Hemophilia Gene Therapy wins Conditional Approval

Part 1

Paul Clement

It has been almost 30 years since the New York Times in 1994 ran the headline “Cure for Hemophilia Is Seen by Year 2000,” regarding a prediction by the World Health Organization. But the first approval of a gene therapy for hemophilia has finally arrived!

In June, the European Medicines Agency (EMA), the European equivalent of the US Food and Drug Administration (FDA), recommended granting a conditional approval to BioMarin’s ROCTAVIANTM, the brand name of its gene therapy product, valoctocogene roxaparvovec, to treat patients with severe hemophilia A.1 On August 24, 2022, the European Commission (the EC is the executive arm of the European Union or EU) granted conditional marketing authorization to Roctavian. The EC also endorsed EMA’s recommendation for Roctavian to maintain orphan drug designation, thereby granting a 10-year period of market exclusivity, and the EC is further requiring patients treated with Roctavian to be monitored for 15 years, to ensure the long-term efficacy and safety of this gene therapy.

How does it work?

Roctavian is a single injection of trillions of copies of an adeno-associated virus (AAV) which have had their genetic material removed and replaced by a good copy of the gene for factor VIII. Once the AAV has had its genetic material removed, it can no longer replicate itself and it does not cause disease—it is now merely a transport vehicle called a “vector,” designed to get good copies of the factor VIII gene into liver cells where the liver can then produce functional factor VIII. There a many different varieties of AAV, which are given numbers to distinguish one variety from another. Roctavian uses AAV5 as a vector, which has a relatively low (4% to 50%) incidence of natural immunity (antibodies) against the vector. Roctavian does not become part of the individuals DNA and it cannot be passed on to children.

Who is eligible?

  • Only adults (18 years or older) with severe hemophilia A (factor VIII deficiency) are eligible. (In children, the liver is rapidly increasing in size as the child grows, which would dilute the effect of the gene therapy).
  • Only individuals who do not have factor VIII inhibitors.
  • Only individuals without detectable antibodies to the vector, AAV5. The incidence of antibodies to AAV5 can vary widely, from 4% to 50%, and varies with geographic region and increases with age. (Unless the individual is immuno-suppressed, antibodies will neutralize the gene therapy treatment, rendering it ineffective.) BioMarin is running a Phase 1/2 trial, called 270-203 ( #NCT03520712), evaluating a single dose of Roctavian in about 10 men with severe hemophilia A who carry pre-existing antibodies against the AAV5 viral vector.
  • Only individuals who do not have liver disease. (This will likely eliminate many older people with hemophilia who were infected with hepatitis C through contaminated factor products in the 1970s and early 1980s.)

Are there risks involved?

  • Roctavian can cause transient inflammation of the liver, which can trigger the immune system to destroy liver cells which have the new factor VIII gene and are producing functional factor VIII. Obviously, this is not good, as it may potentially neutralize the gene therapy treatment or reduce its efficacy. This immune response can be tamped by using a corticosteroid in combination with the Roctavian infusion. BioMarin has recently completed a clinical trial, called “GENEr8-3,” of this combination treatment ( # NCT04323098), with results expected in early 2023.
  • A person’s response to Roctavian can vary widely. For many, Roctavian will not be a “cure,” but will convert a person’s severe hemophilia to mild hemophilia (factor levels between 6% and 40%).
  • In clinical trials, the efficacy of Roctavian has decreased over time. This could potentially render the treatment ineffective after several years. And because the body produces antibodies against the vector after treatment, this will likely prevent the individual from receiving another gene therapy treatment using the same vector.

The very high cost of Roctavian will present challenges to its uptake, and it will also face severe competition with Hemlibra, a bispecific antibody that mimics the function of factor VIII and can be injected under the skin as infrequently as once a month. However, according to a report by the newsletter Fierce Pharma, recent market research showed that healthcare professionals in EU estimated Roctavian could capture 35% of eligible patients, in line with BioMarin’s own projection. Plus, about 80% of surveyed doctors in both EU and the U.S. expect to treat at least one patient with Roctavian within 12 months of an approval.2

In the second of this two-part series, we will look at the timeline for approval of Roctavian in the US and what it might cost.

