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The treatment landscape for hemophilia is expanding. Improvements to established therapies and the development of novel strategies, such as the recently FDA approved gene therapies, are relieving the treatment burden of prophylaxis and improving patient lives.

 

Hemophilia A and B

Hemophilia A and B are genetic X-linked bleeding disorders caused by missing or defective clotting factor VIII (FVIII) or factor IX (FIX), respectively.1,2 It is estimated that there are between 30,000 and 33,000 males with hemophilia living in the United States.1 Hemophilia is categorized depending on the levels of clotting factor present as mild (6 – 49% of normal levels), moderate (1 – 5%) or severe (≤ 1%).1,2

Treatment for hemophilia is typically prophylactic, preventing bleeds by allowing clot formation. This can be achieved through factor replacement therapies, non-replacement therapies or, more recently, gene therapies.3

 

Factor Replacement Therapies
Plasma-derived and recombinant therapies

Prophylactic factor replacement therapy is recognized as the standard of care for hemophilia, where the missing clotting factor is replaced by regular intravenous administration of a plasma-derived (pd) or recombinant factor (r).3,4

A major issue with factor replacement therapies is the development of alloantibody inhibitors to the factor.5 Inhibitors develop in ∼25 – 40% of patients with severe hemophilia A within the first 50 exposure days to FVIII.5 

Furthermore, infusion of replacement factor multiple times a week, due to the relatively short half-lives of these treatments, comes with a high treatment burden and cost for patients.5,6 Recently, steps have been taken to extend the half-lives of replacement factors.5

 

Extended half-life factor replacement therapy

Extended half-life (EHL) factor products currently exist for both hemophilia A and B. These products are typically fusion proteins – for example, recombinant factor fused to an IgG Fc region to promote its recycling.4,6

Eftrenonacog alfa is a rFIXFc EHL product which was approved by the FDA in March 2014 as prophylaxis for patients with severe hemophilia B based on the B-LONG Phase III trial (NCT01027364).8 Here, a significant decrease (83% and 87%) in annualized bleeding rate (ABR) was observed in the groups receiving weekly and interval-adjusted prophylaxis compared to the group receiving episodic treatment.7 Eftrenonacog alfa also displayed an 82.1 hour half-life, significantly longer than that of recombinant FIX.7

The efficacy of a similar product for hemophilia A, efanesoctocog alfa (rFVIIIFc) was recently investigated in the XTEND-1 Phase III trial (NCT04161495). For patients receiving once-weekly prophylaxis with efanesoctocog alfa, the mean ABR decreased from 2.96 (95% CI, 2.00 to 4.37) to 0.69 (95% CI, 0.43 to 1.11) and the treatment displayed superiority over prestudy FVIII prophylaxis.9 On the basis of this trial, the FDA granted Breakthrough Therapy designation to efanesoctocog alfa in June 2022.10

Despite the success of EHL therapies, the treatment burden of prophylaxis remains high, and infrequent bleeding events can still result in cumulative joint damage.5 

New opportunities are arising in the form of non-replacement therapies, which aim to alter the hemostatic balance of a patient by enhancing thrombin generation or coagulation.5

 

Non-Replacement Therapies
Emicizumab

Emicizumab is a substitution treatment for patients with hemophilia A. It is a bispecific antibody which binds FX and FIXa, restoring the missing function of FVIII in the clotting cascade.5 As emicizumab has no structural homology to FVIII, it can be used in patients with FVIII inhibitors.5 

Emicizumab was approved by the FDA for patients with hemophilia A with and without inhibitors in 2018.11 This was based on the Phase III HAVEN 3 (NCT02847637) and HAVEN 4 (NCT03020160) trials, where treatment reduced the ABR of patients with and without inhibitors compared to no prophylaxis.11

Recently, the HAVEN 6 (NCT04158648) trial investigated the safety and efficacy of emicizumab prophylaxis for patients with non-severe hemophilia A without inhibitors. A strong reduction in ABR was observed.12 On the basis of this study, emicizumab was approved by the EMA for patients with moderate to severe, rather than only severe, hemophilia A.13

 

 

At the 31st Congress of the International Society on Thrombosis and Haemostasis (ISTH), Johannes Oldenburg spoke on HAVEN 6 and expanded on the benefits of subcutaneous prophylactic emicizumab in terms of treatment burden and patient benefit.

