treatment

Prepare for Big Changes

When we use the word “transitions” in hemophilia, we normally think about our child’s life cycle (or our own) and how it impacts healthcare: Children transitioning into adulthood at age 18 need to see an adult hematologist, not a pediatric hematologist. Adults finishing college or trade school need to transition into the workforce. Adults at age 26 need to transition off their parents’ health insurance. We may have joint issues as we age.

But we can also view transitions as something happening to hemophilia treatment, because that has a life cycle too. And right now, hemophilia treatment is undergoing massive, rapid change. New products, novel therapies, and gene therapy…can the US market of roughly 20,000 with hemophilia support all the products? Will insurance cover them all?

A Look Back: Our Infancy

If we accept that hemophilia treatment has a life cycle, let’s look back at its infancy and development. Early treatment for hemophilia involved whole blood transfusion and later, human plasma. Fresh frozen plasma (FFP) allowed treatment to be stored and then thawed when needed. Whole blood and FFP were both only marginally effective at controlling a bleed, due to the low level of factor VIII and large volumes that needed to be infused. Then, in the mid-1960s, came cryoprecipitate: rich in factor VIII, and created from thawed human plasma. Its higher factor VIII level in a smaller volume made administration easier, faster, and more effective.

A breakthrough came with commercial clotting factor concentrate in 1968, made from donated human blood or blood plasma. This new plasma-derived concentrate was freeze-dried and reconstituted with water when needed. Factor in a bottle! Now treatment could be done at home or away, freeing patients to travel and live more normal lives. Infusion time was tremendously shortened, meaning treatment could stop bleeding faster, reducing pain and helping to prevent joint disease. But these early factor concentrates were not treated to inactivate viruses. Tragically, in the late 1970s and early 1980s, contamination of the nation’s blood supply from donors infected with HIV, hepatitis C, and other viruses meant that clotting factor was also contaminated. Thousands of people who had hemophilia and used factor concentrates were infected and died.

In the mid-1980s, a new stage in the life cycle of hemophilia treatment emerged: the creation of factor that was virally inactivated. Viral inactivation processes, such as heat or solvent/detergent wash, could destroy the fragile HIV. Today, all clotting factor is considered safe.

The deaths of so many led to another groundbreaking stage in the life cycle of hemophilia treatment: recombinant clotting factor. Recombinant factor is produced in a lab, using human genes that are inserted into genetically altered mammalian cells. In 1992, the first recombinant factor VIII clotting factor product (Recombinate, manufactured by Baxter) was approved by the FDA. In 1997, the first recombinant factor IX product (BeneFix®, manufactured by Genetics Institute) entered the market. And now? There are now about 20 recombinant factor products on the market to treat hemophilia. We’ve come a long way.

The Family Expands: Crying for Attention

Why so many products? There are some things to know about the factor market. First, the US is the largest market. Not in population—that would be China. But in dollars. Estimates are $4.6 billion annually.1 This lucrative market attracts competitors. But factor products are protected by patents. So to avoid patent infringement, changes or improvements are made to products, making them slightly different. Some of these changes have involved production processes; and the quest to remove unnecessary human and animal proteins gave us “generations” of recombinant factor products.

Now we have three recognized generations of factor products: First-generation products use animal blood proteins in the cell culture medium, and add human albumin, a blood protein, to the final formulation to stabilize the factor. Second-generation products stabilize the factor with sucrose, not albumin. Third-generation products use no added animal or human proteins, either during processing or in the final formulation.2 Today, all factor products except for Recombinate and Kogenate® FS are third generation. A special shout-out to Octapharma’s Nuwiq®, a recombinant factor VIII product that uses a human cell line instead of an animal cell line in its production process.

Recombinant products, by reducing the potential for viral transmission, are an improvement over past products. And yet first-generation products remain in use, as do plasma-derived products. So far, there seems to be a purpose and a place for all products.

Growth Spurt!

But consumers want more. Researchers found ways to keep infused factor circulating in the body longer, by extending its half-life—meaning fewer infusions and less burdensome treatment. Eventually, extended half-life (EHL) factor was created. After a relatively calm 10 years in the marketplace with what is now called “standard half-life” or just “standard” factor, EHL factor came along, resulting in a big growth spurt in the life cycle of hemophilia treatment. Hailed as the next best thing, EHL factor was and still is heavily promoted. Biogen created the first two EHL products, which were soon followed by EHL products from Baxter (now Takeda), Novo Nordisk, Bayer, and CSL Behring.

  The creation of EHL products seemed like the exciting, wild teen years for our community. Children with hemophilia lived even more normal lives, without infusing so often. Freedom!

