Post on 12-Sep-2021
Advances in the Treatment of Rare Diseases
Contained within these pages are the realized hopes and dreams of millions of
Americans affected by rare diseases. A Decade of Innovation doesn’t just describe a
period of stunning medical advances, it documents a brief window in time during
which people without hope learned to believe again that they might have a future.
This book tells the stories of numerous individuals and the remarkable legislation
—the Orphan Drug Act of 1983—that has given them back their lives. The National
Organization for Rare Disorders (NORD) is grateful to PhRMA for focusing this
spotlight on rare diseases. We look forward to continued partnership with all those
involved in the rapidly unfolding drama of bringing safe and effective new treat-
ments to market for the 25 million Americans with rare diseases.
Abbey S. Meyers Carolyn Asbury, PhD
President Chairman, Board of Directors
NORD NORD
Genetic Alliance applauds these advances in treating rare diseases. We are grateful
that the continuum of basic science to medical services is infused with the time,
energy, and resources of many talented individuals, particularly those who are part
of the member companies of PhRMA. Genetic Alliance members, 600 disease
advocacy organizations, representing over 1,000 diseases, look forward to the day
they too will celebrate a treatment. Meanwhile, we stand beside you in gratitude and
support your marvelous accomplishments.
Sharon F. Terry
President and CEO
Genetic Alliance
• interstitial cystitis: pentosan polysulfate sodium • neurocystericercosis and hydatid disease:
albendazole • symptomatic orthostatic hypotension: midodrine
hydrochloride
2004
2005
2003
2001
1998
1996
1995
• T-cell acute lymphoblastic leukemia and T-cell lymphoblastic lymphoma: nelarabine
• chronic iron overload: deferasirox• advanced renal cell carcinoma: sorafenib tosylate• myelodysplastic disorder: lenalidomide• mucopolysaccharidosis VI: galsulfase• severe primary IGF-1 deficiency: mecasermin• glioblastoma: temozolomide
• secondary hyperparathyroidism: cinacalcet• malignant pleural mesothelioma: pemetrexed• acute lymphoblastic leukemia: clofarabine• pulmonary arterial hypertension: iloprost
• CD20-positive follicular non-Hodgkin’s lymphoma:tositumomab and Iodine-131 tositumomab
• Fabry disease: agalsidase beta• type 1 Gaucher disease: miglustat• acromegaly: pegvisomant
• hereditary tyrosinemia type 1: nitisinone• Cryptosporidium parvum or Giardia lamblia:
nitazoxanide• cataplexy associated with narcolepsy: sodium oxybate • pulmonary arterial hypertension: treprostinil
• chronic myeloid leukemia: imatinib mesylate• pulmonary arterial hypertension: bosentan
• acute promyelocytic leukemia: arsenic trioxide• acute myeloid leukemia: gemtuzumab
• hypoxic respiratory failure in newborns: nitric oxide • respiratory distress syndrome in premature infants:
poractant alfa • anaplastic astrocytoma: temozolomide
1999
• Crohn’s disease: infliximab • pulmonary tuberculosis: rifapentine • narcolepsy: modafinil • erythema nodosum leprosum: thalidomide • thrombocytopenia: lepirudin
• pediatric respiratory distress syndrome: calfactant • hemophilia B: recombinant human Factor IX
• amyotrophic lateral sclerosis: riluzole • primary pulmonary hypertension: epoprostenol
1997
2000
2002
RARE DISEASES
TABLE OF CONTENTS
Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .3
Metabolic Disorders
Fabry Disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .4
Gaucher Disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .4
Mucopolysaccharidosis VI . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .5
Rare Blood Pressure Disorders
Pulmonary Hypertension . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .6
Hypotension . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .7
Crohn’s Disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .8
Interstitial Cystitis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .8
Hyperparathyroidism . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .10
Acromegaly . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .10
Diseases of the Developing World
Cryptosporidiosis and Giardiasis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .12
Neurocysticercosis and Hydatid . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .12
Tuberculosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .13
Blood Disorders
Thrombocytopenia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .14
Hemophilia B . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .14
Leprosy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .15
Childhood Diseases
Respiratory Distress Syndrome . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .16
Tyrosinemia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .16
Primary IGF-1 Deficiency . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .17
Narcolepsy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .18
ALS/Lou Gehrig’s Disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .18
Cancer . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .20
Leukemia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .22
Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .24
Endnotes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .26
In the last 10 years, biopharmaceutical companies have
made great progress in the fight against rare diseases.
Over 160 drugs were approved during the past decade
(1995–2005) to treat rare or “orphan” diseases that
affect 200,000 or fewer people in the United States.
This compares with 108 approvals in the decade before
(1984–1994) and fewer than 10 in the 1970s.1 Each of
these medicines offers hope and relief to patients with
diseases that often have no other treatment options.
According to the National Institutes of Health Office of
Rare Diseases, there are 6,000–7,000 rare diseases
affecting a total of 25 million Americans.2,3 One in every
10 Americans receives a diagnosis of a rare disease.4
This population is particularly in need of medicines
because, as the FDA estimates, 85–90 percent of rare
diseases are serious or life-threatening.5
Why has the number of orphan drugs being approved
grown so much in recent years? One factor is advances
in science; a better understanding of molecular and
genetic causes of disease has given us new tools to
explore rare diseases, which are often more complex
than more common diseases. Another factor is the huge
and growing investment in research and development
in general, as well as in orphan diseases specifically.
The Orphan Drug Act, passed in 1983, provided tax
relief and some marketing exclusivity for companies
who develop an orphan drug. This legislation is
credited with the explosion in drug approvals
for rare diseases after the Act was passed in 1983.
Today, the number of new drugs in development for
rare diseases continues to rise. This report high-
lights some of the many important drugs for rare
diseases that have been approved in the last decade.
These medicines have meant a completely differ-
ent life today for many patients with rare diseases
compared with just a few years ago. And, scientists
are working each day to make the coming decades as
bright as the last was for patients with rare diseases.
Fabry Disease
Gaucher Disease
Patients with Fabry disease are deficient in a particular
enzyme involved in the breakdown of fats, which causes a
buildup of fat in their blood vessels and organs. The symp-
toms of this potentially fatal genetic disorder are diverse
and can make diagnosis difficult.6 They include burning
sensations in the hands and feet, skin rash, excessive
sweating, fever, severe gastrointestinal problems after eat-
ing, and cloudiness of the eye. Fabry disease patients often
survive into adulthood but are at increased risk of strokes,
heart attack and heart disease, digestive problems, and
kidney failure. Fabry disease affects an estimated 1 in
117,000 people, most of whom are male.7,8
PHARMACEUTICAL ADVANCES■ The First to Attack Fabry Disease at Its Root Agalsidase beta, approved in 2003, is the first drug that
treats the cause of Fabry disease rather than lessening its
symptoms. This enzyme replacement reduces the
accumulated fat within the blood vessels and organs
and decreases the symptoms of the disease.9
4
The foods we eat every day are filled with the building blocks of life: carbohydrates, aminoacids, and fats. But to use these materials, the body must break down complex foods intothese simpler, usable forms. Any problems in this process, which is called metabolism, cancause a metabolic disorder, many of which are rare and difficult to treat.
