Gene Therapies Reduce Bleeding in Hemophilia A and B

Two investigational treatments using adeno-associated virus (AAV) to deliver human factor coding may be promising for the treatment of hemophilia A and B, according to data from two studies published this week in the New England Journal of Medicine.

Valoctocogene roxaparvovec, which uses an AAV vector to transfer a DNA coding sequence for B-domain–deleted human factor VIII to patients with hemophilia A, resulting in endogenous factor VIII protein production in hepatocytes. Likewise, etranacogene dezaparvovec (Hemgenix) uses an AAV vector to transfer a DNA coding sequence for human factor IX to patients with hemophilia B, also increasing endogenous factor IX production. Both treatments substantially reduced bleeding in men with hemophilia A/B.

Valcoctogene roxaparvovec infusion resulted in an 84.5% decrease in the mean annualized treated bleeding rate among patients rolled over from a previous study from baseline to data cutoff (a mean of 111 weeks) in an open-label, single-group, multicenter, phase III trial. The annualized rate of exogenous factor VIII used dropped 98.2%.

The study included 134 men with severe hemophilia A; 112 of these were part of a rollover from a previous study. Severe hemophilia A was defined as a factor VIII activity level less than 1 international unit (IU) per deciliter. All participants were receiving regular prophylaxis with exogenous factor VIII at baseline. They received valoctocogene roxaparvovec in one dose of 6×10¹³ vector genomes/kilogram.

The annualized occurrence of all bleeding events during following the end of the prophylaxis period decreased 4.1 events per year (^-77%) from baseline in the rollover population, demonstrating superiority of valcoctogene roxaparvovec compared with factor VIII prophylaxis.

No new safety signals were seen at 2 years post-infusion. Elevated alanine aminotransferase level (in 88.8% of the participants) was the most common adverse event at 2 years, as seen in previous trials. These elevated levels were treated with immunosuppressants. The mean total duration of glucocorticoid use per participant was 34.7 weeks. This study was sponsored by BioMarin Pharmaceutical. The company, which makes valcoctogene roxaparvovec, also designed the study with input from the authors.

In the second study, treatment of hemophilia B with etranacogene dezaparvovec resulted in a decrease in the annualized bleeding rate from 4.19 to 1.51 between the first 6 months (prophylaxis with factor IX replacement) and months 7-18 (post-infusion of etranacogene dezaparvovec).

The open-label, phase III study included 54 men with moderate to severe hemophilia B. For the first six months (lead-in) patients received prophylactic factor IX. Patients were then infused with etranacogene dezaparvovec at 2×10¹³ genome copies per kg.

The mean factor IX use per participant decreased by 248,825 IU per year from the lead-in and post-prophylactic periods.

Of 465 adverse events in total, 14 were considered severe. Notably, 11 participants had increased levels of alanine aminotransferase (ALT) that were reported as adverse events; none were considered severe.

In November 2022, the FDA approved etranacogene dezaparvovec for the treatment of adults with hemophilia B. With a price tag of $3.5 million per treatment, it has been dubbed the most expensive drug in the world. The study was supported by uniQure and CSL Behring, which makes the drug.