HFA: Together We Rock!

Laurie Kelley and Chris Seistrup
Laurie Kelley with Chris Seistrup, a cyclist who will raise money for Save One Life

The Hemophilia Federation of America sure knows how to throw a party! And a three-day meeting, all aimed at educating the community about bleeding disorders while providing a busy but intimate venue for meeting up with old friends, acquaintances and business colleagues. And held in Cleveland, with a final evening a celebration at the Rock and Roll Hall of Fame, the theme “Together, We Rock” was absolutely true and we did!

I was able to attend some sessions while there, in between visiting our Save One Life booth and greeting sponsors, donors and interested people, and chilling with some very great friends (Debbi Adamkin, Neil Herson, Ray Dattoli, Melissa Compton, to name only a few). First was an invitation-only meeting with Genentech about mlibra, and specifically the recently reported deaths. About 20 consumers, all key opinion leaders associated with hemophilia organizations) attended. I won’t go into that here in much detail, as the meeting completely corroborated with the article Paul Clement wrote in the May issue of PEN, available on our website.


Laurie Kelley and Liliana Gomez, with her award for her work in Puerto Rico

In a nutshell, though, Genentech shared how Hemlibra has been granted Breakthrough Designation Status by the US FDA to fast-track approval of Hemlibra for noninhibitor patients, based on the HAVEN 3 study data. Conversation turned to the five deaths, out of the 600 current users of Hemlibra globally. Genentech walked us through each death, one by one, what was known and what was reported. We now know that two were Americans, one of whom was in a clinical study. While the explanations all made sense, Ray Datolli, a COTT representative, remarked, “It’s always a clinical study, and it’s always 1981.” The other attendees also commented that the delay in learning of the five deaths was a problem; the community wants to know sooner about these “adverse events.” Genentech then reviewed why they cannot comment on the deaths, for reasons we spell out clearly in our article, and in some cases, the families of the deceased themselves did not want the information released.

Debbi Adamkin, executive director of the Florida Hemophilia Association commented too that the community needs to be educated that Hemlibra is not a cure, and many think it is!

Laurie Kelley with Crystal Higgins and Tracy Farmer

To learn more about Hemlibra, please read our article in the May issue of PEN.

Another good session was on inhibitors, by Vanessa Byams of the CDC. We learned that the CDC hosted a second national inhibitor summit in January 2017 and is closely following inhibitor trends in our community. Its goal is to share information from the community, and to discuss how to collect high quality data, to make sure inhibitor tests are accurate. NHF’s MASAC has an Inhibitor Prevention and Eradication Working Group, which has led to a national collaborative effort to increase enrollment of babies with hemophilia and inhibitors in the CDC Surveillance study. The bottom line is, all hemophilia patients are at risk of inhibitors (with certain exceptions) and there is a lot of research happening on inhibitors. Vanessa said that in the last 18 months alone there is “an incredible movement and action” regarding inhibitor research. “The road to inhibitor prevention starts with national surveillance, including regular screening and early detection If you detect it early, the better the chance of eradicating it.”

One clear hole in our weekend was Barry Haarde: we were all missing his presence, as HFA was truly a home away from home for him. His sister Emily came to fill in for him, and we all shared Barry stories, while admiring his contributions to HFA and Save One Life, which helped so many around the world. With sadness and sweetness, we all felt his absence all too well.

Metallica fans rock!

On Saturday morning, Novo Nordisk sponsored a “B Yourself” symposium for families with hemophilia B. It was very lively, as the audience could participate in answers using the buttons at their desks; answers were tallied and displayed instantly on the screens, from tables designated with rock and roll names: The Rolling Stones, the Beatles, Prince, etc. It made it all the more fun. The topic was mostly about pharmacokinetic (PK) testing, with different patients sharing about their different half-lives, and different dosing schedules. It got pretty technical but was fascinating. It really is imperative that every person with hemophilia know their PK levels, because we now know that you cannot dose just by weight and correction percentage—you do need to know your half-life. We will have some great articles about that in the November issue of PEN.

Laurie Kelley and Pat DeRatto, long time
friends and hemo-moms!

I spoke with dozens of people, all involved in the community, from patients, to advocates, to chapter leaders to industry reps. Two main themes really became clear, one scary and the other exciting.