Advances in the Treatment of METABOLIC DISORDERS
Gaucher disease, another rare metabolic disorder, is a
deficiency of the enzyme glucocerebrosidase, which
breaks down and recycles glucosylceramide. The deficien-
cy causes quantities of this fatty substance to accumulate
in the spleen, liver, lungs, bone marrow, and, in rare cases,
the brain.10 This buildup results in bruising, clotting diffi-
culties, fatigue, enlargement of the liver and spleen, weak-
ening of the skeleton, and in some instances, lung and
kidney impairment.
This rare genetic disorder is classified into three differ-
ent types based on clinical severity and course, and by
the presence
or absence of
neurological
complications.
An estimated
6,000 individu-
als in the
United States
have Gaucher
disease.11,12
PHARMACEUTICAL ADVANCES■ Oral Treatment for Patients who Need Another OptionFor patients who cannot receive the standard enzyme
treatment due to allergies, hypersensitivity, or poor venous
access, miglustat, an oral treatment, was approved in 2003for treatment of mild to moderate disease.13 Miglustat
works by reducing the production of glucosylceramide so
that the available glucocerebrosidase enzymes are not
overwhelmed and are able to properly break down the sub-
stance and clear it from the body.14 Miglustat is proven to
decrease the size of the liver and spleen and increase
platelet and hemoglobin levels, which decreases bruising
and fatigue.15
5
Many Symptoms, One Disease
Donna never expected an eye exam would
change her family’s outlook on life. After an
eye doctor noticed clouding in her 8-year-old
daughter’s eyes, Donna and her two sons
were checked for similar symptoms. All four
had corneal opacities. Donna and her chil-
dren were sent to genetic counseling where
doctors confirmed that they had Fabry disease.
Not all Fabry disease diagnoses are as fast as
Donna’s due to the wide variety of symptoms
associated with the disease. Patients with the
disease experience problems ranging from
stomach cramps and vomiting to body aches
and heat intolerance. Another patient,
Adrian, had symptoms that baffled doctors
for years before he was diagnosed. He
eventually visited a rheumatologist who
was able to make sense of his symptoms,
and get him proper medical treatment for
the disease.
Today, Fabry disease patients depend upon
both enzyme replacement therapy (ERT)
and symptom management to manage the
disease. While ERT does not cure Fabry
disease, it can reduce the symptoms of
the disease, giving patients like Donna
and Adrian a second chance at a
normal life.22,23
Between 85 and 90 percent of orphan diseases are seriousor life-threatening.21
Patients with mucopolysaccharidosis VI (MPS VI), also
known as Maroteaux-Lamy syndrome, face many health
problems, which can be devastating depending on the
severity of the disease.
In MPS VI, patients lack a particular enzyme called aryl-
sulfatase B, which breaks down and recycles glycosamino-
glycan (GAG), a complex sugar. GAGs are used to provide
structure for various tissues including bones, cartilage,
skin, and airways. When GAGs accumulate, however, they
can cause a variety of symptoms including thickening of
the nose, lips, and tongue; breathing problems due to
narrowed airways; short stature; frequent ear infections
leading to hearing loss; heart disease as a result of mal-
functioning heart valves, thickening of the heart muscle,
and narrowed blood vessels; and stiff joints.16 Because the
signs and symptoms are so varied, diagnosis is often
difficult and delayed. The disease is also quite rare;
approximately 1,100 people worldwide have MPS VI.17
PHARMACEUTICAL ADVANCES■ First Therapy Targeted Toward Cause of Devastating
Genetic Disorder
Approved in 2005, galsulfase is the first enzyme replace-
ment therapy for MPS VI to treat the cause of the disorder
by breaking down the built-up stores of GAGs instead
of improving symptoms related to the disease.18,19 Because
of the problems associated with the disease, patients with
MPS VI often become tired easily and cannot withstand
long periods of physical activity. In clinical trials, galsulfase
was shown to improve the walking and stair-climbing
capacity of patients.20
Mucopolysaccharidosis VI
Bosentan, the first in a new class of medicines called
endothelin-receptor antagonists, was approved in 2001 for
the treatment of primary pulmonary hypertension to
improve exercise ability and to decrease the rate of disease
progression. Taken orally twice a day, it works by decreas-
ing the stiffness of the blood vessels as well as widening
them to allow blood to flow more easily.28
Treprostinil was approved in 2002 for patients with the
New York Heart Association (NYHA) Class II—IV pulmo-
nary arterial hypertension.29 Heart disease patients are clas-
sified according to the NYHA classification system, which
is based on the capacity of patients with heart diseases to
participate in physical activities, with Class IV disease
resulting in discomfort
with any activity and
symptoms of the disease
occurring even at rest.
In other words, trepros-
tinil treats patients with
moderate to severe PAH,
those who experience
limitations on physical
activity as a result of the
disease. Administered by
continuous infusion, tre-
prostinil works by dilating
the arteries and prevent-
ing blood clot formation.30
Iloprost is the newest medicine for treatment of pulmo-
nary arterial hypertension and was approved in 2004 for
use by patients with NYHA Class III or IV pulmonary
arterial hypertension to increase exercise ability and de-
crease symptoms.31 It is a novel treatment in that it is
inhaled by mouth using a special nebulizer. It works by
dilating the arteries and prevents blood clot formation.32
Pulmonary Hypertension
The pulmonary artery is the blood vessel that carries
blood from the heart to the lungs to be re-oxygenated. In
pulmonary arterial hypertension (PAH) there is continu-
ous high blood pressure in the pulmonary artery. Possible
causes of the increased pressure may include tightened
muscles within the artery walls, thickened walls of the
pulmonary arteries or scar tissue making the arteries
narrower. Tiny blood clots may form within the smaller
arteries and cause blockages. The heart, as a result, must
work harder to supply the body with enough oxygen-rich
blood, and over time the heart muscle weakens.
Shortness of breath is the primary symptom of PAH.
People with PAH might also experience tiredness,
dizziness, chest pain, or a racing pulse. As the disease
progresses, energy level decreases, and these symptoms
can occur even when resting.24
There are two types of pulmonary hypertension: primary
and secondary. Primary pulmonary hypertension is
inherited or occurs for no known reason. Secondary pulmonary hypertension is caused by another condition,
such as chronic heart or lung disease or blood clots in the
lungs.25 According to the American Heart Association, an
estimated 500 to 1,000 new cases of pulmonary hyperten-
sion are diagnosed each year.26 Although this condition is
very rare, four new orphan drugs have been approved to
treat it in the last decade.
PHARMACEUTICAL ADVANCES■ Helping Blood Get to the Lungs
Epoprostenol was approved in 1995 for treatment of
primary pulmonary hypertension. It is an intravenously
administered medicine that works by dilating the arteries,
which allows more blood to flow through the vessel, and
by preventing blood clot formation.27
A person’s blood pressure is continually changing depending on activity, temperature, diet,emotional state, posture, physical state, and medication use. Blood pressure is a measure-ment of the force applied to the walls of the arteries as the heart pumps blood through thebody. It is determined by the force and amount of blood pumped, and the size and flexibilityof the arteries. When any of these factors is compromised, disease may occur.
Advances in the Treatment of RARE BLOOD PRESSURE DISORDERS
6
7
Women with PAH Face Tough Decisions
While both men and women are at risk for pulmonary arterial hypertension (PAH),it is more likely to affect women. Approxi-mately 60 percent of PAH patients hospital-ized between 1995 and 1998 were women.Among those women, 37 percent wereyounger than 65.
