NIH Program: Therapeutics for Rare and Neglected Diseases NIH ANNOUNCES NEW PROGRAM TO DEVELOP THERAPEUTICS FOR RARE AND NEGLECTED DISEASES
The National Institutes of Health is
launching the first integrated, drug development pipeline to produce new
treatments for rare and neglected diseases. The $24 million program
jumpstarts a trans-NIH initiative called the Therapeutics for Rare and
Neglected Diseases program, or TRND.
The program is unusual because TRND
creates a drug development pipeline within the NIH and is specifically
intended to stimulate research collaborations with academic scientists
working on rare illnesses. The NIH Office of Rare Diseases Research
(ORDR) will oversee the program, and TRND's laboratory operations will
be administered by the National Human Genome Research Institute (NHGRI),
which also operates the NIH Chemical Genomics Center (NCGC), a
principal collaborator in TRND. Other NIH components will also
participate in the initiative.
A rare disease is one that affects fewer
than 200,000 Americans. NIH estimates that, in total, more than 6,800
rare diseases afflict more than 25 million Americans. However, effective
pharmacologic treatments exist for only about 200 of these illnesses.
Many neglected diseases also lack treatments. Unlike rare diseases,
however, neglected diseases may be quite common in some parts of the
world, especially in developing countries where people cannot afford
expensive treatments. Private companies seldom pursue new therapies for
these types of illnesses because of high costs and failure rates and the
low likelihood of recovering investments or making a profit.
"NIH is eager to begin the work to find
solutions for millions of our fellow citizens faced with rare or
neglected illnesses," said NIH Acting Director Raynard S. Kington, M.D.,
Ph.D. "The federal government may be the only institution that can take
the financial risks needed to jumpstart the development of treatments
for these diseases, and NIH clearly has the scientific capability to do
The drug development process is
complicated and expensive. Studies suggest that it currently takes more
than a dozen years and hundreds of millions of dollars to take a
potential drug from discovery to the marketplace. And the failure rate
"This initiative is really good news for
patients with rare or neglected diseases," said ORDR Director Stephen
C. Groft, Pharm.D. "While Congress has previously taken important steps
to help these patients, such as providing incentives for drug companies
under the Orphan Drug Act, this is the first time NIH is providing
support for specific, preclinical research and product development known
to be major barriers preventing potential therapies from entering into
clinical trials for rare or neglected disorders. While we do not
underestimate the difficulty of developing treatments for people with
these illnesses, this program provides new hope to many people
Typically, drug development begins when
academic researchers studying the underlying cause of a disease discover
a new molecular target or a chemical that may have a therapeutic
effect. Too often, the process gets stuck at the point of discovery
because few academic researchers can conduct all the types of studies
needed to develop a new drug. If a pharmaceutical company with the
resources to further the research does get involved, substantial
preclinical work begins with efforts to optimize the chemistry of the
potential drug. This involves an iterative series of chemical
modifications and tests in progressively more complex systems - from
cell cultures to animal tests - to refine the potential medicine for use
in people. Only if these stages are successful can a potential
treatment move to clinical trials in patients.
Unfortunately, the success rate in this
preclinical process is low, with 80 to 90 percent of projects failing in
the preclinical phase and never making it to clinical trials. And the
costs are high: it takes two to four years of work and $10 million, on
average, to move a potential medicine though this preclinical process.
Drug developers colloquially call this the "Valley of Death."
TRND will work closely with
disease-specific experts on selected projects, leveraging both the
in-house scientific capabilities needed to carry out much of the
preclinical development work, and contracting out other parts, as
scientific opportunities dictate. Its strategies will be similar to
approaches taken by pharmaceutical and biotechnology companies, but TRND
will be working on diseases mostly ignored by the private companies.
Importantly, TRND will also devote some of its efforts to improving the
drug development process itself, creating new approaches to make it
faster and less expensive.
If a compound does survive this
preclinical stage, TRND will work to find a company willing to test the
therapy in patients. There are several stages to the clinical trials
process that can take several years before the safety and efficacy of a
new drug is determined. FDA will only approve a drug for general use
after it passes these trials. The clinical trials process is also
expensive, but the failure rate is lower at this stage.
