Inhibitors are the most troubling complication of hemophilia A treatment today. In this week’s blog, I share with you a new publication concerning the SIPPET study, which sheds light on factor VIII products and inhibitors.
New Publication Answers Questions About the SIPPET Study
An article written by noted hematologist Dr. Flora Peyvandi and colleagues was recently published in the medical journal Haemophilia. This article directly addresses and answers several questions that were raised about the 2016 publication of the Survey of Inhibitors in Plasma-Product Exposed Toddlers, or SIPPET study.1
With this new article, SIPPET: methodology, analysis and generalizability, the authors respond to the 17 most common questions associated with the design, methodology, and results of the SIPPET study, including1:
Is the inhibitor risk higher in SIPPET than in previous reports?
Could differences in treatments between countries have affected the results?
Could the results have been affected by the way the study was randomized?
Do the SIPPET results also apply to other recombinant factor VIII (rFVIII) products
beyond the 1st and 2nd generation products used in the study?
Is there a difference in inhibitor risk between the different brands within the plasmaderived and recombinant groups?
Original SIPPET Study
The SIPPET study, conducted by Dr. Peyvandi and colleagues, was the first randomized trial to compare the incidence of inhibitors in plasma-derived factor VIII (pdFVIII/VWF) products and rFVIII products in previously untreated patients (PUPs).2
Results from this landmark study showed that there was an 87% higher rate of inhibitor development in patients who received rFVIII compared with patients who received pdFVIII containing von Willebrand factor (VWF).2
Based on the results of the SIPPET study, the National Hemophilia Foundation’s Medical and Scientific Advisory Council (MASAC) now recommends that pdFVIII/VWF be considered as one of several treatment options in PUPs.3
Visit www.inhibitorinfo.com to Learn More About Inhibitors Inhibitors are the most serious and challenging hemophilia A treatment complications. All patients with hemophilia A are at risk for developing inhibitors, regardless of age and disease severity.
Inhibitorinfo.com is a comprehensive website that provides important information and resources about inhibitors and the risk of inhibitors. There is a discussion guide patients can download and use to talk with their hematologists about inhibitors. Visitors can also read about the results of the SIPPET study and watch leading hematologists talk about its implications.
When visitors sign up for updates at inhibitorinfo.com, they will receive access to the full SIPPET study, as well as updates about hemophilia, inhibitors, and the latest clinical data.
References: 1. Peyvandi F, Mannucci PM, Palla R, Rosendaal FR. SIPPET: methodology, analysis
and generalizability [published online ahead of print March 17, 2017]. Haemophilia. doi:
10.1111/hae.13203. 2. Peyvandi F, Mannucci PM, Garagiola I, et al. A randomized trial of factor VIII
and neutralizing antibodies in hemophilia A. N Engl J Med. 2016;374(21):2054-2064. 3. National
Hemophilia Foundation. MASAC Update on SIPPET. National Hemophilia Foundation website.
https://www.hemophilia.org/Newsroom/NHF-Community-News/MASAC-Update-on-SIPPET.
Published March 9, 2016. Accessed April 27, 2017.
This is a paid public announcement from Grifols and does not constitute an endorsement of
products or services. When you click on the links in this blog entry, you will be directed to
the Grifols website. LA Kelley Communications always advises you to be a savvy consumer
when contacting any company; do not reveal identifying information against your will.
National Hemophilia Foundation recommends recombinant factor as the standard of choice for treatment of hemophilia, but did you know that many factor products used to treat
hemophilia are developed from human blood, specifically human plasma? In fact, one person with hemophilia can require up to 1,200 plasma donations for a one year’s supply of factor
products. Plasma products are especially important for those undergoing immune tolerance therapy to treat inhibitors, for those with von Willebrand disease and for those in developing countries.
And plasma can come from you! Think of making a blood donation, during this time of Thanksgiving and holidays.