  1. BioMarin is a California-based biopharmaceutical company, known as BioMarin Pharmaceutical Inc. in the US and BioMarin International Limited in Europe.

Texts That Protect

If something big were happening, you’d want to know about it right away, especially if it concerned the factor you or your loved one uses. The Patient Notification System (PNS) is a free service that will notify you about any withdrawals, recalls or warnings concerning your specific product, and even ancillaries. Are you signed up with it?

Launched in 1998 by the Plasma Protein Therapeutics Association (PPTA), a group that is supported by manufacturers of plasma-based products and recombinant products, this system has diligently sent out hard copy, telephone and email notices of any changes in your prescription drugs.

There was a time in the early 2000s when these were frequent, as there were shortages, plant shut-downs, recalls, products taken off line, and more. You can imagine that the specter of the mass HIV infections in the blood supply in the 1980s led to this unique and vital service.

There’s good news now: stringent manufacturing practices, better donor screening and genetically-engineered products means that notices of safety concerns are almost a thing of the past.

Are you signed up? You should be. It’s free, confidential, and now fast! Just recently, the PNS added notifications by text, probably the fastest route these days.  You will want to be up to date on any changes in the product you use.

Sign up for the PNS at or call 888-UPDATE-U.

Factor Products: How Factor is Made?

Safety and purity are considered along every step of the factor manufacturing process. For most factor concentrates, the manufacturing process has four basic steps:

1. Sourcing factor

2. Viral removal and inactivation

3. Purification

4. Final formulation

Sourcing Factor

Plasma-derived products come from human blood plasma. Plasma donors undergo strict screening for disease risk factors, and their plasma is tested for several viral diseases. Recombinant products are not derived from blood; they originate from genetically engineered mammalian cells containing the human gene for factor. Recombinants are produced in large bioreactors, with human and animal proteins used in the culture medium in first- and second-generation recombinant factor. Third-generation products contain no human or animal proteins in the culture medium or the final product. Fourth-generation products are made from human cell lines.

Although plasma-derived products potentially risk transmitting blood-borne viruses, all US factor products, whether plasma derived or recombinant, are considered safe by the FDA. (See last week’s blog on purity vs safety to learn more)

Viral Removal and Inactivation

These methods remove or inactivate most blood-borne viruses including HIV, hepatitis A, hepatitis B, and West Nile virus, making them noninfectious. But no viral inactivation method used on factor concentrate can inactivate all viruses. The two most common viral inactivation methods are heat treatment (pasteurization) and chemical

inactivation. Heat treatment involves exposing the factor to a high temperature for 30 minutes to 72 hours, depending on the method.

Chemical inactivation involves mixing the liquid factor in a tank with a solvent-detergent (SD) wash for four to six hours. SD viral inactivation is very effective against certain types of viruses, such as HIV and hepatitis B and C, but is ineffective against hepatitis A and some other viruses. Viruses are also removed by the purification process, especially

immunoaffinity (monoclonal) purification. Viruses can also be filtered from factor IX through a process called nanofiltration.

All plasma-derived products use one or more viral inactivation processes, and so do some recombinant products. Yet other recombinant products use no viral inactivation process. Why? The risk of viral contamination is only theoretical, because the product is not exposed to blood plasma.


This step separates the desired factor from unwanted viruses, proteins, and other foreign substances, to get the purest product containing only the factor you need. For example, when plasma is processed to make factor VIII concentrate, the serum may also contain von Willebrand factor (VWF), factor I, and other proteins. The higher the listed purity of a product, the fewer the unwanted proteins.

Monoclonal products have a higher purity than intermediate products. Recombinant concentrates have the highest purity of all products.

Final Formulation

Even if the viral inactivation and purification processes create a safe and highly pure product, the final formulation—the way a product is packaged and prepared for market—may alter it. In this final step, other components may be added into the concentrate. For example, albumin is added into the final formulation in the last manufacturing steps of first-generation recombinant products. Albumin helps to stabilize and bulk up the product.7 In second-generation recombinant factor, sugar is added in place of albumin at the final formulation step to stabilize the product. In third-generation products, sugar is added to stabilize the final product, and no human blood component or animal proteins are used in the culture medium.