"NIH traditionally invests in basic
research, which has produced important discoveries across a wide range
of illnesses," said NHGRI Acting Director Alan E. Guttmacher, M.D.
"Biotechnology and pharmaceutical companies have enormous strength and
experience in drug development, but to maximize return-on-investment
work primarily on common illnesses. TRND will develop promising
treatments for rare diseases to the point that they are sufficiently
"de-risked" for pharmaceutical companies, disease-oriented foundations,
or others, to undertake the necessary clinical trials. NIH's goal is to
get new medications to people currently without treatment, and thus
NIH already has many components of the
drug development pipeline within its research programs. TRND will begin
its work in collaboration with the NIH Chemical Genomics Center (NCGC), a
center initially developed as part of the NIH Roadmap for Medical
Research. NCGC has developed a robotic, high-throughput screening system
and a library of more than 350,000 compounds that it uses to make basic
discoveries and probe cellular pathways. NCGC also has developed a team
of researchers skilled in developing assays representing disease
processes that can be tested in its screening system, and has extensive
experience building collaborative projects with investigators from
across the research community. Molecules with potential therapeutic
properties that emerge from the NCGC screening process could be fed into
the TRND drug development pipeline.
"With this new funding, TRND will
develop teams of scientists who can do the hard work of optimizing
chemicals that we or others discover that may treat rare diseases and
turn them into actual drugs," said NCGC Director Christopher P. Austin,
M.D., who is also the Senior Advisor for Translational Research to the
NHGRI Director. "This will still be hard work and it will take time and
produce failures. Unlike traditional drug development, however, where
only successes are published, we will publish our failures as well, so
everyone in the drug development community can learn from them. That
alone could be revolutionary."
If all the preclinical hurdles can be
crossed, a possible treatment must still be tested in a series of
clinical trials. TRND will seek to take advantage of several NIH
resources that can help launch human studies, including the NIH Clinical
Center, the NIH Rapid Access to Interventional Development (NIH-RAID),
and the Clinical and Translational Science Awards (CTSA) program.
Numerous obstacles impede the
development of new drugs for rare and neglected diseases. In addition to
the reluctance of private companies to risk their capital on a
potentially low return, relatively few basic researchers study rare
diseases, so the underlying cause of the illness frequently remains
unknown. And, because rare diseases are rare, researchers often have
difficulty recruiting enough people with the disorder to participate in a
clinical trial once a candidate compound reaches the stage where it can
be tested in people. Moreover, for many rare diseases, the natural
history of the disease is poorly understood, so researchers lack the
needed clinical measures (such as blood pressure) that can demonstrate
whether a treatment is working.
To address these difficulties, TRND will
seek a wide range of collaborations with academic researchers, as well
as partnerships with patient advocacy organizations, disease-oriented
foundations and others interested in treatments for particular
illnesses. TRND's leaders hope that the collaborations will help lay the
groundwork for clinical trials once that point in drug development is
TRND is currently setting up an
oversight process to help it decide which projects that address
thousands of rare and neglected diseases will be pursued. Leadership
currently envisions a small number of diseases being studied each year,
with strict criteria used to determine which molecules will be studied
for which diseases. NIH expects to use existing intellectual property
policies to transfer licenses for TRND-discovered drugs to private
companies or others for development, clinical testing and marketing.
Frequently asked questions about this new program are available online at:
The Office of Rare Diseases Research is
one of the programmatic offices in the Office of the Director of the
NIH. For more about ORDR, visit http://rarediseases.info.nih.gov/.
The Office of the Director, the central
office at NIH, is responsible for setting policy for NIH, which includes
27 Institutes and Centers. This involves planning, managing, and
coordinating the programs and activities of all NIH components. The
Office of the Director also includes program offices which are
responsible for stimulating specific areas of research throughout NIH.
Additional information is available at http://www.nih.gov/icd/od/.
The National Human Genome Research
Institute is one of the 27 institutes and centers at the NIH, an agency
of the Department of Health and Human Services. The NHGRI Division of
Intramural Research develops and implements technology to understand,
diagnose and treat genomic and genetic diseases. Additional information
about NHGRI can be found at its Web site, www.genome.gov.
