Hemophilia B is an X-linked genetic disorder leading to deficiency of factor IX. Persons with hemophilia can present with bleeding manifestations corresponding to the degree of factor activity, ranging from a mild deficiency (>5%-40% activity) — corresponding to bleeding with trauma — to a severe phenotype of undetectable coagulation factor activity (<1%), with spontaneous bleeding or major bleeding after minimal trauma.1
Management of hemophilia has seen significant evolution over the course of the past decade, with therapy initially relying solely on intravenous (IV) replacement of coagulation factors through repeat and frequent infusions based on the half-life of the factor concentrate, ranging in administration from daily to every 14 days for prophylaxis.2 The drawbacks of IV factor exposure include cost, burden of administration, development of a coagulation factor inhibitor, and — sometimes — bleeding and joint damage despite aggressive prophylaxis.3 As a single gene disorder with reliable serum biomarker, hemophilia represents an ideal target for gene therapy,4 offering the potential for one-time treatment that can provide sustained endogenous factor IX production. Since 2022, two adeno-associated virus (AAV)-based gene therapies have been approved by the U.S. Food and Drug Administration (FDA) for management of hemophilia B in adults.5-7
However, there have been ongoing concerns about the long-term impact and durability of the response to these gene therapies. Ulrike M. Reiss, MD, and colleagues examined the long-term clinical benefit and safety of scAAV2/8-LP1-hFIXco gene therapy in 10 patients with severe hemophilia B, seven of whom were using factor IX concentrate prophylaxis at baseline. All 10 patients received a single infusion of the scAAV2/8-LP1-hFIXco vector in one of three doses: 2x1011 vector genomes (vg)/kg of body weight, 6x1011 vg/kg, or 2x1012 vg/kg. The patients were followed for a median of 13 years, with study assessments of factor IX activity, annualized bleeding rate, and factor IX concentrate.
From a safety perspective, none of the patients developed a factor IX inhibitor, thrombosis, or recurrent or persistent transaminitis, and there were no deaths. Four of the 10 study participants did experience grade 1 or 2 transaminitis between week 1 and 12 of the vector infusion. All four of these patients had received high-dose vector, with two noting a reduction in factor IX expression. Mean factor IX activity remained stable within each dosing group from year 3 to 13, with dose-depending factor activity noted. The low-dose vector group’s mean factor IX activity levels were 1.8+/-0.7 international units (IU)/dL at three years and 1.7+/-0.3 IU/dL at 13 years. In the intermediate-dose group, mean factor IX levels were 2.5+/-0.9 IU/dL at three years and 2.3 IU/dL at 13 years, while the levels were 5.1+/-1.7 IU/dL at three years and 5.2 IU/dL at 13 years in the high-dose group. Three of the 10 participants resumed prophylaxis, with factor IX levels between one and three IU/dL and experience of spontaneous hemarthropathy. Median annualized bleeding rate decreased from a baseline of 14 episodes to 1.5 episodes. Overall, the infusion of factor IX concentrate decreased significantly following gene therapy.
In Brief
We are entering a new era in the management of hemophilia. Gene therapy is now an established treatment for the management of hemophilia B, with two FDA-approved options. However, the adoption of this groundbreaking therapy has been rather slow, with several factors contributing to poor uptake. First and foremost, there are concerns about the durability of response, particularly as the AAV vectors do not integrate into the human genome and may be lost with hepatocyte turnover. There are also unknown long-term effects, as well as the financial toxicity associated with the therapy’s hefty price tag.
This study alleviates some concerns about the durability and long-term safety of scAAV2/8-LP1-hFIXco hemophilia B gene therapy. It is important to point out that while only mild improvements are noted in the transgene expression of factor IX (1.7-5.2 IU/dL) over the median 13 years of follow-up, the stable reduction in annualized bleeding rate from 14 to 1-1.5 (depending on the vector dose administered) appears to demonstrate long-term clinical relevance to patients. Further, significant reduction in the need for factor IX replacement in up to 70% of the patients also addresses the issue of financial toxicity over a patient’s lifespan.
Interestingly, persistently elevated levels of immunoglobulin G antibody and neutralizing antibodies against AAV serotype 8 capsid were detected at 13 years. This might suggest that gene therapy may be a one-time opportunity for each patient if AAV vector is used as a vehicle for therapy.
The landscape of hemophilia therapy continues to evolve rapidly. Beyond the standard-of-care replacement factor concentrates, there are several novel agents such as small interfering RNA (fitusiran) and monoclonal antibodies targeting tissue factor pathway inhibitors (concizumab, marstacimab) that offer alternative approaches for management of hemophilia B. Shared decision-making with a highly tailored approach for individual patients — with careful selection of patients who would benefit the most from gene therapy — is imperative.
Disclosure Statement
The authors indicated no relevant conflicts of interest.
