Gene Therapy and the Treatment of Haemophilia
July 23, 2019

Gene therapy is a growing area of interest for the treatment of several diseases. These therapies are intended to offer a one-time treatment to modify a person’s genes through a variety of mechanisms in order to treat or cure a disease.  These mechanisms include: i) replacing the gene with a healthy copy of the gene, ii) inactivating a gene that is not working properly, or iii) introducing a new/modified gene into the body. Over the last decade, several important scientific advances have been made in this field and these therapies are now being submitted for regulatory and reimbursement evaluation.1

Recently approved gene therapies by the US Food & Drug Administration (FDA) and Health Canada include Chimeric antigen receptor (CAR) T-cell therapies, such as KYMRIAH® (tisagenlecleucel) and YESCARTA® (Axicabtagene ciloleucel); the FDA has also approved the Adeno-Associated Virus (AAV) therapy, LUXTURNA® (Voretigene neparvovec-rzyl).

Haemophilia, which impacts approximately 1 in 10,000 people, is a rare bleeding disorder that is characterized by the body’s impaired ability to make blood clots, leading to increased risks of bruising and bleeding; the most common site of bleeding occurs into the joints or muscles.2

Haemophilia is classified as mild, moderate or severe based on the clotting factor level. The most common type, representing 80-85% of cases, is Haemophilia A which is caused by mutations in the clotting factor gene leading to a deficiency in coagulation Factor VIII (FVIII);2 while Haemophilia B is caused by missing or defective Factor IX (FIX).3

The treatment guidelines for patients with haemophilia focus on the prevention of bleeding and joint damage, prompt management of bleeding, the management of complications (e.g. joint and muscle damage due to bleeding) and attention to psychosocial health.2 Currently patients with haemophilia A are treated with an intravenous injection of FVIII concentrate a) as bleeds happen (on-demand therapy), or b) to prophylactically prevent future bleeds.2,4,5 For patients with severe haemophilia, lifelong prophylactic treatment is started in childhood.2 However, due to the costs associated with frequent dosing and specialized care requirements, access to treatment with FVIII is largely limited to patients in developed, affluent countries, and treatment is often further complicated due to differing pharmacokinetic responses across patients.6 Additionally, studies have demonstrated that there is still a need to improve treatment strategies for patients with haemophilia due to persistently high bleeding rates.5,7

Gene therapy also offers a promising new approach for the treatment of haemophilia, presenting a lasting cure with a single administration by replacing the defective gene sequence with a corrected version.8,9  Currently, a handful of gene therapies are in development for haemophilia:

  •       BioMarin is currently developing a gene therapy for the treatment of haemophilia A using an adeno-associated viral (AAV) factor VIII vector, valoctocogene roxaparvovec (valrox), which has shown reductions in annualized bleed rates, including elimination of bleeds in target joints. Patients are currently being enrolled in two Phase III trials. 10,12
  •       Spark Therapeutics Inc and Pfizer Inc are investigating an AAV factor IX therapy, fidanacogene elaparvovec (formerly, SPK-9001) for the treatment of patients with hemophilia B. Pfizer has initiated the pivotal Phase III trial program to investigate the use of fidanacogene elaparvovec for the treatment of patients with hemophilia B.11,13
  •     uniQure is developing an AAV5 viral vector carrying factor IX gene therapy, AMT-061, for the treatment of patients with Haemophilia B. The company is currently enrolling patients in the phase III clinical trial, HOPE-B. 11,14
  •       uniQure is also developing an AAV5-based factor IX gene therapy, AMT-180, for patients with Haemophilia A.11,14

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  1.     US Food & Drug Administration. What is Gene Therapy? 2018. (accessed June 28 2019).
  2.     Srivastava A, Brewer AK, Mauser-Bunschoten EP, et al. Guidelines for the management of hemophilia. Haemophilia : the official journal of the World Federation of Hemophilia 2013; 19(1): e1-47.
  3.     National Hemophilia Foundation. Hemophilia B. 2019. (accessed June 28 2018).
  4.     Richards M, Williams M, Chalmers E, et al. A United Kingdom Haemophilia Centre Doctors’ Organization guideline approved by the British Committee for Standards in Haematology: guideline on the use of prophylactic factor VIII concentrate in children and adults with severe haemophilia A. British journal of haematology 2010; 149(4): 498-507.
  5.     Berntorp E, Dolan G, Hay C, et al. European retrospective study of real-life haemophilia treatment. Haemophilia : the official journal of the World Federation of Hemophilia 2017; 23(1): 105-14.
  6.     Collins PW, Fischer K, Morfini M, Blanchette VS, Bjorkman S. Implications of coagulation factor VIII and IX pharmacokinetics in the prophylactic treatment of haemophilia. Haemophilia : the official journal of the World Federation of Hemophilia 2011; 17(1): 2-10.
  7.     Mazepa MA, Monahan PE, Baker JR, Riske BK, Soucie JM. Men with severe hemophilia in the United States: birth cohort analysis of a large national database. Blood 2016; 127(24): 3073-81.
  8.     Murphy SL, High KA. Gene therapy for haemophilia. British journal of haematology 2008; 140(5): 479-87.
  9.     Perrin GQ, Herzog RW, Markusic DM. Update on clinical gene therapy for hemophilia. Blood 2019; 133(5): 407-14.
  10.   BioMarin Pharmaceutical Inc. BioMarin Provides 2 Years of Clinical Data in 6e13 vg/kg Dose from Ongoing Phase 1/2 Study in Valoctocogene Roxaparvovec Gene Therapy for Severe Hemophilia A at World Federation of Hemophilia 2018 World Congress. 2018.
  11.   Luxner L. Gene Therapies Advancing in Trials Offer Hope to Hemophiliacs, But Concerns Abound. 2018.
  12.   BioMarin Pharmaceutical Inc. Current Clinical Trials: Hemophilia A. 2019. (accessed June 28 2019).
  13.   Spark Therapeutics. Pfizer Initiates Pivotal Phase 3 Program for Investigational Hemophilia B Gene Therapy.  Phase 3 lead-in study initiated following completion of the transfer of Spark Therapeutics’ hemophilia B gene therapy program to Pfizer; 2018.
  14.   uniQure. Gene Therapy: Hemophilia. (accessed June 28 2019).