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Transcript
The Twenty-Third Annual Report of the
Fibrodysplasia Ossificans Progressiva (FOP)
Collaborative Research Project
Frederick S. Kaplan, MD
Robert J. Pignolo, MD, PhD
Eileen M. Shore, PhD
May 2014
Contents
Part III: Are We There Yet? . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 33
Part I: Introduction. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4
A. The Heart and Soul of the FOP Community . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5
B. The Journey . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7
Part II: Notable Developments in 2013 . . . . . . . . . . . . . . . . . . . 11
The Cali-Weldon FOP Pre-clinical Drug Testing and Biomarker Development Program . . . . . . . . . . . . . . . . . . .
Baby Teeth Are Vital for FOP Research: The Tooth Ferry Program at the FOP Lab. . . . . . . . . . . . . . . . . . . . . . .
Disease-, Stage-, and Drug- Specific Biomarkers for FOP. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Anesthetic Management for Patients with FOP . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Chest Pain Drug a No-Go for FOP: A Small Clinical Trial From Nagoya, Japan . . . . . . . . . . . . . . . . . . . . . . . . .
Do Narcotics Enhance FOP Lesion Formation? . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
What’s the FOP Mutation Doing There?. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
The FOP Mutation Builds a Scaffold for Ectopic Bone Formation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Promoting FOP . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
A Square Dance for FOP. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Another In Vitro Genetic Approach to Inhibiting the FOP Gene. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
The FOP-POH Connection. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
The Dorsomorphin Class: Ready for Matriculation?. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Retinoic Acid Receptor Gamma (RARy) Agonists: De-Railing the FOP Train. . . . . . . . . . . . . . . . . . . . . . . . . . .
FOP in China . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Clinical Reports on FOP from Around the Globe . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
FOP: The Written Word – 2013 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
FOP: The Spoken Word – 2013 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Tell Me a Story. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Awards & Honors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
FOP: What Can I Do to Help? . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
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Why Are Clinical Trials Necessary in FOP? . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
How Does Basic Science Research in FOP Help in the Design of Clinical Trials? . . . . . . . . . . . . . . . . . . . . . . . .
How Can Natural History Studies Enable More Effective Clinical Trials?. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Why Do We Need a Comprehensive Study of FOP Flare-ups?. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Why Do Clinical Trials Fail?. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
What Are Biomarkers and Why Are Biomarkers Needed for Clinical Trials in FOP? . . . . . . . . . . . . . . . . . . . . . .
What Are the Best Pre-clinical Animal Models for Testing Drugs in FOP? . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
What Are Potential Treatment Strategies for Inhibiting FOP flare-ups? . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
What Categories of Drugs Might be Considered for Clinical Trials?. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
What Types of Clinical Trials Might be Necessary in FOP? . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
How Might Clinical Trials Be Designed in FOP? . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
What Will Be the Measureable Endpoints of Clinical Trials in FOP?. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
What Are the Hurdles to Drug Development for FOP?. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Almost Every Month, a Report is Published on a Potential New Treatment for FOP.
What Should We Make of This? . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Do Clinical Trials Mean Treatments? . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Will Clinical Trials in FOP Be Large? . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Will Everyone Be Eligible for Clinical Trials?. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Will Children and Adults Be Enrolled in Clinical Trials? . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Will Individuals with FOP Variants Be Enrolled in FOP Clinical Trials? . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
How Will the Limited Number of Eligible Patients Affect the Design of a Clinical Trial?. . . . . . . . . . . . . . . . . . .
Will Participation in One FOP Clinical Trial Preclude Participation in Another? . . . . . . . . . . . . . . . . . . . . . . . .
Will Placebo Controls be Necessary in FOP Clinical Trials? . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
How Long Will an FOP Clinical Trial last? . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Where Will Clinical Trials Be Conducted? . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Who Will Conduct Clinical Trials?. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
How Many Clinical Trials Will There Be?. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
How Will Clinical Trials for FOP Be Funded?. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
What is an Orphan Disease, an Orphan Drug, NORD, the ODA, the FDA, the RDA, and an IND? . . . . . . . .
What is a Data Safety Monitoring Board (DSMB), and How Will Their Work Affect Clinical Trials? . . . . . . . . .
What is Involved in Conducting a Clinical Trial? . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
When Will Clinical Trials Begin?. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
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Many Thanks to You. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 50
ii FOP Collaborative Research Project Annual Report 2014
FOP Collaborative Research Project Annual Report 2014 iii
PART I:
Introduction
Introduction
Oklahoma, or at a Burns Supper in Aberdeen, Scotland,
or in a ballroom in New York City, or on a frozen lake in
Iowa, or on the back nine in Massachusetts, or in a
hundred other cities, villages, or hamlets around the
globe – because that is what this story is about.
A. The Heart and Soul of the
FOP Community
Molecular pathway identification, preclinical drug
testing, medicinal chemistry evaluation, pluripotent stem
cell modeling, somatic mutation analysis, FOP gene
silencing . . .
Much of this year’s science news seems to come straight
from the set of "Mission Impossible." There were plenty
of incredible developments in the science of FOP in
2013 and we will discuss them, but not yet.
The main story of 2013 was not about science. It was
not about genes. It was not about mice. It was not about
molecules. It was not even about drugs that will soon
enter clinical trials and that we are all extremely excited
about. Yes; those are all important, and that is where we
are now. But, how did we get here?
Part I
Mr. Harold Kaplan (left) of Boca
Raton, Florida with Richard
and Gail Simcox of Banchory,
Scotland at the IFOPA 25th
Anniversary Celebration and
FOP Family Gathering
4 FOP Collaborative Research Project Annual Report 2014
We are going to
begin this story at a
gas station in
California, or in a
parking lot in New
Jersey, or at a bingo
hall in Pennsylvania,
or at a country fair in
At Lincoln’s Legacy in Sioux City
Iowa from left to right:
Lucas Whitmore (Illinois), Kyle
McWilliams (Iowa), Adrienne
Bailin (Oregon), Lincoln
Wheelock (Iowa), Dr. Fred Kaplan
(Pennsylvania), and Sivapriya
Saravanakumaran (Minnesota)
It is not about
bones. It is about
the heart. It is
about the power
and commitment
of individuals to
make a difference.
It is about the soul
of a small
worldwide
community that
flourishes on every
habitable
continent. It’s
about you!
As individuals, as
families, as friends, you shared your raw emotions which
you forged into your dreams, and you put those dreams
to work. That is what got us involved – all of us. Our
minds followed your hearts; not the other way around.
Francizka and Saskia Muelhoff
(left) with their parents Fredy
and Kirsten Muelhoff (right) of
Plettenberg, Germany and
Dr. Bob Pignolo and Petra
Seeman (center) at the FOPev
Family Meeting in Valbert,
Germany
Some think that
this story is
primarily about
science, but it is
not. That is not
why we are here.
The science is a tool
to get us where we
want to be, but the
story is not about
the tool. It is about
you.
You have shared
your stories, your
medical histories,
your hearts and your souls, your triumphs and your
losses, your blood, your bodily fluids, and even your baby
teeth. But, you have done more than that.
FOP Collaborative Research Project Annual Report 2014 5
As doctors and scientists, we do not work in isolation.
We have gotten to where we are in this journey because
of you. Because you gave of yourselves – from the heart
– and you have been with us every step of the way –
patients, families, patrons and friends – you’ve made it
happen. You, the individuals, have fueled this entire
journey.
In 2013, the
International
FOP Association
(IFOPA), which
was founded by a
true visionary,
Jeannie Peeper, to
connect and
represent each
individual in the
IFOPA President and Founder Jeannie
worldwide FOP
Peeper with Dr. Fred Kaplan at the
IFOPA 25th Anniversary Celebration
community,
and FOP Family Gathering in
celebrated its
Orlando, Florida
25th Anniversary
with a patient
and family gathering in Orlando, Florida. Fifty-nine
patients and over 279 individuals attended including
patients, doctors, researchers, families, friends, and
representatives of pharmaceutical companies from
around the globe.
community when we work together, and it will only
grow stronger over time. This work is by you, for you,
and about you. Your dream is our dream.
Fifty years ago this past August, the late Reverend
Martin Luther King stood on the steps of the Lincoln
Memorial, poised to give a speech that moved a nation.
He reached into his suit pocket for his notes. Behind
him stood the famous opera singer, Mehalia Jackson. She
moved forward and whispered to Dr. King.
“Martin,” she said, “Tell them what’s in your
heart. Not what’s in your head. Tell them about
the dream.”
Where the heart leads, the head follows – to see the
way things could be, rather than the way they are.
Where the heart leads, the head follows. We are where
we are because of you. You have led us on this journey to
the gene discovery and beyond, to the gates of clinical
trials where we are today. As the saying goes, “If you want
to go fast, go alone; if you want to go far, go together.”
This is your community; this is your dream. It’s our
dream too.
At the meeting, FOP patients registered to participate
in a patient reported outcome study (sponsored by
Clementia Pharmaceuticals) to define functional
endpoints for future clinical trials, and a biomarker
study (sponsored by Novartis Institute for Biomedical
Research) to find molecules that define the evolving
stages of an FOP flare-up. These studies are among the
first of their kind and will be critical for the development
of clinical trials long into the future.
During this past year, you achieved an unprecedented
73 percent worldwide response to the FOP flare-up
survey – a vehicle that will serve as a standard for
designing clinical trials for years to come. The data are
immense and are presently being analyzed by physicians
and statisticians. The results will be the subject of several
papers and an inexhaustible database for clinical trial
design. This is an example of the power of the FOP
6 FOP Collaborative Research Project Annual Report 2014
B. The Journey
In a monumental award-winning article entitled,
“The Mystery of the Second Skeleton,” which appeared
in the June 2013 edition of the Atlantic Monthly,
Carl Zimmer wrote: “A tiny percentage of the world’s
population suffers from fibrodysplasia ossificans
progressiva which locks its victims in cages of superfluous
bone. For centuries, these patients were dismissed as a
lost cause. But recent genetic and technical advances
have propelled researchers towards an understanding
of this disease that may transform the lives not just of
people who suffer from it, but of those afflicted by much
more common ailments. Rare diseases, it turns out, are
more relevant than we ever imagined.”
Worldwide
interest in FOP
research
blossomed after
the discovery of
the FOP gene
in 2006. New
technologies
are being
Fadel Al-Garni of Saudia Arabia and
developed at a
his children Ahmed Al-Garni and
rapid pace and
Norah Al-Garni meet Dr. Kaplan at
new ideas are
the University of Pennsylvania
being forged
daily. FOP research is now an international enterprise. At
least 30 distinct venues perform research on FOP, with
the core activity at the Center for Research in FOP &
Related Disorders at the University of Pennsylvania.
Scientists and physicians at university laboratories,
researchers at corporations, pharmaceutical companies,
biotechnology firms, and international government
agencies have expressed keen interest in FOP and are
engaged in a worldwide effort to create better treatments
and a cure.
Dr. Ursula Schramm (Novartis Pharmaceuticals),
Dr. Fred Kaplan (UPenn), Whitney Leckenby
(Olympia, Washington), Dr. Robert Pignolo (UPenn),
and Dr. Donna Grogan (Clementia Pharmaceuticals)
At the Center for Research in FOP & Related
Disorders at the University of Pennsylvania physicians
and scientists pursue research initiatives that move us
closer to our common goal and dream of establishing
more effective treatments and eventually a cure for FOP.
In 2013, we have:
• Collaborated with international pharmaceutical
companies to develop promising compounds for
clinical trials
• Conducted a global survey of FOP flare-ups that
will be used to design clinical trials
Edixon Guancha (center) and his
mother Gloria (right) of Valencia,
Carabobo, Venezuela meet with
Amanda Cali at the IFOPA 25th
Anniversary Celebration
• Completed the first-year of a comprehensive preclinical drug-testing and biomarker discovery
program using FOP mouse models for testing
possible treatments for FOP
• Developed in vitro model systems using mouse and
human adult stem cells for pre-clinical drug testing
• Studied microenvironmental factors in early
FOP lesions that lead to increased signaling from
the mutant FOP receptor and the subsequent
formation of heterotopic bone; and, importantly,
identified a drug to block it in an FOP animal
model
• Examined neuro-inflammatory triggers of FOP
flare-ups, and importantly, investigated a class of
drugs to block it
• Developed a research program to investigate the
interaction of the innate immune system with
tissue progenitor cells that lead to FOP flare-ups
FOP Collaborative Research Project Annual Report 2014 7
• Investigated molecular mechanisms by which ultrarare FOP variants trigger promiscuous signaling
leading to flare-ups
• Identified important intermediates in FOP lesion
formation and a key biomarker to monitor disease
progression in mice and humans.
• Explored the bone marrow cell contributions to
triggering FOP flare-ups
Our researchers at all
levels - high school,
undergraduate, medical,
Ph.D. candidates, postdoctoral fellows, and
senior scientists at the
Center for Research in
Dr. Julia Haupt in the FOP
FOP and Related
Laboratory
Disorders continue to
ask fundamental questions that make the future:
• Initiated studies to identify the extreme
physiological variability in classic FOP
• How does the lesional tissue microenvironment
influence the progression of FOP?
• Identified critical molecular cross-talk in genetic
pathways of endochondral and intramembranous
bone formation relevant to FOP and its sister
disease progressive osseous heteroplasia (POH),
and in the process identified new therapeutic
targets for each condition
• What is the identity of progenitor cells in FOP
lesion and bone formation?
• Established that the FOP mutation directly
impacts cartilage cell formation, a process that
precedes the formation of heterotopic bone in FOP
• What is the relationship between the immune
triggers and the FOP stem cells in initiating FOP
flare-ups?
• Investigated limb patterning and joint specification
pathways relevant to the congenital abnormalities
and early arthritis of FOP
• How do some FOP flare-ups resolve spontaneously
without forming scar tissue, cartilage, or bone?
• Continued work on FOP receptor variants that
provide therapeutic clues for allosteric drug
development
• What are optimal in vivo systems in which to
model FOP disease activity and progression and in
which to test the effects of drugs that are relevant
to the design of clinical trials?
Francois Jacob, the French war hero, geneticist, and
Nobel Prize laureate who elaborated how traits are
inherited stated:
“What mattered more than the answers were the
questions and how they were formulated. In the
best case, the answers led to more questions.
It was a system for concocting expectation, a
machine for making the future.”
• How do the FOP mutation and associated
microenvironmental factors re-program somatic
cells to a new cell fate?
• How do activating mutations in ACVR1/ALK2
alter the specification and fate of the skeleton
and joints and what does this tell us about ways
to prevent degenerative arthritis in FOP and in
others?
• How do the ultra-rare genetic variants of
FOP which affect only 2-3% of FOP patients
worldwide inform our understanding of the broken
genetic switch that propels renegade heterotopic
ossification in FOP?
• Which drugs are amenable to the most rapid
development for early clinical trials?
8 FOP Collaborative Research Project Annual Report 2014
Investigations at the Center focus on six major research
areas. The researchers pursuing these studies have taken
us to new levels in our understanding of FOP.
Experiments on immunologic
and microenvironmental
mechanisms that induce and
sustain FOP flare-ups are
conducted by graduate student
Michael Convente, pre-medical
student Carter Lindborg, and
postdoctoral fellows Julia Haupt
Dr. Salin
and Haitao Wang. Stunning
Chakkalakal
new therapeutic targets and
at work on his
computer in the
opportunities are emerging from
FOP Laboratory
their work, and it is possible
that one or more such targets
will become the basis for clinical trials with
re-purposed drugs.
In vitro and in vivo FOP
model development – is
conducted by post-doctoral
fellows Julia Haupt and
Salin Chakkalakal, by Dr.
Andria Culbert, by research
Research scientist Dr.
specialists Ruth McCarrick
Vitali Lounev at his desk
Walmsley, Deyu Zhang,
in the FOP Laboratory
and pre-medical student
Carter Lindborg. This work is critically important for
drug discovery and development.
