inhibitors

New Publication Answers Questions About the SIPPET Study

Laurie Kelley June 25, 2017
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.
BN/A8/0517/0275

Happy Mother’s Day !

Laurie Kelley May 14, 2017
A bleeding disorder diagnosis brings out the mama bear in most
mothers who have a child with a bleeding disorder. Maybe even more so in
those who have children with inhibitors. Below, Cazandra MacDonald, a
personal friend and wonderful mom of two boys with hemophilia (and
inhibitors) shares her thoughts on inhibitors in hemophilia. 
Happy Mother’s Day to all the incredible moms who have children with bleeding disorders!
What’s in a Number?
Written by Cazandra Campos-MacDonald
Originally published in PEN May 2017


Numbers, numbers, numbers. Our society is flooded with numbers. From Social Security numbers to birthdays, PINs, passcodes and checking our weight, we can hardly get through a day without numbers. When you are living with a bleeding disorder, you monitor the assays of your factor, track the number of bleeds per month, check how many doses of product are on hand, and measure the circumference of a swollen knee. But when you live with an inhibitor, there’s another number that can become the focus of treatment: the Bethesda unit (BU).
The Bethesda inhibitor assay is a test that measures the titer (strength) of the inhibitor, described in Bethesda units. Inhibitor titers may range from less than 1 BU to thousands of BU. Knowing this number will help determine how bleeds are treated. If the inhibitor registers as low titer (less than or equal to 5 BU), bleeds may be treated with high doses of standard factor concentrate. If the inhibitor registers as high titer (greater than 5 BU), standard factor concentrates are ineffective and special factor concentrates called bypassing agents are used instead. Attempting to treat bleeds in the presence of inhibitors is less effective than treating bleeds without inhibitors—so the goal is to eradicate the inhibitor. If the inhibitor registers as less than 10 BU, this is when many providers will have patients begin immune tolerance therapy (ITT), also called immune tolerance induction (ITI), a treatment protocol designed to eliminate the inhibitor.1 Knowing your BU is crucial in order
to take the next step in working toward that goal.
It’s easy to put your faith completely in the numbers. Knowing your current BU is important, but know first that every individual is unique and there are several different ITT protocols. Each person does not react to ITT in the same way. One body may accept ITT easily, and his BU will come down in a short time. Others on the protocol may take years to get the same results. Numbers do not dictate that the treatment for one person will be the same as for another. For example, two brothers, both with severe hemophilia and inhibitors and with the same parents, can live very different lives with an inhibitor. My older son, Julian, was one year old
when he was diagnosed with a low-titer inhibitor; it never rose above 5 BU. He immediately had a port inserted, and he started ITT for two and a half years. He tolerized, meaning his inhibitor dropped to zero, and he has never had an inhibitor resurface.
My younger son, Caeleb, was 11 months old when diagnosed with a high-titer inhibitor that registered over 2,200 BU. His titer dropped to 0 BU at one point after ITT, but now he is living with a low-titer inhibitor, and he receives factor daily
to maintain his tolerance. My sons both reached 0 BU after ITT, but they had different outcomes.
The numbers can be promising and sometimes disappointing. But ultimately, the numbers are a key component to treatment.
Everyone who tracks his BU has an ultimate goal in mind: to lower the titer to zero. If your titer is 323 BU, your goal may first be 299 BU, then 250 BU.2 Another person may be hoping to get to double digits, and another to single digits. Of course, when you’re tracking your BU, you want to get to zero and stay there. When you reach 0 BU, you may think that the inhibitor is now a thing of the past—but not necessarily. Once 0 BU is attained, the next step is to monitor the half-life of the factor. To be successfully considered tolerized (this is also called complete tolerance), the following must be maintained:
• The inhibitor titer can no longer be measured.
• Factor recovery is greater than 66% of normal.
• The half-life of factor VIII is greater than six hours.3