First, learn a bit more about plasma, Plasma is the straw-colored liquid that makes up
approximately 55 percent of total blood volume. A single liter of plasma yields
coagulation factors essential for blood clotting, immunoglobulins used to
combat viruses and bacterial infections, and albumin, a major plasma protein
that regulates blood volume and other essential functions.
In addition to treating hemophilia, plasma-derived therapies
are used in everyday medicines, emergency and critical care situations, as well
as preventive medicine. Albumin, for example, is used to treat burns, shock,
trauma, liver conditions and cardiopulmonary illnesses; immunoglobulins are
indicated for Rh incompatibility, pediatric HIV, hepatitis, and animal bites.
Plasma is an expensive raw material and represents between 40 to 60 percent of the cost
of plasma-derived product production. This is due primarily to its biologic
nature: plasma protein therapies are not interchangeable, have no generic
variations or substitutions, and are defined as sole-source biologic products
by global regulators.
Since plasma is biological in nature, complex regulation and
oversight measures are in place—including collection, processing, and storage
and handling requirements—to ensure plasma donor health, as well as product
purity and efficacy for patients.
The majority of the world’s plasma comes from plasma donors
in the U.S. Collectively, the Food and Drug Administration (FDA) and its Center
for Biologics and Research (CEBR) are responsible for regulatory oversight of
the U.S. blood supply. Blood collection centers are either registered or
licensed by the FDA, and are held to quality standards comparable to those of pharmaceutical
manufacturers. Blood establishments located outside of the U.S. that import or
offer for import blood products are also required to register with the FDA.
CEBR regulates the collection of blood and blood components
used for transfusions, as well as for the manufacture of pharmaceuticals
derived from blood and blood components. CEBR develops and enforces quality
standards, inspects blood establishments and monitors reports of errors,
accidents and adverse clinical events.
Manufacturing processes begin with fractionation,
followed by purification and virus inactivation. Fractionation is a time
consuming and complex process that extracts, or “fractions off,” specific
plasma proteins that have a proven health benefit. Fractionation requires
multiple processing steps, which involve manipulating solution pH, temperature,
ionic strength and alcohol concentration.
Once fractionated, plasma proteins are further subjected to
virus inactivation, a complex purification processes that includes prion
removal, nanofiltration, solvent/detergent
treatments and incubation, to ensure sterility and purity of the final product.
The complete manufacturing process, from plasma collection at a donor
center to the FDA’s lot release, takes seven to 12 months.
So donate now! Next year at this time, your donation could be used to save a life!
Sponsored by ASD Healthcare.
Great Book I Just Read
The Climb to Hell [Kindle]
Jack Olsen
Olsen sure can write a page-turner. In 1957, one of the most audacious and stunning rescues to ever take place occurred on the north face of the Eiger, one of the most notoriously difficult challenges to scale, located in the heart of the Swiss Alps. The Eiger is feared for its avalanches, fast-changing weather, and sheer facade. When two poorly-prepared Italians set off to make history by being the first Italians to scale it, they become stuck for eight days, in zero-degree weather, unable to get off the mountain. This launches an international rescue effort, that leads to surprising outcomes, including national rivalry, clashing personalities, extreme risk taking and uncertain success. Fantastic story, well told and must-reading by all mountaineers. Four/five stars.
I spent last week in Italy. IIt was quite a change from two weeks in India. All I need is Indonesia and I will have done my Eat, Pray, Love hemophilia pilgrimage. Except I managed to eat in India, pray in Italy…. The rest has yet to be seen!
I spent a few days in Florence before heading slightly north for the real purpose of my trip. Florence is a city I studied intensely as a teen. While other girls were going to dances, I studied the Renaissance and became quite an “expert” at a young age. I copied paintings of the masters, as I loved art, and when I first arrived at age 17, knew more about where to go than our high school guide. So returning for my fourth time, I resolved to wander the streets and churches, revisit the masters, and stand
in awe of the treasures of Italy. Nothing man-made captures my stunned, silent
respect and worship like the statue of David.
