ROCTAVIAN: BIOMARIN’S FIRST GENE THERAPY FOR HEMOPHILIA A MAKES HEADWAY

1 out of every 5,000 males is born with Hemophilia A. Every year, around 400 babies are born with this inherited bleeding disorder.

People with hemophilia A have a mutation in the gene responsible for producing factor VIII, a protein that stops bleeding by helping the blood form clots.

BioMarin’s new gene therapy for hemophilia A, Roctavian, delivers a functional factor VIII gene to the body to help it produce the clotting factor by itself. Consequently, patients with severe hemophilia A will no longer need continuous infusions to prevent future bleeding episodes.   

Two years after its rejection, this novel hemophilia A gene therapy received conditional authorization from European drug regulators. BioMarin expects the FDA’s decision on its hemophilia A gene therapy Roctavian in early 2023.   

Read on to learn more about the new hemophilia A gene therapy in 2022 Roctavian, how it works, the evidence supporting it, and its approval status.  

What Is Hemophilia?

Hemophilia is a rare bleeding disorder in which the blood doesn’t clot normally. In most cases, hemophilia is inherited, passed on through the genes, and mainly affects only men.

When a person’s blood doesn’t clot properly, they can bleed extensively from a cut or a wound (external bleeding) or on the inside of the body (internal bleeding).

Hemophilia affects men almost always. However, in rare cases, women can develop hemophilia after childbirth or during the late stages of pregnancy. 

Hemophilia can lead to the following complications:

• Bleeding in the muscles and joints of the hips, knees, and other joints. Bleeding in the joints can cause pain and chronic joint disease.
• Bleeding in the brain, also known as brain hemorrhage or a brain bleed. That can lead to dangerous health complications such as paralysis and seizures.
• Death can occur if the bleeding could not be stopped or if it occurs in vital organs such as the brain.   

The two types of inherited hemophilia are:

• Hemophilia A: The most common type of this inherited bleeding disorder is Hemophilia type A, also known as classic hemophilia. It results from a deficiency in an essential protein that helps the blood clot, called factor VIII.  
• Hemophilia B: Also called Christmas disease, Hemophilia type B results from a deficiency in another protein that helps the blood clot, called factor IX.

Common hemophilia signs and symptoms include:

• Pooling of blood under the skin (hematomas) that would appear like unexplained skin bruises
• Swelling, pain, and discomfort in the joints, especially the knees, elbows, and ankles
• Excessive bleeding after a cut, a wound, or receiving a shot (such as vaccination)
• Bleeding in the mouth and gums and excessive bleeding after losing a tooth
• Bloody urine or stool
• Frequent nosebleeds that are hard to stop

What Causes Hemophilia A?

Hemophilia A is the result of a mutation in the clotting factor VIII gene.

Inherited hemophilia happens because of mutations (changes) in the genes of clotting factor proteins. 

When you’re bleeding, the clotting factor proteins in your body form clots to stop the bleeding. If there’s a mutation in the genes responsible for making these proteins, the coagulation factors that control the bleeding either aren’t produced or don’t work well.      

This deficiency in clotting factor proteins causes the inherited hemophilia bleeding disorder.

In the case of hemophilia type A, the mutation happens in the gene of coagulation factor VIII.

How Is Hemophilia Usually Treated?

The available hemophilia A treatments replace the deficient blood clotting factors to restore the body’s ability to form clots and stop bleeding. That is called factor replacement therapy.

The treatments for hemophilia A involve injecting (infusing) hemophilia patients with coagulation factor concentrates. These concentrates are prepared at a lab to compensate for the deficiency in clotting factors in patients. 

Patients with hemophilia A receive concentrated factor VIII protein infusions into their bloodstream.  

People with mild hemophilia A only need to receive infusions before surgery or after an injury to replace the missing clotting factors and help their blood clot.

People with severe hemophilia A need to perform these infusions regularly as a prophylactic measure to prevent bleeding episodes. 

These infusions provide a short-term solution for the lack of efficient coagulation factors. Nonetheless, they do not correct the root of the problem, which is the mutation in the genes of these factors.   

What Is Hemophilia A Gene Therapy?

Hemophilia A gene therapy is a novel medical approach that treats the bleeding disorder by fixing the underlying genetic problem which causes this disease. It delivers the missing genes to the body via a gene therapy product. 