FOP lesional stem cell
identification and
differentiation is
investigated by Vitali
Lounev, Michael Convente,
Salin Chakkalakal, Will
Towler, Andria Culbert,
Dr. Andria Culbert at work
Ruth McCarrick Walmsley,
the FOP Laboratory
and Robert Caron. These
studies identify the specific cells and mechanisms that
can be targeted to block heterotopic ossification
Studies on the molecular pathways of ALK2
Signaling in FOP are conducted by Meiqi Xu, Salin
Chakkalakal, Julia Haupt, Michael Convente, Haitao
Wang, and Andria Culbert. This vital research enables the
development of drugs that target these pathways.
Graduate student
Will Towler in the
FOP Laboratory
Investigation of pathway crosstalk during developmental and
postnatal life is conducted by Will
Towler, Michael Convente, Julia
Haupt, Andria Culbert, Girish
Ramaswamy, Haitao Wang, John
Fong, and Carter Lindborg –
studies that deepen our
understanding of common
molecular mechanisms relevant to
all forms of heterotopic ossification.
Pre-clinical drug testing is
conducted by Haitao Wang, Carter
Lindborg, Deyu Zhang, and Salin
Chakkalakal.
Clinical trials are on everyone’s
minds and they are not far away.
The theme of 2013 was how you,
the FOP patients and families
Dr. Deyu Zhang
worldwide, have laid the
in the FOP
foundation for clinical trials by
Laboratory
your participation in FOP research
– from your global contribution to defining the natural
history of FOP flare-ups, through your participation in
new biomarker studies, to your contributions to patient
reported outcome
studies in FOP, to
your generous
donations of blood,
teeth, urine and
tissue specimens for
ongoing research,
and to your
fundraising and
From left to right: Francisco
educational efforts in
Romero, Jineth Valecillos
and Ariana Romero from Los
the broader
Teques, Miranda, Venezuela
community
at the IFOPA 25th Anniversary
worldwide. You
Celebration and FOP Family
make all of this
Gathering in Orlando, Florida
possible. This work
will continue and expand into 2014 and beyond.
FOP Collaborative Research Project Annual Report 2014 9
In Part II of this year’s Annual Report, we will
highlight notable developments in FOP research in 2013
at home and around the globe.
In Part III of the Annual Report, by popular demand,
we will review important questions and principles that
will guide clinical trials.
Kay Rai greets Jordyn
and Bryan Bugarin of
Baltimore, Maryland
Dr. Bob Pignolo of
Philadelphia meets
with Dr. Olli Morhart of
Garmisch-Partenkirchen
at the FOPev Family
Meeting in Valbert,
Germany
In Japan, the crane is a holy or mystical
creature and is said to live for a thousand years.
It is believed that anyone who folds a thousand
origami paper cranes (or Senbazuru) will be
granted a wish. Saskia Blonk, the mother of
Yorick Blonk, a young boy with FOP from
the Netherlands, learned to fold paper cranes
during her childhood and always remembered
the story of the thousand cranes that could
grant a wish. In December 2012, she launched
a “folding” campaign among friends and family.
Within days, the first crane started to “fly in.” In
November 2013, she presented a “Senbazuru”
of a thousand colorful paper cranes made
into a tapestry to the research team from the
University of Pennsylvania. Perhaps, this little
bit of magic and artistry will help our mutual wish
for a cure for FOP to come true.
Pictured with the tapestry, now hanging in
the FOP Laboratory at the University of
Pennsylvania is Dr. Eileen Shore and Dr.
Frederick Kaplan.
10 FOP Collaborative Research Project Annual Report 2014
Notable Developments in
2013
Four generations of FOP physicians
from left to right: Drs. Michael Zasloff,
Fred Kaplan, Robert Pignolo and
Vincent Whelan meet to discuss
FOP at the IFOPA 25th Anniversary
Celebration in Orlando, Florida
Part II
IFOPA Board Chairman Mark Gambaiana (left) and Dr. Fred
Kaplan (right) greet Mya Watts and her mother Tamera
Watts of Marietta, Georgia at the IFOPA 25th Anniversary
Celebration in Orlando, Florida.
FOP Collaborative Research Project Annual Report 2014 11
Part II:
commercially available for use in other indications and
could be re-purposed for FOP, while others are novel and
are being developed specifically to target FOP.
Notable Developments
in 2013
The Cali-Weldon FOP Pre-clinical
Drug Testing and Biomarker
Development Program
The FOP Scientific Retreat (August 2011;
Philadelphia) consolidated new frontiers in FOP
research, and identified new targets for therapeutic
intervention. Never before has there been both a
repertoire of existing candidate drugs and a sound
scientific foundation for testing new drugs in animal
models of FOP. With so many potential therapies
available, we began a preclinical drug testing program
and biomarker discovery program.
Ian and Amanda Cali (right) of
Mountain Lakes, New Jersey meet
with friends Julie Schmidt and Sherie
Sobke at the IFOPA 25th Anniversary
Celebration in Orlando, Florida
With the
identification
of the FOP
gene mutation
and the
development
of high fidelity
animal models
of FOP, the
goal of a
treatment for
FOP is now
more
achievable
than ever.
The aims of this novel program are to:
1. Test the efficacy of currently available drugs and
experimental compounds to inhibit heterotopic
ossification (HO) in animal models of FOP.
2. Identify disease-specific and stage-specific
biomarkers of FOP in animal models of FOP.
Joey Hollywood (seated next to
Dr. Kaplan) and his parents Joseph
and Suzanne Hollywood (seated
on couch at left and center) of
Bridgewater, New Jersey visit with
Dr. Ursula Schramm (standing, left,
from Novartis), and Dr. Donna Grogan
(seated, left, from Clementia) and (left
to right) Dr. Pignolo, Dr. Kaplan, (both
from UPenn), Dr. Hsiao (UCSF) and
Marilyn Hair (IFOPA Board Member
and Chair as of January 2014).
The goal of this program is to test drugs that are most
promising in the short term and most likely to be
validated for clinical trials in the foreseeable future. Some
of the compounds already tested (and to be tested) are
12 FOP Collaborative Research Project Annual Report 2014
During Year-1 of this Program, we performed multiple
rounds of drug testing, including evaluation of six drugs
and one candidate biomarker.
Of the drugs tested, we identified an approved
medication that appears to offer the best combination
of efficacy, deliverability, and availability in decreasing
heterotopic ossification. This medication will be studied
intensively in 2014 in another more-specific mouse
model of FOP and has possibility of entering clinical
trials in the future, as a re-purposed drug for FOP.
We also identified a second compound that appears
highly effective in inhibiting HO in a mouse model,
but the route of delivery and bioavailability remain
outstanding issues for human use at this time.
Importantly, we identified a novel biomarker that is
a stage-specific biomarker of FOP lesion progression in
mice and in humans.
Based on our experience during the first year of this
Program, an additional Research Specialist will be
hired in 2014 to help implement the mandates of this
Program, sponsored by the Cali and Weldon families.
We will continue to develop this extremely successful
Program within the Center for Research in FOP &
Related Disorders with the goal of bringing currently
available drugs to clinical trials as soon as possible.
Baby Teeth Are Vital
for FOP Research:
The Tooth Ferry Program
at the FOP Lab
The participation of so many patients and families who
contribute blood/DNA samples to advance FOP research
has been invaluable and is enormously appreciated. These
samples were critical for discovering of the FOP gene
and for identifying the specific DNA sequence changes
that occur in classic and variant forms of FOP. Although
much FOP research is now done using mouse models of
FOP, it will always be essential to have patient cells and
tissues in order to confirm that the information that we
learn from mice holds true in humans.
We relied on blood
samples from patients for
many years since blood can
be safely obtained without
risk of triggering an FOP
flare-up. However, blood
Clara Bouchard of
cells provide limited
Montreal, Canada and
Jaxon Hamilton of Ottawa,
information about FOP
Canada
lesion formation.
Fortunately, recent
advances have identified additional types of human cell
and tissue samples that can be obtained safely and are
vitally important to our work. One of these cell types is
“SHED cells”.
SHED stands for Stem cells from Human Exfoliated
Deciduous teeth – a long name that describes the stemlike pluripotent cells that are inside primary or baby
teeth. When a baby tooth falls out naturally, we can
recover the cells from inside the tooth. We have used
baby teeth from FOP patients to show that these cells can
be grown in our lab and treated in special ways to form
cartilage and bone cells, providing us with an informative
system to examine how the FOP mutation affects the
differentiation potential of cells involved in an FOP
lesion.
A few years ago, the FOP Center started a “Tooth
Ferry” program to encourage families to send FOP baby
teeth to us so that cells from these teeth could be used for
FOP research. These cells have already given us bountiful
information about the effects of the FOP mutation
on cartilage and bone cell formation. These cells were
used in our recent studies to down-regulate the mutant
(damaged) copy of the FOP gene and are being used in
our ongoing studies on the effects of microenvironmental
factors on FOP flare-ups and lesion formation. Thus,
SHED cells continue to be extremely vital for many
of our laboratory experiments. Because the cells have a
limited lifespan and since multiple samples from a person
are very informative, we continually need additional
“donations” to continue to conduct our studies with
SHED cells.
Anyone with a child who
is losing teeth can
participate in “The Tooth
Ferry Program.” When
your child loses a tooth or
needs to have one pulled at
the dentist’s office, you can
A.J. Gonzales and his
mother Kristi during a visit
send it to us in a
to UPenn
preassembled kit that we
will provide to you. Teeth
from siblings and non-family members are also welcome
for comparison. In addition to baby teeth, we are also
happy to receive wisdom and other permanent teeth
from people with FOP. Permanent teeth also contain
stem cells and we are currently investigating their use and
applicability in FOP research.
FOP Collaborative Research Project Annual Report 2014 13
Ruth McCarrick-Walmsley is heading up our effort
to collect the teeth and study SHED cells. There is a
brief window of opportunity for receiving the teeth
with still-healthy cells, so we have developed specific
instructions for their handling and shipping. If you
decide to participate, we will send you a kit including
all of the necessary return packaging (for several teeth),
return FedEx labels, Ruth’s contact information, a tooth
diagram to fill out and return, and a copy of instructions.
We are also providing information about the program
on the IFOPA website, however it is very important that
you contact us before sending a tooth – if teeth arrive
by surprise at the lab, we may not be ready and able to
prepare them optimally.
The tooth ferry
kit is very simple
to use. This is an
IFOPA supported
program and
there is no cost to
you. If you have
children with
teeth still to lose
or are being
Ruth McCarrick-Walmsley at work
pulled, please
with tissue culture in the FOP Lab
contact Ruth
by phone (610-513-4470) or email [email protected]
upenn.edu and a “Tooth Ferry Kit “ will be on its way to
you soon!
Disease-, Stage-, and Drug- Specific
Biomarkers for FOP
In 2013, we continued a comprehensive study of
biomarkers from serum and urine samples from patients
with FOP to look for readily detectible markers that
are FOP disease-specific, lesion-specific, and stagespecific, which can be used to monitor for drug-specific
effects. In addition, we began a comprehensive urine
biomarker study sponsored by Novartis Institute for
Biomedical Research (NIBR) in order to identify stagespecific biomarkers associated with FOP flare-ups. This
essential work is vital to the design and implementation
of future clinical trials. Collection of serum and urine
samples from FOP patients for the prospective study of
biomarkers will help validate clinical findings of flare-up
14 FOP Collaborative Research Project Annual Report 2014
stages. In addition, biomarker analysis from FOP mouse
models will be instrumental in this ongoing analysis over
the next several years.
Read Dr.Kilmartin and her colleagues' paper at
http://www.ifopa.org/news-and-events/latestnews1/429-anesthesia-and-dental-workshops.html
Anesthetic
Management
for Patients
with FOP
Anesthetic
management for
patients with FOP is
Dr. Annamarie
challenging. Cervical
Horan, Director of
spine fusion, locking of
Clinical Research in
the temporomandibular
Orthopaedics, with
Patrick Hesketh,
joints, thoracic
Research Director of
insufficiency syndrome,
the FOP Urinary
restrictive chest wall
Biomarkers study
disease, acute airway
reactivity, and extreme sensitivity to oral trauma
complicate airway management and anesthesia, and pose
life-threatening risks. Numerous single-case reports
describe the anesthetic management of individuals with
FOP, but until now no comprehensive study has been
published on the anesthetic management of patients with
FOP.
FOP patients no longer have to wonder about issues
of general anesthesia. In a landmark clinical paper in the
Journal of Anesthesia and Analgesia entitled, “General
anesthesia for dental procedures in patients with
fibrodysplasia ossificans progressiva: a review of 42 cases
in 30 patients,” Kilmartin and colleagues from Jefferson
University and the Center for Research in FOP &
Related Disorders at the University of Pennsylvania
describe the detailed multidisciplinary approach to the
perioperative management of patients with FOP.
The paper specifically reviews general anesthesia
for dental procedures but is applicable to the
general anesthetic management of FOP patients for
any procedure. Key findings of the paper will be
incorporated into upcoming revisions of the FOP
Treatment Guidelines and will be available on the
IFOPA website.
Chest Pain Drug a No-Go for FOP:
A Small Clinical Trial
From Nagoya, Japan
Two studies from Nagoya University Graduate School
of Medicine in Nagoya, Japan investigated the clinical
applicability of anti-anginal agents (drugs used in treating
cardiac-related chest pain) to suppress transformation of
muscle cells into bone cells in mice and humans.
The papers, published in the Journal of Bone and
Mineral Metabolism and the Orphanet Journal of
Rare Diseases, describe the screening of FDA-approved
drugs to suppress a downstream regulator of FOP gene
expression. The investigators found that two antianginal agents, fendiline hydrochloride and perhexiline
maleate suppressed the promoter (regulatory element)
of a downstream target of the FOP gene. Mice taking
perhexiline showed a 38 percent reduction in the
volume of heterotopic bone compared to control mice.
Mice taking fendiline showed only a slight reduction of
heterotopic ossification. The study led by Yamamoto and
colleagues provided the rationale for a small clinical trial
of perhexiline maleate in the treatment of FOP.
In the follow-up paper in the Orphanet Journal
of Rare Diseases entitled “Perhexiline maleate in the
treatment of fibrodysplasia ossificans progressiva: an
open-labeled clinical trial,” authors Kitoh and colleagues
from Nagoya University, Nagoya, Japan assessed the
ability of perhexiline to suppress heterotopic ossification
in a small group of Japanese FOP patients. In this
open-label single-center study, FOP patients were
treated with perhexiline maleate for a total of twelve
months and followed for a consecutive twelve month
period after medication was discontinued. The safety of
treatment was assessed regularly by physical and blood
examinations. The efficacy of perhexiline in preventing
heterotopic ossification was evaluated by the presence
of flare-ups, measurement of serum bone markers,
and changes in total bone volume calculated by three-
dimensional quantitative computed tomographic
(QCT) images.
Ultimately, the authors could not prove the efficacy of
oral perhexiline maleate in the prevention of heterotopic
ossification in FOP. Although serum alkaline phosphatase
appeared to be a promising biomarker for monitoring the
development of ectopic bone, perhexiline maleate showed
no beneficial effect in the prevention or treatment of
FOP. Importantly, quantification of changes in total
bone volume by whole body CT scanning proved to be a
reliable evaluation tool for disease progression and might
be used in subsequent clinical trials of FOP.
The authors stated that “while pharmaceutical
companies do not invest a large amount of research in
developing novel therapeutic agents for orphan diseases
including FOP, a promising alternative for orphan
diseases is a drug repositioning strategy in which a drug
currently used for patients with one disease is applied to
another disease. The advantage of this strategy is that the
identified drug can be readily applied to clinical practice,
because the optimal dose and adverse effects are already
established.” This is a guiding principle of the CaliWeldon FOP pre-clinical drug testing and biomarker
development program described in this annual report.
Dr. Kaplan (UPenn) and James Dizon
of Richmond Hill, Ontario in London,
Ontario at the Canadian FOP
Family Meeting
Do Narcotics Enhance
FOP Lesion Formation?
In a paper published in Inflammation Research
entitled, “Opioid signaling in mast cells regulates injury
responses associated with heterotopic ossification,” Lixin
FOP Collaborative Research Project Annual Report 2014 15
Kan, John Kessler, and colleagues from the Department
of Neurology at Northwestern University describe how
heterotopic ossification is worsened by narcotics in a
BMP4 transgenic mouse model (the FOPPY mouse).
