Gene and Disease-Modifying Therapies for Hemophilia
Written by Margaret Anne Rockwood | Last updated August 6th, 2026
Medically reviewed by Shannon Walker, MD
Hemophilia care is currently undergoing its most significant transformation since the introduction of recombinant clotting factor concentrates in the early 1990s. While prophylactic factor replacement remains highly effective, recent advances in gene therapy and non-factor therapeutics are redefining treatment goals, shifting the focus from bleed prevention alone toward sustained normalization of hemostasis, reduced treatment burden and, in selected patients, a functional cure.
Gene Therapies
The most dramatic advance has been the emergence of adeno-associated virus (AAV)-based gene therapies. These therapies deliver a functional copy of the deficient clotting factor gene to hepatocytes, enabling endogenous production of factor VIII or factor IX after a single intravenous infusion.
Gene therapy is particularly attractive to physicians and patients alike because relatively modest increases in factor levels can substantially reduce bleeding risk. The treatment raises endogenous factor levels from the severe range (<1%) into the mild or moderate range, dramatically reducing bleeding frequency and treatment burden. Uptake remains limited, however, due to limited eligibility criteria and low numbers of sites that offer treatment.
Note that some patients still require occasional factor support after gene therapy.
Gene Transfer Options
Several gene transfer therapies, administered in a single intravenous (IV) infusion, have now reached clinical practice. The AAV vector delivers a working F8 or F9 transgene mainly to hepatocytes. The new gene usually remains episomal rather than integrating into the genome, so it provides an added working copy rather than correcting the inherited mutation.
For adults with hemophilia B, etranacogene dezaparvovec (Hemgenix, CSL Behring) has demonstrated sustained factor IX expression and marked reductions in annualized bleeding rates, leading to regulatory approval by the US FDA in 2022. Similarly, in 2023, valoctocogene roxaparvovec (Roctavian, BioMarin) became the first FDA-approved gene therapy for adults with severe hemophilia A who do not have detectable pre-existing antibodies to AAV5. Fidanacogene elaparvovec-dzkt (Beqvez, Pfizer) was FDA-approved for hemophilia B in 2024, but the manufacturer discontinued the drug just one year later due to limited demand.
Long-term follow-up studies suggest that many patients maintain clinically meaningful clotting factor expression for years after gene therapy treatment, although durability remains more predictable in hemophilia B than hemophilia A. As real-world experience accumulates, patient selection, management of liver enzyme elevations, and long-term monitoring will become increasingly important components of care.
AAV Eligibility
Eligibility criteria for current AAV therapy differ by product. Evaluation generally includes age, hemophilia severity and treatment history, liver health, inhibitor history, and product-specific testing for antibodies against the relevant AAV capsid.
Valoctocogene roxaparvovec is indicated for adults with severe hemophilia A who lack detectable pre-existing anti-AAV5 antibodies. Etranacogene dezaparvovec is indicated for adults with hemophilia B who use factor IX prophylaxis, have had life-threatening hemorrhage, or experience repeated serious spontaneous bleeding. Other considerations for both drugs include the patient’s liver health, inhibitor history, treatment goals, and preference for follow-up.
Pediatric patients are not currently eligible for approved hemophilia gene therapy. Growing liver tissue may dilute episomal vector genomes, and immune responses generally prevent straightforward repeat dosing. Children and adults who are ineligible can continue to receive standard preventive treatments, including conventional or extended-half-life factor concentrates, emicizumab for hemophilia A, and approved rebalancing agents when appropriate.
Despite the excitement surrounding gene transfer, several limitations to gene replacement therapy remain. Pre-existing immunity to AAV vectors may exclude some patients.
As a naturally occurring virus to which many people are exposed during childhood or adulthood, AAV exposure can induce neutralizing antibodies against the viral capsid used in gene therapy to deliver the factor gene to the hepatocytes. These antibodies may bind the therapeutic vector before it reaches hepatocytes and reduce effective gene delivery. Another issue is that after an AAV gene-therapy infusion, recipients generally develop high-titer anti-capsid antibodies, making repeat dosing difficult.
These challenges have stimulated the development of next-generation engineered AAV capsids and alternative delivery methods. Research goals include lower vector doses, nonviral delivery systems such as lipid nanoparticles that avoid antibody complications, and genome-editing platforms that insert, correct, or regulate genes directly through one infusion.