Family Feud

In the midst of this growth spurt and innovation, some major shifts were taking place in the hemophilia marketplace. Companies were separating, divorcing, getting married, taking on lovers, adopting other products. Baxter split off its biological division (which made its factor products) to become Baxalta. Genetics Institute was bought by Wyeth, which was then bought by Pfizer. In the early 2000s, Bayer had divested its plasma division, which became Talecris. Then Grifols bought Talecris (you can still see the primary color bar on the Koate®-DVI box, the same bar that appears on Kogenate FS). Biogen, soon after launching its groundbreaking EHL products, suddenly divested its hemophilia group, which became Bioverativ. Soon after the new sign was up at Bioverativ’s headquarters, it was bought by Sanofi Genzyme. Baxalta must have been a very attractive mate, because soon after it was spun off by Baxter, it was snatched up by Shire, an Irish pharmaceutical company. Just when everyone was getting used to Irish brogues, Shire was purchased by the Japanese company Takeda, a pharma titan.

 Perhaps no products have changed hands more than those of CSL Behring, starting in the 1980s, when it was Armour Pharmacuetical. And although CSL Behring has remained the parent company since 2007, it has recently abandoned some hemophilia products: Helixate® FS and Monoclate-P®. Its focus is now on EHL products only for hemophilia.

And this is the concern for the future life cycle of hemophilia treatment: Can the market sustain 20 recombinant products? Which products will be removed next from the marketplace? Will product change come from the consolidation of companies buying each other and reducing overlapping product lines? Will it come from flagging sales, if one product dominates the market? Or will product change come from a novel treatment—using no factor at all?

Newest Child

One product getting a lot of attention these days is the newest addition to the family—Hemlibra®, a nonfactor antibody product that mimics the action of factor VIII in the body. It’s used for prophylaxis in people with hemophilia A and inhibitors, and in those without inhibitors. The product’s clinical success has many patients cheering on Facebook, some advocates cautioning consumers to wait and see, and some doctors already prescribing it for newborns. Hemlibra is called a “market disruptor” for a reason. It’s created a whole new way to treat hemophilia: with weekly to monthly subcutaneous injections. And people with inhibitors are reporting no bleeds for weeks, even months in some cases. Will factor concentrate still be needed? Read Wendy Owens’s feature article in this issue to learn the answer!

The life cycle of hemophilia treatment has entered a new phase, perhaps similar to young adulthood, where there are many options, and our community has been educated and prepared. We’re ready for greater independence from this disorder, and ready to live life more on our own terms.

But like all young adults, we still need advice from our elders, from our blood brothers, from our physicians. And we need to do our own homework. We need to read about current products and new ones that will enter the marketplace. Do you feel informed enough to choose? Will your insurance cover all the new products? Will you switch to another product, if one day your insurance company no longer covers yours?

 Stay in touch with the life cycle of hemophilia treatment: name changes of the corporate players, which products belong to whom, and especially, the manufacturer of the product you use. Decisions at the top—by government, by corporations, and by insurance companies—may eventually impact your choice of treatment.

We have more freedom and more choices than ever before, but we need to exercise responsibility, by learning all we can. Because one thing is for certain: we are only in the young adult stage of hemophilia therapy. Prepare for more growth and more change.  It’s coming.

  1. Mark Terry, “A Look at Hemophilia Drug Prices and the Market,” biospace.com, July 3, 2018 (accessed June 2, 2019).
  2. Recombinate is a first-generation recombinant product. Kogenate FS is a second-generation product. Advate, Adynovate, Afstyla, Alprolix, BeneFix, Eloctate, Idelvion, Ixinity, Jivi, Kovaltry, Novoeight, Nuwiq, Rebinyn, Rixubis, Vonvendi, and Xyntha are third-generation products.

A Personal Approach to Healthcare

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Ever hear of personalized healthcare (PHC)? PHC means tailoring a treatment regimen specific to an individual patient. It acknowledges that every patient is different, with different physiology, biology, reactions to medicine, and lifestyle. A treatment regimen that works for one patient may not work for another with the exact same ailment.

The goal of PHC is to improve your quality of life as a patient with a specific disease or disorder, by taking into
account your individual needs and lifestyle, and then tailoring a treatment plan. How does that happen? It’s a collaborative process involving you and your medical team. Your HTC medical team knows all the treatment options, but you know yourself, your body, and your lifestyle. To develop your own PHC, you’ll need to share with the team every aspect of your past health, current health, needs, and desires. Only then can you all explore treatment options that best suit you.