The National Institutes of Health (NIH)
-- The Nation's Medical Research Agency -- includes 27 Institutes and
Centers and is a component of the U.S. Department of Health and Human
Services. It is the primary federal agency for conducting and supporting
basic, clinical and translational medical research, and it investigates
the causes, treatments, and cures for both common and rare diseases.
For more information about NIH and its programs, visit www.nih.gov.
How many times have you been looking
for something at your house but you accidentally find something you
previously were missing? Wouldn’t it be a shame if the prize you were
seeking was within reach but you discounted that it could be that easy?
What if understanding Niemann-Pick Type C disease opened up the door to
help millions of Americans with other disorders involving cholesterol?
Of course nothing in life is easy nor will it always be within reach.
With being human comes the tendency to make oversights. It
has been almost 13 years in July 2010 that the NPC1 gene, on Chromosome
18 for Niemann-Pick Type C was shared with the world on its discovery.
This was a huge step and monumental discovery with associating
cholesterol with a certain gene/chromosome at that time. To arrive at
this point, it took decades of work which shed an abundant light into
how a cell metabolizes cholesterol. In short, Niemann-Pick Type C causes
progressive deterioration of the nervous system by blocking the
movement of cholesterol within cells.
From a press release dated July 10, 1997 from Bethesda, MD: “This discovery is an excellent
example of how research on rare brain disorders often pays off in other
ways,” says Zach W. Hall, Ph.D., Director of the National Institute of
Neurological Disorders and Stroke (NINDS). “By identifying this gene, we
not only take a crucial step forward in understanding this devastating
disorder, but also gain insights into problems that affect every one of
In 2001, cardiovascular disease was
responsible for more than 39 percent of all deaths in the United States
(American Heart Association: Heart Disease and Stroke Statistics 2004).
Atherosclerosis is a disease where plaque builds up in your arteries. We
all know those aren’t important to our lively hood at all. OK, just
joking but plaque is made up of fat, calcium, cholesterol, and other
substances found in our blood that over time builds up but hardens in
the passage ways of our arteries. Imagine if you’re driving through a
two way tunnel but one side is now closed off? It would be kind of hard
to get through to the other side in a timely and relaxing manor with
additional objects in your way? Just like that situation, this affects
how we get our blood to important areas in our bodies. With millions of
people dying each year, this is a huge number of people. What if
Niemann-Pick Type C could provide some insight?
diseases such as Adult onset Alzheimer’s, Stroke, Cystic Fibrosis,
Duchenne Muscular Dystrophy, and even HIV-Aids will benefit from the
research into Niemann-Pick Type C. Did you know that children can
experience dementia to? Crazy to imagine because most of us think that
only our elderly family members get that! With the combination of deaths
due to these diseases, could you imagine if we had a more collaborative
research environment? Unfortunately big companies aren’t going to
sacrifice revenue opportunities to help a blip on the radar screen but
they will invest if they see it helping thousands of people; this means a
return on their investment. This reality is sad but true. Rare diseases OUR important to you,
me, and everyone we know. Each of us has a Chromosome 18 that is vital
to us being a living human being. I encourage you to help out in some
way. That could be donating to several charities that fund research for
NPC like the National Niemann Pick Disease Foundation, Ara Parseghian Medical Research Foundation, Hide and Seek Foundationor the Niemann-Pick Children’s Fund.That
could be becoming and advocate in lobbying our government for better
health care. It could be you just passing the word and spreading
awareness. We all are in this together and have
been affected in some way by one of the diseases mentioned in this post.
One person can make a difference in the world and that person could be
FDA Grants Mom’s Wish; Gives Orphan Drug Designation By Amy Dockser Marcus
A mother from Reno, Nev.
who was a force behind an application for an orphan drug designation has
gotten good news: the FDA approved the request.
Chris Hempel, whose twin
daughters have a fatal cholesterol metabolism disorder known as
Niemann-Pick Type C (NPC), said that the designation was approved last
week. An official at the FDA’s Office of Orphan Products Development
confirmed the designation, for a form of a compound called cyclodextrin.
The FDA’s move is the first step in the process of developing drugs for
rare diseases that affect fewer than 200,000 Americans.
