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PubMed This is a summary of 18 peer-reviewed journal articles Updated
Hematology

Gene Therapy and Rebalancing Agents: The Future of Care

At a Glance

Hemophilia B treatment now includes FDA-approved one-time gene therapies like Hemgenix and Beqvez, as well as non-factor rebalancing agents. These new therapies aim to reduce or eliminate the need for regular intravenous infusions, though they require specific eligibility testing and monitoring.

The landscape of Hemophilia B treatment is changing rapidly. Beyond replacing the missing Factor IX, scientists have developed ways to either give the body the instructions to make its own factor or to “rebalance” the blood’s natural clotting system to prevent bleeds.

Gene Therapy: A One-Time Blueprint

Gene therapy aims to provide a long-term solution by delivering a functional F9 gene directly to the liver [1]. Once the liver receives this new “blueprint,” it can begin producing Factor IX on its own, potentially eliminating the need for regular infusions [2].

Currently, there are two FDA-approved gene therapies for adults with Hemophilia B:

  • Etranacogene dezaparvovec (Hemgenix): Approved in 2022, it uses a delivery vehicle (vector) called AAV5 [1][3].
  • Fidanacogene elaparvovec (Beqvez): Approved in 2024, it uses a different vector called AAV-Rh74 [1][4].

Eligibility and Considerations

Gene therapy is currently only for adults (18+) with severe or moderately severe Hemophilia B [3][4]. Key factors include:

  • Neutralizing Antibodies (NAbs): Your body may have “pre-existing” antibodies to the viral vectors used in gene therapy, which could block the treatment from working [5]. While Hemgenix can work in some patients with these antibodies, Beqvez requires a negative antibody test before treatment [6][4].
  • Liver Health and Steroid Use: Because the treatment targets the liver, your doctor will evaluate your liver health [7]. After treatment, many patients experience a temporary rise in liver enzymes (transaminitis), requiring them to take steroids (like prednisone) for a few months to protect the new gene [2][8]. It is important to know that these steroids are not a minor detail—they can cause significant side effects, including weight gain, mood swings, insomnia, and immune suppression. You and your doctor should discuss exactly how to manage these side effects before starting therapy.

Non-Factor “Rebalancing” Agents

Unlike traditional therapy that adds Factor IX, rebalancing agents work by slowing down the natural “brakes” in your blood’s clotting system [9][10]. This allows the blood to form clots even when Factor IX is low. These are given as subcutaneous (under the skin) injections rather than into a vein [11].

Medication Mechanism Status
Fitusiran An siRNA (messenger silencer) that lowers antithrombin, a protein that normally prevents clotting. [12][13] FDA Approved for ages 12+ [12]
Marstacimab A monoclonal antibody that blocks TFPI (Tissue Factor Pathway Inhibitor), another natural “brake” on clotting. [14][15] FDA Approved for adults and children 12+ (without inhibitors) [16]

Why “Rebalance”?

These therapies offer a very different experience:

  • Frequency: They are typically injected once a month or even less frequently [11][17].
  • Consistency: They provide a steady level of protection without the “peaks and valleys” of factor infusions [11].
  • Safety Note: Because these agents “turn up” the clotting system, there is a small risk of blood clots (thrombosis). Patients must be carefully monitored, especially if they need to take extra factor for a breakthrough bleed or surgery [12][18].

Common questions in this guide

Who is eligible for Hemophilia B gene therapy?
Gene therapy is currently approved for adults 18 and older with severe or moderately severe Hemophilia B. Your healthcare provider will also evaluate your liver health and test for pre-existing neutralizing antibodies to ensure the treatment will be effective for you.
What are rebalancing agents for Hemophilia B?
Rebalancing agents are non-factor medications that slow down your blood's natural anti-clotting proteins. Instead of replacing the missing Factor IX, they allow your blood to form clots even when factor levels are low. They are given as under-the-skin injections.
Why are steroids needed after Hemophilia B gene therapy?
After receiving gene therapy, many patients experience a temporary rise in liver enzymes as the body reacts to the viral vector. Steroids are temporarily prescribed to protect the liver and the new gene, but they must be managed carefully due to side effects like mood swings and weight gain.
What are the risks of non-factor treatments for Hemophilia B?
Because rebalancing agents enhance your body's ability to clot, there is a small risk of developing unwanted blood clots (thrombosis). Patients require careful monitoring, especially if they need to take traditional factor to treat a breakthrough bleed or prepare for surgery.
Do I need an antibody test before getting gene therapy?
Testing is highly recommended or required depending on the specific therapy. If your body has pre-existing neutralizing antibodies to the viral vectors used in the therapy, it could block the treatment from working.

Questions to Ask Your Doctor

Curated prompts to bring to your next appointment.

  1. 1.Am I (or is my child) a candidate for gene therapy based on our current Factor IX levels and liver health?
  2. 2.Do you offer testing for AAV neutralizing antibodies, and which specific vector (AAV5 or AAV-Rh74) should I be tested for?
  3. 3.What is the long-term follow-up plan after gene therapy, and how often would I need blood tests for liver enzymes?
  4. 4.How do the risks of 'rebalancing agents' like fitusiran compare to the risks of traditional factor replacement for my specific situation?
  5. 5.If I start a non-factor therapy, how will we manage treatment if I have a breakthrough bleed or need surgery?

Questions For You

Tap a prompt to share your answer — we'll use it plus this page's context to start a tailored conversation.

References

References (18)
  1. 1

    Gene-ius at work: Hemophilia B treatment enters a new era.