Unfortunately, pregnancy aggravates the condition, so for women with PAH, preg-nancy can be life-threatening. Within 35 daysof childbirth, the death rate for new motherswith PAH is between 30 and 56 percent.37
A woman with PAH often must choosebetween having a family and risking herown life to have a baby.
Despite the discouraging statistics,researchers are making progress. A 2001 case study in Chest reported thatepoprostenol therapy combined with ananticoagulant can improve outcomes formother and child when used before, dur-ing, and after delivery, without negativeside effects on the child.38 For nonpreg-nant patients, survival also appears to beincreasing. Many people can managethe disorder for up to 20 years. Geneticstudies and pharmaceutical researchare providing hope for the developmentof new treatments of PAH and possi-bilities for a cure in the future.39
Hypotension is an abnormal condition in which a person’s
blood pressure is lower than it should be. It causes symp-
toms such as dizziness or lightheadedness and inadequate
blood flow to the heart,
brain, and other vital
organs. Orthostatichypotension results from
a sudden change in body
position, usually from
lying down to an upright
position.33 This condition
affects 156,000 people34
and can be caused by
certain medicines,
dehydration, or heart
failure/attack.35
PHARMACEUTICAL ADVANCES
■ Drug Makes Standing Up a Safe Activity
Midodrine hydrochloride is used to treat symptomatic
orthostatic hypotension. It works by stimulating the
blood vessels to tighten, thereby raising blood pressure.
Midodrine was approved in 1996 based on its ability to
increase one-minute standing systolic blood pressure.36
Hypotension
The Orphan Drug Act was enacted in 1983 and encourages companies to develop and manufacturedrugs for rare conditions.
PHARMACEUTICAL ADVANCES■ Finally, Remission and Better Quality of Life for
Those with Painful Bowel Disease
Infliximab, the first therapy for Crohn’s disease, is a
genetically engineered antibody that targets a protein that
promotes inflammation in the body. Administered intra-
venously, infliximab decreases inflammation along the lin-
ing of the intestines and is effective in closing sores
between the bowel and skin.42 In clinical trials, a clinical
improvement or remission occurred in 65 percent of
patients with severe to moderate Crohn’s disease after a
single dose.43 The FDA estimates that this drug can help
about 175,000 people in the United States.44
Imagine needing to run to the bathroom up to 60 times a
day. You might have to get up five times in the middle of
dinner at a restaurant or wake up every 25 minutes in the
night to use the bathroom. Patients with interstitial cystitis(IC) often need to urinate frequently and urgently, and they
may have recurring pain and tenderness in the bladder
and pelvic region.45 These symptoms can disrupt the lives
of patients, making it impossible for 63 percent of them to
work full time.46
These unpredictable symptoms may disappear without
explanation or recur with an event such as a change in
diet, treatment, or menstruation.47 Even when symptoms
disappear, they may return after days, weeks, months,
Crohn’s Disease
Advances in the Treatment of CROHN’S DISEASE & INTERSTITIAL CYSTITIS
8
Interstitial Cystitis
For patients with Crohn’s disease, attacks can bring
everyday activities to a screeching halt as the incurable,
inflammatory bowel disease ravages their gastrointestinal
tract. The 1998 approval of infliximab to treat moderate
and severe Crohn’s was the first therapy approved for the
disease; the compound successfully reduces symptoms
and improves patients’ sense of well-being.40
While scientists are deepening their understanding of the
effects of Crohn’s disease, the cause remains a mystery.
The most popular theory is that the body’s immune sys-
tem reacts to a virus or a bacterium by launching an attack
against the microbes and causing ongoing inflammation
in the intestine. People with Crohn’s disease tend to have
abnormalities of the immune system, but doctors do not
know whether they are a cause or result of the disease.41
Crohn’s disease is characterized by chronic inflammation
of the intestinal wall or any part of the gastrointestinal tract
and causes symptoms of abdominal pain, chronic diarrhea,
loss of appetite, weight loss, joint aches, and fatigue.
Two serious complications are abnormal enlargement of
the colon and intestinal obstruction; the disease also can
cause lesions, abscesses, and grooves in the intestinal wall
and surrounding area.
9
A Decade-Long Struggle with Crohn’s: John’s Story
Diseases can seem especially devastating
when they strike people in their youth. At
age 19, John was diagnosed with Crohn’s
disease. A healthy, active teenager, John
found Crohn’s disease incredibly debilitat-
ing. “My life was on hold—I was not able
to work or go to college for four years.”
Eating became painfully difficult; he says
food felt like broken glass going through
his intestines. Within a month, he had
dropped from 165 to 115 pounds. “I felt
like I was wearing my disease—a disease
no one understood.” After 10 surgeries,
John became “desperate for a solution
that did not include surgery.” That solu-
tion came on his 29th birthday with his
first treatment of infliximab. “It was the
best birthday present I could have ever
received.... I had just about given up
hope, but with this treatment I felt like
I had my life back.”53
or years. Scientists have yet to find the cause of this
disease that affects more women than men. It is most
likely to strike around age 40, but many patients are much
younger. There are 100,000 known cases in the United
States.48
PHARMACEUTICAL ADVANCES■ Soothing the Symptoms of Unpredictable Pelvic
Pain Disorder
Pentosan polysulfate sodium was approved in 1996 and
is the first and only orally administered medicine devel-
oped specifically for relief of IC symptoms. It is believed
that it works by creating a buffer layer on the inside of the
bladder to prevent urine from irritating the bladder wall.49
In clinical trials, the drug was shown to bring relief of
bladder pain to 42 percent of patients who had been
treated for up to six months, and 60 to 62 percent of
those treated for 24 months.50 Patients also experienced
reductions in frequency of urination.51
In the decade after the OrphanDrug Act was passed, there wereabout 10 times as many drugsapproved for rare diseases com-pared with the decade before.52
PHARMACEUTICAL ADVANCES■ First-In-Class Treatment Counteracts Overactive
Parathyroid Glands
Cinacalcet lowers the level of parathyroid hormone
and calcium by increasing the sensitivity of the calcium-
sensing receptor on the surface of the parathyroid gland.56
In doing so, it lowers the risk of altered metabolism of
calcium and phosphorus, bone pain, fractures, and risk for
cardiovascular death. With cinacalcet’s 2004 approval, it
became the first specific pharmaceutical therapy for hyper-
calcemia associated with parathyroid cancer as well as for
secondary hyperparathyroidism.
When a manufactured protein became available in 2003for people with acromegaly, a hormone disorder, it marked
the first in a new class of drugs that block the effect of the
growth hormone. This potentially fatal disease is a result
of the pituitary gland’s producing excess growth hormone.
This excess hormone causes abnormally enlarged hands,
feet, and facial features. Once recognized, acromegaly is
treatable in most patients, but because of its slow and often
insidious onset, it frequently is not diagnosed correctly.57
Hyperparathyroidism
Cinacalcet is the first in a new class of drugs known as
calcimimetics, now available to patients whose parathy-
roid glands (located behind the thyroid gland in the neck)
are producing too much parathyroid hormone. Often, the
cause of hyperparathyroidism is unknown, but in some
cases the overactivity is caused by other conditions, such
as kidney failure or parathyroid cancer. In that case, the
condition is called secondary hyperparathyroidism.