In March, the WSJ reported about a new effort by the FDA to get more applications by holding workshops
offering on-the-spot advice. The first one, held in February at the
Keck Graduate Institute in California, was attended by Hempel and Ron
Browne, a scientist hired by a group of families with children who have
NPC. The next one is slated for August, at the University of Minnesota. At the workshop, Hempel
stuck out from a crowd consisting mainly of pharmaceutical and biotech
company representatives; the binders that held her application were hot
pink, her daughters’ favorite color.
The approval is important
for a few reasons. Last year, only 160 applications — out of 250
requests –received an orphan drug designation. So cyclodextrin is now in
an elite group. Moreover,”ultra orphan” diseases — affecting fewer than
6,000 patients in the U.S. — such as NPC face particularly steep
challenges. These ultra orphans make up less than 15% of orphan
designations even though they represent more than 80% of identified rare
diseases, according to data prepared by the Kakkis EveryLife Foundation
and BioMedical Insights.
Hempel hopes the
designation will attract pharmaceutical and biotech companies or
investors who might develop cyclodextrin into a drug to help treat NPC.
The FDA’s move makes the group eligible to pursue special tax credits
that could apply to clinical trials and research. “The designation helps
legitimize what we are doing,” says Hempel. “It’s no longer just a mom
saying it — the FDA is saying this is a promising compound.”
FDA Approval Received! Children’s
Hospital Oakland Receives FDA Clearance to Begin World’s First
Cyclodextrin Administration Into the Brains of Twins with Rare and
Deadly Cholesterol Disease
Molecule Used In Common Food and Household Products Like Febreze®
Fabric Refresher Called Hydroxypropyl Beta Cyclodextrin (HPßCD) Will be
Delivered into Twins’ Central Nervous System in an Attempt to Stop
Neurological Progression of Niemann Pick Type C Disease
September 23, 2010 –
Oakland, Calif. – Children’s Hospital & Research Center Oakland
announced today that the US Food and Drug Administration (FDA) has
granted clearance of an Investigational New Drug (IND) application
to introduce Trappsol® Cyclo™ (Hydroxypropyl Beta Cyclodextrin or
HPßCD) into the brains of six year old identical twin girls dying of a
rare brain-destroying cholesterol disease called Niemann Pick Type C
(NPC). Known as “childhood Alzheimer’s,” NPC is a deadly progressive
neurological condition that causes severe dementia and other
debilitating symptoms in children. The FDAs approved use of Trappsol®
Cyclo™ marks the first time in medical history that HPßCD will be
delivered directly into the brain of a human being in an attempt to
arrest a progressive and fatal neurological condition.
Within days, Addison and
Cassidy Hempel will travel from their home in Reno, Nev., to Children’s
Hospital Oakland to start ongoing injections of Hydroxypropyl Beta
Cyclodextrin (HPßCD) into their central nervous systems. Initially, the
twins will receive six cyclodextrin treatments of Trappsol® Cyclo™ via
lumbar injection over a 12-week period. If Trappsol® Cyclo™ is well
tolerated and no adverse side effects occur, the twins are then expected
to undergo brain surgery to implant access ports allowing HPßCD to be
delivered into the brain’s ventricle system.
HPßCD is a ring of seven
sugar molecules known as a cyclic oligosaccharide that is derived from
starch. Derivatized cyclodextrins are used extensively in research labs
to remove cholesterol from cultured cells and are well known in the
pharmaceutical industry for their ability to solubilize drugs.
Underivatized cyclodextrins are used throughout the food industry to
make cholesterol-free products, such as fat-free butter, eggs and milk
products. HPßCD is recognized as a GRAS (Generally Recognized As Safe)
material for use in food products in Asian and European countries and is
being considered for similar certification in the United States.
Hydroxypropyl Beta Cyclodextrin, the chemical compound that will be
administered into the twins’ central nervous system, is also an active
ingredient found in Procter & Gamble’s Febreze® Fabric Refresher and
is used to help eliminate odors from fabrics. Millions of people
worldwide are exposed to small amounts of cyclodextrin compounds every
day in food, cosmetics and household products.
“It is remarkable to be
in position to try a genuine medical intervention that may retard or
restore neurological function in children suffering from Niemann Pick
Type C disease,” said Caroline Hastings, MD, the Children’s Hospital
Oakland pediatric hematologist/oncologist who diagnosed the twins. Dr.