But someone may live with 0 BU for many years without these three characteristics. This is called partial tolerance. For example, if your child has 0 BU and a three-hour half-life of factor in his body, he will probably continue with the same ITT therapy, which may be daily infusions. ITT is not always successful: an ITT attempt in which inhibitor titers fail to decrease at least 20% over three to six months, or remain over 5 BU after three to five years, is considered a failure. This example shows that not only is BU important, but monitoring the number of hours for the half-life is critical to treatment. So how does a family live with the numbers?
“Lab work disappointment” is a phrase Kari Atkinson’s family used when the numbers were not what they had expected for their son. “We had so much hope that the inhibitor would go away.” But now, says Kari, “we are not as concerned about the number because we can tell when [the BU is] up and down by how our son bleeds.” How an individual’s body reacts to treatment is the ultimate measure of success. If you’re living a full life with few bleeds and an active inhibitor, the important thing is that you are healthy, happy, and thriving. Eric Frey’s son, age seven, has lived with an inhibitor for over five years. “After time, we learned two things: First, we already knew what the results [BU] were going to show by the way our son was bleeding, bruising, and behaving. Second, the Bethesda number is far less important than how our son was bleeding, bruising, and behaving.”
Despite living full, healthy lives with an inhibitor, many families still worry about the numbers. “Making peace” with the inhibitor is something that most people don’t want to do. It can feel as if you’re giving in and accepting that the inhibitor will always be present. In order to live a life where hemophilia is not the center of everything, making peace is crucial. “We have had enough experience that we know if the inhibitor is under 7 BU, we are living pretty good,” says Kari. Her family is not focusing on 0 BU, but for now, they know that anything under 7 BU is acceptable. “It’s really hard to not focus on the numbers, especially when you have the active inhibitor and either you need to get below 10 BU to start ITT, or you are doing ITT and trying to get down to zero,” says Eric. “We understand how hard that is. Focus on health. Focus on wellness.”
Numbers are essential for people living with inhibitors. Keep track of bleeding episodes because this is a significant tool to see if your treatment is appropriate. Continue your regular blood draws according to your provider’s recommendations. Even if you’re not a slave to the BU, it’s vital to monitor the progress of your inhibitor. The key is to enjoy life. Savor every moment. When things aren’t going well, try to remember that life will get better. And when life is good, soak it in.


Cazandra Campos-MacDonald is a motivational speaker, educator, and patient advocate for families with bleeding disorders. She writes a blog chronicling the journey of her two sons with severe hemophilia and inhibitors, and has written articles and blog posts for other publications. Cazandra’s older brother, Ronaldo Julian Campos, died of complications from hemophilia as an infant. Cazandra lives with her family, Rev. Joe MacDonald, Julian (20), and Caeleb (11), in Rio Rancho, New Mexico.
Click here to see Caz’s Ted Talk
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1. ITT is a proven treatment toward eradicating inhibitors. Larger-than-normal doses of factor are given in the hope of overriding the inhibitor. ITT protocols can differ in frequency of infusing, depending on the physician’s and individual’s needs.
2. Once you achieve 10 BU, it doesn’t matter if the BU gets lower, because all infused factor is inactivated in minutes. Even so, families living with an inhibitor will find emotional relief when the numbers get closer to zero.
3. D. M. DiMichele, W. K. Hoots, S. W. Pipe, G. E. Rivard, and E. Santagostino, “International Workshop on Immune Tolerance Induction: Consensus Recommendations,” Haemophilia 13(2007): 1–22.

