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Hemophilia Gene Therapy is a Sweet Dream for Patients and Pharmaceutical Companies. It is Coming True in 2020

Two Pain Points of Hemophilia

Patients with hemophilia lack blood clotting factors needed to close off damaged vessels and to prevent excessive bleeding. 

Hemophiliacs are faced with sporadic internal bleeding events creating irreversible damage to joints, brain, and internal organs. 

In the modern world, they mostly don’t get those.

Instead of living in a constant fear of a bleeding event, patients inject themselves with regular prophylactic doses of a clotting factor. While the factor is circulating in their bloodstream, they are free to live normal lives. Today, the life expectancy for a person with hemophilia is only about ten years less than for those without it (1).

If you winced at the thought of regularly injecting yourself with a clotting factor, you are right. Living with hemophilia means a lifetime of injections, which need to be done every two or three days. That is pain point one.

Pain point two is the cost of blood clotting factors.

In the United States, the yearly cost of factor injections for a person with hemophilia is USD $700,000 (2). In Europe, the yearly factor cost per patient is EUR $200,000 (3). Luckily, the costs are absorbed by insurers and government agencies.

Even though the total number of people living with hemophilia is relatively small, its financial burden on society measures in billions of dollars. Pharmaceutical companies, on the other hand, view the disease funding as a juicy pie that could provide good return on investments.

Genetics of Hemophilia

I could not figure out how to talk about hemophilia gene therapy without first looking into the genetics of the condition. So here it is.

Hemophilia A is the most common form of the disease. It occurs in about 1 of every 5000 male births. Hemophilia A results from a mutation in a gene called F8, which is responsible for production of blood clotting Factor VIII.

Hemophilia B is the second most common form of hemophilia. Its frequency is lower, approximately 1 in 20,000 male births. A gene involved is F9. This gene produces another blood clotting factor, Factor IX.

Genetics of Hemophilia

Both blood clotting factors are proteins that float freely in the bloodstream. When a blood vessel is damaged, the clotting factors participate in a blood coagulation cascade that leads to clot formation. 

If you noticed, hemophilia affects mostly men. That’s because genes F8 and F9 are located on the X chromosome. Human females have two copies of the X chromosomes, while males have an X chromosome and a Y chromosome. When a woman inherits an X chromosome with a faulty hemophilia gene, she has a backup copy on another X chromosome. The amount of clotting factor produced by a gene on the second chromosome is sufficient to prevent hemophilia. When a man inherits an X chromosome with an F8 or F9 mutation, he is out of luck (4, 5).

Technology of Hemophilia Gene Therapy

The vector of choice in hemophilia gene therapy is adeno-associated virus, or AAV.

AAV can deliver its genetic payload to non-dividing cells, like hepatocytes. AAV DNA settles in the cell nucleus and remains there for years, providing a blueprint for production of a missing blood clotting factor.

The safety profile of AAV is solid. The virus does not cause disease. Its recombinant form does not integrate into the human genome, meaning there is no risk of activating a cancer gene. 

Technology of Hemophilia Gene Therapy

On the flip side, most people have been exposed to a wild type AAV strain. Natural immunity against AAV is common. It reduces efficiency of gene therapy and is listed among patient exclusion criteria in clinical trials (6, 7). 

In recombinant AAV used for gene therapy the viral genes are replaced with either F8 or F9 gene. 

A problem for Hemophilia A gene therapy is that the F8 gene is about 7,000 nucleotides long, while AAV vector DNA packaging capacity is 4,800 nucleotides. Luckily, Factor VIII protein has a component, called B-domain, that is not required for blood clotting activity. F8-BDD, a truncated gene version with B-domain deletion, fits into AAV vector and provides therapeutic benefit to Hemophilia A patients (8).

The F9 gene used in Hemophilia B gene therapy also has a genetic trick. There is a naturally occuring mutation of F9 that leads to an 8-fold increase of the activity of FIX protein. The mutated protein is called FIX-R338L-Padua. R338L stands for amino acid substitution, and Padua is a University in Italy where the mutated gene was discovered (9, 10).

Hyperactive Factor IX Padua allows the use of a vector dose that reduces risks of adverse effects while maximizing therapeutic benefits.