Hastings also manages the satellite hematology/oncology clinic at Renown
Regional Medical Center in Reno where the girls receive much of their
treatment. “This family’s tremendous courage to move forward with this
groundbreaking treatment to deliver cyclodextrin into the brains of
their twins provides real hope for all children afflicted by this
mind-robbing condition and possibly others suffering from cholesterol
and lipid related disorders.”
In April 2009, the FDA
approved an Investigational New Drug protocol that allowed Addison and
Cassidy Hempel to undergo weekly intravenous infusions of Hydroxypropyl
Beta Cyclodextrin into their bloodstreams through a Medi-Port catheter
implanted in their chest walls. However, research conducted by David
Begley, PhD, a leading blood-brain barrier expert at Kings College
London, discovered that Hydroxypropyl Beta Cyclodextrin does not cross
from the bloodstream into the brain. While the Hempel twins have shown
improvements with ataxia and have less difficulty swallowing following
intravenous intervention with HPßCD, they continue to decline
neurologically and there are no other treatment options available to
save their lives. The twins have lost most of their ability to speak and
are experiencing intermittent seizures and dementia; however, the girls
can still walk, see, and communicate to their parents with a range of
sounds and gestures.
On June 13, 2010, Dr. Hastings filed a revised protocol
to the Hempel twins’ Investigational New Drug applications with the FDA
requesting permission to deliver Trappsol® Cyclo™ directly into the
central nervous system of the twins in order to bypass the blood-brain
barrier. Researchers studying Niemann Pick Type C afflicted cats and
mice have discovered that when HPßCD is delivered directly into the
brains of these animals, HPßCD has a remarkable life extending effect
and appears to arrest the progression of this deadly neurological
condition. It is currently unknown exactly how HPßCD is working to
achieve these astonishing neurological effects in NPC animals or if it
will have the same effect in humans.
For Chris Hempel, mother
of the twins, the start of cyclodextrin treatments into the central
nervous system of her twins “creates new hope that was unimaginable even
a few years ago for an ultra rare disease with a certain death
sentence.” Since receiving the NPC diagnosis in October 2007, Ms. Hempel
has worked tirelessly with doctors and researchers around the world to
search for a lifesaving treatment for her twin daughters. In May 2010,
she worked with Dr. Hastings to receive one of the few orphan drug
designations granted by the FDA for the compound Trappsol® Cyclo™.
“It’s extraordinary to
think that a sugar compound used in common products found in my
refrigerator and laundry room could have such a profound effect on human
cholesterol metabolism and may actually save our daughters lives,” said
Hempel. “We are incredibly grateful for the support we have received
from the medical, regulatory, pharmaceutical, and academic communities
who have worked to help us bridge the scientific gap and turn a
treatment idea into a treatment reality.
children worldwide have been diagnosed with double genetic mutations on
the Niemann Pick Type C cholesterol gene, yet what scientists learn
about these children may have implications that reach far beyond this
ultra rare genetic cholesterol disease. Recent published research
reports of the role for the NPC1 gene in Alzheimer’s disease and human
immunodeficiency virus infection (HIV) make Niemann Pick Type C disease
and gene research relevant to millions of people worldwide.
Genetic Counseling is the process of helping people
understand and adapt to the medical, psychological, and familial
implications of genetic contributions to disease. This process
integrates: The interpretation of family and medical histories to assess the chance of disease occurrence or recurrence; Education about inheritance, testing, management, prevention, resources, and research; Counseling to promote informed choices and adaptation to the risk or condition. A genetic counselor is a health professional with
specialized graduate degrees and experience in the areas of medical
genetics and counseling. Genetic counselors provide supportive
counseling to families, serve as patient advocates, and refer
individuals and families to community or state support services. They
serve as educators and resource people for other health care
professionals and for the general public. Some counselors also work in
administrative capacities. Many engage in research activities related to
the field of medical genetics and genetic counseling. To learn more general information about genetic
counseling, tips on how to prepare for a genetics clinic appointment,
and details about different specialties in the field of genetics, please
see the new Genetic Alliance collaborative publication Making Sense of Your Genes: A Guide to Genetic Counseling. The National Niemann-Pick Disease Foundation has
contracted for the services of a board certified Genetic Counselor, Cate
Walsh Vockley, MS, CGC as Coordinator of Education, Referral and
Advocacy and a member of the Family Services team. Cate is available to
immediate and extended families and to their health care providers to
provide initial genetic counseling, assistance in arranging diagnostic
and molecular testing, referrals to local genetic and health-related
services, supportive counseling, and a wide range of assistance on other
issues. NNPDF has a variety of educational and resource materials that are available on this web site including:
Information about Niemann-Pick disease types A, B, and C for health care providers, and for family and friends
CYCLO (Cyclodextrin) CYCLO
research is only in the very early stages but it is something we are
watching very closely. The Hemple twins are currently receiving
Cyclodextrin infusions now.