Because they produce excessive parathyroid hormone,
which helps the body absorb calcium from food and
regulates the level of calcium in the blood, hyperparathy-
roidism patients have abnormally high levels of calcium
in the blood (hypercalcemia). Hypercalcemia is associat-
ed with bone pain, fractures, kidney stones, and risk of
cardiovascular death.54 According to the FDA, about
37,000 people in the United States have hypercalcemiaas a result of parathyroid cancer.55
Advances in the Treatment of HYPERPARATHYROIDISM &
10
Acromegaly
11
The “Gentle Giant” with the Devastating Disease
Andre the Giant (born Andres Roussimoff)
built his successful wrestling and acting
career living with acromegaly. Already 6'7"
at age 17, Andre began wrestling as the
“Monster Eiffel Tower” in France. His enor-
mous size, eventually 7'4" and 500 pounds,
jolted Andre to the top of the wrestling
world, with fans dubbing him “The Eighth
Wonder of the World.”
Though he became an international icon as
one of the World Wrestling Federation’s
toughest wrestlers, Andre preferred to
think of himself as a “gentle giant,” like his
character, Fezzik, in The Princess Bride.
Shortly after his death in 1993 due to the
effects of acromegaly, Andre the Giant was
the first wrestler ever inducted into the
WWF/WWE Hall of Fame.63
Today, acromegaly is treatable with
surgery, radiation, and medicines, which
can help normalize levels of growth
hormone and insulin-like growth
factor-1 (IGF-1) in the bloodstream.
There are three drugs available among
three different classes to treat the
condition.64
PHARMACEUTICAL ADVANCES■ Manufactured Protein to Block Growth Hormone
Pegvisomant works by binding to the growth hormone
receptor and blocks the effects of the growth hormone
and reduces the signs and symptoms of the disorder.58
It is indicated for use in patients whose acromegaly has
not responded to surgery, radiation, or other medi-
cines.59 In clinical trials, researchers found that more
than 90 percent of patients responded to the medicine.60
Acromegaly, which is most common in middle-aged
adults, can lead to serious health complications such as
arthritis, diabetes, high blood pressure, and increased risk
of cardiovascular disease. It affects at least 40 to 60 out of
every million people at any time.61
In the pipeline are potentialtreatments for anthrax, cysticfibrosis, and West Nile Virus,which have been granted orphanstatus by the FDA.62
ACROMEGALY
Both neurocysticercosis and hydatid disease are parasitic
diseases from worms and affect approximately 300
Americans annually.71 Neuro-
cysticercosis, caused by pork
tapeworm larvae (eggs), is
usually spread through con-
taminated water or food.
It causes cysts to develop
throughout the body and can
cause headaches and seizures
if they develop in the brain
tissue.72 It is the most common
infectious cause of seizures
worldwide.73
People can contract hydatid disease, also known as
Echinoccocus, by eating contaminated food containing
Echinococcus granulosus worm eggs. The infection causes
cysts in the liver first but they can also develop in the
lungs, brain, bones, and other organs. If the cysts rupture,
severe illness results, including fever, low blood pressure,
and shock.74,75
PHARMACEUTICAL ADVANCES■ First Treatment for Two Kinds of Cyst-Causing Worms
In 1996, albendazole became the first treatment approved
to treat both neurocysticercosis and hydatid.76 Albendazole
kills the worm by preventing it from absorbing sugar (glu-
cose), which it needs to survive.77 This drug was found to
destroy cysts in 40 to 70 percent of patients with neurocys-
ticercosis. Among patients with hydatid disease, albenda-
zole eliminates the cysts in about 30 percent of patients
and reduces their size in an additional 40 percent
of patients.78
Cryptosporidiosis and Giardiasis
Cryptosporidiosis and giardiasis, parasitic infections that
cause diarrhea, mainly affect people living in developing
countries around the world, but even in the United States
there are cases every year.65
The parasite cryptosporidium can be found in drinking or
recreational water and contaminated food. Once it enters
the body it lives in the intestinal tract, but outside the body
it can survive for long periods because of a tough outer
shell. The parasite causes vomiting and nausea, dehydra-
tion, stomach pain, and weight loss.66 Giardiasis is an
infection caused by a single-celled parasite called Giardialamblia or, simply,
Giardia. If left
untreated in children,
complications from
these parasites
include malnutrition,
impaired growth,
and death.67
PHARMACEUTICAL ADVANCES■ Killing Parasites That Cause Dangerous
Waterborne Illnesses
Nitazoxanide, an antiprotozoal approved in 2002, is used
to treat children up to 11 years of age with diarrhea caused
by cryptosporidiosis and giardiasis. It is the first new drug
approved for giardiasis in over 40 years.68 Nitazoxanide is
the only drug approved for treating cryptosporidiosis and
the only drug approved for giardiasis for children one to 11
years of age. Nitazoxanide works by stopping the growth of
the infecting organisms.69 The FDA estimates that nitazox-
anide could help 2,500 people in the United States.70
Advances in the Treatment of DISEASES OF THE DEVELOPING WORLD
12
Neurocysticercosis and Hydatid
Some diseases considered rare in the United States are actually very common around theworld. For these diseases, new treatments being developed in the United States are helpingmillions of men, women, and children in the developing nations. Even before the horrors ofHurricane Katrina spotlighted waterborne hazards, here in the world’s wealthiest nation,handfuls of Americans have been affected every year by outbreaks of illnesses that are leadingcauses of death in developing countries.
13
Tuberculosis—A Disease from Antiquity
Tuberculosis has ravaged human culture
since ancient times. Egyptian mummies
tell the story of deadly tuberculosis infec-
tions thousands of years ago. Fragments
of the spinal columns of mummies
dating back to 2400 B.C. show evidence
of damage caused by the bacteria. Later,
around 460 B.C., Hippocrates wrote
that tuberculosis was the most wide-
spread disease of the time in Greece
and was nearly always fatal.84 Today,
tuberculosis infections still occur in
all parts of the world, but mankind is
fighting back. Scientists are using the
vast knowledge and powerful tools
that the Egyptians could not have
dreamed of to develop new treat-
ments for this age-old foe.
Tuberculosis (TB) is still the most common cause of death
and morbidity in the world, killing 30 million people
worldwide in the 1990s, according to the WHO.79 In the
United States, fortunately, it is a rare condition affecting
just 15,000 people in 2003.80
TB is a contagious bacterial infection that primarily affects
the lungs but can attack any part of the body. It is caused
by Mycobacterium tuberculosis and is typically spread
through the air from a cough or sneeze of someone who is
infected with the bacteria. If not treated properly, TB can
be fatal.
PHARMACEUTICAL ADVANCES■ Modern Treatment for Ancient “Consumption”
In 1998, the first new drug to treat TB in 25 years,
rifapentine, was approved for treatment of pulmonary
tuberculosis. It works by stopping the cell multiplication
process of the bacteria and is used in combination with
other anti-tuberculosis drugs to treat pulmonary tuberculo-
sis.81 Before rifapentine was approved, the health care com-
munity was worried about resistance to older drugs that
was developing over time. This treatment offers another
tool to fight tuberculosis. Also, the dosing regimen for this
drug is simpler than other drugs, so patients are more
likely to take it.82
Tuberculosis
In the last decade (1995–2005),over 160 orphan drugs wereapproved, compared with 108from 1984 to 1994 and only 10 inthe decade prior to the passage ofthe Orphan Drug Act in 1983.83
Thrombocytopenia
Thrombocytopenia is caused by too few platelets in the
blood, which are responsible for forming clots along with
clotting factors if damage occurs to the blood vessels.