Concizumab

Concizumab is a monoclonal antibody which inhibits the tissue factor pathway inhibitor (TFPI).5 TFPI inhibits clotting factors, and inhibition of TFPI has been shown to reduce bleeding in animal models.5 Concizumab can be used to treat hemophilia A and B and is unaffected by factor inhibitors because its mechanism of action is independent of FVIII and FIX.14 

Recently, concizumab in patients with hemophilia A/B with inhibitors was investigated in the Phase III explorer7 trial (NCT04083781). ABR was reduced with concizumab prophylaxis compared to no prophylaxis and the treatment was well tolerated.15 The FDA has not yet approved concizumab and has recently requested additional information for re-evaluation.16

 

Other anti-TPFI antibodies are under investigation, as well as inhibitors of activated protein C, which downregulates thrombin activation.5

Alongside these novel therapies, gene therapies which act to rebalance hemostasis or induce long-term replacement of the missing factor are emerging to treat hemophilia.

Gene Therapies
RNAi gene therapy

Small interfering RNA (siRNA) can prevent the translation of specific mRNAs. Fitusiran is a siRNA which binds to the mRNA of anti-thrombin, disrupting anti-thrombin production and ultimately increasing the concentration of active thrombin.5

Fitusiran is factor-independent – it can be used in patients with hemophilia A or B with and without inhibitors. Two recent Phase III trials investigated fitusiran prophylaxis in patients with hemophilia A/B with inhibitors (ATLAS-INH; NCT03417102) and without inhibitors (ATLAS-A/B; NCT03417245), receiving once-monthly fitusiran or on-demand treatment with clotting factors or bypassing agents.17,18 In both studies, the ABR of the group receiving fitusiran prophylaxis was significantly lower than the group receiving on-demand treatment.17,18

At the 30th Congress of the International Society on Thrombosis and Haemostasis (ISTH), 2022, we spoke to Alok Srivastava about the mechanism of action and benefits of fitusiran. Dr Srivastava highlighted the advantage of achieving steady-state levels through subcutaneous injection.

 

 

 

 

AAV-based gene therapy

The most recent and compelling development in hemophilia treatment was the approval of the first gene therapies for hemophilia B (etranacogene dezaparvovec; November 2022) and hemophilia A (valoctocogene roxaparvovec; June 2023).19,20 Both of these treatments are adeno-associated virus (AAV) vector-based gene therapies, which use a viral vector carrying the gene for the missing clotting factor in a one-time treatment.19,20

Etranacogene dezaparvovec was approved based on the results of the HOPE-B trial (NCT03569891) where FIX activity increased by 34.3% at 18 months after treatment.19,21

Valoctocogene roxaparvovec’s approval was based on the GENEr8-1 trial (NCT03370913) where the mean FVIII activity level at weeks 49 through 52 increased by 41.9 IU/dL (95% CI, 34.1 to 49.7; P<0.001) from a baseline value of 1IU/dL.20,22 These results indicate that patients were expressing the added gene, allowing many patients in these trials to remain off prophylaxis.23

At this year’s Congress of the European Hematology Association (EHA), Michiel Coppens spoke about AAV therapies in hemophilia. Dr Coppens highlighted some of the differences seen between hemophilia A and B, noting that FVIII expression in patients with hemophilia A appears to peak and then decline following gene therapy. This gradual decline could suggest the effects of valoctocogene roxaparvovec may decrease over time.

 

There are further challenges associated with gene therapy. For example, AAV-based therapy is only beneficial in patients who do not possess anti-AAV5 antibodies, which patients should be tested for prior to treatment.20 Additionally, access to one-time high-cost gene therapies is not universal, particularly for patients in low- to middle-income countries (LMICs).24 

Despite these challenges, gene therapy is a bold new field in the treatment of genetic disorders such as hemophilia, and the recent approval of etranacogene dezaparvovec and valoctocogene roxaparvovec represent great steps forward in this area.

The novel approaches discussed here increase treatment options for patients with hemophilia who develop inhibitors from factor replacement therapy, or who cannot afford or manage weekly infusions. Novel non-replacement therapies are effective for patients with hemophilia A and B regardless of their inhibitor status, and the recently-approved AAV-based gene therapies offer the potential for a one-time treatment for hemophilia A and B. 

While there are still hurdles regarding the treatment and financial burden on patients, the therapeutic landscape for hemophilia is constantly evolving and improving.