Scary? Funding in the community is being restricted. Every executive director of a chapter I spoke to commented on this. Our pharmaceutical sponsors are pulling back funding, perhaps as the marketplace is glutted with products, and we expect some consolidations and acquisitions (like Sanofi buying Bioverativ, and Takeda making moves on Shire?). No one is sure what will happen, but some programs may need to be cut.

Exciting? Gene therapy. More than one person said to me, “It’s not a matter of if anymore, but when.” Gene therapy is coming. How will it impact our lives, both as patients and as community employees?

We don’t know yet, but as we rocked the night away Saturday night to a great band at the Rock and Roll Hall of Fame, we celebrated the great advocacy and grassroots work of HFA and its team, celebrated being a family of people with bleeding disorders, and excited about what the future holds.

Plasma-Derived vs Recombinant

A year ago we renewed a match between two heavy-weight contenders in hemophilia: plasma-derived products versus recombinant. The question: which product is more likely to cause inhibitor formation? In the fight to avoid inhibitor formation, some groups and opinion leaders read the initial results of the SIPPET project and declared plasma-derived the winner. But it’s a bit more complicated than that. Read Paul Clement’s excellent article on SIPPET; it will take many more rounds before we declare an outcome. The good news is that so much clinical scrutiny is underway.
Paul Clement
A bombshell was dropped at the Plenary Scientific Session of
the 57th annual meeting of the American Society of Hematology (ASH) on December
6, 2015, in Orlando. Study coordinators of the SIPPET project (Study on
Inhibitors in Plasma-Product Exposed Toddlers)1 presented surprising
preliminary findings: recombinant factor VIII products are associated with an
87% increased risk of inhibitor development compared to plasma-derived factor
VIII products. 2
            In other
words, for every 10 people treated with recombinant factor VIII as opposed to
plasma-derived factor VIII, 1 patient can be expected to develop high-titer
            As a parent
of a toddler who does not have inhibitors, you may feel stunned, angry, or
scared when you read these findings. Should you be? Before you rush to make a
product change, learn how the study was conducted, what its potential
shortfalls are, and why you should take a deep breath!
Shock and Awe
Understandably, many consumers are concerned. Some news
releases describing the study results only heightened the alarm. Hemophilia
Federation of America (HFA) issued a press release requesting that National
Hemophilia Foundation’s (NHF) Medical and Scientific Advisory Council (MASAC)
“consider the temporary suspension of recommendations… that state any
preference for recombinant factor products until the results of the full SIPPET
study can be reviewed.” 3
            Is this a
reasonable reaction, or is this jumping the gun? It helps to examine how the
study was conducted—and why.
Fighting Invaders
Why was the study looking to see if plasma-derived products
are less immunogenic than recombinant products—that is, less likely to lead to
developing inhibitors?
            In the
blood, factor VIII is normally tightly bound to another protein called von
Willebrand factor (VWF). VWF has several functions, including protecting factor
VIII from being digested and cleared from the bloodstream. Some researchers
suggest that in doing this, VWF masks some of the sites on the factor VIII
protein where antibodies attach, potentially making factor VIII with VWF less
immunogenic. Note:
Intermediate/high-purity plasma-derived factor VIII products are the only ones
that contain VWF.
Recombinant and ultra-high-purity (monoclonal purified) plasma-derived factor
VIII products contain no VWF.
Without the protection of its VWF “bodyguard,” the immune
system may recognize these factor VIII products as intruders and develop
inhibitors to neutralize them.
The problem is, no one really knows for sure what causes
inhibitors, and no one knows whether factor VIII with VWF is less immunogenic.
SIPPET Strategy
SIPPET set out to answer this question: Is plasma-derived
factor VIII with VWF less immunogenic compared to recombinant factor VIII
without VWF?
researchers designed a study called a prospective
randomized controlled trial
(RCT). Prospective means looking forward,
before the patient has developed an inhibitor (in contrast to retrospective studies, in which
researchers look backward, after someone has developed an inhibitor).
Controlled means that there are two groups: (1) an experimental group that will
use factor VIII containing VWF, and (2) a control group that will use factor VIII
without VWF. This second group is used as a standard of comparison against the
experimental group. Randomized means that no one involved in the study
influenced which group a patient was assigned to. Randomization is often done
by a computer.
            RCT studies
are often considered the gold standard, thought to produce more reliable data
than other types of studies. Although an RCT can show relationships between
variables being studied, it cannot prove causality. So the RCT used for SIPPET
can’t prove that the presence or absence of VWF in factor VIII caused the observed results.
            SIPPET was
conducted between 2010 and 2015, and data was collected on 251 patients from 42
participating sites in 14 countries from Africa, the Americas, Asia, and
Europe. The patients were younger than six years old, had severe hemophilia A,