Patients with this disorder bleed even with minor injuries,
and in severe cases with no injury at all. This deficiency
of platelets can be caused by a few factors, including low
platelet production by the bone marrow, infection, other
diseases, or sometimes drugs.85 Heparin, a drug used to
prevent blood clots and to “thin” blood by inhibiting clot-
ting factors in situations such as acute coronary syndromes
including heart attacks, can cause thrombocytopenia in
some patients.86
PHARMACEUTICAL ADVANCES■ Alternative Blood-Thinning Treatment
In 1998, lepirudin was introduced as the first alternative
to heparin for patients who experience heparin-induced
thrombocytopenia. Lepirudin is a derivative of the saliva
of a medicinal leech, a bloodsucking aquatic worm that
is sometimes used in blood withdrawal. Lepirudin
blocks thrombin, which is an enzyme that aids in clot
formation. Lepirudin also promotes a rapid increase of
platelets.87 The FDA estimates that 180,000 people
could benefit from this new drug.88
Advances in the Treatment of BLOOD DISORDERS &
14
Hemophilia B
Our bodies depend on small, specialized cells that make up blood to transport nutrients,gases, and waste products throughout our bodies. An imbalance of too many or too fewspecific cells can cause illnesses. Today’s pharmaceutical innovations, however, are revolu-tionizing treatments for people with rare blood diseases.
Hemophilia B is a rare congenital disorder caused by
the lack of clotting Factor IX, a type of protein that works
with platelets to form clots when damage to a blood vessel
occurs. Hemophilia B affects approximately 18,000
Americans.89 People with this disease bleed excessively
and for longer than other people. It can be life-threatening.
PHARMACEUTICAL ADVANCES■ DNA-Derived Clotting Factor: A Better Treatment
Option for Patients
Recombinant human Factor IX was approved in 1997for the prevention and control of excessive, potentially
life-threatening bleeding in hemophilia B patients.
Recombinant DNA-derived clotting factors are lab-
produced using Chinese hamster ovary cells that have
been modified to express the human Factor IX gene.90 The
advantage of recombinant human Factor IX over other
sources of Factor IX is that it is free from the risk of
transmitting human viruses.
15
Leprosy—RLeprosy—Reason for Exile ineason for Exile inthe Old Wthe Old Worldorld
Tales of leprosy date back to biblical times.
During those times, leprosy was thought to
be transmitted by contact with infected
people. To decrease the possibility of catch-
ing the disease, leprosy sufferers were
often shunned. “…[I]n Europe during the
Middle Ages, leprosy sufferers had to wear
special clothing, ring bells to warn others
that they were close, and even walk on a
particular side of the road, depending on
the direction of the wind. Even in mod-
ern times, leprosy treatment has often
occurred in separate hospitals and live-in
colonies called leprosariums because of
the stigma of the disease.”98 However,
new medicines continue to combat
leprosy infections, and the number of
known cases is falling.
Leprosy is an infectious disease caused by the bacteria
Mycobacterium leprae with symptoms of disfiguring skin
lesions and sensory loss in the skin, muscle weakness, and
progressive debilitation caused by peripheral nerve dam-
age. Symptoms can take as long as 20 years to develop.
Through ancient times, leprosy was regarded by the com-
munity as a contagious, mutilating and incurable disease.
Today, leprosy is treatable and curable, and we now know
it is difficult to transmit.91,92
While leprosy is most common in temperate, subtropical
and tropical climates, approximately 100 cases are diag-
nosed each year in the United States. Children are more
susceptible than adults to contracting the disease.93
Erythema nodosum leprosum (ENL) is a serious inflam-
matory complication of leprosy that can include severe
skin lesions, nerve pain, loss of nerve function, joint
swelling and high fever.94
PHARMACEUTICAL ADVANCES■ Ancient, “Incurable” Disease Now Treated with
“Second Chance” Drug
Nearly 40 years after thalidomide was first found to pro-
duce severe birth defects when used as a treatment for
morning sickness associated with pregnancy in coun-
tries around the world, it was approved for the first time
by the FDA in 1998. With tight restrictions, it is now
used to treat debilitating skin sores that result from
ENL.95 In clinical trials, treatment with thalidomide
caused improvement in at least 70 to 80 percent of
patients with ENL, compared to approximately 25 percent
of patients given placebo.96
Leprosy
Since the Orphan Drug Act,over 1,450 drugs in developmenthave been designated as orphanproducts.97
LEPROSY
Poractant alfa, approved in 1999, treats RDS in premature
babies by reducing the amount of air trapped in the lining
of the lungs. A natural porcine-derived surfactant, porac-
tant alfa increases lubrication within the lung’s air sacs
thus improving expansion and ventilation.104
Children with the genetic, metabolic disorder tyrosinemiagradually develop liver failure and liver cancer, but a new
drug, nitisinone, approved in 2002, can extend their lives.
These children lack the enzyme that breaks down the
amino acid tyrosine. Normally, the liver is where tyrosine
is broken down; when it accumulates in the blood, it can
lead to progressive liver failure and, often, cancer.
Tyrosinemia may also cause damage to the kidneys, eyes,
skin, and nervous system.
The most common and severe form of the disease is acute
tyrosinemia, with which children are born or develop soon
after birth. Infants with acute tyrosinemia exhibit rapid
onset of symptoms, and they often fail to gain weight and
grow. Infants with the less prevalent chronic tyrosinemia
have a more gradual and less severe onset of symptoms.
Children who experience liver failure or are diagnosed
with liver cancer as a result of tyrosinemia rarely make it
into their twenties without a liver transplant. According
to the FDA, this disorder affects 2,500 children in the
United States.105
PHARMACEUTICAL ADVANCES■ Patients’ Pathway to Longer Life
Nitisinone opens the door to an extended lifespan for chil-
dren with tyrosinemia. It decreases the level of tyrosine
in the blood, thereby reducing the likelihood of liver
failure and liver cancer. In combination with a diet restrict-
ed in the amino acids tyrosine and phenylalanine, this
drug has been shown to increase the four-year survival
rate of children who were diagnosed at less than two
months of age to 88 percent. Historical data for children
treated with dietary restrictions alone shows a survival
rate of 29 percent for the same time period.106
Respiratory DistressSyndrome
Premature babies face an uphill battle as their fragile,
still-developing systems fight to overcome many issues—
including immature lungs struggling just to breathe.
Respiratory distress syndrome (RDS) is caused by an
infant’s lack of surfactant, a natural lung-wetting agent,
which normally develops between the 34th and 37th week
of pregnancy. Without surfactant, the lungs cannot in-
flate.99 Its absence in premature infants causes breathing
difficulties and collapsed lungs. Prompt treatment is
required for high-risk and premature infants. This treat-
ment may include medicines, supplemental oxygen, and
use of a ventilator.100
Of the 250,000 infants born prematurely each year, up to
50,000 will suffer from infant RDS, and 5,000 will die
from it.101 RDS usually occurs right after birth.
Three new medicines have been approved in the last decade
for this one rare condition,
advancing the way that
neonates with immature
lungs are treated. With
these medicines, prema-
ture infants have a better
chance of surviving this
life-threatening disorder.