On day four I headed to Lucca, to visit a pharmaceutical company called Kedrion. Kedrion came to our attention in the US a few years ago when it was contracted by Grifols to handle distribution of Koate-DVI, a plasma-derived factor VIII product. Originally produced by Bayer, it was divested, along with all the Bayer plasma division, to Talecris. Eventually Talecris was bought by Grifols. But the US government, leery that Grifols now had two plasma derived FVIII products, required Grifols to have a different company handle distribution of Koate-DVI. Enter Kedrion.
Kedrion may be new to the US, but not to Europe. Kedrion is a leading global pharmaceutical company specializing in the development, production and distribution of a wide range of protein products derived from human plasma. The company’s products are used to treat hemophilia, immune deficiencies, infectious diseases and other serious medical conditions in over 60 countries. The company owns four production facilities: two in Italy,
one in Hungary and one in the United States (currently leased to Grifols).
I was thrilled to be offered a tour of the production plant. The plant is nestled among the Tuscany hills in Lucca, an ancient city famed for its fortress-like walls that protect the denizens, once Romans in 180 BC. The scenery—snow capped mountains rolling away to the sea; petite, puffy clouds touching down on factories and churches— is breathtaking from the patio of the Renaissance (how appropriate) hotel, perched on a mountain and once owned by the Marcucci family, which also owns Kedrion.
I had dinner the night before the tour with Paolo Marcucci, CEO of Kedrion, and wife Paola Pardini, whom I have met before and who sponsor 17 children through Save One Life. With us was also Danilo Medica, Italy country manager for Kedrion, who I had also met before at a WFH event. Social events are always lovely with Italians, who know the fine art of socializing, eating and drinking, and offering sincere and mutual respect
and hospitality.
Laurie at Kedrion plant, with Charles Waller
So my purpose in visiting was to see the
plant, and learn more about this newcomer to the US market. Also, Kedrion has
been for a few years now our largest single donor of factor products to
Project SHARE, my factor donation program. We are now collaborating on ways to
secure even more factor to donate to the regions of the world where the 75%
live—those people with hemophilia with little or no access to treatment. Like…
some of the places I had just seen in India.
First, a snapshot: Kedrion was founded by the Marcucci family; current CEO Paolo is son of the founder. It offers technology transfer of plasma collection to Macedonia, Turkey, and Iran, as well as plasma-derived product sales to about 60 countries. It has 15 plasma collection centers (nine of which are in the US). About 95% of its products are plasma derived. Kedrion is one of the few factor manufacturers that is
considered part of a government healthcare system. About 75% of the company is owned by the Marcucci family; 25% is owned by government.
Kedrion experienced enormous growth in the past few years. Its business used to be only in Italy until just 2007; now it’s been global for five years. A dominant 60% of its business is international, part of this switch attributed to production acquisition sites in the US. It has a FV product in the pipeline, even though there are only 5-6 patients with FV deficiency in Italy. Clearly, Kedrion continues to have its eyes set on the world.
And hemophilia in Italy? There are 3,481 hemophilia A patients; 1,688 are severe, 1,320 mild, and 473 moderate. In 2013, FVIII consumption was about 555 million IU, with plasma-derived product use actually increasing, driven by IT therapy for inhibitor patients. Still, recombinant products dominate the hemophilia market, at 66% of sales.
PLANT TOUR
On a frosty Wednesday morning, I removed my jewelry, washed my hands thoroughly, suited up, and entered the plant with my hosts, to tour how plasma products are made. The plant fractionates 1 million liters (about 264,172 gallons) every year, using 24,000 liter tanks. First I watched a film on the plant: how plasma arrives, is checked, monitored and inventoried. How plasma is separated by centrifuge creating cryo paste for fractionation. There are 480 employees in Lucca, and the plant operates 7 days a week, 24 hours a day. It will be closed over Christmas for maintenance and
cleaning. The instruments and suites where products are made are cleaned daily.
