Recombinant

The Age of Gene Therapy: Why Plasma?

Laurie Kelley December 4, 2022

It’s happened: gene therapy is available, at least for hemophilia B patients in the US. The idea that hemophilia can be treated as a “cure,” or at least using one shot to cover your bleeding episodes for at least a few years, is tantalizing. And if not that, we still have recombinant products that have never touched human blood.

We just updated our factor chart here, which compares all the products available on the market for hemophilia A and B. You have lots of treatments to consider! But why are we still making plasma-derived products?

A few reasons. But first, understand where plasma-derived products come from.

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.

Why would anyone intentionally choose a plasma-derived product instead of recombinant? After all, recombinant factor is the product recommended by NHF’s MASAC. And now we have gene therapy for hemophilia B. Why inject anything other than the missing factor into your child?

For some people, it’s all about cost. Plasma-derived factor is less expensive than recombinant factor. And gene therapy is expected to cost about $3.5 million per shot. 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 therapy, always discuss options with your HTC! Use our factor product guide here, which now includes bispecific antibody products and gene therapy, and bring it with you, and ask what’s best for your loved one or you.

Factor Products: Gen H… for Hemophilia

Laurie Kelley May 16, 2021

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

Laurie Kelley May 9, 2021

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.

Types of Factor Concentrate

Laurie Kelley May 2, 2021

Last week we shared new about Sevenfact, a commercial blood clotting recombinant product made from transgenic rabbits. But that made me think: maybe we should step back and review what types of factor products there are to begin with.

There are different kinds of factor concentrates, all with distinct brand names and made by different companies, but all blood-clotting factor concentrates are classified as one of two types:

• Plasma derived • Recombinant

The major difference between the two types is the origin of the factor, called the source material.

• Plasma-derived factor originates from human blood plasma.

Recombinant factor originates from genetically engineered mammalian cells containing the human gene for factor (not from human blood).

You might think that recombinant products have an advantage because they don’t come from human blood, but some still contain extraneous (unwanted) proteins—human and even animal. To understand the differences among products, you first need to know how various factor products are manufactured.

Plasma-derived factor concentrates are categorized by their degree of purity. Recombinant factor concentrates are categorized by how they are produced. Different—although very similar—manufacturing processes can create products with slight molecular differences in the factor protein and with varying degrees of extraneous proteins in the final product. Here are classifications of factor products, based on varying degrees of purity or differing manufacturing processes:

Plasma derived

• intermediate purity • high purity • ultrapure (monoclonal)

Recombinant

• first generation • second generation • third generation • fourth generation

Several recombinant factor products also have a prolonged half-life, allowing you to infuse less frequently. The first of these new products was introduced in 2014.

Why are there so many kinds of manufacturing processes? Why not just use one method to produce factor? In some cases, it’s partly a legal matter: if manufacturer A creates an effective way to produce factor, then A usually patents the process. No one else can use it. Manufacturer B will need to find another way! So manufacturers have developed a variety of slightly differing processes to produce factor.

It’s also a matter of purity and safety. Different products use differing source material and require specific types of manufacturing methods to ensure safety. Due to varying production methods and the type of factor, the relative purity of the final products varies. Purity and safety are two terms you must understand to know which brand of factor to choose, because not all factor concentrates are created equal.

Do you know the difference between purity and safety? It’s easy to confuse them. We’ll review them next week!

Excerpted from Raising a Child with Hemophilia, Laureen A. Kelley 2016

Plasma Showdown!

Laurie Kelley June 8, 2009

I was lucky enough to be a speaker at the North Carolina Hemophilia Foundation event last weekend, and on my favorite subject–hemophilia in the developing world. This was a jam-packed event with an all star list: Ray Stanhope of the NHF; Mike Rosenthal of the WFH; Carl Weixler of HFA, Richard Atwood, president of NCH. Richard writes a column for my newsletter called “Richard’s Review” and I think is the foremost authority on any book or movie ever released in history that might even mention the word hemophilia! It was great to see everyone at the event.

But the best presentation was the “showdown” between famed Dr. Harold Roberts and the ever-delightful Dr. Albert Farrugia of the PPTA, who speaks with a lovely Maltese accent. Both men are brilliant and excellent speakers. Dr. Roberts is decidedly pro-recombinant factor, and Dr. Farrugia strongly makes a case for plasma-derived, and with lots of wit and fun, they sparred about their topics, until Dr. Roberts said good-naturedly, “Why don’t you go back to Australia?” The audience roared with laughter; they were educated and entertained!

Seriously, this is a fascinating topic–plasma-derived vs. recombinant–and one we will explore in PEN in August. Be sure to sign up for a copy!

Thanks to Sue Cowell, executive director of NCH, for inviting me to such a great event.

Book I Just Read: Pete Duel: A Biography

This book reveals the darker side of celebrity, in the story of a 1970s TV star, best known for his role as Hannibal Heyes in the TV series Alias Smith and Jones. The show was a spin off of the 1969 Best Picture nominee Butch Cassidy and the Sundance Kid, starring Paul Newman (who is beloved to the hemophilia community for his Hole in the Wall Gang camps). Duel was a talented rising star, but battled epilepsy and alcoholism, but more than likely something undiagnosed, like manic depression. Like his name, he exhibited a personality described alternatively as sweet and loving, kind and generous, then venomous and raging. He hated the TV show that made him famous, and hated TV in general. He committed suicide at age 31 in December 1971 while in an alcoholic stupor. The book tries to detail his life, but comes across as flat, unsympathetic and groping for answers, which don’t materialize. The book seems more a tribute to Duel with heavy input by Duel’s sister, but it’s depressing overall. Duel simply did not accomplish that much in his young life, compared to others who died young, like James Dean or Jim Morrison. One star.