Compound that releases trapped cholesterol identified
1 March 2009 Researchers
at University of Texas Southwestern Medical Center have identified in
mice a compound that liberates cholesterol that has inappropriately
accumulated to excessive levels inside cells.
findings shed light on how cholesterol is transported through the cells
of the body and suggest a possible therapeutic target for Niemann-Pick
type C disease (NP-C), an inherited neurodegenerative disorder
characterised by abnormally high cholesterol levels in every organ.
we've shown is that very quickly after administration of this compound,
the huge pool of cholesterol that has just been accumulating in the
cells is suddenly released and metabolised normally," said Dr John
Dietschy, professor of internal medicine at UT Southwestern and senior
author of the study appearing online and in an upcoming issue of the Proceedings of the National Academy of Sciences. "With just one dose, you excrete a large portion of this pool of cholesterol."
in the body comes from dietary sources and is also made by the body
itself. It is essential for many biological processes, including the
construction and maintenance of cell membranes. Cholesterol normally is
transported through cells and is excreted by the body.
with Niemann-Pick type C have a genetic mutation that causes excessive
amounts of cholesterol to accumulate in compartments within cells called
lysosomes. This cholesterol accumulation leads to liver disease,
neurodegeneration and dementia. There is no specific level at which
cholesterol levels become abnormal, but the vast majority of children
diagnosed with NP-C die before they are 20 years old and many before age
10. Late onset of neurological symptoms such as clumsiness, mild
retardation and delayed development of fine motor skills can lead to
longer life spans, but few people diagnosed with NP-C reach age 40.
the current research, researchers injected a single dose of a
cholesterol-binding agent known as CYCLO into 7-day-old mice with the
Niemann-Pick mutation. Shortly after administration, the mice that
received CYCLO began to process cholesterol just as their healthy
counterparts did. After 49 days, the mice treated with a single
injection continued to show substantially lower tissue cholesterol
levels than the untreated mice, as well as improved liver function and
Dietschy, who has been studying cholesterol metabolism for nearly 50
years, cautioned that the findings in no way represent a Niemann-Pick
key idea is that we appear to have overcome the transport defect in the
lysosome that is brought about by the genetic defect or mutation," Dr
Dietschy said. "We do not yet understand what is happening at the
molecular level, but it is clear that this compound somehow overcomes
the genetic defect that causes individuals to accumulate cholesterol."
next step in Dr Dietschy's investigation is to determine the
concentration of CYCLO needed to trigger the cholesterol's release.
Researchers also hope to determine in animals the additional lifespan
CYCLO administration provides, as well as how long the drug's affects
treating at seven days, we eliminated approximately one-third of the
accumulated cholesterol almost immediately," Dr Dietschy said. "Now we
want to see what happens if we give it every week. Can we maintain low
cholesterol levels? That's what we're looking at now."
UT Southwestern researchers involved in the research were Dr Benny Liu,
lead author of the study and postdoctoral researcher in internal
medicine; Dr Stephen Turley, professor of internal medicine; Dr Dennis
Burns, professor of pathology; Anna Miller, student research assistant;
and Dr Joyce Repa, assistant professor of physiology.
work was funded by the US Public Health Service, the Harry S. Moss
Heart Trust, the Ara Parseghian Medical Research Foundation and the
Dana's Angels Research Trust.
(Source: University of Texas Southwestern Medical Center: Proceedings of the National Academy of Sciences: March 2009)