PHARMACEUTICAL ADVANCES■ Rescuing the Tiniest Lungs
Calfactant, approved in 1997, is used to treat babies with
RDS, and also to prevent premature babies from develop-
ing RDS.102 A natural bovine-derived surfactant, calfactant
attaches rapidly to the surface of the air-to-liquid inter-
face within the lung’s air sacs and modifies surface
tension similarly to natural lung surfactant, thereby
allowing the air sacs to expand and improving newborns’
breathing ability.
Nitric oxide, approved in 1999, reduces the common com-
plications of lung hypertension in newborns by expanding
blood vessels in the lungs.103 Nitric oxide reduces the need
for ventilator support and helps regulate the muscle tone
in the arteries of the lungs.
Advances in the Treatment of CHILDHOOD DISEASES
16
Tyrosinemia
17
Hope is in the Pipeline forChildren with Progeria
Medical researchers are racing to beat the
clock in search of a cure for progeria, a
premature aging condition that afflicts just
14 children in the United States and
usually leads to death near age 13. In 2003,
scientists were able to isolate the gene
mutation that causes this rare disease. In
2004, researchers were able to explain
how the gene mutation works.112 Now,
NIH scientists and others are testing a
group of cancer drugs donated by phar-
maceutical companies. These drugs
appear to repair cells damaged due to
the disease. By halting the rapid aging
process associated with the disease and
restoring damaged cells, medical
research gives children living with
progeria hope that their time will not
run out before they reach adulthood.113
Primary IGF-1 Deficiency
The number of orphan drugs is expected to rise in the comingyears as more new medicines aredeveloped that target specificgenetic disorders.111
Kids labeled as having “short stature” are shorter than
97.5 percent of other children their same age and gen-
der. Short stature can be caused by several factors,
including family genetics, hormone problems, or
various diseases.107
Recently, it has been found that
short stature can also be the
result of low insulin-like
growth factor-1 (IGF-1) levels.
This condition is called
Primary IGF-1 Deficiency(Primary IGFD). If left
untreated, Primary IGFD
can lead to other complications
such as lipid disorders, obesity,
diabetes, or decreased
bone density.108
PHARMACEUTICAL ADVANCES■ First Medicine to Treat Primary IGFD
In 2005, the FDA approved mecasermin, the first treat-
ment for approximately 6,000 children in the United
States with severe Primary IGFD.109 Mecasermin is a
manufactured protein that functions like the natural
human protein as a growth catalyst. This protein must
be present for children’s bones, cartilage, and organs to
grow properly. An eight-year clinical trial demonstrated
that, on average, children grew one inch per year for
each year of therapy using this new medicine.110
Currently, there is no medicine available that allows
narcolepsy patients to maintain a normal level of aware-
ness consistently, but some of the most severe symptoms,
such as EDS and cataplexy, can usually be controlled with
medications.118
The cause of narcolepsy remains unknown,
but genetic factors may play a role.119
PHARMACEUTICAL ADVANCES
■ Easing Worst Symptoms of Sleep Disorder
Modafinil was approved in 1998 for the treatment of
narcolepsy and is the first new stimulant for treatment in
the last 20 years. Modafinil promotes wakefulness without
affecting memory, concentration, or learning.120 It also has
a lower habituation potential than other stimulants that
are often used for treatment of narcolepsy.121 In clinical
trials, modafinil proved to be effective in alleviating EDS
while producing fewer, less serious side effects than
other medications.122
Sodium oxybate is the first approved treatment for cata-
plexy. Available since 2002, it reduces the number of
cataplexy attacks,123 which can cause a patient’s muscles
to feel weak or paralyzed.
Amyotrophic lateral sclerosis (ALS), also known as LouGehrig’s Disease, is a progressive disease that affects
motor nerve cells in the brain and spinal cord. Motor
neurons degenerate and eventually die, causing the brain
to lose its ability to control muscle movement. The pro-
gressive loss of muscle strength and coordination
eventually interfere with the ability to perform routine
activities, such as going up steps, swallowing, or rolling
over. Eventually it leads to death, often because it affects
the muscles needed for breathing. ALS, however, has no
effect on a person’s ability to think or reason.124 It is usually
fatal within five years of diagnosis.125
Narcolepsy
Advances in the Treatment of NARCOLEPSY &
18
In people with narcolepsy the brain does not properly
regulate sleep and wake cycles, so they experience episodes
of frequent, uncontrollable daytime sleeping. It is
estimated that narcolepsy, which is generally a lifelong
condition, affects 135,000 people in the United States.114,115
For these patients, falling asleep in unlikely situations is
much more than an inconvenience; it can jeopardize
their education, ruin relationships, or endanger their
lives when driving.
Excessive Daytime Sleepiness (EDS) is the most common
symptom of narcolepsy patients, but they can also have
cataplexy (sudden loss of muscle tone), sleep paralysis
(temporary inability to use muscles), and hallucinations
before and/or after sleep episodes.116 A cataplexy episode is
often triggered by emotions such as surprise or anger,
causing a range of effects, from a simple slumping of
the head or a more dramatic collapse of the body. An
estimated 20,000 to 50,000 narcolepsy patients
experience cataplexy.117
ALS/Lou Gehrig’s Disease
19
An “orphan” or rare diseaseaffects fewer than 200,000 people in the United States.131
Symptoms usually do not develop until after age 50. In
about 10 percent of cases, ALS is caused by a genetic
defect. In other cases, the cause of the nerve deterioration
is unknown.126 ALS affects approximately 30,000 people in
the United States, and about 5,000 new cases are
diagnosed each year.127
PHARMACEUTICAL ADVANCES
■ Breakthrough Treatment a First After 126 Years
ALS was first identified in 1869, but the first drug,
riluzole, was not approved for treatment until 1995. It is
the first drug to show any increase in survival for ALS
patients.128 The increase is a modest three months on
average, but it offers hope.129 The drug is based on a theory
that the disease is caused by toxic levels of glutamate in
the brain. Neurons in the central nervous system use
glutamate to communicate with one another. The brain
normally regulates glutamate levels, but glutamate has
been found at abnormally high levels in the cerebrospinal
fluid of some ALS patients. Scientists theorize that gluta-
mate toxicity might be killing motor neurons, leading to
progressive muscle degeneration in people with ALS.
Riluzole, however, inhibits the release of glutamate in
the brain.
According to Dr. Jeffrey Rothstein of Johns Hopkins
University School of Medicine, this medicine offers great
hope despite the fact that the improvement is not dramatic:
“This is against the background of decades when no drug
ever did anything for the disease. Initial therapies for
many diseases, like leukemia and other cancers, had the
same kind of effect... a modest increase in survival. But
they were followed by better therapies that, over time,
increased patients’ survival…. It’s a daunting task, but I
envision that someday it will be possible to develop drugs
that will not only stop motor neurons from dying but
replace them and reverse the course of ALS.”130
AMYOTROPHIC LATERAL SCLEROSIS
A PA Pitch for ALSitch for ALS
Sixty-five years after baseball legend Lou
Gehrig announced his battle with ALS to
the world, Red Sox pitcher Curt Schilling
brought the disease back to international
attention. During game two of the 2004
World Series, Schilling, pitching with an
injured ankle, wrote “K ALS,”meaning
strikeout ALS, on his shoe, just below his
blood-stained sock. Photographers looking
to capture images of an athlete persever-
ing through pain instead told the story of
a man fighting for the 30,000 Americans
living with ALS.
