-year results from the same study showing that the treatment was effective.

"Our new data are critical in helping the scientific and medical communities understand this pioneering technology," Prof Parsi said in a news release. "This latest study confirms both safety and the long-term beneficial impact of the treatment."

He told Medscape News UK that he and his colleagues are "really excited" by the findings.

"The big thing is that patients with Haemophilia A have a huge historic treatment burden, with intravenous injections every other day to prevent bleeding," Prof Parsi said.

"Here, they have a one-off treatment, and they’re still expressing really good levels of factor VIII two, 3 years down the line. None of them is having to give themselves regular injections to prevent bleeding and their bleeding rates have dropped absolutely 'ginormously'.

"It’s a huge impact on their life."

Approvals Submitted

On the strength of these results, the manufacturers recently announced that they have submitted applications for market authorisation to both the US Food and Drug Administration and to the European Medicines Agency, and a phase III study of the therapy is in development.

If the treatment is approved, Prof Parsi estimates that it could benefit up to 2000 men in the UK with severe haemophilia.

However, he cautioned that it is currently only available for adults without significant liver disease as "the genes that we transfer sit separate from the host genome and so if the cell divides you can potentially lose that transferred gene".

Consequently, they are treating "adults whose livers are not turning over", with the aim of addressing how to manage that issue in children "further down the line".

Study Details

Haemophilia A accounts for approximately 80% of all cases of haemophilia, and is caused by a lack of factor VIII.

The resulting inability of the blood to clot leaves patients needing at least three intravenous injections per week to control and prevent bleeding.

The latest results come from an ongoing efficacy and safety trial of a single infusion of complementary DNA-encoding factor VIII, delivered via an AAV serotype 5 vector.

The researchers gave the infusion at various dose levels to 15 adult men with severe Haemophilia A, defined as a factor VIII level ≤1 IU/dl, and assessed factor VIII levels, as well as bleeding event rates and other measures, for up to 3 years.

All but one of the participants were using prophylactic factor VIII replacement therapy at baseline, at doses in the previous year ranging from 833–7661 IU/kg. Patients also experienced as many as 41 bleeding events per year on annualised rates.


The team found that, 3 years after the single infusion, two patients had factor VIII expression of less than 1 IU/dl.

Of the remaining 13, seven had median factor VIII expression of 20 IU/dl. They had a median annualised bleeding event rate of zero, and the median use of exogenous factor VII reduced from 138.5 infusions per year to zero.

Moreover, the results showed that bleeding in all target joints, defined as major joints with ≥3 bleeding events within 6 months, resolved to no more than two bleeding events within 12 months.

In addition, six patients had median factor VIII expression of 13 IU/dl two years after the infusion, with a median annualised bleeding event rate of zero.

Among these patients, the median use of exogenous factor VIII was reduced from 155.5 infusions per year to 0.5 infusions per year, and target joint bleeding resolved in five cases.

Approach May Have Other Uses

In terms of safety, the most common adverse event was increased alanine aminotransferase levels, comprising thirteen grade 1 events and one grade 2 event.

No participants withdrew from the study, and the team reports that no patients developed factor VIII inhibitors or other factor VIII antibodies. There were also no thromboses, deaths or persistent changes on liver function tests.

Prof Parsi believes that their approach could be used in other clotting disorders, and underlined that there are numerous similar programmes underway in patients with haemophilia B.

However, he pointed out that those diseases are "much rarer" than haemophilia A, "so that might influence whether we actually see it being done.

"But as a paradigm for a treatment where you want the liver to produce a secretable protein, it would appear that this would be a good model for that," Prof Parsi said.

The study was funded by BioMarin Pharmaceutical.

Pasi reports Scientific Advisory Board membership for Apcintex, BioMarin Pharmaceutical, Biotest, catalyst bio, Chugai Pharmaceutical Co., Ltd, F. Hoffmann-La Roche, Novo Nordisk, Sanofi Pasteur Biologics, Sobi, Takeda; Speaker fees for Bayer Healthcare, Biotest, Novo Nordisk, Octapharma, Pfizer, Shire, Sobi; Steering group membership for BioMarin Pharmaceutical.

N Engl J Med 2020; 382:29-40. doi: 10.1056/NEJMoa1908490


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