Hemgenix, is this time to revolutionize Hemophilia treatment?

By: Dr.Farhat Naz

FDA approves the most expensive drug HEMGENIX for Hemophilia B on 22nd November, 2022, what is hemophilia, types, symptoms, risks, treatments, life threatening risks and future.

What is Hemophilia?

Hemophilia is a genetic disease where a patient’s blood delays or fails to clot due to absence or deficiency of specific clotting factors, causing a risk of life threatening hemorrhage.

How Hemophilia is caused?

Hemophilia is caused by a mutation/change in one of the genes that directs the production of clotting factor proteins (factors VIII & IX) needed to form blood clots. This change prevents proper functiong of these proteins or they may be absent at all.

Where the genes for clotting factors VIII and IX are located and why hemophilia mostly affects males?

These genes are located on the X chromosome, with males having one X and one Y chromosome (XY) and females having two X chromosomes (XX).

Males inherit an X chromosome from mother and a Y chromosome from their father.

A female inherits her one X chromosome from each parent.This means that males only have one copy of most of the genes on the X chromosome, whereas females have 2 copies.

Thus, males can have a disease like hemophilia if they inherit an affected X chromosome that has a mutation in either the factor VIII or factor IX gene.

Can females get Hemophilia?

Females can also have hemophilia, but this is much rarer. In such cases both X chromosomes are affected or one is affected and the other is missing.

Why hemophilia is life threatening?

Hemophilia can result in:

Bleeding within joints leading to chronic pain and stiffness.

Bleeding inside brain causing stroke.

Death may occur if bleeding cannot be stopped or involve vital organs like brain.

What are the types of hemophilia?

There are several different types of hemophilia. The following two are the most common:

Hemophilia A (Classic Hemophilia)

clotting factor VIII deficiency

Hemophilia B (Christmas Disease):

clotting factor IX deficiency

How common is hemophilia?

According to US data hemophilia A affects about 1/5000 male births. Hemophilia A is about four time more common than hemophilia B.

What are bleeding symptoms of hemophilia?

Bleeding from mouth, gums, after brushing or tooth extraction, bleeding under skin, bleeding in urine and stool, inside the joints causing chronic pain and stiffness, bleeding after circumcision, frequent nose bleeds and sometimes life threatening bleeding inside the brain.

How hemophilia is diagnosed?

Most people with hemophilia are diagnosed at very young age. Patients with severe hemophilia are diagnosed in first year of life, while babies with mild deficiency are also diagnosed in first 36 months of life.

In suspected patients clotting factors VIII and IX essay are performed to confirm the type and severity of disease.

How hemophilia is treated?

Hemophilia is treated by replacing the deficient clotting factors through infusion of either factor VIII or factor IX concentrates. The following preperations are available:

Plasma derived clotting factors: Plasma is liquid yellow color portion of blood which contains many clotting factors and proteins, Human plasma is collected from many people and clotting factors are separated, tested for viruses, dried and packaged for commercial use.

Recombinant clotting factors: These are commercially prepared genetically engineered factor VIII and IX concerntrates, which are free of albumin and other proteins found in plasma, so there are lesser chances of transmission of blood borne viruses.

In patients with moderate to severe deficiency prophylaxis with clotting factors is given to avoid life threatening bleeds, which causes high cost to healthcare.

Other treatment options include:

Hemlibra (also known as ACE 910 or emicizumab): This drug acts like factor VIII to control bleeding but does not replace deficient clotting factors.

DDAVP or Stimate (Desmopressin Acetate): This is synthetic preparation similar to natural hormone vasopressin. It causes release of patient’s own factor VIII and used for mild to moderate disease.

Amicar (Epsilon Amino Caproic Acid): This drug strengthen the formed clot and prevents the clot from dissolving.

Cryoprecipitate: This is clotting factor rich concentrate derived from plasma and used to treat major bleeding episodes but not used as a part of routine treament,

What are inhibitors and how they cause a challenge in Hemophilia management?

Inhibitor is immune response to infused clotting factor concentrates, due to which standard treatment with clotting factor concentrates becomes ineffective. About 30-50% patients with Hemophilia A and 1-4% patients with Hemophilia B develop inhibitor which is a real management challenge. In patients developing inhibitor the cost of treatment is much increased.

What is cost of hemophilia treatment?

Lifetime treatment cost of treating moderate to severe hemophilia is very high estimated millions of dollars. Most of the patients with moderate to severe hemophilia need prophylaxis with plasma derived or recombinant clotting factors on weekly basis. The cost of treatment is much higher is patients with inhibitors.

What is gene therapy for hemophilia?

Gene therapy is the treatment which causes genetic modification of cells through repairing or reconstitution the defective gene.

What is Hemgenix?

Hemgenix is new drug approved by FDA for treatment of hemophilia B given through one time intravenous infusion.

How Hemgenix will treat hemophilia?

Hemgenix is drug based on gene therapy. This drug is carried to blood through viral based factors and inside the liver where it delivers DNA to target cells and this information is replicated in target cells instructing them to form target protein (factor IX)

What is the cost of Hemgenix? Hemgenix is marketed as one of the most expensive drug ever and price of one injection is 3.5 million USD.

What is future of Hemgenix?

The drug is found promising in two clinical trials and caused sustained increase in factor IX level by 50%, much reducing the need for clotting concentrates and blood. Developers claim that cost of drug is far more less than the lifetime cost of treating Hemophilia through transfusions and clotting factors.

It is expected to be a promising drug in treatment of hemophilia and with advancement of research it is hoped that gene therapy will be available for Hemophilia A as well.

Is gene therapy approved for Hemophilia A?

Roctavian is the first recommended gene therapy for severe Hemophilia A, approved by European Medicines Agency (EMA) in June 2022, for adults who do not have factor VIII inhibitors and have no detectable antibodies to adeno-associated virus serotypes.

No gene therapy for hemophilia A is approved by FDA till date. The gene therapy for hemophilia was found promising in initial stages of clinical trials but the level of factor VIII synthesis started declining after one year with persistent fall in subsequent years. This fall in factor VIII was due to immune response to viral vectors.

New clinical trials with novel recombinant gene therapy are underway and it is hoped that soon gene therapy will be available for hemophilia A. 

Will gene therapy eliminate the inhibitor?

Adeno associated vius (AAV) vector liver directed gene therapy, in hemophilia animal models induces immune tolerance to factor VIII and factor IX through factor specific regulatory T cells,which is a strong evidence that gene therapy can eliminate inhibitors through immune tolerance.

 In summary, hemophilia is a serious genetic disorder with high social and economic implications. Gene therapy has the potential to cure the disease and revolutionize the treatment of this disorder. One of the most important concern is cost of treatment which will overcome with advancement in technology. So, apparently the approval of gene therapy is the beginning of new era not only for treatment of hemophilia but many other debilitating non-curable genetic diseases.

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