Curt Schilling is the pitcher for the 2004World Series Champion Boston Red Sox. He and his wife, Shonda, becameinvolved in the fight against ALS aftermeeting Dick Bergeron, an ALS patient,in 1992.
medication in the comfort of their own homes rather
than having to receive intravenous treatments at a physi-
cian’s office or hospital.
■ Dual-Action Therapy Initiates Immune Responseand Attacks Tumor Cells Directly
Non-Hodgkin’s lymphoma is a cancer of lymphatic
tissues, such as lymph nodes, spleen, and other immune
system organs. There are several different types of non-
Hodgkin’s lymphomas. One of those types, follicular
lymphoma, makes up 22 percent of all non-Hodgkin’s
lymphomas. Follicular lymphoma is not curable, but
due to its slow growth, 60 to 70 percent of patients live
at least five years; it occurs mainly in adults, with an
average age of 60.141 People with follicular non-Hodgkin’s
lymphoma usually have lymphoma in many parts of the
body. According to the FDA Office of Orphan Products,
the condition affects 193,500 people in the United States.
With the 2003 approval of tositumomab and Iodine-131tositumomab, patients with a subset of follicular non-
Hodgkin’s lymphoma—CD20 positive follicular non-Hodgkin’s lymphoma—gained a new treatment option
with an innovative therapeutic twist. The drug is made up
of an immune system protein, called an antibody, attached
to radioactive Iodine-131. Combined, they form a “radiola-
beled” monoclonal antibody that is able to bind to a
protein found only on the cancer cells, thus targeting the
radioactivity directly
to the cancer cell,
killing it.142,143
This new medicine is
used for patients with
CD20 positive follicu-
lar non-Hodgkin’s
lymphoma who have
not responded to
other treatments or
whose cancer has
returned after
chemotherapy.144 For
more than two years,
Cancer
Cancer is a group of diseases in which abnormal cells
develop and spread through parts of the body. Anyone can
develop cancer. The National Cancer Institute estimates
that 9.8 million Americans with a history of cancer were
alive in 2001. Some were cancer-free; others were continu-
ing to undergo treatment.132
PHARMACEUTICAL ADVANCES
■ Disrupting DNA Adds Months for Severe Brain Cancer Patients
In the two most aggressive forms of astrocytoma, brain
tumors grow rapidly and spread to other parts of the body.
Astrocytoma is classified into four grades (Grade I being
the least aggressive and IV most aggressive). Grade III
is anaplastic astrocytoma, which affects 2,000–3,000
people a year with an average survival of two to three years.
Grade IV is glioblastoma multiforme, which affects
8,000–10,000 people each year and is usually fatal within
one year.133
Temozolomide can add an average of two and a half addi-
tional months—an enormous amount of time in the world
of cancer treatment—for patients with glioblastoma
multiforme.134,135 “It doesn’t sound like much… but if you
can demonstrate that you can extend life for two or three
months for the average patient, that’s a significant
advance,” says Dr. Warren Mason, the co-author of a
New England Journal of Medicine study about the drug.136
Patients taking temozolomide for treatment of anaplastic
astrocytoma experienced an average survival time of nearly
16 months.137
Approved in 1999, temozolomide is the first major new
treatment for anaplastic astrocytoma in 20 years, and with
a second indication approved in 2005, it is the first in over
30 years for glioblastoma.138,139 It works by disrupting DNA
to prevent cancer cells from multiplying and prolongs
survival when combined with standard radiation.140
Additionally, it is a more convenient therapy for patients;
it is an oral treatment allowing patients to take their
Finding treatments for rare cancers at specific stages for patients unresponsive to existing treatment might be the toughest—and most gratifying—work a scientist could ever attempt.
Advances in the Treatment of CANCER
20
21
There are approximately6,000–7,000 rare diseases.149
Thankful for Another Day
Karl, like many people, was not one to visit
his doctor often, even if he was feeling
under the weather. However, after days and
days of feeling tired and eventually having
difficulty just getting in and out of the car,
Karl decided it was time to see a doctor.
After an x-ray and other tests, he was diag-
nosed with mesothelioma. Karl’s daughter,
who works in a hospital, was familiar with
the disease and understood the prognosis
was poor. Fortunately, after several chemo-
therapy treatments with pemetrexed,
Karl’s condition began to improve. Karl’s
wife is thankful, noting, “Every day, we
are both thankful for our lives. And, he
is improving every day and he is doing
more and more: He is in the yard, or we
are going shopping together, or we can
drive in town together. He could not
drive before. Now, little by little, it’s
getting better and better and we are
very grateful for that.”150
on average, two-thirds of patients who took this medica-
tion during clinical trials experienced either improved
condition or full remission of the disease.145
■ First Ray of Hope for Asbestos-Related Lung Cancer
When someone first experiences symptoms and is diag-
nosed with malignant pleural mesothelioma, the fatal
cancer is often already in advanced stages, and doctors
expect them to live just nine to 13 months.146 Malignant
pleural mesothelioma is a cancer of the lining of the lung
and chest cavity, called the pleura. This is a very rare type
of cancer affecting only 2,000 new people each year, and it
is associated with exposure to asbestos.
Now the first drug approved for this rare cancer,
pemetrexed, combined with other treatments, gives
patients 40 percent longer survival time compared with
current treatment alone. “Before [pemetrexed] was
available, patients suffering from mesothelioma had no
hope—rarely living a year after diagnosis,” said
Nicholas J. Vogelzang, MD, Director of the Nevada
Cancer Institute in Las Vegas. “At 18 months, there is
still a statistically significant difference in survival, which
demonstrates patients are living longer when treated with
this [pemetrexed] combination,” Volgelzang said.147
Approved in 2004, pemetrexed is a novel antifolate, a class
of drugs that targets the folic acid metabolic pathway,
which affects availability of certain B complex vitamins.148
It is indicated for patients with the advanced form of the
disease who have already had chemotherapy. Pemetrexed
was found in clinical trials to be as effective as other can-
cer drugs, but with fewer side effects, such as hair loss and
subsequent infections.
Leukemia
In leukemia, the bone marrow produces abnormal white
blood cells—the leukemia cells, which in time may crowd
out normal white blood cells, red blood cells, and platelets.
Types of leukemia vary according to which type of blood
cells are affected, how developed the cancer cells are at the
time of diagnosis, and how different they are from normal
cells.151 According to the National Cancer Institute, there
were 30,600 new cases of leukemia in the United States
in 2003.152
PHARMACEUTICAL ADVANCES
■ Ancient Medicinal Offers New Hope to Young Adults
Contrary to images people may conjure up when hearing
“arsenic,” it actually has given new hope to patients with
acute promyelocytic leukemia (APL), which is most com-
mon in young adults and causes fatigue and tendency
to bleed. Arsenic-containing preparations, dating back
more than 2,000 years, were used more than 100 years
ago for leukemia therapy but were replaced by modern
chemotherapy. Because
some Chinese arsenic-
containing treatments
showed effectiveness
against leukemia,
attention again turned
to arsenic.”153
Arsenic trioxide was
approved in 2000 to
treat APL patients whose
disease has recurred or
failed to respond to stan-
dard treatment (about
400 of the 1,500 diagnosed cases per year).154 About 75
percent of APL patients can be cured with other combina-
tion therapies, but those who do not achieve remission or
who relapse can now be treated with arsenic trioxide.155
■ From Texas Soil to New Class of Anticancer Therapy
The story of gemtuzumab began with a soil sample
gathered in Kerrville, Texas, in 1981 and finally burst to the
forefront of oncology in 2000 as the first in a new class of
drugs, “antibody-targeted chemotherapy.” Scientists study-
ing the soil discovered a powerful cancer-fighting substance,
calicheamicin, which destroyed the DNA of cancer cells
and proved to be stronger
than any anticancer drugs
at the time. But it was up
to 10,000 times more toxic
to normal cells than other
anticancer drugs. Research-
ers discovered that by
attaching calicheamicin to
an antibody (immune
system protein), they could
safely bring it directly to
the tumor, bypassing most
normal cells. In May 2000, the FDA approved the first
antibody-targeted chemotherapy, gemtuzumab, for use
in patients over age 60 with relapsed acute myeloidleukemia (AML).