Previous work has established that mast cells are
abundant at every stage of FOP lesion formation in
mice and humans and that mast cell activation may play
a major role in the induction of FOP lesions. Additional
studies strongly suggest that targeting mast cells might
have a beneficial therapeutic effect in mouse models
of FOP.
and that blocking opioid receptors, blocked mast cell
activation and heterotopic ossification.
Thus, blocking opioid signaling in mast cells may
be a potential therapeutic target in heterotopic
ossification. This study has important implications
for the treatment of FOP patients and suggests that
the use of narcotics in FOP may enhance FOP lesion
formation. Additional experimentation is necessary to
test this important hypothesis.
This work was supported, in part, by an Ian Cali
Developmental Research Grant to Dr. Kan from the
Center for Research in FOP and Related Disorders.
What’s the FOP Mutation
Doing There?
Four papers published in the April 6, 2014 online
issue of Nature Genetics report the mysterious and
unexpected presence of ACVR1/ALK2 mutations in
highly malignant childhood brain tumors called diffuse
intrinsic pontine gliomas (DIPGs). DIPGs have a
universally poor prognosis. Neither chemotherapy nor
any other drug shows survival benefit in clinical trials of
children with DIPGs.
Kathleen Degenhardt of
Goodsoil, Saskatchewan
pauses on her Segway to
greet Dr. Robert Pignolo of
Philadelphia at the Canadian
FOP Family Meeting in
London, Ontario.
A previous study by Kan and Kessler using the FOPPY
mouse model also showed that increased expression of
the pain-inducing mediator, substance P (SP) enhanced
local injury responses associated with heterotopic
ossification and that mast cells were required for this
response.
In the present study, Kan, and colleagues investigated
the role of the pain sensing pathway in mast cell
activation and found that opioid (narcotics) signaling
was intimately linked to the mast cell. Remarkably, they
found that opioid receptors were expressed on mast cells
16 FOP Collaborative Research Project Annual Report 2014
DIPGs are known to harbor somatic mutations in
histone proteins, part of the support structure for DNA
in the nucleus of cells. These mutations in histone
proteins are thought to be involved in the tumor-forming
process. Importantly, investigators also found mutations
in ACVR1/ALK2 that were identical to those seen in
patients with fibrodysplasia ossificans progressiva (FOP).
These FOP-identical mutations occur in approximately
20-30 percent of DIPGs. As in FOP, ACVR1/ALK2
mutations in DIPGs over-activate the BMP signaling
pathway. Unlike in FOP, however, the ACVR1/ALK2
mutations in DIPGs do not occur in all the cells of the
body but only in the cells of the malignant brain tumor.
Their potential role in promoting initiation or growth
of the brain tumor is unknown, but the highly selective
mutations in ACVR1/ALK2 (identical to those seen in
FOP) are thought to provide some selective advantage to
the cells of the malignant brain tumor.
These dramatic new findings, reported independently
by four groups, have critical implications for research in
brain cancer and in FOP:
1. Importantly, FOP patients do not have a predisposition to develop brain cancer and patients
with brain cancer do not develop FOP. However,
the extremely high rate and specificity of ACVR1/
ALK2 mutations (identical to those seen in
FOP) in DIPGs suggests that the ACVR1/ALK2
mutations might provide a selective advantage
for the malignant brain tumor. But what might
be the molecular basis of that selective advantage
or its function in tumor stem cells? Perhaps the
opposite is true – that the ACVR1 mutations
are a brake on tumor growth? Research into
the molecular pathophysiology of FOP lesions
and DIPGs will provide clues that are vital for
understanding the activation of FOP lesions as well
as for understanding the growth of pediatric brain
tumors and perhaps the common basis for the
activation and growth of both.
2. DIPGs and FOP have an identical molecular target
and a common scientific bond. But, what is that
bond? What do cartilage lesions and brain tumors
have in common? Present studies focus on the
microenvironment of both lesions for important
clues.
3. Treatments for FOP may help children with
DIPGs, and treatments for DIPGs may help
children with FOP.
Maria Wray of Rochester, New York
wears a terrific smile after enjoying a
delicious snack
In summary,
mutations in
ACVR1/
ALK2,
identical to
those seen
in FOP
have been
identified
in 20-30
percent of
tissue samples
from the
childhood brain cancer, DIPG. ACVR1/ALK2
mutations thus present a novel therapeutic target for two
incurable diseases – FOP (a developmental disease of
tissue metamorphosis), and DIPG (a childhood brain
cancer). These findings have the potential to be
translated quickly into the clinical arena given the poor
clinical prognosis of both conditions.
The FOP Mutation Builds a
Scaffold for Ectopic
Bone Formation
Two independent papers in 2013, one by Culbert,
Shore and colleagues from the Center for Research
in FOP & Related Disorders at the University of
Pennsylvania (Penn), and one by Matsumoto, Hsiao,
and colleagues from the University of California San
Francisco (UCSF) established that the FOP mutation
directly favors enhanced cartilage formation as the basis
for lesion formation and subsequent heterotopic bone
formation.
In a seminal paper in Stem Cells entitled, “ALK2
regulates early chondrogenic fate in FOP heterotopic
endochondral ossification,” Culbert and colleagues
demonstrated that the classic FOP mutation directly
enhances the early stages of chondrogenesis (cartilage
formation). They further showed that this process is
regulated by the FOP receptor during early chondrogenic
commitment. This important finding established a direct
role for the FOP mutation in promoting heterotopic
ossification through a cartilage intermediate and
identified ALK2-specific BMP signaling at the onset
of chondrogenesis as a therapeutic target to prevent
heterotopic ossification. The work also showed that the
ALK2 receptor is required for ectopic chondrogenesis,
and that the FOP mutation does not promote
spontaneous cartilage differentiation in the absence of
BMP stimulation.
This work establishes ALK2 as a therapeutic target
during very early stages of FOP lesion formation and
provides direct evidence for the use of drugs that prevent
the preliminary cartilage scaffold from being formed.
FOP Collaborative Research Project Annual Report 2014 17
In a related
paper in
Orphanet
Journal of
Rare Diseases,
entitled,
“Induced
pluripotent
stem cells from
patients with
Left to right: Drs. Ed Hsiao, Michael
Zasloff, Eileen Shore, Fred Kaplan, and
human
Charles Hong in Orlando, Florida
fibrodysplasia
ossificans
progressiva showed increased mineralization and cartilage
formation,” Hsiao and colleagues provide proof-ofconcept for using human induced pluripotent (iPS cells)
to probe the mysteries of FOP. The difficulty of obtaining
tissue samples from FOP patients and limitations in
mouse models of FOP prompted the study which
addressed these challenges by developing a “disease model
in a dish.”
Hsiao and colleagues created human iPS cells derived
from normal and FOP skin fibroblasts by two separate
methods, and tested the cells’ ability to contribute to
endochondral bone formation. They found that FOP iPS
cells showed enhanced cartilage formation in vitro. This
feature could be suppressed with a Dorsomorphin-like
inhibitor of BMP signaling that was developed in the
laboratory of Dr. Charles Hong at Vanderbilt.
Thus, two independent studies, one by Culbert and
colleagues from Penn and one by Hsiao and colleagues
from UCSF showed that the FOP mutation directly
enhances chondrogenesis and validates a direct cell and
tissue target for drug therapy.
In a press release from the University of California
San Francisco, Dr. Hsiao said, “The new FOP model
already has shed light on the disease process in FOP by
showing us that the mutated gene can affect different
steps of bone formation. These different stages represent
potential targets for limiting or stopping the progression
of the disease and may also be useful for blocking
abnormal bone formation in other conditions beside
FOP.”
18 FOP Collaborative Research Project Annual Report 2014
In 2013, the Center for Research in FOP and
Related Disorders awarded an Ian Cali Developmental
Research Grant to Dr. Edward Hsiao at the University
of California San Francisco. This project will investigate
various aspects of FOP pathology using human iPS cells.
Dr. Hsiao has been a pioneer in the study of iPS cells. Dr.
Yamanaka from the University of Kyoto in Japan, and
the Gladstone Institute of Cardiovascular Diseases at The
University of California, San Francisco was a co-author of
the Hsiao paper. Dr. Yamanaka was the recipient of the
2012 Nobel Prize in Medicine for his pioneering work in
developing the iPS cell technology (described in detail in
the 22nd Annual Report; “Discovery for Making Stem
Cells Wins Nobel Prize and Attracts Attention of FOP
Community.”
Read Drs. Kaplan, Pignolo and Shore's summary of
this work on the IFOPA website.
http://www.ifopa.org/news-and-events/latestnews1/363-nobel-prize-for-cloning-and-stem-celldiscoveries-attract-attention-of-fop-community.html
Promoting FOP
In a paper entitled, “Identification and characterization
of regulatory elements in the promoter of ACVR1, the
gene mutated in fibrodysplasia ossificans progressiva,”
Giacopelli, and colleagues from the Medical Genetics
Unit of the Gaslini Institute in Genoa, Italy, reported
the structure and composition of the promoter of the
ACVR1 gene. The promoter is the part of a gene that
provides the genetic information to regulate the “recipe”
for making a protein and determines when, where, and
how the gene is turned on.
Giacopelli, and colleagues showed that a number of
factors were critical in regulating exactly where, and
how the FOP gene is turned on, thus providing novel
targets for future therapies for FOP. The authors found
that the promoter of the ACVR1 gene (as with many
genes) is highly sensitive to the cells in which the gene
is expressed. This important paper provides insight into
targeting FOP therapies to specific cells.
A Square Dance for FOP
It is rare to find a protein that acts alone. The FOP
receptor ACVR1/ALK2 is no exception. Like four
partners a square dance, the FOP type I receptor, ALK2,
partners with a second type I BMP receptor and two
type II receptors to form a four-receptor complex that
doe-see-does its partners. Under normal circumstances,
the four receptor complex requires BMP ligand to
initiate signaling. The question is: In FOP, will the overjuiced ALK2 receptor dance by itself? The answer is a
resounding, “No.”
Previous investigations by Mary Mullins, our colleague
at Penn who has worked with us through a Cali
Developmental Grant, showed that, at least in some cells,
the ALK2 type I receptor functions best when its type I
BMP receptor partner is different than another ALK2
receptor. In a
recent paper
published in
Molecular
and Cell
Biology,
Bagarova, Yu
and colleagues
from Harvard
University
Adrian Bailon of El Paso, Texas and his
confirmed
parents Gerardo and Vanessa Bailon
previously
meet with Dr. Kaplan in Orlando
published
work by Kristi Wharton from Brown University and
showed that: “Constitutively active ALK2 receptor
mutants require type II receptor cooperation.” The
authors showed that the type II receptors were required
for downstream signaling even in the presence of the
mutant receptor. “Importantly, the contribution of BMP
type II receptors was independent of their enzymatic
function but still required for signaling.” The paper
demonstrated that FOP mutant receptors require a nonenzymatic scaffolding function provided by type II
receptors to “form functional, apparently ligandindependent signaling complexes.” Thus, in FOP as in
the wild type molecular square dance, it takes four
dancing partners to get things moving. This finding
helps elucidate the structure of the mutant signaling
complex and has important implications for the
development of new therapies for FOP including those
that target the binding of type I to type II receptors.
Another In Vitro Genetic Approach
to Inhibiting the FOP Gene
In a paper entitled, “Antisense-oligonucleotide
mediated exon skipping in ACVR1: inhibiting the
receptor that is overactive in FOP,” Shi, and colleagues
from Leiden University Medical Center in the
Netherlands report a genetic approach to knock down
ALK2 expression by means of exon skipping (to skip over
the damaged/mutated portion of the FOP gene). This
novel approach compliments a previously reported study
using inhibitory RNA technology reported by
investigators at the Center for Research in FOP &
Related Disorders in 2012. In this present study,
genetic probes called antisense-oligonucleotides were
designed to selectively modulate the expression of the
ALK2 gene. The
authors showed that
their genetic
approach could
decrease ALK2
messenger RNA
levels.
In a related
paper, “Delivery
and evaluation of
RNAi therapeutics
for heterotopic
ossification
pathologies,”
published in
Methods in
Emma Albee and her mother
Molecular Biology
Patricia Pinkham of Seal Cove,
by Shrivats and
Maine meet with Dr. Kaplan in
Orlando, Florida.
Hollinger from
Carnegie Mellon
University in Pittsburgh, the authors describe RNA
interference as a powerful tool to develop therapies for
heterotopic ossification including FOP. However, the
authors acknowledge a lack of consensus in the literature
on approaches to delivering RNAi safely and effectively
to cells and tissues in living organisms. The authors
described polymer-based RNAi therapeutics as possibly
FOP Collaborative Research Project Annual Report 2014 19
a safer strategy than viruses for delivering small genetic
regulators of heterotopic ossification. Their in vitro
strategy holds much promise but needs to be verified in
in vivo systems.
Clearly, the use of any genetic strategy for selective
gene silencing will depend on safe and effective methods
to deliver small genetic molecules to patients.
The FOP-POH Connection
The best way to really see something is to look at it
from more than one perspective. What we learned most
clearly about FOP in 2013 came from looking at its sister
condition called progressive osseous heteroplasia (POH),
another rare genetic disorder of renegade bone formation
which we first described and named in the early 1990s,
and for which The Center for Research in FOP &
Related Disorders discovered the causative mutation
in 2002.
FOP and POH
share the
distinguishing
feature of
progressive
heterotopic
ossification
during childhood
although the
clinical,
radiographic,
and pathological
features of the
two conditions
are distinctly
different. FOP is
Lincoln Wheelock of Des Moines,
caused by over
Iowa with his parents Lee Wheelock
activity of a cell
and Dr. Trisha M. Gambaiana
Wheelock at Lincoln’s Legacy for
surface receptor
FOP Research
called ACVR1 (or
ALK2), whereas
POH is caused by under activity of an intracellular relay
switch called Gs-alpha (encoded by the GNAS gene).
Amazingly, it turns out that both ALK2 and Gs-alpha are
connected (albeit by entirely different mechanisms) to
the same downstream pathway called the Hedgehog (Hh)
20 FOP Collaborative Research Project Annual Report 2014
pathway, one of the five ancient signaling pathways
involved in all animal development over the past billion
years. The significance of this finding is that the control
of Hedgehog signaling determines exactly where bone
formation can and will occur. Importantly, Hedgehog
signaling is necessary and sufficient to result in
heterotopic ossification. This implies that drugs that
block Hedgehog signaling may have clinical applications
in both diseases.
In a landmark paper published in Nature Medicine
entitled, “Activation of hedgehog signaling by loss of
GNAS causes heterotopic ossification,” Jean Regard,
Yingzi Yang and their colleagues from the NIH and
Frederick Kaplan and Eileen Shore from the Center for
Research in FOP & Related Disorders at the University
of Pennsylvania described this important discovery.
In the paper, the authors note that, “Heterotopic
ossification (HO), the pathologic formation of
extraskeletal bone, occurs as a common complication of
trauma or in genetic disorders and can be disabling and
lethal. However, the underlying molecular mechanisms
are largely unknown. Here, we demonstrate that
Gs-alpha restricts bone formation to the skeleton
by inhibiting Hedgehog signaling in mesenchymal
progenitor cells. In progressive osseous heteroplasia
(POH), a human disease caused by null mutations in
GNAS (which encodes Gs alpha), Hedgehog signaling
is upregulated in ectopic osteoblasts and in progenitor
cells. In animal models, ectopic Hedgehog signaling
is sufficient to induce heterotopic ossification, whereas
inhibition of this signaling pathway by genetic or
pharmacological means strongly reduces the severity of
HO. The pharmacologic studies in the mouse model,
suggest that Hedgehog inhibitors currently used in the
clinic for other conditions such as cancer, may possibly
be repurposed for treating heterotopic ossification.”
The results of this landmark work show that:
1. Loss of Gnas leads to POH-like skeletal anomalies
and heterotopic ossification
2. Gnas is required to inhibit Hedgehog signaling
3. Active Hedgehog signaling causes heterotopic
ossification
4. Inhibition of Hedgehog signaling diminishes
heterotopic ossification.