were previously untreated with factor, and had minimal exposure (less than five
times) to blood components. Of the 251 patients, 125 were treated with one of
the plasma-derived factor VIII products containing VWF. The remaining 126
patients were treated with a VWF-free recombinant factor VIII product.4 The
patients were followed to see if they developed an inhibitor, for 50 exposure
days (days they received factor infusions) or three years, whichever came
important to note that only one of
the plasma-derived products used in this study is available in the US, and that
the study was funded by manufacturers of plasma-derived products. Is this a
conflict of interest? Does it influence the findings?
SIPPET Shortcomings?
The preliminary findings were startling: of the 251
patients, 76 developed an inhibitor, and 50 of those were high-titer
inhibitors. And 90% of these inhibitors developed in the first 20 days of
treatment. Most important: recombinant factor VIII products were associated
with an 87% increased risk of developing an inhibitor compared to
plasma-derived factor VIII products containing VWF.
            Remember, these are not final results and have not yet
been reviewed by researchers outside of the study
. Before you decide
whether to switch your toddler to a plasma-derived factor VIII containing VWF,
know that many other variables affect inhibitor formation. In any experiment,
variables not directly being tested, but which could have an effect on the
outcome, are called confounding variables.
example, the single greatest risk factor for developing inhibitors is the type
of genetic mutation that caused your child’s hemophilia. If the mutation in the
factor VIII gene resulted in no factor VIII being produced in his body, then he
is already at significantly higher risk of developing an inhibitor. This is one
of many confounding variables in the SIPPET study.
            One way to
reduce the effects of confounding variables on the data is to use a large study
sample. If the sample size is large enough and patients are randomly assigned
to two groups, then each group should have about the same number of patients
with the same confounding variable, so its effect will be canceled. The problem
is that the more confounding variables you have, the larger your study sample
size must be—perhaps several thousand patients. And many variables affect
inhibitor development.
            Another way
to account for the effects of confounding variables is to identify and measure
them, and then to separately compare and analyze the data from patients who
share the same confounding variable. This process is called stratification (meaning to separate into
layers) and was used by SIPPET along with other statistical analysis methods.
But the study identified and measured only six confounding variables: (1) age
at first treatment, (2) intensity of treatment, (3) type of factor VIII gene
mutation, (4) family history, (5) ethnicity, and (6) country site. What about
the effects of the other confounding variables that were not measured? If the
study sample size was too small to reduce the effects of other, unmeasured,
confounding variables, then the study’s conclusions are questionable and might
be explained in other ways.
Don’t Jump Ship Yet
At the time of this writing, SIPPET has not been published
in a medical journal. That means researchers—outside of those conducting the
study—don’t know much more about the study than you do after reading this
article. Only a short synopsis of the SIPPET study was presented at the ASH
annual meeting—just enough to cause a stir and raise many questions. You can be
sure that as soon as the journal article is released, it will be examined by
bleeding disorder experts worldwide. Questions will undoubtedly be asked about
the handling of confounding variables and whether the study sample size was
large enough.
            And experts
will have another question, too: Why didn’t the study include any of the new
prolonged half-life products, several of which appear to have a lower
immunogenicity than other recombinant factor VIII products?
            Should you
switch your toddler from a recombinant to a plasma-derived factor VIII product
containing VWF based on the preliminary SIPPET results, in the hope that it
will reduce the risk of developing an inhibitor? This is a question for you and
your hematologist, but if you were a betting person, the answer would be no. To
bleeding disorder experts, the results of SIPPET are not a bombshell, but
merely a piece of the puzzle that is inhibitors.5 The conclusions of this study
contradict those of several other studies. It may take years, and several
additional studies, to sort everything out. MASAC is on top of this, and as the
data becomes available, you can be assured that NHF will share its expert
opinion. So keep calm and carry on!
1. (accessed Feb. 7,
2. Inhibitors are
a major complication of hemophilia in which a person’s immune system mistakenly
recognizes infused factor as a foreign (and potentially dangerous) protein, and
develops antibodies (inhibitors) to inactivate the factor, making factor
infusions ineffective.
(accessed Feb. 7, 2016).
4. The VWF-rich
plasma-derived factor VIII concentrates used by SIPPET: Alphanate (Grifols),
Fandhi (Grifols), Emoclot (Kedrion), or Factane (LFB). The VWF-free recombinant
factor VIII products used: Recombinate (Baxalta), Advate (Baxalta), Kogenate SF
(Bayer), or Refacto AF (Pfizer).
5. Visit the
Believe Limited website for an excellent interview by Patrick James Lynch of
bleeding disorder expert Dr. Steven Pipe about the SIPPET findings:
(accessed Feb. 7, 2016).