Patient Selection for Gene Therapy
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| Hemophilia A
|
Hemophilia B
|
Additional considerations |
| Adults with severe or moderately severe hemophilia A
No active factor VIII inhibitors |
Adults with severe or moderately severe hemophilia B No active factor IX inhibitors |
Adequate liver function
Absence of certain neutralizing antibodies to the viral vector Ability to undergo long-term monitoring |
Overall, gene therapy is one of the biggest advances in hemophilia, but is primarily used in adults and is not routinely recommended for children.
Gene Editing
Gene editing is still experimental, but raises the possibility of one-time interventions capable of lifelong therapeutic benefit.
CRISPR-based approaches in particular are being investigated to either directly correct disease-causing mutations or rebalance coagulation by targeting endogenous anticoagulant pathways. For example, antithrombin can be reduced with editing, which then permits more thrombin generation, partially “rebalancing” coagulation despite absent FVIII or FIX.
Direct F8 or F9 correction and antithrombin editing have primarily been evaluated in cell and animal models, with some broader liver-directed editing platforms entering early human development for other diseases.
Despite the transformative potential of gene therapy, current use remains largely limited to select adult patient populations. Pediatric use has been constrained by ongoing liver growth, concerns regarding durability of expression, inability to readily re-dose AAV-based therapies, and the availability of highly effective prophylactic alternatives, such as the factor VIII mimetic emicizumab (Hemlibra, Genentech).
Additional barriers include cost/reimbursement, inability to re-dose current AAV vectors, questions about long-term durability, and the need for extensive pre-treatment evaluation.
Non-Factor Therapies
Non-factor therapies are also expanding quickly as treatment options for hemophilia.
Amplifying coagulation signals
In the Haven trials, emicizumab demonstrated that effective prophylaxis can be achieved without directly replacing the missing clotting factor (FVIII). Emicizumab functions by bridging activated factor IX and factor X, thereby restoring the critical amplification step in the coagulation cascade that is lacking in hemophilia A. Its efficacy, favorable safety profile, long half-life, subcutaneous administration have fundamentally altered management of hemophilia A, particularly in patients with inhibitors.
There is no FIX mimetic equivalent to emicizumab that is in routine use for hemophilia B, because emicizumab requires FIXa to bridge to FX and hemophilia B lacks FIX/FIXa. Hemophilia B non-factor prophylaxis is being addressed by rebalancing agents such as anti-TFPI drugs and antithrombin-lowering approaches.
Reducing anticoagulant activity
Rather than replacing missing clotting factors, non-factor therapies are also able to rebalance coagulation by reducing endogenous anticoagulant activity. Fitusiran (Qfitlia, Sanofi) is a small interfering RNA (siRNA) therapeutic that lowers circulating antithrombin levels and enhances thrombin generation. Fitusiran is FDA indicated for adults and patients aged 12 years and older with hemophilia A or B, with or without inhibitors.
Essentially, the drug is a workaround rebalancing therapy: siRNA lowers antithrombin, reducing natural anticoagulant braking and increasing thrombin generation. Because its mechanism is independent of factor VIII or factor IX, the drug has potential utility in both hemophilia A and hemophilia B, including in patients with inhibitors.
Dampening coagulation suppressors
Another major therapy class includes inhibitors of tissue factor pathway inhibitor (TFPI). Concizumab (Alhemo, Novo Nordisk) and marstacimab (Hympavzi, Pfizer) enhance coagulation by reducing TFPI-mediated suppression of the tissue factor pathway. Marstacimab is FDA-approved for patients aged 6 years or older with hemophilia A/B, without inhibitors, and concizumab or hemophilia A/B with or without inhibitors.
Both agents are administered subcutaneously and have demonstrated substantial reductions in bleeding rates. Importantly, these therapies expand prophylactic options for patients with hemophilia B, an area in which non-factor therapies have historically lagged behind hemophilia A.
Looking ahead, the treatment landscape for hemophilia is increasingly shifting toward individualized therapy, with growing options in long-acting factor replacement, subcutaneous non-factor prophylaxis, and gene therapy. Biomarkers capable of predicting durability, thrombosis risk, and treatment response are likely to play a growing role in therapeutic decision-making.
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