In an editorial in Nature
Rheumatology entitled,
“Hedgehog signaling
linked to heterotopic
ossification in POH,”
Jeannie Buckland
writes, “Frederick Kaplan
Birte Hollensteiner of
and Eileen Shore at
Germany and Meike
Mrugalla of Austria
[the Center for
enjoying summer
Research in FOP &
sunshine at the FOPev
Related Disorders]
Family Meeting in Valbert,
the University of
Germany
Pennsylvania, also
co-authors on this paper, found that POH is caused by a
defect in Gnas, the gene encoding Gs-alpha, which is a
downstream mediator of signaling by G-protein coupled
receptors; however, the molecular mechanism responsible
for the pathogenesis of this disease remains poorly
understood. Here, the researchers generated mice that
lacked the expression of both copies of Gnas in limb
connective tissue progenitor cells. Loss of both copies of
Gnas resulted in progressive heterotopic ossification and
POH-like phenotypes in these mice. The authors
established that this phenotype resulted from ectopic
bone cell differentiation resulting in progressive
intramembranous bone formation and that these mice
therefore represent a model of POH.”
“The significance of our work”, says Dr. Yingzi Yang,
“is that we have figured out a fundamental mechanism
that restricts bone formation to its normal location which
has to be strictly controlled in skeletal development and
regeneration.”
Further work will test whether inhibition of Hedgehog
signaling leads to suppression of heterotopic ossification
not only in POH but in FOP and other more common
disorders of heterotopic ossification, such as occurs
following injury or surgery.
It is possible that the underlying molecular
mechanisms of non-hereditary forms of heterotopic
ossification are a combination of those underlying
POH and FOP. In fact, the development of ectopic
cartilage formation orchestrated by dysregulated BMP
signaling also upregulates Hedgehog signaling at ectopic
sites (showed by Zhang et al. from the University of
Rochester, 2006). Therefore, combining Hedgehog
inhibitors and the nuclear retinoic acid receptor
gamma agonists (such as Palovarotene) which block
chondrogenesis may be a promising strategy for FOP
and POH as well as common non-hereditary forms of
heterotopic ossification.
In a related paper entitled, “Somitic disruption of
GNAS in chick embryos mimics progressive osseous
heteroplasia,” published in the Journal of Clinical
Investigation, Cairns, Zhang and colleagues from Tufts
Medical Center in Boston along with Pignolo, Brennan,
Lindborg, Xu, Kaplan and Shore from the Center for
Research in FOP & Related Disorders at the University
of Pennsylvania reported findings that shed light on the
mosaic nature of heterotopic ossification in POH.
Interestingly, POH lesions have a bewildering mosaic
distribution, unlike that of FOP. Using clinical,
radiographic, and photographic documentation, the
authors found that most of the individuals studied had a
lesional bias towards one side or the other, even showing
exclusive sidedness of lesions. Most strikingly, all had a
distribution of heterotopic ossification that suggested
involvement of the early nervous system in heterotopic
ossification. The authors hypothesized that somatic
mutations in a progenitor cell from an embryonic
building block of the body combined with a germline
mutation in Gnas leads to the unilateral distribution of
POH lesions. Taking
advantage of the chick
system, the authors
examined this hypothesis
by mimicking near total
loss of Gnas expression by
introducing inactive Gnas
Carli Henrotay of Saint
genes into a subset of chick
Louis, Missouri and Tim
early embryo building
Hazlett of O’Fallon, Illinois
blocks called somites, the
progenitors that give rise to
skin and muscle. The authors observed rapid ectopic
cartilage and bone induction in a unilateral distribution
corresponding to the injected somites, a finding which
suggests that blocking Gnas activity in a targeted
population of progenitor cells can lead to ectopic
ossification reminiscent of that seen in POH.
FOP Collaborative Research Project Annual Report 2014 21
These papers in Nature Medicine and Journal of
Clinical Investigation shed important new light on the
molecular mechanisms of heterotopic ossification, and
helped clarify the seminal relationship between FOP and
POH at the molecular level.
The Dorsomorphin Class:
Ready for Matriculation?
“With so much being discovered about how
the BMPs act, it might be possible to develop
drugs that would block some part of the BMP
pathway and therefore prevent the progression
of what is a horrible, nightmare disease.”
- Brigid Hogan, Ph.D., Developmental
Biologist (c.1996)
The ultimate goal
of FOP research is
the development
of treatments that
will prevent, halt,
or even reverse the
progression of the
condition. The
identification of
the single
nucleotide
mutation that
causes FOP in all
classically affected
individuals
provides a unique
Dr. Kaplan with IFOPA Board
pharmacological
Member Nancy Sando of Petoskey,
target and a
Michigan
rational point of
intervention in a critical signaling pathway. Therapeutic
strategies for inhibiting BMP signaling in FOP include
gene silencing approaches, monoclonal antibodies
directed against ACVR1/ALK2, blocking downstream
targets in FOP lesional progenitor cells, and orally
available small molecule signal transduction inhibitors
(STIs) of ACVR1/ALK2.
22 FOP Collaborative Research Project Annual Report 2014
STIs are important molecular tools for studying
BMP signaling in FOP, and have the potential to be
developed into powerful therapeutic drugs for FOP. In
2006, around the time of the gene discovery, a small
molecule STI, Dorsomorphin, was identified in a screen
for compounds that perturb BMP-regulated embryonic
pattern formation in zebrafish. Dorsomorphin and
its derivatives inhibit all type I BMP receptors (ALK2,
ALK3, and ALK6), and block downstream BMP
signaling. However, a safe and effective STI for FOP
must specifically inhibit ACVR1/ALK2 (the FOP gene)
over ALK3 and ALK6, rather than completely blocking
all BMP signaling, and must not affect other critical
cellular receptors. STIs designed to block ACVR1/ALK2
must have specificity, efficacy, tolerance to resistance,
acceptable safety profiles, and be shown to lack toxic
rebound effects before they can enter clinical trials for
FOP. Extensive testing in animal models of classic FOP
will be necessary to completely evaluate potential efficacy,
safety, dosage, duration, timing, treatment window and
rebound issues. Much progress is being made but much
work remains to be done.
Taking the leap from biology to drug discovery is
never an easy path. Recent developments by medicinal
chemists show that second and third generation small
molecule BMP inhibitors, which are more specific than
Dorsomorphin, have been developed and suggested as a
potential therapy for FOP.
During the past year, there has been considerable
activity in laboratories worldwide to develop safe
and effective small molecule inhibitors for long-term
suppression of the FOP gene. In three important
papers, one in Bioorganic and Medicinal Chemistry
Letters from Vanderbilt University, another in ACF
Chemical Biology from Harvard University, and the
third in PLOS One from Oxford University, the authors
describe improved Dorsomorphin-like compounds for
ALK2. These recent medicinal chemistry developments
represent a step forward in developing selective inhibitors
that target ALK2 over the other highly homologous
BMP type I receptors and offer additional hope that the
medicinal chemists will be able to develop inhibitors
that are safe and selective for ALK2. The medicinal
chemistry refinement of Dorsomorphin-like inhibitors
will continue in 2014.
Retinoic Acid Receptor Gamma
(RARγ) Agonists: De-Railing the
FOP Train
As far back as the 1980s, retinoids, used for the
treatment of acne, were known to cause skeletal birth
defects (if taken during pregnancy) because they interfere
with the formation of the cartilage scaffold on which the
embryonic skeleton is built. The idea of using retinoids to
treat FOP flare-ups was simple, and elegant: if retinoids
caused birth defects by disrupting the formation of the
cartilage scaffold of the normal skeleton, perhaps they
might disrupt the formation of the cartilage scaffold of
the heterotopic or second skeleton in FOP.
In the mid1980s, more
than 20 years
before the
FOP gene
was
discovered,
Dr. Michael
Zasloff, then
at the
National
From left to right: Jade Hill, Ana
Martin, Ally Martin, Dilyn Martin, Dr.
Institutes of
Fred Kaplan, and Derek Martin from
Health,
Kotzebue, Alaska
conducted a
pioneering
clinical trial of isotretinoin (13-cis-retinoic acid;
isotretinoin), a powerful retinoid, for the prevention and
treatment of FOP. Although the results of the clinical
trial were equivocal, the idea of using a retinoid to
prevent or treat FOP flare-ups was far ahead of its time.
Theresa Brodie (left) and Ian Brodie
(2nd from right) with Drs. Friedman,
Pignolo and Kaplan in London, Ontario
Over the past
30 years, the
nuclear
retinoid
receptors
have been
identified,
and specific
agonists
(molecules
that activate specific retinoid receptor subtypes) that
possess far greater specificity and far fewer side effects
than isotretinoin have been developed.
In the April 2011 issue of Nature Medicine,
Drs. Masahiro Iwamoto and Maurizio Pacifici and their
colleagues (now at Children’s Hospital of Philadelphia
and the University of Pennsylvania) described a novel
approach to derail heterotopic ossification, not prior
to induction, but after the process of building a second
skeleton had begun. The authors built on previous work
that retinoic acid was a potent skeletal inhibitor that can
be exploited to interfere with the cartilage scaffold of
heterotopic endochondral ossification (HEO) before the
dreaded end-stage of disabling heterotopic ossification
was reached.
In their landmark study, the authors showed that the
early chondrogenic (cartilage producing) stage of the prebone scaffold was exquisitely sensitive to the inhibitory
effects of retinoic acid receptor gamma (RARγ). By using
compounds that specifically activate the RARγ receptor,
the authors were able to critically target and inhibit the
pre-cartilage and cartilage cells that form the scaffold of
mature heterotopic bone.
In their mouse experiments, the authors employed
a comprehensive approach using implanted stem cells,
BMP induction of HEO, and a conditional transgenic
mouse that forms FOP-like HEO and showed that RARγ
agonists potently inhibited HEO. Remarkably, when
the RARγ agonists were stopped, no significant rebound
effect occurred, indicating that the RARγ effect may be
irreversible.
Dr. Kaplan meets with Amie Darnell
Specht and Matthew Specht of
Denton, Texas.
Importantly,
the authors
showed that
this class of
compounds
was effective
in inhibiting
HEO in
animal models
during a wide
treatment
window that
FOP Collaborative Research Project Annual Report 2014 23
included the pre-cartilage mesenchymal stem cell phase,
up to, but not including, the bone formation phase.
These tantalizing findings suggested that the successful
inhibition of HEO in patients may be possible even after
the clinically elusive induction phase had occurred.
Most
remarkably,
the authors
showed that
this class of
compounds
may actually
redirect cell fate
decisions in
mesenchymal
Drs. Robert Pignolo (far left) and Fred
stem cells to a
Kaplan (far right) of Philadelphia meet
non-bone
with Dr. Rolf (Olli) Mohart of GarmischPartenkirchen, Germany and Dr. Petra
lineage, an
Seemann of Berlin, Germany at the
observation
FOPev Family Meeting in Valbert,
with wideGermany.
reaching
implications for skeletal oncology, vascular biology, and
tissue engineering.
Taken together, the authors provided a tour-deforce in identifying a potent, orally available class of
compounds that can prevent HEO in animal models by
inhibiting the cartilage scaffold, and by diverting stem
cells to a more benign soft tissue fate while avoiding the
rebound phenomena seen in other classes of experimental
medications.
The authors’ remarkable findings raise intriguing
questions. Most importantly, given that the formation
of heterotopic bone requires participation of the BMP
signaling pathway, how do RARγ agonist compounds
impair HEO from a constitutively active BMP type I
receptor as in FOP, or in the FOP-like transgenic mouse
model in which the constitutively active ACVR1/ALK2
receptor is conditionally activated by inflammation? The
answer lies, at least in part, with the unusual mechanism
of action. The authors show that the RARγ agonists
dramatically and irreversibly down-regulate BMP
signaling by promoting the degradation of molecules
in the molecular relay race immediately downstream of
the overactive FOP receptor. These activated molecules,
24 FOP Collaborative Research Project Annual Report 2014
called “phosphorylated BMP-pathway specific Smads,”
are thus blocked from entering the nucleus of the
mesenchymal stem cells and early cartilage cells, and thus
prevented from activating heterotopic ossification.
The therapeutic implications of this work for
preventing HEO in common, sporadic forms of
heterotopic ossification and in FOP are enormous, but
some clinical caveats remain. First, RARγ agonists, like
the earlier molecules used, cause birth defects and their
use in woman of childbearing age must be monitored
carefully. Second, the authors predictably show that
RARγ agonists delay endochondral bone formation
during fracture repair. Thus, these agents may have
limited applicability in patients with long bone fractures
in addition to their heterotopic ossification-prone
injuries. (This is most likely in wounded soldiers and
civilians with multiple traumatic injuries that induce
heterotopic ossification) Third, long term use of these
compounds may adversely affect the cartilaginous growth
plates, and additional studies are necessary before RARγ
agonists can be considered for long-term use in children.
It is difficult to
find effective
molecular
targets for
intractable
diseases.
Successful
therapeutic
sabotage of
highly conserved
signaling
pathways, as in
FOP, requires
exquisite
planning and
good fortune.
Kay Rai greets Cody Hickmott of
Iwamoto,
Abilene, Texas in the Orthopaedics
Pacifici et al.
library at the UPenn
combined both
in their elegant study. They identified RARγ agonists as a
class of compounds that profoundly inhibit the BMPinduced cartilage scaffold of FOP. The beauty of this
approach is that it does not just broadly target the BMP
signaling pathway in many tissues in the body, but rather
it targets a specific pathological process of tissue
metamorphosis (cartilaginous scaffold formation) that
requires the BMP signaling pathway to cause disablingdisease. Thus, it has the desired features of targeting the
molecular basis for FOP in the very cells that form HEO,
hopefully with minimal collateral damage. The authors
have thus identified a new and powerful class of
compounds to derail the cartilaginous scaffold of HEO
in FOP. Without the cartilage scaffold, there is no HEO
in FOP. With some additional work, these compounds
seem RARing to go in clinical trials for FOP patients and
others, who are desperately waiting for clinical answers.
During 2013, robust work has continued on the
development of an RARγ agonist for use in clinical trials
in FOP. One of these compounds, Palovarotene, has
been through human safety trials in adults, and efforts
are currently being directed towards the institution of a
clinical trial in 2014 with this compound in adults with
flare-ups of FOP.
From left to right: Bob Pignolo, Gilles Keller,
Irwin Klein, Alain Klein (seated), Gabby Klein,
Claude Keller, Eileen Shore, Edith Keller and
Fred Kaplan in Basel, Switzerland
While there are many intangibles in the development of
such a clinical trial, plans are proceeding, and updated
information will be forthcoming in the very near future.
Presently, this is a high priority in FOP therapeutics
because we think that it has potential to be effective for
FOP and because we may be able to bring it to clinical
trials (initially for adults) more quickly than any other
potential medication. It is unlikely that any one
medication will accomplish all of our goals, but that
should not deter us from trying.
FOP in China
In 2013, Zhang and colleagues at Tongji University
in Shanghai along with Shore and Kaplan from the
Center for Research in FOP & Related Disorders
at the University of Pennsylvania Perelman School
of Medicine, reported in an article in Bone, “The
phenotype and genotype of fibrodysplasia ossificans
progressiva in China: a report of 72 cases.” The
authors studied 72 new patients with FOP in China
and analyzed their phenotype and genotype comprising
the world’s largest ethnically homogenous population
of FOP patients. Ninety-nine percent of FOP patients
were of Han nationality, and one percent of patients
were of Hui nationality, reflecting the ethnic distribution
of the Chinese people. Based on clinical examination,
92 percent of patients had classic FOP; four percent of
patients had FOP plus, and four percent of patients were
FOP variants. Importantly, all individuals with FOP
had mutations in the protein-coding region of ACVR1/
ALK2. Ninety-seven percent of FOP patients had the
canonical FOP mutation while three percent of FOP
patients had variant mutations in ACVR1/ALK2. Taken
together, the genotypes and phenotypes of individuals
with FOP from China are similar to those reported
elsewhere in the world and support the fidelity of this
ultra-rare disorder in the world’s most highly populated
nation and across wide, racial, ethnic, gender, and
geographic distributions.