The Frontrunners

The leader in Hemophilia A gene therapy race is BMN 270, or Valrox, developed by BioMarin.

Valrox is an adeno-associated virus packaged with the F8-BDD gene. In Phase 1/2 clinical trials patients treated with Valrox reached median blood Factor VIII levels of 77 IU per deciliter (11). A range of Factor VIII activity observed in healthy individuals is 50 – 150 IU per deciliter.

BioMarin’s Biologics Licence Application for Valrox has been accepted by the FDA. The application review should be completed by August 21, 2020 (12).

Two other Hemophilia A treatments that are gaining momentum are SPK-8011 from Spark Therapeutics and SB-525 from Pfizer. Both therapies did well in Phase 1/2 trials and are moving into Phase 3 (13, 14).

My bet on Hemophilia B gene therapy goes to AMT-061 from uniQure. AMT-061 is an AAV with Factor IX Padua variant. It entered Phase 3 clinical trials at the end of 2018. A unique feature of this therapy is that it works in patients with preexisting antibodies to AAV, meaning that it may be available to the entire Hemophilia B population (15).

The Concerns

Hemophilia gene therapy is past its proof of concept stage. Multiple Phase 2 clinical trials show that it is working. But as with any new technology, there are challenges (8, 16):

  • The therapy is not suitable for children. AAV is a non-integrating vector. Its DNA settles in the cell nucleus as an independent piece of genetic material. When cells divide, as it happens in young livers, the AAV genetic material gets diluted, reducing the therapeutic effect
  • Most of the human population have been exposed to wild type strain of AAV. 25% of hemophilia patients could be ineligible for gene therapy because they have antibodies that destroy AAV particles
  • A common side effect of AAV vector injection is liver inflammation. Luckily it responds to steroid treatment
  • The expectation is that the effects of gene therapy would last a lifetime. But we only have data from up to six years of observation

Cost of Hemophilia Gene Therapy

In January 2020 there was first news about pricing of hemophilia gene therapy. BioMarin’s Chief Executive Jean-Jacques Bienaimé said that Valrox would cost between $2 million and $3 million US dollars (17).

The shocking price is justified. When considering the current yearly cost of factor injections, Valrox will pay for itself after four years. Most likely it will reduce lifetime cost of care several fold.

Zogensma and Luxturna, two other gene therapies on the US market, have similar price tags. The payers understand why gene therapy is expensive, and are ready to embrace the benefits.

For the patients no price is too high. Living without regular injections and without risk of bleeding is priceless.

References

  1. Hemophilia News Today. Hemophilia Prognosis and Life Expectancy
  2. Haemophilia. Croteau et al. Regional variation and cost implications of prescribed extended half-life factor concentrates among U.S. Haemophilia Treatment Centres for patients with moderate and severe haemophilia
  3. Orphanet Journal of Rare Diseases. O’Hara et al. The cost of severe haemophilia in Europe: the CHESS study 
  4. NIH Genetics Home Reference. Hemophilia 
  5. Centers for Disease Control and Prevention. Hemophilia 
  6. BioDrugs. Gene Therapy for Hemophilia: Progress to Date 
  7. ClinicalTrials.gov. NCT03370913 
  8. Human Molecular Genetics. Advances and challenges for hemophilia gene therapy 
  9. The New England Journal of Medicine. Hemophilia B Gene Therapy with a High-Specific-Activity Factor IX Variant 
  10. Molecular Therapy. Hyperactive Factor IX Padua: A Game-Changer for Hemophilia Gene Therapy 
  11. The New England Journal of Medicine. AAV5–Factor VIII Gene Transfer in Severe Hemophilia A 
  12. Hemophilia News Today. Valrox, Potential Hemophilia A Gene Therapy, May Cost Up to $3 Million, BioMarin Says 
  13. Hemophilia News Today. SPK-8011 
  14. Hemophilia News Today. SB-525 for Hemophilia A 
  15. uniQure. uniQure has built a potential first- and best-in-class hemophilia gene therapy program 
  16. Haematologica. Hemophilia therapy: the future has begun 
  17. The Wall Street Journal. BioMarin Explores Pricing Experimental Gene Therapy at $2 Million to $3 Million