Roctavian (valoctocogene roxaparvovec) is a new first-of-its-kind gene therapy for hemophilia type A developed by BioMarin pharmaceuticals.

This new therapy is for adults with severe hemophilia A who don’t have factor VIII inhibitors or adeno-associated virus serotype 5 (AAV5) antibodies, both of which can decrease the drug’s effectiveness. 

How Does Roctavian Hemophilia A Gene Therapy Work?

In BioMarin’s new hemophilia A therapy, the gene therapy product is valoctocogene roxaparvovec, the active ingredient of Roctavian. 

Valoctocogene roxaparvovec is a modified adeno-associated virus serotype 5 (AAV 5). This virus contains the gene of the missing clotting factor VIII and is modified to safely enter the human body without causing disease or illness. 

Once injected, the viral vector delivers the coagulation factor VIII gene to the liver cells allowing them to produce the missing factor VIII. Consequently, the body can produce sufficient clotting factor protein, which reduces or prevents bleeding episodes.    

What’s The Difference Between Roctavian And Other Hemophilia A Treatments?

During the traditional hemophilia type A treatments, clotting factor VIII protein is injected, which doesn’t last for very long periods. Therefore, patients would require making multiple lifelong infusions of factor VIII concentrates.

Alternatively, the new hemophilia A gene therapy delivers the gene of coagulation factor VIII instead of the protein, which allows the body to produce the missing clotting factor by itself.

Consequently, a single infusion of Roctavian can last a person longer than an infusion of factor VIII protein concentrate.

Clinical studies supporting Roctavian

During a phase-3 study, researchers evaluated the safety and efficacy of Roctavian gene therapy in 134 adult males with severe hemophilia A.

A single infusion of valoctocogene roxaparvovec decreased bleeding in hemophilia type A patients by 83.8% after four weeks.

Moreover, the patients’ need for factor VIII concentrate infusions decreased by 98.6%. That indicates that the livers of patients with hemophilia A could produce clotting factor VIII after Roctavian treatment.

This effect lasted for at least two years in almost all the patients.

Therefore, a Roctavian (valoctocogene roxaparvovec) treatment can significantly reduce bleeding and prevent future bleeding episodes in hemophilia A patients for a prolonged time.

Side Effects Of Roctavian

85.8% of patients had elevated alanine aminotransferase levels (a liver enzyme) after treatment with Roctavian. That was the most common side effect of hemophilia A gene therapy. 

The increase in this liver enzyme indicates hepatotoxicity (liver damage). However, this condition was successfully treated by immunosuppressants such as corticosteroids.

Other side effects of Roctavian included:

• Headaches (in 38.1% of patients)
• Nausea (in 37.3% of patients)
• An increase in aspartate aminotransferase (another liver enzyme) levels (in 35.1% of patients)

The Approval Status Of Roctavian

In 2022, the European Medicines Agency (EMA) granted Roctavian conditional marketing authorization in the European Union. Making BioMarin’s Roctavian the first gene therapy for treating adults with severe hemophilia A approved in European countries.  

This approval came after the European drug regulators found that the benefits of Roctavian (valoctocogene roxaparvovec) outweighed its possible risks in hemophilia A patients.

In October 2022, the Food and Drug Administration (FDA) accepted BioMarin’s Biologics License Application (BLA) for Roctavian (valoctocogene roxaparvovec). The drug is a new investigational AAV gene therapy for adults with severe hemophilia A.   

The drug makers expect the FDA’s decision regarding Roctavian by March 2023. Gaining FDA approval would make Roctavian the first gene therapy for treating adults with severe hemophilia A in the US.

These approvals come as positive progress in the journey of BioMarin’s hemophilia type A gene therapy which was turned down by the FDA and the EMA back in 2020 for lack of sufficient data.

Despite Roctavian’s recent progress, patients treated with this new hemophilia gene therapy will be monitored for the next 15 years to determine the long-term efficacy and safety of the drug. 

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Sources:

• Gene Therapy For Hemophilia A
• Gene Therapy for Hemophilia: The Clot Thickens - PMC 
• First gene therapy to treat severe hemophilia A | European Medicines Agency
• Valoctocogene Roxaparvovec Gene Therapy for Hemophilia A
• Gene therapy for hemophilia: what does the future hold? - PMC 

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