Considering the extreme rarity of FOP and the
predicted point prevalence of approximately one in two
million, one would estimate the existence of at least 650
patients in China, the world’s most populous nation
with more than 1.3 billion people. Until recently, only
a few patients from China had been reported. Zhang
and colleagues reported approximately twelve per cent
of the estimated population of FOP patients in China.
Therefore, 88 percent of the expected FOP patients in
China remain either undiagnosed or unknown and are at
risk of lifelong complications from misdiagnosis unless
active educational programs are instituted to identify
patients. This study highlights awareness of this patient
population in the international FOP community, aids
in understanding worldwide trends in natural history
and associated genotype, identifies a new population for
participation in future clinical trials, and raises critical
FOP Collaborative Research Project Annual Report 2014 25
awareness in the Chinese medical community so that
prompt and correct clinical diagnosis might ensue and
diagnostic errors might be avoided for the remaining
Chinese FOP patients yet to be diagnosed.
Clinical Reports on FOP from
Around the Globe
In 2013, additional clinical reports on new FOP
patient communities and FOP gene analysis have
appeared from:
• China
Dr. Zhang is a clinical endocrinologist and Director of
the Department of Endocrinology at Tongji Hospital
affiliated with Tongji University in Shanghai. Dr. Zhang
met his first FOP patient in 2008, and was inspired to do
research on FOP. With the help of TV, newspapers, and
the internet, Dr. Zhang has acquired a substantial
number of FOP patients in the Shanghai area of China.
In late 2012, the IFOPA announced that Dr. Keqin
Zhang, M.D., Ph.D. of the People’s Republic of China
accepted an invitation to join the International President
Council of the IFOPA
• Nature Medicine
• Orphanet Journal of Rare Diseases
• Pediatric Endocrinology Review
• Denmark
• PLoS ONE
• Egypt
• Primer on the Metabolic Bone Diseases and
Disorders of Mineral Metabolism
• France
Dr. Shinya Yamanaka of Kyoto, Japan and
Dr. Fred Kaplan of Philadelphia exchange
greetings at the Annual Meeting of the
American Society for Clinical Investigation
in Chicago.
• Molecular and Cellular Biology
• Hong Kong
• India
• Japan
• Peru
• Stem Cells
As of January 1, 2014, the classic paper in Nature
Genetics (April 2006) describing the discovery of the
FOP gene has been cited in more than 385 major
scientific publications.
• Turkey
In 2013, major worldwide publications on FOP and
FOP-related issues appeared in peer-reviewed journals
and books including:
• Journal of Clinical Investigation
26 FOP Collaborative Research Project Annual Report 2014
• Association of American Colleges; Washington,
D.C.
• Association of American Physicians; Washington
D.C.
• FOPev; Valbert, Germany
• FOP Italia Annual Meeting; Parma, Italy
• Foundation for Biomedical Research; Washington,
D.C
• Bioorganic and Medicinal Chemistry Letters
• Inflammation Research
• American Society for Bone & Mineral Research
Annual Meeting; Baltimore, Maryland
• FASEB Summer Research Conference; Steamboat
Springs, Colorado
• Anesthesia and Analgesia
• Gene
• American Academy of Orthopaedic Surgeons
Research Symposium; Rosemont, Illinois
• Children’s Hospital Research Institute;
Philadelphia, Pennsylvania
FOP: The Written Word – 2013
• Expert Opinion on Orphan Drugs
• Advances in Mineral Metabolism Annual Meeting;
Snowmass; Colorado
• Children’s Hospital of Philadelphia; Philadelphia,
Pennsylvania
• ACF Chemical Biology
Ann Sofi Klint (seated) of Lulea,
Sweden and her mother Eva Klint
(left), and Katarina Mansson
(far right) with Drs. Pignolo
and Kaplan
During 2013, major lectures on FOP by members of
the Center were presented at the:
• Canadian FOP Network; London, Ontario
Thus, these reports have expanded the knowledge and
reach of the FOP patient and scientific community into
new regions of the world.
• Bone
FOP: The Spoken Word – 2013
Members of the Center for Research
in FOP and Related Disorders at
the University of Pennsylvania
meet with Scientists at the Novartis
Institutes for Biomedical Research
in Basel Switzerland. Clockwise
from the top: Dr. Thomas Ullrich,
Dr. Michaela Kneissel, Dr. Annabelle
Heier, Dr. Fred Kaplan, Dr. Ina
Kramer, Dr. Eileen Shore, Dr. Ursula
Schramm, Dr. Sabine Guth, and
Dr. Herve Jullien de Pommeroli. In
The Center is Dr. Robert Pignolo.
• International Conference on the Chemistry and
Biology of Mineralized Tissues; Lake Geneva,
Wisconsin
• Jefferson University; Philadelphia, PA
• Novartis Institute for Biomedical Research; Basel,
Switzerland
FOP Collaborative Research Project Annual Report 2014 27
• Perelman School of Medicine at the University of
Pennsylvania; Philadelphia, Pennsylvania
• Stanford-Burnham Rare Disease Symposium; La
Jolla, California
• St. Luke’s Medical Center; Sioux City, Iowa
a mesmerized class of incoming medical students and
received a standing ovation in a packed amphitheater at
the nation’s oldest medical school. She held the students
spellbound with her insight, wisdom, positive attitude,
and hopeful outlook as she spoke from her motorized
wheelchair.
• Thames Valley Children’s Center; London, Ontario
Mrs. Amanda Cali and Dr. Robert
Pignolo
• 25th Anniversary Celebration of the IFOPA;
Orlando, Florida
The National Organization for Rare Disease (NORD)
and the European Organization for Rare Diseases
(EURODIS) named Frederick S. Kaplan, M.D. and
Eileen M. Shore, Ph.D. of the Center for Research in
FOP & Related Disorders to the Rare Disease Research
Hall of Fame.
• University of California Ostrow School of
Dentistry; Los Angeles, California
• University of Western Ontario; London, Ontario
During 2013, highlights of FOP research by members
of the Center were presented at local, regional, national,
and international FOP family meetings and gatherings
in:
• Allentown, Pennsylvania
• Basel, Switzerland
• London, Ontario
• Orlando, Florida
• Parma, Italy
• Philadelphia, Pennsylvania
• Sioux City, Iowa
• Valbert, Germany
Tell Me a Story
When teaching a class of medical students, one
is teaching the next generation. Last August, Laura
Rossano generously shared her FOP story with the first
year medical students at the University of Pennsylvania’s
Perelman School of Medicine as part of their
introductory course in human genetics. Laura spoke to
28 FOP Collaborative Research Project Annual Report 2014
Associate
Professor in the
Departments of
Medicine and
Orthopaedic
Surgery at the
University of
Pennsylvania’s
Perelman
School of
Medicine.
From left to right: Dr. Eileen Shore, Ruth
McCarrick-Walmsley, Carly Moramarco, Sara
Wilson, Laura Rossano, Tom Wilson, Barbara
and Anthony Rossano, graduate student
Michael Convente, and Ahmed Elbording
Laura’s session was ranked among the best sessions in the
entire first year medical school curriculum. Comments
included: “Wonderful presentation; amazing and
inspiring.” “This was an excellent session with a
phenomenal patient.” “Laura was phenomenal!” “Very
inspiring, Wonderful presentation; Laura was awesome.”
“Very moving; I learned a lot and I was moved by Laura’s
story.”
In addition to learning about short great toes and
the FOP gene, the freshmen medical students learned
firsthand the human dimensions of FOP from an
extraordinary individual. Laura remarked, “I have FOP,
but it is not who I am.”
Awards & Honors
2013 was a year of distinguished promotions, awards,
and honors in FOP education and research:
Dr. Robert J. Pignolo, M.D., Ph.D., the Ian Cali
Clinical and Research Scholar at the Center for Research
in FOP & Related Disorders, was promoted to
Dr. Charles C.
Hong, M.D.,
Ph.D.,
Associate
Professor of
Medicine,
Pharmacology,
Cell and
Dr. Charles Hong of Vanderbilt
Developmental
University in Nashville, Tennessee
Biology at
meets with IFOPA Board Member
Vanderbilt
Brian Harwell of Amelia, Ohio
School of
Medicine was elected to the American Society for
Clinical Investigation. Dr. Hong discovered
Dorsomorphin, the first small molecule inhibitor of
BMP type I receptors as well as other small molecule
inhibitors of key developmental pathways. Dr. Hong is
currently exploring therapeutic potential of the
Dorsomorphin class of BMP inhibitors for FOP, as well
as other small molecule molecular inhibitors for heart
failure, anemia, atherosclerosis, and wound healing.
The American Academy of Orthopaedic Surgeons
honored Carl Zimmer with the Media Orthopaedic
Reporting Excellence (MORE) Award for his story, “The
Mystery of the Second Skeleton,” which appeared in the
June 2013 issue of the Atlantic Monthly. The MORE
Award honors worldwide journalistic excellence that
furthers the public understanding of musculoskeletal
health.
The 12th Annual Michael E. DeBakey Award
sponsored by the Foundation for Biomedical Research
and the Association of American of Medical Colleges was
presented to K.W. Hillis, a staff writer for the Lawton
Constitution for her article on FOP. The DeBakey
Award in Journalism honors excellence in biomedical
journalism.
The DeBakey Award was presented to K.W. Hillis at
the Mayflower Hotel in Washington, D.C on Tuesday,
May 14, 2013, and was accompanied by the following
presentation by Dr. Kaplan:
“K.W. Hillis, a staff writer for The Lawton Constitution
wrote about a little girl with FOP for which she is being
honored tonight with a 2013 Michael E. DeBakey Award
in Journalism.
FOP, or fibrodysplasia ossificans progressiva, is an ultra-rare
and catastrophically disabling disease. FOP affects one in
two million individuals. Fewer than 800 people worldwide
are afflicted with this condition in which the body’s muscles
turn to bone and progressively imprison children in a
second skeleton.
The feature article by
K.W. Hillis entitled,
“Ellaina’s Disease
Causes Runaway
Factory for Making
Bone,” was a great shot
in the arm
for the FOP community.
But, those who suffer
from FOP cannot have
shots because the simple
injury of an injection
causes muscle to turn to
K.W. Hillis of Lawton,
bone and locks the
Oklahoma receives the Michael
E. DeBakey Journalism Award
surrounding joints in a
for her story on FOP.
state of permanent
immobility. Even injections of local anesthetic for dental
procedures will cause the jaw to lock shut. Presently, there is
no treatment or cure; but there is hope.
The discovery of the FOP mutation by our group in
2006 — a single genetic letter out of six billion letters in
FOP Collaborative Research Project Annual Report 2014 29
the human genome that causes classic FOP in every single
individual in the world — flung open the gates of research
and has propelled global investigation to find a cure for this
miserable affliction. Our journey to find the FOP gene will
lead to clinical trials of new drugs for FOP, hopefully in the
next several years, and provides hope which is a powerful
medicine to Ellaina and other FOP children worldwide.
K.W. Hillis’ story about Ellaina McAlister, age 4 of
Lawton, Oklahoma is not just a story about a rare disorder,
but rather a child’s face on a problem suffered by many, albeit
in less extensive form – like the soldier who returns from
Iraq and Afghanistan with disabling extra bone formation
at the amputation site; like the elderly arthritic patient who
suffers from extra bone formation that ruins her total hip
replacement; like the middle-aged woman who suffers a severe
head injury in an automobile accident and ends-up with
several joints immobilized with heterotopic bone; or like the
young athlete who suffer a sports-related injury and locksup his knee and elbow with extraskeletal bone – just like in
FOP. Answers for Ellaina’s FOP will likely provide answers
for many thousands of individuals who have more common
forms of extraskeletal bone formation.”
FOP: What Can I Do to Help?
Patients, families, friends, even casual visitors to the
Center for Research in FOP & Related Disorders often
ask: “What can I do to help?” The answer is simple.
“Anything you can.”
As Kate Griffo and
John Glick at The
University of
Pennsylvania’s
Perelman School of
Medicine said, “In
philanthropy, as in
medicine, even brief
Bingo for a Cure in Allentown,
inaction can do
Pennsylvania in Honor of Joshua
harm. A hiatus in
Scoble to benefit the IFOPA.
fundraising may
mean that a
promising treatment or a new line of inquiry may come
to an untimely and devastating end. A break in efforts
could halt progress toward finding a treatment that could
relieve suffering or save lives.”
30 FOP Collaborative Research Project Annual Report 2014
Research is laborious, time consuming, often
frustrating, and costly, and is filled with false starts, blind
alleys, glimmers of hope and the fog of frustration, but
so too is the FOP we are trying to cure. Formidable
enemies require formidable opponents, and teamwork
requires resources. When seminal discoveries are made
and ignorance is extinguished, the fog lifts, and the
summits and the paths between them become clear.
When knowledge advances, it illuminates the next
horizon. It is a powerful beacon that changes the world
like nothing else can. The feeling of accomplishment
for all who contribute to this endeavor lights a fire of
personal fulfillment and brings knowledge that they have
contributed something important and enduring for other
human beings for generations to come.
When modern
FOP research
began 23 years
ago in a small
laboratory at the
University of
Pennsylvania,
there was little
basic knowledge
Robert Anderson, Marie Peeper,
about this terrible
IFOPA Founder and President
disease, and little
Jeannie Peeper and Dr. Fred
Kaplan
hope outside an
infinitesimally
small inner circle of believers who knew in their heart
that something could be done to change it. Hope
prevailed - hope fueled by the faith and commitment of a
dedicated and persistent few who year after year funded
studies to create and sustain a team devoted to make a
difference. Over the years, that team has grown and
expanded and its reach now extends around the world.
The often-heard comment, “Call us when you have a
treatment or a cure,” is an option, but not one that will
help us find a cure. Everyone has a stake in this effort.
We need your help in getting there: bake sales, swimming
events, Burns’ Suppers, barn dances and bingo; chicken
barbeques and spaghetti dinners, garage sales and
silent auctions; country fairs and benefit concerts at
the Metropolitan Opera; raffles and rodeos, sales of
holiday cards and embroidered quilts, 5K runs and ice
fishing contests; chamber music benefits and Hard Rock
concerts; horse-plowing contests and competitive swims;
golf tournaments and bowling parties; wine tasting
events and lemonade stands on busy street corners.
Dr. Kaplan (far right) with the
McWilliams family of Victor, Iowa
from left to right: Michelle, Margie,
Kyle and Curtis McWilliams
No idea or
endeavor is
too small or
too outlandish
to help. Every
second counts.
Please help
cure FOP.
Joshua Scoble (Allentown,
Pennsylvania) announces a
winning number at Joshua’s Future
of Promises: Bingo for a Cure
fundraising event
benefiting the IFOPA
Greetings from the FOP Laboratory from left
to right: Dr. Eileen Shore, Meiqi Xu, Dr. Julia
Haupt, Dr. John Fong, Dr. Deyu Zhang,
Dr. Girish Ramaswamy, Alexandra Stanley,
Dr. Haitao Wang, Dr. Vitali Lounev, Will Towler,
Bob Caron, Dr. Andria Culbert, Dr. Robert
Pignolo, Ruth McCarrick-Walmsley, Michael
Convente, and Dr. Fred Kaplan
Through a sustained effort at the Center for Research
in FOP & Related Disorders, research is eradicating the
stifling ignorance that was prevalent just two decades ago.
Barrier after barrier has fallen and achievable goals are
in reach. FOP research holds real promise of preventing,
treating, and curing FOP. It is no longer an imaginary
dream. We need your help now more than ever to make
this a reality.
FOP Collaborative Research Project Annual Report 2014 31
Are We There Yet?
IFOPA Makes its Debut on
NASCAR
Seven-year old Lincoln Wheelock,
pictured with his grandma, Robin
Gambaiana, holds the Jimmie Johnson
Foundation/Blue Bunny’s “Helmet of
Hope” at the IFOPA’s 25th Anniversary
Celebration held in Orlando, Florida in
November of 2013.
