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Potential Hemophilia B Gene Therapy

Hemophilia B: Current and Future State

Hemophilia B is a hereditary and chronic life-threatening disease that results when a person does not have enough clotting factor IX (FIX). People with the condition are particularly vulnerable to bleeds in their muscles, internal organs, and joints, leading to pain, swelling, and joint damage. Hemophilia B affects about 1 in 20,000 people in the United States. Hemophilia B can be mild, moderate, or severe, depending on how much clotting factor is in an affected person’s blood. Approximately two thirds of patients have moderate to severe hemophilia B. Current treatments include on-demand and prophylactic infusions of FIX to temporarily replace or supplement low levels of the blood-clotting factor. Treatment can help prevent life-threatening bleeds and reduce joint bleeding events, which can help preserve joint function.

Infographic: Living Life Between Highs and Lows of Factor IX Replacement

 

Life with Prophylaxis

While prophylaxis treatment has helped improve quality of life for many people with hemophilia B, people must still plan their lives around the highs and lows of their FIX levels, which rise immediately after an infusion but drop over time -- leaving them more vulnerable to bleeds in the days before their next infusion. Prophylactic FIX replacement therapy may at times fail to control unobservable micro-bleeds in the joints, meaning that the degeneration can continue despite regular infusions. Missing an infusion may increase the likelihood of bleeding and joint damage, and in some rare cases, may lead to premature death due to bleeding into the brain.i ii Infusions can be painful and may cause veins to collapse over time. On rare occasions, a person’s immune system may also generate inhibitors against the replacement factor, lessening its benefit.iii

Impact on Work and Lifestyle

Hemophilia B may also have an impact on formal education and employment. Many adults with hemophilia B noted that there was a negative impact on their work or educational pursuits, requiring some to stop working or shift to working part-time because of the demands of managing their disease.iv

Research on Gene Therapy is Under Way

Researchers are currently developing what some hope will be a new form of treatment with potential long-lasting benefits: gene therapy.

Hemophilia B gene therapy is designed to replace the defective or missing FIX gene that causes hemophilia B. Hemophilia B gene therapy is being researched to see if it could be a one-time treatment, providing people with the ability to generate their own levels of FIX sufficient enough to reduce – or even eliminate – the need for external FIX for many years – this would be what doctors would refer to as  a “functional” cure.v

How Gene Therapy Works

Several forms of gene therapy use modified non-disease-causing viruses called “vectors” that can enter certain cells. Vectors act as delivery vehicles, carrying a package of genetic instructions to specific cells. Once delivered, the package acts like a generator that plugs into the cellular machinery, allowing a person to generate their own levels of a missing or defective protein.  

A certain type of vector, called an adeno-associated virus, or AAV, dissolves after delivering its package. The genetic instructions remain, but do not become a part of a person’s own DNA and cannot be passed on to children. Click here to see an infographic about AAV.

There are two AAV-based gene therapies currently approved in the USA and the EU: Zolgensma®, to treat spinal muscular atrophy (SMA); and Luxturna®, to treat retinal disease, which use AAV as a vector.

A gene therapy in Phase III of clinical development, etranacogene dezaparvovec, also known as AMT-061 or EtranaDez, is being studied for potential use in hemophilia B, and carries the Padua gene. It uses a specific type of AAV, called AAV5, as its delivery vehicle.

i Vasquez-Loarte., et al. 2020; Witkop et al., 2015
ii The Coalition for Hemophilia B. https://www.hemob.org/faq
iii Hemophilia B. https://rarediseases.org/rare-diseases/hemophilia-b/
iv Impact of mild to severe hemophilia on education and work by US men, women, and caregivers of children with hemophilia B: The Bridging Hemophilia B Experiences, Results and Opportunities into Solutions (B-HERO-S) study. https://onlinelibrary.wiley.com/doi/pdf/10.1111/ejh.12851
v Delivering on the promise of gene therapy for haemophilia. https://onlinelibrary.wiley.com/doi/full/10.1111/hae.14027