Resources for People with Inhibitors

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.
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.
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?
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.
Managing Your Child’s Inhibitor
Laureen A. Kelley and Paul Clement
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:
The Great Inhibinator!
Chris Perretti Barnes
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
To order:
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:
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:
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
Nordisk also offers product and copay assistance programs to eligible patients
who have been prescribed Novo Nordisk products.
For info:
1-844-NOVOSEC (1-844-668-6732)
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.
Baxalta Resource Helpline 888-229-8379
To enroll in CARE: 855-322-6282

Inhibitor Summits are Coming!

I was present way back at the first ever inhibitor summit meetings, brainchild at the time of George McAvoy of Novo Nordisk, and funded by Novo Nordisk. Now run by National Hemophilia Foundation (NHF) with funding from Novo Nordisk, NHF is pleased to announce the 2014 Inhibitor Education Summits, designed to specifically cater to your inhibitor educational needs. Come join this dynamic event and interact with expert healthcare professionals as well as other patients and their families for a weekend of education designed to improve your overall health and quality of life.

The Summits provide:

• Travel and lodging financial assistance provided for eligible patients and their caregiver(s)

• Both locations accessible to wheelchairs and other mobility devices

• Four different educational tracks tailored to suit your needs as a patient or caregiver

• An Interactive Education Camp for Youths, including an off-site activity (Ages 4-12)

• Childcare for infants-3 years old

To learn more, contact NHF:  877-560-5833 or

or go to

Largest Ever Inhibitor Meeting

The Novo Nordisk Dallas Inhibitor Education Summit was the largest ever gathering of inhibitor patients in the world–very impressive! Over 75 families attended. In the US, there are only about 1200 people with inhibitors. Trying to get this small group together for weekend is not easy, but they came from Wisconsin, Massachusetts, Florida, California and Pennsylvania, as well as many other states. It was great to see both old friends and make some new friends.

On Friday, I facilitated the Novo Nordisk Consumer Council Meeting, which brought together for the last time a team I have worked with for two years. Our role is to offer feedback to the marketing team at Novo Nordisk about product enhancement, educational materials, and needs in the inhibitor community. We also reviewed the first winner of the Uninhibited Achievement Award, Mike McNamara, whom we had all selected at a previous webcast conference. Gar Park of Novo Nordisk reviewed our achievements of the past two years, and they were amazing! I think of all the consumer advisory groups I’ve worked with or facilitated this has been the most productive.

There were lots of tears shed when parting came (right, Theresa?), and we are now accepting applications for the next two years. If you know anyone with inhibitors or is a caregiver of a person with inhibitors who might be eligible and available, please let us know! We will need about 10 new council members.

The rest of the weekend was a series of excellent lectures and panel discussions on topics ranging from factor IX and inhibitors (an incredibly rare combo) to pain meds to advocacy. Excellent speakers, audience participation and flawless event planning by Cadent Medical made for a memorable weekend.

Next year the Summits will be held, but maybe with some changes in venue and direction. Be sure to check with both the NHF and HFA to learn where and when they will be held. If you have inhibitors, you will not want to miss these! All travel expenses have been paid by Novo Nordisk so it will cost you nothing to attend, and you have everything to gain!

(Photos: top down, Panel discussion; Consumer Council at Work; Mario and his mom, from San Antonio; Laurie with Deena and son Tyler; Jessica and Kerry; Laurie and Kerry with Cowboy Jim!)

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