    Northington MW, Rice SE, Holmes AL, Watts Alexander CS

    American journal of health-system pharmacy : AJHP : official journal of the American Society of Health-System Pharmacists 2025; (82(18)):960-969 doi:10.1093/ajhp/zxaf005.

    PMID: 39868419
  2. 2

    Hemophilia Gene Therapy: The End of the Beginning?

    De Wolf D, Singh K, Chuah MK, VandenDriessche T

    Human gene therapy 2023; (34(17-18)):782-792 doi:10.1089/hum.2023.112.

    PMID: 37672530
  3. 3

    Etranacogene Dezaparvovec: First Approval.

    Heo YA

    Drugs 2023; (83(4)):347-352 doi:10.1007/s40265-023-01845-0.

    PMID: 36802324
  4. 4

    Fidanacogene Elaparvovec: First Approval.

    Dhillon S

    Drugs 2024; (84(4)):479-486 doi:10.1007/s40265-024-02017-4.

    PMID: 38472707
  5. 5

    Gene Therapy with Fidanacogene Elaparvovec in Adults with Hemophilia B.

    Cuker A, Kavakli K, Frenzel L, et al.

    The New England journal of medicine 2024; (391(12)):1108-1118 doi:10.1056/NEJMoa2302982.

    PMID: 39321362
  6. 6

    Etranacogene dezaparvovec in people with hemophilia B with preexisting adeno-associated virus 5 neutralizing antibodies: 4-year subgroup results from the HOPE-B trial.

    Klamroth R, Monahan PE, Van der Valk P, et al.

    Research and practice in thrombosis and haemostasis 2026; (10(1)):103360 doi:10.1016/j.rpth.2026.103360.

    PMID: 41756540
  7. 7

    Liver dysfunction in AAV-mediated Hemophilia B gene therapy: Mechanisms and management strategies.

    Song X, Ding B, Jia H, Zhou H

    Blood reviews 2026; (75()):101356 doi:10.1016/j.blre.2025.101356.

    PMID: 41381305
  8. 8

    Etranacogene dezaparvovec gene therapy for haemophilia B (HOPE-B): 24-month post-hoc efficacy and safety data from a single-arm, multicentre, phase 3 trial.

    Coppens M, Pipe SW, Miesbach W, et al.

    The Lancet. Haematology 2024; (11(4)):e265-e275 doi:10.1016/S2352-3026(24)00006-1.

    PMID: 38437857
  9. 9

    The Vascular Endothelium and Coagulation: Homeostasis, Disease, and Treatment, with a Focus on the Von Willebrand Factor and Factors VIII and V.

    De Pablo-Moreno JA, Serrano LJ, Revuelta L, et al.

    International journal of molecular sciences 2022; (23(15)) doi:10.3390/ijms23158283.

    PMID: 35955419
  10. 10

    Antithrombin lowering in hemophilia: a closer look at fitusiran.

    Young G, Lenting PJ, Croteau SE, et al.

    Research and practice in thrombosis and haemostasis 2023; (7(4)):100179 doi:10.1016/j.rpth.2023.100179.

    PMID: 37358958
  11. 11

    Fitusiran: A Novel Antithrombin-Targeting Therapy for Hemophilia A and B, With or Without Inhibitors.

    Alashqar MT, Nahata MC

    The Annals of pharmacotherapy 2026; (60(7)):700-709 doi:10.1177/10600280251403512.

    PMID: 41450180
  12. 12

    Rebalancing Hemostasis: Fitusiran as a First-in-Class RNAi Therapy in Hemophilia A and B.

    Rehman RU, Fatima R, Akilimali A

    Health science reports 2026; (9(1)):e71702 doi:10.1002/hsr2.71702.

    PMID: 41473775
  13. 13

    An investigational RNAi therapeutic targeting antithrombin for the treatment of hemophilia A and B.

    Machin N, Ragni MV

    Journal of blood medicine 2018; (9()):135-140 doi:10.2147/JBM.S159297.

    PMID: 30174468
  14. 14

    Rebalancing agents in hemophilia: knowns, unknowns, and uncertainties.

    Van Thillo Q, Hermans C

    Haematologica 2025; (110(12)):2902-2912 doi:10.3324/haematol.2025.288245.

    PMID: 40820726
  15. 15

    Efficacy and safety of marstacimab prophylaxis in hemophilia A/B with inhibitors: results from the phase 3 BASIS trial.

    Matino D, Acharya SS, Taylor CT, et al.

    Blood 2026; (147(9)):920-931 doi:10.1182/blood.2025031065.

    PMID: 41351884
  16. 16

    Marstacimab for the Treatment of Hemophilia A or B.

    Mahlangu J

    Biologics : targets & therapy 2025; (19()):379-386 doi:10.2147/BTT.S500480.

    PMID: 40584300
  17. 17

    Safety and efficacy of a fitusiran antithrombin-based dose regimen in people with hemophilia A or B: the ATLAS-OLE study.

    Young G, Kavakli K, Klamroth R, et al.

    Blood 2025; (145(25)):2966-2977 doi:10.1182/blood.2024027008.

    PMID: 40053895
  18. 18

    Challenges in Balancing Hemostasis and Thrombosis in Therapy Tailoring for Hemophilia: A Narrative Review.

    Kenet G, Levy-Mendelovich S, Livnat T, Brenner B

    International journal of molecular sciences 2026; (27(3)) doi:10.3390/ijms27031373.

    PMID: 41683793

This information about Hemophilia B gene therapies and rebalancing agents is for educational purposes only. Always consult your hematologist to discuss which specific treatment options are safe and appropriate for your condition.

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