The IFOPA received a $10,000 grant
from the Jimmie Johnson Foundation
Blue Bunny Helmet of Hope in honor
of Lincoln, and the IFOPA logo was
included on the five-time NASCAR
Sprint Cup Series champion’s helmet as
he participated in a race at the Michigan
International Speedway in August
2013. The IFOPA was among 10
charities selected for the award from more
than 3,000 applications. The winning
application was written by Lincoln’s aunt
Kristina Sligh.
Bobby Johnson of Warren,
Pennsylvania shows his
magic balloon to Dr. Kaplan.
Joey Hollywood of
Bridgewater, New Jersey
visits with Dr. Kaplan at the
University of Pennsylvania
Part III
Left to right: Dr. Ed Hsaio, Dr. Donna Grogan
(Clementia), Dr. Zvi Grunwald, Dr. Ursula Schramm
(Novartis), Sherie Sobke, Andrea Silvia Gomez, Walter
Javier Fernandez, Dr. Charles Hong, Dr. Clive Friedman,
Dr Kaplan, and Nicole Candela (from Buenos Aires,
Argentina) in Orlando, Florida.
32 FOP Collaborative Research Project Annual Report 2014
FOP Collaborative Research Project Annual Report 2014 33
PART III:
ARE WE THERE YET?
Last year, we asked you to picture the proverbial
driveway at the beginning of the family trip – the car
is loaded; fully gassed. Everyone is buckled up. The
thousand mile journey is about to begin. And, then,
one of the children asks: “Are we there yet?” That is
the theme, once again of Part III of this year’s Annual
Report.
In late 2012, Yak Aguilar Gamboa, a young medical
student with FOP who possessed wisdom, courage and
humility beyond his years, travelled alone from his home
in Mexico to see us at the clinic.
He remarked, “We need hope, and if we have
hope, we will be okay.”
The words resonated deeply.
Yesterday, there came a boy of healthy look,
and about 14 years of age, to ask of us at
the hospital, what should be done to cure
him of many large swellings on the back,
which began about three years since, and
have continued to grow as large on many
parts as a Penny Loaf, particularly on the left
side: they arise from all of the vertebrae of
the neck, and reach down to the os sacrum;
they likewise arise from every rib of his body,
adjoining together in all parts of his back, as
the ramifications of coral do, they made, as
it were, a fixed bony pair of bodices. If this
be found worthy of your thoughts, it will be
a pleasure to gentlemen. Your most humble
servant, John
Freke.”
The same motivation that moved a young boy from
London in 1740 “to ask of us at the hospital what should be
done to cure him,” compelled a young man from Mexico
in 2012, to remind us about the nature of hope.
Are we there yet?
There is nothing in the FOP community that
engenders more hope or more excitement than the
prospect of a treatment or a cure. And, there is nothing
that will get us there faster or more assuredly than
clinical trials.
“Are we there yet?”
Medical student Yak Aguilar Gamboa of Puebla, Mexico
visits with Dr. Kaplan in his office at The Hospital of the
University of Pennsylvania
Two hundred seventy three years ago, Dr. John Freke of
St. Bartholomew’s Hospital in London, England penned
a plaintive letter to The Royal Society. In it, he wrote:
34 FOP Collaborative Research Project Annual Report 2014
There is nothing in the FOP world more shrouded in
mystery and misconception than the nature of clinical
trials. Clinical trials conjure many images in the mind
of patients and families, and raise many questions. But,
once laboratory research and animal studies identify the
targets and drugs for treating FOP, clinical trials are an
essential path to better treatments for FOP.
“Are we there yet?”
This special section of the Annual Report will update
information and dispel myths and misconceptions
surrounding clinical trials and provide guidance and
insight about their prospects and conduct. It is not meant
as a definitive map of eventual clinical trials for FOP, but
rather a helpful guide on the first stage of the journey. We
have listened to your questions and will try our best to
answer them.
“Are we there yet?”
The incredible discoveries and groundbreaking
developments of the past several years have brought us
closer to the dream of clinical trials. In this portion of the
Annual Report, we will provide simple and informative
answers that will guide us through the next phase of the
journey.
Although such studies would be extremely difficult to
conduct in the FOP community considering the few
patients afflicted with the disorder, the erratic natural
history of the disease, and the extreme interpersonal
and intrapersonal variability of FOP, such a design
still remains a plausible (but by no means a foregone)
approach for obtaining unambiguous answers to our
most perplexing dilemma – the proper assessment of true
therapeutic utility.
Why Are Clinical Trials
Necessary in FOP?
The rarity of FOP and the unpredictable nature of
the condition make it extremely difficult to assess any
therapeutic intervention without a controlled trial, a
fact recognized as early as 1916, by Julius Rosenstirn, a
physician who cared for FOP patients at Mount Zion
Hospital in San Francisco:
“The disease was attacked with all sorts of
remedies and alternatives for faulty metabolism;
every one of them with more or less marked
success observed solely by its original author
but pronounced a complete failure by every
other follower. In many cases, the symptoms of
the disease disappear spontaneously, so that
the therapeutic effect (of any treatment) should
not be unreservedly endorsed.”
These words ring as true today as they did when they
were written nearly a century ago. Presently, there is no
proven prevention or treatment for FOP. The discovery
of the FOP gene in 2006 has propelled understanding
of the pathology and molecular genetics of FOP. As
a result, new pharmacologic strategies are emerging
to treat FOP. Presently, physicians are faced with an
increasing number of potential medical interventions.
Unfortunately, clinical experience using presently
approved medications for FOP is mostly anecdotal.
The gold standard for all medication efficacy studies is
a double-blinded randomized placebo-controlled study.
Katie, Will and Susan Hayes of
Chester, New Jersey during a visit to
the University of Pennsylvania
In a recent publication entitled, “Informing the Future:
Critical Issues in Health,” from The Institute of Medicine
of the National Academy of Sciences the challenge is
well-stated, “The route from scientific discovery to useful
medical products, including drugs, is long and complex
and in recent years, the nation’s research and medical
communities have faced many difficulties in navigating
this path. Clinical trials, a crucial and extremely complex
step in the drug development pathway, are conducted in
humans and are key in evaluating the safety and efficacy
of new or existing drugs in other interventions.”
How Does Basic Science Research
in FOP Help in the Design
of Clinical Trials?
The history of FOP research over the past 20 years has
been a textbook in how insights and knowledge from the
scientific study of FOP provide clues and tangible targets
for possible therapies.
One of the most important questions we ask ourselves
is, “Do we find the best treatments for today, or do we do
the best science today in order to find the best treatments
for tomorrow?” We clearly must do BOTH.
FOP Collaborative Research Project Annual Report 2014 35
The identification of the genetic cause of FOP in
2006 provided a new and specific focus and immediately
identified ACVR1/ALK2 as druggable target. The
revelation of the causative gene for FOP also led
to studies on the molecular pathophysiology of the
condition which further defined initiating triggers, target
progenitor cells, and microenvironmental factors that are
themselves targets for pharmacologic intervention.
The identification of the FOP gene and the specific
mutation in that gene that causes classic FOP in
97 percent of FOP patients worldwide enabled the
development of high-fidelity animal models of genuine
FOP that are absolutely essential for pre-clinical drug
testing.
How Can Natural History Studies
Enable More Effective
Clinical Trials?
described. However, the data from these studies are more
than twenty years old, coming from an era when there
were no more than 40 patient-members of the IFOPA,
and from a time when the symptomatic treatment of
FOP was very different than it is now.
Today, there are nearly twenty times the numbers of
known individuals with FOP worldwide. Importantly,
a larger percentage of the world’s population of FOP
patients routinely uses powerful steroidal and nonsteroidal anti-inflammatory medications to quell the
symptoms of acute flare-ups. Intervention can change
outcome, and yesterday’s data may not be reliable to
predict tomorrow’s therapy. Any proposed new diseasealtering medication would likely be added to those
currently being used to symptomatically treat FOP, and
it is imperative to understand how those currently used
medications affect flare-ups today.
In order to advance the lessons learned from ongoing
animal studies into the design of meaningful clinical trials
for individuals with FOP, it is first necessary to obtain a
comprehensive and contemporary understanding of the
natural history of FOP. Detailed knowledge of how flareups (new episodes of disease activity) behave and progress
in the context of present symptomatic management
is essential before a meaningful clinical trial can be
designed.
The successful design of clinical trials requires a solid
contemporary context for assessing the potential benefit
of any possible new treatment. Before we can answer
the question “Does a new drug reduce or prevent the
complications of FOP?” we have to know with certainty
the natural history (clinical course) for each FOP flareup, and the variability for each region of the body that is
affected.
Flare-ups of FOP are usually sporadic and generally
unpredictable, and there is great individual variability
in the rate of disease progression. Several historical
studies on the natural history of FOP have confirmed
the extreme difficulty in predicting the onset, duration,
or severity of an FOP flare-up, although characteristic
anatomic patterns of disease progression have been
36 FOP Collaborative Research Project Annual Report 2014
Miranda Friz and her Mother Karen Munro of
Burnaby, British Columbia (center) meet with
Drs. Grunwald, Pignolo and Kaplan at the
Canadian FOP Family Meeting in London,
Ontario.
Recent reports from academia, international regulatory
agencies, small biotech companies and large
pharmaceutical corporations emphasize that the most
common cause for failure of clinical trials in rare diseases
is not a lack of appropriate molecular targets or a lack of
potentially useful drugs, but a lack of comprehensive
knowledge of the natural history of the disease. “Natural
history studies are not sexy”, said one federal regulator at
a recent symposium on the natural history of rare diseases
at The National Institutes of Health, “but natural history
studies are of utmost importance in the design of
successful clinical trials.” Essentially, before one can
determine if a drug of interest alters the natural history of
a disease, one must know what the natural history of the
disease actually is!
With the extraordinary dedication and commitment
of the IFOPA Board of Directors and the IFOPA
International Presidents Council, we have completed
a major survey to determine the contemporary natural
history of FOP flare-ups in every country and every
continent where there are known individuals with FOP.
The results of this extraordinary global survey will serve
us well, long into the future. It is a critical stepping-stone
to clinical trials and a new path to a better tomorrow.
The results of the survey are being analyzed and will be
published next year.
In other words, without knowing the natural course
and variability of FOP within each individual patient and
between patients in our worldwide FOP community, we
cannot accurately evaluate whether any drug improves
the condition.
For FOP, comprehensive, contemporary knowledge
of the natural history of flare-ups is of paramount
importance in the design of any clinical trial.
Mechanisms of drug action, safety profiles, off-target
side effects, and interactions with other drugs need to be
understood in the context of spontaneous and traumainduced FOP flare-ups and in the context of real world
experience across every geographic, ethnic, and cultural
boundary. Such comprehensive knowledge of the natural
history of FOP flare-ups becomes even more important
when one contemplates the clinical complexity of FOP
– the progressive developmental stages and evolving time
course of each lesion, the various anatomic sites involved
in the disease process, the variable clinical course of
flare-ups even in the same individual, and the range of
individual responses to symptomatic measures over time.
Add to that the spectrum of diverse regional and cultural
approaches and constraints to symptomatic management
of flare-ups, the ultra-rare nature of FOP, and the clinical
imperative of knowing with certainty whether a new
pharmaceutical compound might be effective when
contemporary placebo control groups might not be
possible or feasible in a clinical trial. Considering the
overwhelming cost and risk involved, pharmaceutical
companies simply will not embark on clinical trials unless
there are adequate data on the natural history of FOP on
which to base a judgment outcome.
Justin Henke (center) of Middletown,
Delaware with his parents Kevin and
Wendy Henke
Why Do We Need a
Comprehensive Study of
FOP Flare-ups?
Over the years, there have been many small studies
on the natural history of FOP flare-ups, but no
comprehensive study of the topic from the worldwide
FOP community. At first glance, FOP may seem like a
very simple disease. Flare-ups occur and disability results.
But, that hardly tells the story.
FOP is actually an exceedingly complex and erratic
disease. Flare-ups are episodic and unpredictable, and
disability is cumulative. Not all flare-ups lead to loss of
motion and not all loss of motion results from flare-ups.
It is impossible to predict when the next flare-up will
occur, how severe it will be, how long it will last, or what
the interval will be between flare-ups. It is not always
possible to predict which joints will be affected by flareups or how severely they will be affected. Many flare-ups
FOP Collaborative Research Project Annual Report 2014 37
are caused by trauma but trauma does not always lead
to flare-ups. Some immunizations cause severe flare-ups,
and other immunizations apparently don’t cause any.
Some flare-ups resolve spontaneously, and some never do.
Some flare-ups are painful, and some are not. Thus, FOP
is an exceedingly complex and erratic disease.
As the famous American pundit, H.L. Menkin
said in 1920: “There is always a well-known solution
to every problem – neat, plausible, and wrong.”
Clinical trials must be designed so that there are
definitive answers - not illusions.
It is vitally important to understand how FOP behaves
without treatment so that any potential treatment
effect can be assuredly assessed. Unless clinical trials are
designed with the proper controls, definitive results will
not be possible, and thus much time, effort, money, and
valuable human resources will be needlessly squandered.
Worse still, a failed clinical trial will discourage efforts for
subsequent trials.
Why Do Clinical Trials Fail?
There are four major reasons why clinical trials fail:
1. Lack of natural history studies
2. Lack of biomarkers
3. Lack of validated measurement devices
4. Lack of enrollment.
Failure of a clinical trial does not mean that a potential
drug did not work. It often means the trial was not
properly designed to arrive at a conclusive answer
regardless of whether the drug was successful or not.
Jaxon Hamiton of Ottawa,
Canada with Dr. Zvi Grunwald of
Philadelphia
There is nothing more essential for a successful outcome
of a clinical trial than a valid, worldwide, comprehensive
natural history study. This does not mean, of course, that
all clinical trials that are properly designed will lead to
new treatments. It is entirely possible and indeed likely
that some drugs will be tested and found to be
completely ineffective. However, if a definitive answer
can be obtained and a drug can be shown to be
definitively not helpful or useful for FOP, that too will be
useful information, and it will allow us to move forward
to test other drugs.
There is nothing worse than an ambiguous answer to a
clinical trial. Each clinical trial should be designed so that
a definitive answer is obtained – one way or another. A
comprehensive worldwide survey on the natural history
of FOP will provide the basis for such designs.
38 FOP Collaborative Research Project Annual Report 2014
What Are Biomarkers and
Why Are Biomarkers Needed for
Clinical Trials in FOP?
The Institute of Medicine defines biomarkers as
objectively measured indicators of biological processes
or pharmacologic responses to an intervention. For
example, blood cholesterol levels, blood pressure,
and tumor size are biomarkers for heart disease,
hypertension, and cancer respectively. Biomarkers can
also be measurements from radiographic images (such
as plain X-rays, MRIs, CT, or PET scans). In FOP,
useful biomarkers will be ones that indicate whether an
individual is having a flare-up (even perhaps before a
flare-up is clinically apparent), and which lesional stage
of a flare-up an individual is experiencing. Biomarkers
may be used to measure intermediate effects of treatment
as surrogate endpoints, and may be used to predict effects
of treatment. Importantly, biomarkers can enable faster,
more efficient monitoring of clinical trials.
There are three reasons why biomarkers are needed for
successful clinical trials in FOP:
1. To measure and monitor the variability and
progression of FOP in each individual and between
individuals.
2. To measure and monitor the stages of disease
activity during and between flare-ups.
3. To measure and monitor each individual’s response
to the drug being studied.
Unlike in cancer, a situation in which disease
biomarkers may be the same or similar throughout
the course of the disease, biomarkers will likely vary
in FOP based upon the stage of the disease and the
phase of the flare-up. For example, biomarkers for the
earliest inflammatory phase of an FOP flare-up may be
very different from those in the later cartilage and bone
formation phases of a flare-up.
It will be important to assess, measure, and monitor
the stages of FOP before a new medication is tested. For
example, some medications may work on one phase of a
flare-up but not another phase. Entering a patient into a
clinical trial in an inappropriate phase of a flare-up would
not be useful and would skew the results of the clinical
trial. Thus, it would be important to understand exactly
which phase of the flare-up was being treated for the
drug being tested.