References

  1. National Hemophilia Foundation. Hemophilia A. Available here (Accessed July 11, 2023)
  2. National Hemophilia Foundation. Hemophilia B. Available here (Accessed July 11, 2023)
  3. National Hemophilia Foundation. Current Treatments. Available here (Accessed July 11, 2023)
  4. Kempton CL. Prophylaxis in hemophilia: how much is enough? Blood. 2021 Apr 1;137(13):1709-1711.
  5. Weyand AC, Pipe SW. New therapies for hemophilia. Blood. 2019 Jan 31;133(5):389-398.
  6. Aledort L, Mannucci PM, Schramm W, et al. Factor VIII replacement is still the standard of care in haemophilia A. Blood Transfusion. 2019 Nov;17(6):479-486.
  7. Powell JS, Pasi KJ, Ragni MV, et al. Phase 3 Study of Recombinant Factor IX Fc Fusion Protein in Hemophilia B. New England Journal of Medicine. 2013 Dec 12;369(24):2313-2323.
  8. Biogen. FDA Approves Biogen Idec’s ALPROLIXTM, the First Hemophilia B Therapy to Reduce Bleeding Episodes with Prophylactic Infusions Starting at Least a Week Apart. Available here. (Accessed July 12, 2023)
  9. von Drygalski A, Chowdary P, Kulkarni R, et al. Efanesoctocog Alfa Prophylaxis for Patients with Severe Hemophilia A. New England Journal of Medicine. 2023 Jan 26;388(4):310-318.
  10. National Hemophilia Foundation. FDA Grants Breakthrough Status to BIVV001. Available here. (Accessed July 12, 2023)
  11. U.S. Food and Drug Administration. FDA approves emicizumab-kxwh for hemophilia A with or without factor VIII inhibitors. Available here. (Accessed July 11, 2023)
  12. Négrier C, Mahlangu J, Lehle M, et al. Emicizumab in people with moderate or mild haemophilia A (HAVEN 6): a multicentre, open-label, single-arm, phase 3 study. The Lancet Haematology. 2023 Mar 1;10(3):e168-e177.
  13. European Medicines Agency. Hemlibra. Available here. (Accessed July 12, 2023)
  14. Shapiro AD, Angchaisuksiri P, Astermark J, et al. Subcutaneous concizumab prophylaxis in hemophilia A and hemophilia A/B with inhibitors: phase 2 trial results. Blood. 2019 Nov 28;134(22):1973-1982.
  15. Frei-Jones M, Cepo K, d’Oiron R, et al. Subcutaneous Concizumab Prophylaxis in Patients with Hemophilia A or B with Inhibitors: Efficacy and Safety Results By Hemophilia Subtype from the Phase 3 Explorer7 Trial. Blood. 2022 Nov 15;140(Supplement 1):466-468.
  16. National Hemophilia Foundation. FDA Requests Additional Information on Concizumab from Novo Nordisk. Available here. (Accessed July 12, 2023)
  17. Srivastava A, Rangarajan S, Kavakli K, et al. Fitusiran prophylaxis in people with severe haemophilia A or haemophilia B without inhibitors (ATLAS-A/B): a multicentre, open-label, randomised, phase 3 trial. The Lancet Haematology. 2023 May 1;10(5):e322-e332.
  18. Young G, Srivastava A, Kavakli K, et al. Efficacy and safety of fitusiran prophylaxis in people with haemophilia A or haemophilia B with inhibitors (ATLAS-INH): a multicentre, open-label, randomised phase 3 trial. The Lancet. 2023 Apr 29;401(10386):1427-1437. doi:10.1016/S0140-6736(23)00284-2
  19. U.S. Food and Drug Administration. FDA Approves First Gene Therapy to Treat Adults with Hemophilia B. Available here. (Accessed July 12, 2023)
  20. U.S. Food and Drug Administration. FDA Approves First Gene Therapy for Adults with Severe Hemophilia A. Available here. (Accessed July 12, 2023)
  21. Pipe SW, Leebeek FWG, Recht M, et al. Gene Therapy with Etranacogene Dezaparvovec for Hemophilia B. New England Journal of Medicine. 2023 Feb 23;388(8):706-718.
  22. Ozelo MC, Mahlangu J, Pasi KJ, et al. Valoctocogene Roxaparvovec Gene Therapy for Hemophilia A. New England Journal of Medicine. 2022 Mar 17;386(11):1013-1025.
  23. BioMarin Pharmaceutical. BioMarin Announces Stable and Durable Annualized Bleed Control for ROCTAVIANTM in Largest Phase 3 Gene Therapy Study in Adults with Severe Hemophilia A; 134-Participant Study Met All Primary and Secondary Efficacy Endpoints at 3-Year Analysis. Available here. (Accessed July 12, 2023)
  24. Adair JE, Androski L, Bayigga L, et al. Towards access for all: 1st Working Group Report for the Global Gene Therapy Initiative (GGTI). Gene Therapy. 2023 Apr;30(3):216-221.
Written by Louise Collinson
Edited by Elitsa Kamberska & Thomas Southgate
Publishing date: 19/07/2023

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