On this tour I was able to watch albumin
being made. Albumin is the part of plasma used to bulk-up factor concentrates,
to allow them to be injectible. Alessandro, plant manager and our guide, explained
about different classes assigned to manufacturing suites (A-D), based on sterility
and cleanliness. As each product goes through each manufacturing phase, the
requirements for cleanliness gets more and more complex.
It’s not just that things must be sterile. In the suite, people come and go; there is air, exhalations, and ventilation. The air itself, pressurized like in an
airplane, to push air out if there is a breach, must be monitored constantly. You want a low level of environmental pollutants such as dust, airborne microbes, aerosol particles and chemical vapors. Levels of contamination are specified by the number of particles per cubic meter at a specified particle size. Instruments protruding out of the wall measure constantly the ambient air, and would signal an alarm if the air contained undesirable things in it at a level considered potentially harmful.
We watched as lab employees handled the sterile vials into which the albumin would be placed, all by machine to reduce human contact. The rubber stoppers were placed, and the machines sealed it with
the foil. I learned something new: I always thought the rubber stopper might be at risk to cause a breach of integrity of the vial if the vial got too hot or cold. But Alessandro assured me these stoppers are powerful and not likely to contract or expand with different temperature. It really is about temperature control to keep the protein from degredating and becoming less effective, less powerful.
Speaking of power, the plant must have power at all times. What of there was a black out, someone asked? Kedrion is self-sufficient in power, Alessandro explained. They produce energy themselves
using methane gas production.
Last, we learned about the “KQP”: Kedrion Quality Program, an eight step system, using among other things, regular
qualified donors, NAT testing, pathogen inactivation, and TSE agents, to assure that the products are safe.
The Italian Health System is complex, making me realize we aren’t the only ones with healthcare budgetary woes. With 19 regions that are traditionally independent, 645 public hospitals, 50 HTCs, and an ongoing economic crisis, the federal government is trying to consolidate hospitals, and is asking for additional cost reductions from
industry. And yet Kedrion must continue to fractionate Italian blood and return plasma-derived products back to the various regions.
One concern is that Italy’s not self-sufficient in any product. Consumption is growing faster than production, but consumption includes imported products at much higher per unit prices. In the face of an economic crisis, slashed healthcare budgets, the question is: can Italy use the products it has already to alleviate demand?
So that’s the point of my visit: in April 2013, Italian laws have changed regarding plasma. Previously Italian plasma had to be used by Italians, but now the law allows Italian regions to recover costs
by selling the plasma products to other countries. Or maybe, donating? To India, to Africa? We will see.
The name Kedrion comes from the Greek language for lemon tree (or juniper or citrus, depending on your source). Its symbol represents the deep roots Kedrion has in Italy, where the company was
built on Italian plasma and by a family dynasty, and its branches go out into the air, the world. I’m hoping they continue to branch towards developing countries, to patients waiting to know this unique company and benefit from its products.
The perfect book for reading while in Florence. My hotel was about 200 feet from Santa Maria del Fiore, and when I
stepped into the cobblestone streets each morning, the massive façade, capped by the
astounding dome, greeted me. This book goes into great detail about what it
took to create the 37,000 ton dome, one of the largest cupolas in the world,
completed in 1436. It took 16 years to complete (over 100 for the Cathedral itself!),
and the architectural construction was filled with competition, craftiness and creativity. Brunelleschi
invented all kinds of new ways to transport marble, to hoist the marble. He was
a genius of architecture, and this Dome today still awes and impresses. This
story is compelling, and shows the potential of man to create and persist. Brunelleschi
was foiled many times, faced many obstacles, but finished it, leaving behind
one of the most prominent and important symbols of the Renaissance. A must read
for anyone going to Florence. But a fabulous book on any account. I climbed the
436 stairs to the top and was rewarded with a breathtaking view of Florence, one
of my favorite cities. It boggles the mind how this could have been created, at
such a time, with such vision. You’ll never look at a church steeple or
basilica the same again once you read this. Five/five stars!
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