It is also possible that a drug might be effective but
that this is not revealed in a clinical trial because the
dose, duration of treatment, or stage-specific use of the
drug was incorrect. The monitoring of stage-specific
biomarkers during a flare-up might reveal such critical
information that would be essential in designing future
clinical trials in which a higher dose of the drug was
used or in which more potent medications in the same
drug class were investigated. Without such biomarkers,
it would be impossible to know if a drug being studied
might potentially be useful, but not quite reach optimal
timing, dosage, or potency. Thus, disease-specific, stagespecific, and drug-specific biomarkers will be extremely
helpful in assessing the results of any clinical trial.
The use of validated animal models of the classic FOP
mutation and the cooperation of the FOP community
will be essential to obtain these. Substantial pre-clinical
and clinical efforts are already underway.
What Are the Best Pre-clinical
Animal Models for Testing
Drugs in FOP?
In vivo models are necessary for pre-clinical drug
testing for FOP. The most useful animal models are
mouse models of heterotopic bone formation. Presently,
there are five such mouse models: implantation of
recombinant BMP into skeletal muscle, transgenic
regulation of BMP expression under the control of
various gene promoters, a constitutively active ACVR1
mutation (that does not exist in any known FOP
patient but can lead to heterotopic bone formation), a
chimeric knock-in animal model of genuine FOP, and a
conditionally-active knock-in model of the classic FOP
mutation.
Among these five
mouse models of
heterotopic
ossification, clearly,
the most useful
animal model for
FOP is the genuine
knock-in mouse
model of FOP. Any
potential drug for
FOP considered for
testing in a clinical
trial must first be
tested in a knock-in
Alexandria McKean’s puppy
model of classic
meets the animals in Dr. Fred
FOP that exactly
Kaplan’s Zoo (see necktie).
reproduces the
genetics of FOP by
having one ACVR1 gene carrying the FOP R206H
mutation. This is particularly important in order to
answer a myriad of clinically-relevant questions: Is the
drug effective once a flare-up occurs? Can the drug be
stopped without a rebound effect? What is the proper
window for treating an FOP flare-up? What is the
correct dosage and duration for treating an FOP flare-up?
FOP Collaborative Research Project Annual Report 2014 39
Is the medication effective for spontaneous as well as
induced flare-ups? What are the potential short and
long-term side-effects of FOP treatment in the context of
the classic mutation?
Until such
questions are
answered, effective
clinical trials
cannot safely be
implemented.
Presently, with the
newer animal
models, these
Kelsey Rettinger of Ashtabula,
Ohio with Dr. Kaplan at UPenn
questions can and
are being addressed
and will be critical for the proper design of clinical trials.
What Are Potential Treatment
Strategies for Inhibiting
FOP flare-ups?
The discovery of the FOP gene led rapidly to insights
into ACVR1/ALK2-mediated heterotopic ossification.
Those insights revealed at least four plausible approaches
to the treatment and/or prevention of FOP. Those
approaches include:
1. Blocking activity of the mutant receptor (ACVR1/
ALK2) that causes FOP
2. Inhibiting triggers of FOP flare-ups
3. Directing FOP stem cells to an alternate tissue fate
other than cartilage or bone
4. Blocking the body’s response to
microenvironmental signals that promote the
formation of FOP lesions
Presently, at least six classes of compounds are plausible
candidates for FOP clinical trials within the next several
years, and all are being pursued in pre-clinical studies
in the genuine FOP knock-in mouse model of classic
FOP at Penn. As always, there are daunting safety and
regulatory hurdles that must be surpassed before a clinical
40 FOP Collaborative Research Project Annual Report 2014
trial to test potential drugs for FOP can be considered.
As one investigator recently noted, “Anything with the
power to do good, has the power to do harm.”
What Categories of Drugs Might be
Considered for Clinical Trials?
There are four categories of drugs that might be
considered for clinical trials:
A. Drugs approved for non-FOP use that might be
re-purposed for use in FOP
B. Drugs under development for non-FOP
indications that might be re-purposed for use in
FOP
C. Drugs specifically being developed for use in FOP
D. Drugs approved for use in FOP (currently none)
What Types of Clinical Trials
Might be Necessary in FOP?
As for any condition there are three types of clinical
trials that might be necessary in FOP: Phase I, Phase II,
and Phase III.
Phase I clinical trials examine the safety of a new drug
(side effects), the best way to administer it, how often to
give it, and the duration of administration. Because little
is known about the possible risks and benefits of a new
drug, Phase I studies usually include a small number of
participants who receive different doses of the drug for
variable lengths of time. Very few, if any, participants
benefit from a Phase I study, but Phase I studies are
absolutely necessary for any new drug for any condition,
and will likely be the first clinical trial in FOP.
Phase II clinical trials involve studies that use the
safety and dose that was determined to be most effective
through a Phase I trial. Many more research participants
are tested in this Phase to better define side-effects and to
learn the extent to which the treatment has the desired
effect. Some research participants may benefit from a
Phase II clinical trial.
Phase III clinical trials compare a proposed new
treatment against a standard treatment. Phase II and
Phase III studies may compare the proposed treatment to
a placebo, such as a dummy pill in certain cases or when
no standard treatment is available. Phase III clinical trials
may include many patients (clearly not possible with
an ultra-rare disease like FOP), some of whom receive
the new proposed treatment and others, the standard
treatment. The studies are designed to assess the potential
efficacy of a proposed new treatment modality.
The results of Phase II and/or Phase III clinical trials
may serve as the basis for orphan drug approval in a
condition like FOP.
How Might Clinical Trials Be
Designed in FOP?
There are essentially three scenarios for clinical trials
in FOP, each with its own implication for design and
implementation. The first is the potential short-term
treatment of acute flare-ups. The second is the potential
long-term prevention of acute flare-ups. The third is the
surgical removal of heterotopic bone and the liberation of
joints previously locked-up with heterotopic bone.
Certain medications may lend themselves to one or
more of these clinical trial scenarios. For example, drugs
used to treat acute flare-ups would have to be useful
once a flare-up is identified by the patient. This raises
additional concerns of how each individual defines
a flare-up. Such information will be obtained from
analysis of data from the worldwide survey of FOP
flare-ups completed last year. A drug that might be used
to treat acute flare-ups would have to first be shown to
be effective after a flare-up has begun in a conditional
knock-in mouse model of classic FOP.
Any drug used to possibly prevent acute flare-ups
would have to be incredibly safe over an incredibly long
period of time. Because it is essentially impossible to
predict when flare-ups will occur, it will be necessary
to study such drugs over very long periods of time and
to determine if they can alter the natural history of the
disease and the survival rate of joint mobility over time.
Because such medications will have to be used for very
long periods of time, their long-term safety profiles
would have to be impeccable. And, if the medication
would have to be stopped for any reason, concern about
rebound flare-ups would prevail.
Similarly, any potential drug that is used for removal of
heterotopic bone would first have to be proven to be safe
and effective in a prevention scenario in a mouse model
of classic FOP, and then in human clinical prevention
trials, without any rebound flare-ups once the drug was
discontinued. The life-threatening risk of anesthesia in
FOP along with the uncertain efficacy of any particular
drug that has not been previously tested in FOP patients
makes this approach untenable for preliminary clinical
trials.
The design of clinical trials for FOP must take into
consideration not only these three scenarios, but must be
predicated on whether the potential drug has been shown
to have pre-clinical effectiveness, as well as a dosage and
safety profile that might allow it to be used in a clinical
setting.
What Will Be the Measureable
Endpoints of Clinical Trials
in FOP?
Measureable endpoints of clinical trials will fall into
two broad categories:
1. An easy, safe, logistically feasible, and reproducible
measurement of heterotopic bone formation.
2. An easy, safe, logistically feasible, and reproducible
measurement of joint mobility, daily activities, and
quality of life.
Measurements of heterotopic bone formation alone
may grossly underestimate or overestimate functional
limitations. Similarly, measurements of mobility,
daily activities, and quality of life alone may greatly
underestimate or overestimate the amount of heterotopic
bone formation. Both types of assessments will be
critical in determining the outcome of clinical trials,
and both types of measurement tools are presently being
validated for FOP.
FOP Collaborative Research Project Annual Report 2014 41
What Are the Hurdles to Drug
Development for FOP?
The hurdles to drug development for FOP can be
divided into five basic categories: disease-related, drugrelated, investigator-industry-related, regulatory-related,
and support-group-related.
Disease-related hurdles to drug development for FOP
include the rarity of the condition, the finite number of
druggable targets, the variability of disease progression,
the physiological similarity of heterotopic bone to normal
skeletal bone, the variable stages of disease progression
(a moving target), the lack of target specificity (the FOP
receptor and several other receptors are remarkably
similar), the lack of sufficient natural history, and the
paucity of disease-, stage- and drug-specific biomarkers.
Many of these issues are actively being addressed.
Nevertheless, some of these major hurdles still remain.
From left to right: (standing) Dr.
Pignolo, Annalena Josefsson,
Martin Carlsson, (sitting) Kurt
Carlsson and Augusta Josefsson
Carlsson from Johanneshov,
Sweden with Dr. Fred Kaplan,
at the IFOPA 25th Anniversary
Celebration in Orlando, Florida.
Important drug-related hurdles to drug development
for FOP include drug specificity, toxicity, solubility,
pharmacokinetics, metabolism, and delivery issues.
Each of these is specific to the various drugs under study
and development.
42 FOP Collaborative Research Project Annual Report 2014
Investigator-industry related hurdles to drug
development for FOP include competing financial
interests, competing academic interests, laboratory
secrecy, and biotech-pharmaceutical company proprietary
issues.
Regulatory-related hurdles to drug development for
FOP include investigational review board hurdles, and
hurdles from
regulatory agencies
including FDA
and other
international
regulatory bodies.
Support grouprelated hurdles to
Alexandra Rodriguez of Chicago
drug development
(center) and her mother Araceli
Almeida visit with Dr. Kaplan in
for FOP include
Orlando, Florida.
funding-related
issues and
fragmented international patient group efforts. This
latter issue is particularly important and requires that
the international FOP community speak with one voice
and one intention when it comes to clinical trials. The
rarity of FOP and the potential fragmentation of the
international community over clinical trials will likely
stymie our best efforts to find more effective treatments
and eventually a cure. As Abraham Lincoln said, “A
house divided cannot stand.”
Almost Every Month, a Report
is Published on a Potential New
Treatment for FOP. What Should
We Make of This?
While many of the reports are preliminary, anecdotal,
and observational, some may have potential efficacy.
Individual case reports are often published and may be
helpful in placing a potential new medication on the
radar screen for future pre-clinical studies in animal
models of classic FOP. Case reports of a medication or
therapeutic approach should never be substituted for
pre-clinical studies or a well-designed clinical trial. It is
important to keep this in perspective, as misleading or
misguided claims are sometimes made and can hamper
research progress. We should carefully and critically
examine each new stone as it is uncovered. Who knows
in what form inspiration will arise? What would have
happened if Alexander Fleming had discarded the Petri
dish where penicillin was being secreted? But, let us
never forget the admonition of Julius Rosenstirn from
1916:
“The disease was attacked with all sorts of
remedies and alternatives for faulty metabolism;
every one of them with more or less marked
success observed solely by its original author
but pronounced a complete failure by every
other follower. In many cases, the symptoms of
the disease disappear often spontaneously, so
that the therapeutic effect (of any treatment)
should not be unreservedly endorsed.”
Do Clinical Trials Mean
Treatments?
Dr. Bob Pignolo, Gary and Natalie
McGuire with Drs. Clive Friedman,
Fred Kaplan, and Zvi Grunwald at
the Canadian FOP Family Meeting in
London, Ontario
On the contrary! There are no guarantees that any
study medication will be useful for FOP. In fact, it
is possible that a study drug could paradoxically and
unintentionally be harmful. Clinical trials are conducted
to test new drugs, or old medications in new indications.
Clinical trials imply a certain degree of unpredictability.
No clinical trial would be undertaken without a
substantial indication that the study medication may
be helpful. However, there is always a possibility that a
study medication might make no difference at all in the
condition or might even possibly make the condition
worse through unanticipated side-effects. Any clinical
trial would be closely monitored for such unanticipated
side effects.
Some clinical trials may be successful in identifying
a possible therapy and some may not. All clinical trials
must be designed so that a definitive answer is obtained
for the question at hand. This is especially important
because all clinical trials have inherent risk. Thus, for
some categories of drugs, individuals with FOP may
be the first human beings in the world to have such
medications circulating through their bodies. These
patients will be closely monitored for potential side
effects.
While no clinical
trial will be
commenced if it is
thought that the
medication being
studied is unsafe,
it is always
possible that
safety issues will
Marin Wallace of Toronto,
overshadow any
Ontario visits with Drs. Kaplan
possible
and Pignolo in London, Ontario,
therapeutic
Canada
benefit of a
potential new medication. For all clinical trials, there will
likely be some element of discomfort, inconvenience, and
side-effects as well as off-target effects of study
medications.
FOP patients should not enter into clinical trials
without a very clear understanding that they are putting
themselves at risk to determine if a potential medication
might be useful. Thus, clinical trials should not be viewed
as clinical treatments, but rather as well-controlled and
well-supervised experiments in which a patient is putting
himself or herself at risk to determine if there is potential
benefit to the drug under study.
FOP Collaborative Research Project Annual Report 2014 43
Will Clinical Trials in
FOP Be Large?
Not necessarily! The value of a clinical trial is based not
on how large or inclusive it can be, but how small it can
be to answer the question: Is the drug being tested safe
and effective for the stated indication? In other words,
what is the least number of people who have to be put
at risk to determine if a potential treatment is safe and
effective?
The optimal size of a clinical trial will be determined
by many factors after consultation with statisticians.
A clinical trial must be definitive, but a smaller, more
manageable clinical trial might enable a particular drug
to be assessed so that we can either exclude that drug as
a possibility for FOP or hasten its approval and its use
by all.
The size of a clinical
trial will depend
heavily on the
results of the natural
history survey, the
age of the study
population, the
medication being
tested, as well as the
circumstances under
From left to right: Cameron,
Brooke, and Carrie Connell
which it is tested.
President of FOP Canada, Drs.
For example,
Kaplan, Friedman, Grunwald and
medications that are
Pignolo at the Canadian FOP
tested in children
Family Meeting in London, Ontario
with FOP may need
fewer participants because flare-ups are more common in
childhood. Yet, the anatomic location of flare-ups in
childhood is extremely limited. On the other hand,
medications that are tested in adults with FOP may need
larger numbers of patients because flare-ups are less
frequent. But, again, the anatomic location of flare-ups in
adulthood is vastly different from that in childhood.
Thus, there are many complex issues that need to be
taken into consideration in the optimal size and design of
a clinical study. 44 FOP Collaborative Research Project Annual Report 2014
Will Everyone Be Eligible for
Clinical Trials?
Each clinical trial may have different eligibility
requirements based on safety issues, patient age, potential
side effects of the medication, drug metabolism, and
ability to complete and participate in all aspects of the
study. Importantly, eligibility for a clinical trial will not
necessarily determine the eventual use of a medication
– simply, eligibility reflects the design of the clinical
trial and the study participants that match the study
design. Again, it is important not to view clinical trials
as potential treatments but rather as well monitored, high
risk human experiments designed to determine whether a
potential drug may or may not be safe and/or useful
in FOP.
Will Children and Adults Be
Enrolled in Clinical Trials?
Some clinical trials will include children; some clinical
trials will include adults; and some clinical trials will
include both children and adults. The inclusion of
children and/or adults will depend on the drug being
studied, its safety profile in children and adults, and
the exact clinical questions being studied in a particular
clinical trial. There are many safety and epidemiologic
issues to consider in determining if a particular clinical
trial will enroll children, adults, or both. Many of these
issues will be determined by consultation of the study
designers with officials at regulatory agencies, such as the
FDA, as well as institutional review boards.
Will Individuals with FOP Variants
Be Enrolled in FOP Clinical Trials?
Patients with FOP variants are extremely important in
understanding the natural history and pathophysiology
of FOP and the mechanisms of disease progression.