Resources for People with Inhibitors

Laurie Kelley January 4, 2016

In 2005, when I first sat with US families with inhibitors and
listened—really listened—to their challenges, I was blown away. First, by how
much they struggle: standard factor doesn’t work to clot the blood, different
treatment protocols sometimes fail, children are on prescription painkillers,
with ports and surgeries. Second, by how separated they were from the rest of
the community, shunned almost. “No one understands our challenges,” one mother
told me, “and when we share, they back away.” Hemophilia with inhibitors was
almost like a separate disorder. Third, I was amazed by how stoic and strong
these families are! And even more amazed by the lack of resources for them.
            I’m
happy to say so much has changed in the US since 2005. We now have inhibitor summits,
financial aid programs, books, and even a camp! All for families with
inhibitors. At long last, our hemophilia community has embraced the inhibitor
families, and we’ve united.
            When
I learned about the struggles of inhibitor families, I vowed to write a comprehensive
guide to dealing with and living with inhibitors—and I did! From the interviews
for Managing Your Child’s Inhibitor
emerged the need for a summer camp. A colleague took that idea and eventually
did just that. What will knowing the needs of the inhibitor community lead you
to do?
            Begin
by ordering these free resources and enrolling in the patient assistance
programs. Having inhibitors is tough enough, but knowing there are colleagues
and professionals waiting to help you will ease the path forward.
BOOKS
Managing Your Child’s Inhibitor
Laureen A. Kelley and Paul Clement
2009
Written by parents of children with hemophilia, this
comprehensive resource is the first and only book about inhibitors in the
world. From the parents’ and patients’ point of view, it extensively covers
topics such as pain management, surgery, family life, products, and treatment
regimens. Published by LA Kelley Communications, Inc. with funding by an
unrestricted grant from Novo Nordisk.
To order: www.kelleycom.com
The Great Inhibinator!
Chris Perretti Barnes
2006
This richly illustrated storybook introduces a preschool boy
with hemophilia and an inhibitor. He manages his feelings by becoming a
Halloween superhero called the
Great Inhibinator. Written by the mother of a child with
hemophilia and inhibitors. For ages 4–7. Sponsored by Bayer HealthCare and
BioRX.
To order:
www.biorx.net
PATIENT PROGRAMS
Inhibitor Education Summits
The only national educational forums for inhibitor patients
to meet and learn about their rare complication. Offers lectures from experts
in the field and interactive forums with parents and patients. National
Hemophilia Foundation (NHF) provides these summits only for people living with
inhibitors, covering most travel expenses for participants.
Funded through a grant from Novo
Nordisk Inc. and Baxalta Incorporated.
For info: www.hemophilia.org
Inhibitor Family Camp
Camp addresses the unique needs of children with active
inhibitors, and their families. The full weekend of education, support, and fun
is held twice yearly, with camper costs covered. Funding provided by Novo
Nordisk Inc. Camp is designed and operated by Comprehensive Health Education Services.
For info: www.comphealthed.com
FINANCIAL &
PRODUCT ASSISTANCE
NovoSecure™
Novo Nordisk’s NovoSecure is a comprehensive patient support
program for patients with hemophilia A, hemophilia A or B with inhibitors,
factor VII deficiency, acquired hemophilia, Glanzmann’s thrombasthenia, or
factor XIII deficiency, regardless of product choice. Replacing SevenSECURE®,
NovoSecure allows enrollees to apply for a variety of programs, including
• Competitive scholarship program
• Life coaching with HeroPath™
• Career counseling
• Insurance support
            Novo
Nordisk also offers product and copay assistance programs to eligible patients
who have been prescribed Novo Nordisk products.
For info: www.mynovosecure.com
1-844-NOVOSEC (1-844-668-6732)
CARE
CARE (Coverage, Assistance, Resources,
and Education) to help patients take control of their healthcare needs through
insurance and product assistance. Copay or coinsurance support may be
available to reduce out-of-pocket costs associated with a Baxalta product.
For info: www.baxaltahematology.com or www.hematologysupport.com
Baxalta Resource Helpline 888-229-8379
To enroll in CARE: 855-322-6282

Got Rabbits? Their Milk May Treat Inhibitors Someday

Laurie Kelley March 10, 2014

PEN has printed in the past articles about coming products, like long lasting and human-cell line products. We’ve also mentioned transgenic animals—which express proteins in their milk that can be used for human treatment of certain disorders. Hemophilia is one of the therapies being researched to create products from transgenic animals.

Charlton [Massachusetts] farm to raise rabbits for medicine

By Lisa Eckelbecker TELEGRAM & GAZETTE STAFF

A French biotechnology company that turns milk from genetically engineered goats into medicine plans to expand operations at its farm in Charlton by raising rabbits that produce a blood-clotting agent for patients with hemophilia.
LFB SA and its Framingham-based subsidiary rEVO Biologics plan to build a colony of 1,000 to 1,200 rabbits making a protein called Factor VIIa at the farm, said Dr. William Gavin, a veterinarian and senior vice president of operations for rEVO.

“We’re going to have the first shovel in the ground in August,” Dr. Gavin said. “About one year later we will be producing milk here from the rabbits that produce the Factor VII in their mammary glands.”

The plan represents the first potential product expansion at rEVO, previously known as GTC Biotherapeutics, since it launched a clot-busting drug called ATryn in 2009. ATryn was the world’s first drug made in the milk of genetically altered animals.

LFB has been producing limited amounts of Factor VIIa in the milk of rabbits in France while also testing the protein in humans. The company said Monday it expects to launch the third and final phase of human studies this year.

If approved, LFB would market its Factor VIIa product as a treatment for hemophilia A and B patients who have developed inhibitors, or antibodies, to other clotting proteins known as Factor VIII or Factor IX.

The global market for blood disorders, including hemophilia, is estimated to reach nearly $64.7 billion by 2017, according to analyst Usha Nagavarapu in a market research report published last year by BCC Research of Wellesley.

NovoSeven, a Factor VIIa product sold by Novo Nordisk of Denmark, posted worldwide sales of 8.9 billion kroners in 2012, or about $1.6 billion in current dollars.

Founded in 1993 as part of Genzyme Corp., rEVO has offices and laboratories in Framingham. The company developed transgenic animals as an alternative to traditional biologics manufacturing.

Transgenic animal production generally starts in a laboratory, where scientists inject human genes into an early animal embryo. The embryo then gets implanted in the womb of a surrogate mother. If the procedure is successful, the animal born will carry code for a human protein in its genes. Then the animal can be bred normally to produce offspring with the human code.