Why would anyone intentionally choose a plasma-derived product instead of recombinant? After all, recombinant factor is the product recommended by NHF’s MASAC. Why choose an intermediate product and not an ultrapure one? Why inject anything other than the missing factor into your child?

For some people, it’s all about cost. Plasma-derived factor, especially intermediate purity, is less expensive than recombinant factor. People who have high out-of-pocket expenses need safe products, but may choose less expensive ones. Sometimes, the decision depends on the type of bleeding disorder being treated. For example, intermediate purity factor VIII products contain factor VIII combined with VWF (the way it’s naturally found in the blood) and are useful in treating von Willebrand disease.

When choosing your factor, always discuss options with your HTC! Use our factor product guide here, bring it with you, and ask what’s best for your loved one or you.

Factor Products: Gen H… for Hemophilia

Do you use a recombinant factor product? Do you know how it’s made?

Recombinant products are not produced from human blood plasma. They are produced in large stainless steel tanks, called bioreactors, which contain trillions of cells. Into each of these cells, a gene for human factor has been inserted, or “recombined”—the origin of the name recombinant. These genes produce human factor and release it into the culture medium—a nutritious liquid that keeps the animal (or host) cells alive and growing. Although the source material is not blood, some recombinant products contain extraneous human or animal proteins introduced during the production process or added to the final product.

To distinguish between the various production processes, recombinant products are classified according to generation. Generation refers not only to when the products were first developed and commercially available, but also to the presence of animal or human proteins used in the production process or the final product.

First-generation recombinant products, introduced in 1992, use human or animal proteins in the growth medium. These products also contain human albumin added at the final production stage to help stabilize and bulk up the product.

Second-generation recombinant products contain no human albumin added to the final product, but do use human or animal proteins in the growth medium.

Third-generation recombinant products, first available in 2003, contain no human or animal proteins in the growth medium or added to the final product. They have the lowest risk of transmitting viruses.

And while MASAC (NHF’s Medical and Scientific Committee) has not yet confirmed the nomenclature of fourth generation, Octapharma and Sanofi Genzyme each created a recombinant factor product that is created from a human cell line, not animal. The two companies are calling their products, Nuwiq® (Octapharma) and Eloctate (Sanofi Genzyme) fourth generation.

If you are using recombinant product, what generation is your factor? Download our Factor Comparison Chart and find out!

Factor Products: Purity vs. Safety

Parents and patients often wonder about the safety of their factor product. Our community suffered terrible losses from contamination of the nation’s blood supply in the 1970s and 80s, so safety is paramount for us. But we often confuse purity and safety when describing factor concentrates. Purity and safety often go hand-in-hand, but in a medical context they have very specific meanings.

Purity: a measure of the presence of other proteins, sometimes including other clotting factors, in addition to the specific factor supplied in the concentrate

Safety: the removal or inactivation of potentially harmful substances, including blood-borne viruses, from factor concentrate

So purity refers to how much of your factor concentrate contains just factor, with no other proteins. Safety refers to reducing the risk of viral transmission.

Purity is measured by specific activity, the ratio of the desired clotting factor protein to the total protein in the concentrate, minus any added albumin (a blood plasma protein).

How is factor purified? That is, how are extraneous proteins removed from factor? By a manufacturing process called chromatography. In simple terms, chromatography involves passing a mixture containing factor through a column (like a glass tube). The column normally contains small beads coated with a substance that attracts the factor and removes it from the mixture. The column is then flushed out to release the factor, resulting in a final mixture that is thousands of times higher in purity and more concentrated than the original mixture.

Please don’t be misled by the term intermediate! These products are still of high purity, although not as high as the ultrapure or monoclonal ones. And note that the various purity levels do not mean there is any less quality control or consistency in manufacturing. Recombinant products are not produced from human blood plasma. They are produced in large stainless steel tanks, called bioreactors, which contain trillions of cells. Into each of these cells, a gene for human factor has been inserted, or “recombined”—the origin of the name recombinant. These genes produce human factor and release it into the culture medium—a nutritious liquid that keeps the

animal (or host) cells alive and growing. Although the source material is not blood, some recombinant products contain extraneous human or animal proteins introduced during the production process or added to the final product.

Next week: What do different generations mean?

Excerpted from Raising a Child with Hemophilia by Laureen A. Kelley.

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