However, because the natural history of patients with
FOP variants is quite different from those with classic
FOP, their inclusion in clinical trials may confound the
data evaluation. Thus, while they may not be participants
in every clinical trial, there may be some clinical trials
that include patients with FOP variants. Every attempt
will be made to be as inclusive as possible without
compromising the integrity of the clinical trial or the
safety of the patients enrolled. It is important to keep in
mind that clinical trials are not treatments, but highly
controlled human experiments designed to answer highly
controlled questions of safety and efficacy. How Will the Limited Number of
Eligible Patients Affect the Design
of a Clinical Trial?
FOP is not only a rare condition; it is an ultra-rare
condition. Presently, we know approximately 800
individuals who have FOP worldwide. Depending upon
the design of a particular clinical trial, perhaps only 100
patients might be eligible to participate. Of those 100
patients, perhaps half may not want to participate for one
reason or another. Therefore, the potential participant
pool in any clinical trial may be very small. This will
impose enormous challenges on the successful design of
a clinical trial. Thus, for example, it may not be possible
to use placebo controls in some clinical trials, but instead
use each patient as his or her own control (in other
words, at some phase in the trial, each individual may
receive a study medication and at another phase in the
trial, the same participant may receive a placebo; but
all patients will receive the study medication at some
point during the clinical trial). These are theoretical but
practical considerations that will need to be considered in
clinical trial design.
Will Placebo Controls be
Necessary in FOP Clinical Trials?
FOP is an extremely variable condition. Although all
FOP patients have progressive bone formation, the exact
circumstances of that progression vary from individual
to individual and even from joint to joint within an
individual. Therefore, it would not be valid to compare
one person to another; not even one identical twin with
FOP to another identical twin with FOP.
Conversely, it would be much more valid to compare
each individual to himself or herself so that at one phase
in a clinical trial an individual may receive the study
medication and at another phase in the same clinical
trial an individual may receive a placebo (“cross-over”
design). The identity of the particular treatment at any
particular phase of the trial would be unknown to both
the patient and the doctor conducting the trial and
known only to the pharmacist dispensing the medication.
The evaluation of the various treatment phases would
also be blinded (unknown to the patient and the doctor)
and the code broken only after the evaluation phase was
completed. While all attempts will be made to minimize
placebo controls in clinical trials, it may not be possible
to do that in all circumstances.
Will Participation in One
FOP Clinical Trial Preclude
Participation in Another?
Not necessarily. The entry requirements for clinical
trials will likely differ depending on many factors such
as the drug being tested, safety issues in different age
groups, drug metabolism, potential side-effects (to
name a few). It may be that participation in a clinical
trial requires a “wash-out period” before an individual
could be entered into a subsequent clinical trial. This
may be particularly important where the study drugs are
very similar in nature. It is very clear, however, that no
individual could participate in two clinical trials at the
same time.
Smiling faces left to right: Miranda Friz of Burnaby, British
Columbia, Erin McCloskey of Woodinville, Washington, and
Joey Hollywood of Bridgewater, New Jersey meet at the
IFOPA 25th Anniversary Celebration and Family Gathering
in Orlando, Florida
FOP Collaborative Research Project Annual Report 2014 45
Another potential alternative to a placebo control
group or to a cross-over design would be to compare the
results of individuals receiving a treatment to information
about the same outcome (e.g., loss of function at a
specific joint) from a group of “historical” controls. Data
from so-called historical controls would be the type
of information generated from comprehensive natural
history studies, such as described above. For example, if
we knew from our natural history survey that there was
a specific rate of annual functional decline in a joint (or
joints) that occurred in the vast majority of individuals
with FOP, and a drug in a prevention trial significantly
reduced the rate of functional decline, then this would
be considered an important outcome. The ability to
use historical controls allows all individuals enrolled in
a study to receive the medication for the duration of
the clinical trial. Using historical controls requires that
characteristics of the natural history of a condition occur
commonly enough among all affected individuals that
changes in these characteristics would not be expected to
occur in the absence of an effective intervention.
Where Will Clinical Trials
Be Conducted?
Clinical trials will be conducted at different centers
depending upon who is initiating the trial, who is the
clinical investigator responsible for the trial, and who
is sponsoring the trial. Some clinical trials may be
conducted at a single medical center, while other clinical
trials may be conducted at multiple medical centers.
Regulatory agencies may require that clinical trials be
conducted at several sites.
Who Will Conduct Clinical Trials?
Clinical trials will be conducted by the principal
investigator who initiates the studies along with their coinvestigators and sponsors. Every attempt will be made to
assess potential clinical trials and inform the worldwide
FOP community through the IFOPA website
www.ifopa.org of their potential validity.
How Many Clinical Trials
Will There Be?
Brianne LaChance of Grand Bend,
Ontario meets with Drs. Kaplan
and Pignolo
How Long Will an
FOP Clinical Trial last?
The length of a clinical trial may vary greatly, ranging
from several months to perhaps several years. The length
of a clinical trial will depend on the type of the trial whether it is a Phase I safety trial, or a Phase II or III
efficacy trial to treat ongoing flare-ups or prevent future
flare-ups. Other factors that may determine the length
of the trial are the age of eligible participants, the specific
drugs to be tested, the enrollment rate, and the specific
outcomes to be measured.
46 FOP Collaborative Research Project Annual Report 2014
There will likely be many clinical trials over the course
of many years. As more knowledge is obtained about
FOP and better drugs and targets are identified, more
clinical trials will evolve.
How Will Clinical Trials for
FOP Be Funded?
Clinical trials for FOP will be costly and will likely
range anywhere from several hundred thousand dollars
for a small and limited clinical trial to many millions of
dollars for a large and complex one. All clinical trials for
FOP, even the simplest, will have multiple levels of data
safety monitoring and regulatory oversight.
Clinical trials are research endeavors, not treatments
– and the costs are funded mainly by the sponsor
of the clinical trial. The sponsor will likely vary
from one clinical trial to another, but might include
pharmaceutical companies, small biotech companies,
private foundations, patient organizations, and/or
granting agencies. Funding must be secured for each
clinical trial before the trial begins.
What is an Orphan Disease, an
Orphan Drug, NORD, the ODA,
the FDA, the RDA, and an IND?
An orphan drug is one that has been developed
specifically to treat a rare medical condition known as
an orphan disease. An orphan disease is defined as one
affecting fewer than 200,000 people in the United States.
Obviously, according to these criteria, FOP is an ultraorphan disease!
In the United States and European Union there are
financial incentives intended to encourage the
development of drugs which might otherwise lack a
sufficient profit motive. The assignment of orphan status
to a disease and
to any drugs
developed to
treat the disease
has resulted in
medical
breakthroughs
that might not
have otherwise
been achieved
due to the
economics of
drug research
and
development.
Orphan
drugs generally
follow the same
regulatory
path as any
other pharmaceutical product, in which testing focuses
on pharmacokinetics, dosing, stability, safety and
efficacy. However, some statistical burdens are lessened
in an effort to maintain development momentum. For
example, orphan drug regulations generally acknowledge
the fact that it may not be possible to test thousands
Sarah Fischer of Oberursel,
Germany and Dr. Kaplan at the
FOP Family Meeting in Valbert,
Germany
of patients in a phase III clinical trial, as thousands of
patients do not exist with such diseases. That is obviously
the case with an ultra-rare condition like FOP.
Since the market for any drug with such a limited
application would, by definition, be small and thus
unprofitable by routine standards, government
intervention is often required to motivate a manufacturer
to address the need for an orphan drug.
The Orphan Drug Act (ODA) was ratified in
the US in 1983, with lobbying from the National
Organization for Rare Disorders (NORD) and many
other organizations. The ODA is designed to encourage
pharmaceutical companies to develop drugs for diseases
that have a small market. Under the law, companies that
develop such a drug may sell it without competition
for seven years and may get additional tax incentives.
Orphan drug designation does not mean the drug is
safe and effective or legal to manufacture and market in
the United States. It must be approved by the FDA. In
2002 the Rare Diseases Act (RDA) became law. It also
increased funding for the development of treatments for
patients with rare diseases.
The United States Food and Drug Administration’s
(FDA’s) Investigational New Drug (IND) program is
the means by which a pharmaceutical company obtains
permission to ship an experimental drug to clinical
investigators. The FDA reviews the IND application
for safety to assure that research subjects will not be
subjected to unreasonable risk. If the application is
approved, the candidate drug usually enters a Phase I
clinical trial.
What is a Data Safety Monitoring
Board (DSMB), and How Will
Their Work Affect Clinical Trials?
Data safety monitoring boards (DSMBs) are
established for patient safety and are a necessary
component of most clinical trials. Most clinical trials will
have a DSMB that carefully monitors the patient safety
information (side-effects, tolerability, etc) gathered
during the trial and has the authority and responsibility
to shut-down a trial if they feel that proper standards are
FOP Collaborative Research Project Annual Report 2014 47
not being met. DSMBs also have the capacity to stop a
clinical trial at any point if they feel that the drug being
tested is unsafe or if the encountered risks outweigh the
potential benefits. Conversely, DSMBs also have the
capacity to break the double-blinded codes established
during a trial to
assess who is
receiving
medication vs.
who is receiving
placebo at any
given time.
DSMBs have the
capacity to stop a
Andrew Davis of Birmingham,
clinical trial if
Alabama visits with Drs. Pignolo
they feel that the
and Kaplan
benefits far
outweigh the risks, and the medication should therefore
be given to everyone. DSMBs have enormous power
and responsibility and are vital to the conduct of
clinical trials.
What is Involved in
Conducting a Clinical Trial?
In an informative and enlightening article in Nature,
entitled, “Clinical research: conducting a clinical trial,”
Kelly Rae Chi explains: “Initiating and sponsoring a
clinical trial is an all-consuming team project.” The
planning stages which involve transforming an idea into a
detailed protocol, assessing and procuring resources, and
getting approval to do the study are almost always more
complicated and more time-consuming than expected.
They involve multiple reviews from regulatory agencies,
and a sometimes grueling effort to motivate members of
the team who often have little stake in the outcome. All
these moving parts require careful orchestration.
A clinical trial starts with a scientific question. There
are many cases where you can have a great scientific
idea, but it is not practical to do a clinical trial. Failure
is likely if the trial has too many rigid requirements for
patient inclusion, or is too complex to attract or treat
enough patients. Just calculating the appropriate number
of participants can be a challenge. A biostatistician
or epidemiologist can help. Other concerns include
whether to do a blinded study (in which the participants,
48 FOP Collaborative Research Project Annual Report 2014
researchers, or both are unaware of which treatment
is being administered), a randomized one (in which
participants are assigned to a treatment group by chance),
or both; whether there are any potential sources of bias;
how researchers will analyze the data; why data might
be missing (reasons include patients dropping out of the
study or not complying with the protocols); and how
researchers will deal with missing data points.
Trials can be
expensive. They
range from
$10,000 for small
studies to several
hundred million
for large, multicenter trials
according to a
Megan Donegan, IFOPA Board
Member Gretchen Emmerich,
2010 report from
Patrick Doerr, and Dr. Kaplan meet
the Institute of
at UPenn.
Medicine in
Washington D.C.
Costs vary from nation to nation owing in part to
differing regulatory standards and patient-recruitment
practices. The combination of factors makes financing a
major hurdle.
Before putting together a team or enrolling patients,
clinical trial investigators must secure regulatory approval
for their study. The specifics of the approval process vary
from country-to-country and even within countries
but the basic goal is the same - to protect the safety of
research participants.
In most countries, the protocol is usually examined
by an institutional review board (IRB), affiliated with
the investigator’s hospital or center. IRBs uphold federal,
state, and local regulations, and university policies. Each
board interprets regulations differently, so multiple
studies involving more than one board are often
complicated.
Researchers must be prepared to justify every aspect
of a protocol; for example, if it calls for four x-ray
examinations, the investigator must be able to explain
the reason for each. If the IRB thinks that the risks of
any step outweigh the potential benefits, it will ask for
changes. This back-and-forth can take many months, and
it doesn’t end there: IRBs often ask for updated reports
at regular intervals during the trial.
Researchers in the United States may also need to
allow extra months to file an application for an IND to
the FDA which will do a safety review. This step doesn’t
just apply to a new pharmaceutical compound, it may
also be necessary if for example an investigator is using
a nutritional supplement for treatment. In that case, the
supplement is technically a new drug and requires an
FDA review.
Enrollment in clinical studies should be monitored
at each step by a team member fully invested in the
study. Researchers with sufficient funds can hire a
dedicated recruitment coordinator to screen prospective
participants for any reasons they should be disqualified
from the study as well as to explain the study and its risks
and send out consent forms.
Enrollment challenges are not unusual. A recent study
at one University found that nearly one-third of clinical
studies terminated were under-enrolled for various
reasons.
‘Low recruitment is a big problem in the United
States and elsewhere,’ says William Balke,
a Program Director of Clinical Research
Services at the University of California San
Francisco (UCSF). ‘If we don’t do a better
job at recruitment, we are wasting the public’s
money and we are not advancing science,’ he
adds. ‘One reason for the problem is the lack of
a thorough feasibility analysis to determine, for
example, whether there are enough patients to
do the desired study.’ ”
When Will Clinical Trials Begin?
It is not possible to say with certainty exactly when
clinical trials will begin, as there are many intangibles
and hurdles whose outcome is difficult to predict. Suffice
it to say, clinical trials will begin as soon as possible. It is
likely that a variety of potential new drugs for FOP will
be identified in pre-clinical studies in the next few years.
Some of these drugs may be available and approved for
other indications, in which case their entry into clinical
trials can be expedited. Other drugs, being specifically
developed for FOP will require extensive pre-clinical
and clinical safety testing before being used in a Phase
II clinical trial and will take considerably longer to be
approved for study (given an IND). Other drugs still may
have gone through limited testing for other indications
and may be re-purposed for FOP.
It is unlikely that any one clinical trial will provide the
definitive treatment for FOP (although it is possible). It
is much more likely that a consensus on management of
the disease will arise from the results of at least several
clinical trials over the course of time. The good news is
that the gene discovery and basic research on FOP are
beginning to provide the scientific basis for the rational
design of meaningful clinical trials.
All of us at the Center for Research in FOP and
Related Disorders will continue to keep the FOP
community informed (through the IFOPA website;
www.ifopa.org) about the continuing global efforts to
find a treatment and cure for FOP. Thank you for your
support.
Thus, it is important to understand that clinical trials
are enormously complex and costly ventures. They
are not to be undertaken lightly. They require much
forethought and planning and are time consuming to
implement and carry out. However, for conditions like
FOP, clinical trials are the eye of the needle to new and
better treatments.
FOP Collaborative Research Project Annual Report 2014 49
Many Thanks to You
The members of the Center for Research in FOP and
Related Disorders at the University of Pennsylvania
and at collaborating laboratories around the world are
extremely proud to be a part of this mission, and are
enormously grateful to those who support this vital
research effort:
• The International FOP Association (IFOPA)
• The National Institutes of Health (The People of
the United States of America)
• The Cali Family Endowment for FOP Research
• The Weldon Family Endowment for FOP Research
• The Isaac and Rose Nassau Professorship of
Orthopaedic Molecular Medicine
• The Cali-Weldon Professorship of FOP Research
• The Roemex & Grampian Fellowships in FOP
Research
• The Canadian FOP Families & Friends Network
• FOP Italia
• The FOPeV (Germany)
• A Generous and Anonymous Donor from
Caldwell, New Jersey
• And the many individuals, families, friends, and
communities throughout the world who contribute
generously and tirelessly to the FOP effort.
Greetings of gratitude from the FOP Clinical and Laboratory Team at the University of
Pennsylvania in Philadelphia, Pennsylvania
Seated left to right: Drs. Fred Kaplan, Eileen Shore, Robert Pignolo
Standing left to right: Dr. Deyu Zhang, Meiqi Xu, Dr. Andria Culbert, Ruth McCarrickWalmsley, Dr. Vitali Lounev, Kamlesh Rai, Carter Lindborg, Dr. John Fong, Dr. Haitao Wang,
Michael Convente, Alexandra Stanley, Patsy Hooker, Will Towler, Dr. Julia Haupt, Dr. Girish
Ramaswamy, and Bob Caron
IFOPA provides annual report design, production and printing.
50 FOP Collaborative Research Project Annual Report 2014
FOP Collaborative Research Project Annual Report 2014 51