That is how rEVO built its herd of goats on its 383-acre Charlton farm. Transgenic females in the herd produce milk carrying antithrombin III, a protein involved in blood clotting. The company processes the milk to a sterile powder form of antithrombin III for sale.

Dr. Gavin said rEVO plans to bring transgenic New Zealand White rabbits from France to build a new Charlton colony. The company chose rabbits rather than goats to produce Factor VIIa because rabbits can produce the key protein with certain sugars needed for the best therapeutic results.

Rabbits can also produce 200 milliliters of milk per day, or nearly 7 ounces, and they lactate for about three weeks.

Contact Lisa Eckelbecker at lisa.eckelbecker@telegram.com. Follow her on Twitter @LisaEckelbecker.

So I just saw this in the newswires… and go here to read about my visit to this farm a few years ago, and to see pictures of the goats mentioned in the articles.
https://www.blog.kelleycom.com/search/label/GTC%20Biotherapeutics
You can also learn more here: http://www.transtechsociety.org/livestock.php
Great Book I Just Read
Bonk: The Curious Coupling of Science and Sex [Kindle]
by Mary Roach
This best selling author examines the history of the scientific study of
sex, and researches the sex researchers. It’s at once funny, interesting, witty
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spot on. Four out of five stars

Inhibitor Meeting in UK

Laurie Kelley September 25, 2008


Grifols, a Spanish based company that manufacturers Alphanate and Alphanine, held a one day educational conference on inhibitors for nurses in London yesterday. I was pleased to start the day with a talk on inhibitors in America: how the main struggle is finding a way to afford the treatment that is already available, given mounting pressure from payers and limited lifetime caps. Professor Alessandro Gringeri, of the University of Milan, gave an excellent comparison of ITT protocols around the world. He reminded us that ITT has been with us for 31 years, but since the first attempts, different protocols have developed. He reviewed the specifics of the Bonn, Malmo and Van Creveld Klinick protocols, and how responses to different ITT are either patient related or treatment related. ITT does not work with all patients, particularly those with mild hemophilia.

Dr. Sylvia von Mackensen is a psychologist at the University Hospital Hamburg-Eppendorf, Hamburg, and gave a presentation on Quality of Life Studies: measurements, outcomes and expectations. This is an important subject for inhibitor patients, who suffer a great loss of QoL when by passing agents or ITT are not always effective.

My colleague Becky Berkowitz, RN from the HTC in Las Vegas, Nevada, spoke about nursing in the US. Becky has a unique position working in an enormous state with a small population, and a lean HTC staff: her efforts to visit the native Americans and advocate for their treatment held the audience’s rapt attention.

The rest of the afternoon held presentations by Dr. Mauricio Alvarez-Reyes of Grifols, nurse Allyson Hague of Manchester Children’s Hospital, nurse Kate Khair of Great Ormond Street Hospital and Vicky Vidler, nurse consultant of Sheffield Children’s Hospital. It was a wonderful event, full of information and diverse speakers.

After the program, I took a tour of Great Ormond Street Hospital with Kate Khair, Virginia Kraus (Grifols), Becky Berkowitz, and Mark McDonnell, UK Manager (Grifols). It’s a major HTC, with over 450 pediatric patients, with a beautiful ward. I had always heard of this famous hospital and it was a pleasure to see it from inside.

This has been productive week: I was also able to visit on Tuesday the Haemophilia Society, which I believe was one of the first hemophilia society in the world. Chris James is the relatively new executive director, and he graciously allotted me 3 hours to tell me about their programs and population. We also spoke about sharing my company’s free resources with his members. They have excellent programs and in many ways are one step ahead of many other organizations in terms of programs for inhibitor patients.

Last of all, I saw on Monday an historic site: the Broad Street Pump, the epicenter of the devastating 1854 cholera epidemic of London. This important landmark represents the beginning of modern public health. It was here that a contaminated well led to hundreds dying within one week, and caused English physician Dr. John Snow to buck conventional medical thinking, which thought it was miasma–bad air– that caused the outbreak (this was before germ theory). By using a scientific method and putting himself at great risk, Snow interviewed an entire neighborhood, noting where deaths occurred: the outcome was a map which revolved around the pump and well. After a struggle to convince authorities that water was responsible, Snow had the handle removed. The epidemic was over and a new theory on germs was born. This one pump represents all modern day efforts to provide clean drinking water to overcrowded cities worldwide. It was simply amazing to actually see the pump, and be grateful for the dedicated efforts of this remarkable British physician. (Read The Ghost Map for an excellent recounting of this story)

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