Your Personalized Healthcare Team

The best place to get help with hemophilia and all bleeding disorders is at a hemophilia treatment center (HTC). These are centers of excellence that specialize in diagnosing, treating, and monitoring bleeding disorders. There are over 140 HTCs throughout the US. They follow the model of comprehensive healthcare, which means that they’re not just treating bleeding episodes, but all aspects of living with a bleeding disorder. From orthopedics to psychosocial needs to genetics, the HTC team knows how a bleeding disorder can impact your life.

By using comprehensive healthcare, isn’t your HTC team already implementing PHC?

Maybe not. First, not all HTCs are created equal. Some may lack certain experts you need, such as a pediatric hematology department or a geneticist. And some may have strong beliefs, different from yours, about when—or whether—to start prophylaxis (prophy), or about whether you should try new products.

Parents and patients need to become partners in PHC. Are they ready for this collaboration? Parents of newly
diagnosed children may be too shocked at first, and not even know what questions to ask. Older patients may be overlooked for PHC because they’ve been on the same treatment plan for a long time, their blood work is good, and they don’t complain or ask questions.

It’s important for you to be ready to partner with your HTC and let the team know your needs. But even if you’re comfortable standing up and being heard, what will you say? What will you ask?

1. CHOOSE THE RIGHT TREATMENT

One of the first decisions you need to make about your PHC is which treatment to use. All products licensed in the US are considered safe and effective, but they’re not all the same. How do you find one that’s best for you?

You know that new products are entering the market. You can choose between plasma-derived (made from human blood) and recombinant (made from animal cells containing human genes). Within the recombinant products, there are categories: first, second, or third generation. And there are novel therapies, that are not even factor! So begin by asking your hematologist for opinions on all products.

Your decision about treatment may come down to lifestyle, when selecting a particular brand for prophy. Perhaps the brand you’re using now, three times a week, works well for you or your child. Does a product with an extended half-life offer fewer infusions, saving veins from wear and tear? Or would you benefit from a new, subcutaneous product? Some products might not be available through your insurance. Talk through these choices with your HTC.

2. BLEEDING PATTERNS

Perhaps nothing is more personal than your individual bleeding pattern. People with hemophilia bleed differently, in different places, from different causes. Once your child begins getting bleeds, notice his bleeding pattern, if any. This is where you can really help your HTC team personalize your treatment. The information you share can help prevent a target joint from starting, or can compel the HTC team to put your child on prophy.

You may hear severity levels described like this: Children with severe hemophilia will bleed from trauma, or spontaneously, with no known trauma. Children with moderate hemophilia may bleed on average once a month, with known trauma. Children with mild hemophilia may bleed only after dental extractions and surgery. But what’s the reality? Some children with severe hemophilia bleed only monthly; some with moderate bleed every week, with no known trauma. Your child’s bleeding is unique!

And know his personal symptoms of a bleed: Tingling? Hot? Swollen? Your HTC staff can help you identify symptoms, so you can infuse more quickly at the first sign of a bleed.

3. ESTABLISH A TREATMENT REGIMEN

Personalized healthcare really shines when it’s time to devise a treatment plan. You can use the new, subcutaneous novel therapy. Or you have two options for infusing factor: on-demand (also called episodic) or prophylaxis. On-demand means infusing at the first sign of a bleed. Prophy is the scheduled infusing of factor. It’s designed to keep factor levels in the bloodstream high enough—greater than 1%—to prevent most spontaneous bleeds.

Prophy is the recommended therapy for children with hemophilia in countries like the US with ready access to clotting factor.

And what about your schedule for prophy? This is about as personal as PHC gets! Your HTC team will offer a schedule based on your child’s needs: your family lifestyle, activity level, perhaps pharmacokinetics (PK) data to determine how quickly factor is cleared from the blood after an infusion, and any breakthrough bleeding that might happen.

4. DISCUSS PERSONALIZED MEDICINE

Personalized healthcare is not the same as personalized medicine, a common term. Personalized medicine often refers to using a person’s genetic profile—genomes and specific genetic markers—to guide therapy for cancer and other diseases and disorders, including hemophilia. But PHC includes personalized medicine, and it’s worth discussing with your HTC team because more and more, the hemophilia community is focusing on personalized medicine.

National Hemophilia Foundation (NHF) recognized the importance of this genetic research and launched My Life, Our Future (MLOF). Through this program, you can get a blood test that enables you to learn more about the specific genetic mutation that caused your child’s hemophilia.

So PHC uses personalized medicine to examine your genetic makeup, help predict which medical disorders or diseases your child is most at risk for, and suggest which treatments will be safe and effective (or not) for him. This is particularly important for complications like the risk of getting inhibitors.

We’ve shown you examples of treatment and lifestyle areas to focus on, potential needs to address, and questions to ask your HTC team to design the best life possible with your bleeding disorder. Your HTC team will become one of your most important partners.

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