In patients with AML, unhealthy white and red blood cells
and platelets build up in the bone marrow, blood, and
other parts of the body leading to infections, easy bleeding,
and anemia. AML quickly worsens if not treated.156 It is
estimated that in 2005, 11,960 cases of AML will be diag-
nosed and will cause 9,000 deaths.157 Gemtuzumab was
found to cause remission in about 30 percent of AML
sufferers and produces fewer side effects than traditional
chemotherapies.158
■ A Powerful Attack and a True Trailblazer
The approval of imatinib mesylate in 2001 proved that a
targeted therapy—one that directly turns off the signal of a
protein known to cause cancer—could powerfully attack
cancer with few side effects.159 Imatinib not only benefits
patients with chronic myeloid leukemia (CML), but its
success proves that the targeted therapies scientists
dreamed of do work. With this proof-of-concept, scientists
may be able to create strong, effective targeted therapies
22
Thanks to advances in pharmaceutical treatment and other research, the survival rate ofpeople with leukemia has tripled in the last 40 years.
Advances in the Treatment of LEUKEMIA
23
The Wave of the Future Brings Hope
A new generation of precise and powerful
drugs known as “targeted therapies” may
represent a better way to treat many cancers,
bringing hope for patients with rare cancers.
Leukemia treatments are blazing the trail.
“Slowly, many scientists believe, the drugs are
transforming cancer treatment. But for now,
the drugs are still only a whisper of hope.
They are not a miracle cure and not fully
understood. Many are still in clinical trials.
Those that work often help patients in sub-
sets of disease—one kind of leukemia, one
type of breast cancer…
“Yet for all they are not, it is what the drugs
achieve for the lucky few that captures the
imagination: the stories that patients tell of
teetering near death, only to see a stunning
comeback, at least for a while. They can
mean an extra three months or five
months or a year—another Christmas
with the family, another season to plant a
garden, another passage in the life of a
child. Side effects, the bane of cancer
treatment, are comparatively few.”167
— Donna St. George,
The Washington Post
One in every 10 individuals inthis country has received adiagnosis of a rare disease.166
for other cancers. Clinical trials showed imatinib’s
remarkable efficacy, as most patients receiving the new
drug were experiencing complete normalization of their
blood counts.160
In patients with CML, the bone marrow produces too
many stem cells which develop into a type of white blood
cell called granulocytes. Some of these cells never become
mature white blood cells; these are called blasts. Over
time, the granulocytes and blasts crowd out the red blood
cells and platelets in the bone marrow. CML usually
occurs in middle-aged or older adults.161 It is estimated
that 4,600 new cases of chronic myeloid leukemia will
be diagnosed this year, and 850 people will die from
the disease.162
■ First For-Kids-Only Leukemia Drug in 10 Years
For 10 years, oncologists treating pediatric patients with
acute lymphoblastic leukemia (ALL) treaded water as ther-
apy for the most common childhood leukemia had hit a
plateau.163 Finally, the 2004 approval of clofarabine pre-
sented a new option for children aged 1 to 21 with ALL
who had relapsed or were unresponsive to other treat-
ments. Clofarabine produces remissions and allows some
patients to proceed to bone marrow transplant, the best
chance for long-term survival.164
About 3,830 Americans are diagnosed with ALL, the most
common type of leukemia in patients under age 19, each
year.165 In ALL, abnormal blood cells called lymphoblasts
accumulate, while fewer normal red and white blood cells
are produced.
Clofarabine is an antimetabolite, a drug that prevents can-
cer cells from growing by disrupting the synthesis of
nucleic acids, which are needed to produce DNA and RNA.
Conclusion
Looking back over the last decade, we have clearly made
much progress and because of these new treatments many
lives have changed. These facts offer hope to the many
patients with rare diseases who are still waiting for treat-
ments. Looking forward, the future holds great promise.
Just as the number of new orphan drugs being approved
has grown, the number currently being studied continues
to rise. According to the FDA’s Office of Orphan Products
Development, in 2004 there were a record 160 applications
24
for orphan status among drugs in development. That
number represented a 30 percent increase over the average
of 124 per year in the previous four years.168
Pharmaceutical discovery is entering a new era. Our
new understanding of the genome and powerful scientific
research tools are opening new doors to discovery of
breakthrough medicines. The number of orphan drugs
is expected to rise in the coming years as more new medi-
cines are developed that target specific genetic disorders.169
Progress has been made in the last decade, but the work
continues. Biopharmaceutical companies are working tire-
lessly so that more patients with rare diseases will have
new treatments one day soon.
LOOKING BACK…
In the past year alone, nine new orphan drugs were
approved. These new medicines that provide additional
treatment options for a variety of diseases include:
• Nelarabine—For patients with T-cell acute lympho-
blastic leukemia and T-cell lymphoblastic lymphoma,
this new treatment resulted in complete disappear-
ance of cancer cells in some patients during clinical
trials. 170
• Deferasirox—The first oral therapy for chronic iron
overload, it allows patients to drink their medicine
rather than endure multi-hour nightly infusions to
remove excess iron.171
• Sorafenib tosylate—The first new treatment for kid-
ney cancer in 12 years, it extended time until tumor
progression and until death in patients with this
rare cancer.172
• Lenalidomide—This is an oral treatment for patients
requiring blood transfusions as a result of anemia
caused by myelodysplastic syndrome, which causes
low red blood cell counts. Patients who received this
medicine during clinical trials no longer needed
blood transfusions.173
25
LOOKING AHEAD…
Every day researchers continue to search for and develop
new medicines for rare diseases. Here are examples of the
many potential orphan drugs that scientists currently are
working on:
• Dasatinib—This new compound, currently in review
with the FDA, builds on the success of the first tar-
geted cancer treatment, imatinib. Dasatinib is being
tested as an alternative to treat patients with chronic
myeloid leukemia. One clinical study found 95 per-
cent of patients had progression-free survival in the
first six months.175
• Anti-GDF-8 antibody/MYO-029—Currently in early
clinical trials, this recombinant human antibody
(immune system protein) is being tested to treat
muscular dystrophy (MD) and other muscle-wasting
diseases.176 It is designed to inhibit the protein myo-
statin, which limits muscle growth,177 and it would be
the first treatment to halt the breakdown of muscle
in MD.178
• FK778—The first in a new class of drugs to help
prevent acute rejection after kidney, heart and
liver transplants. FK778 is now in Phase II clinical
trials,179 and to this point, tests indicate that it may
treat both short- and long-term problems that
accompany organ transplantation.180
Amyotrophic Lateral Sclerosis (ALS) 5
Pulmonary Hypertension 6
Interstitial Cystitis 3
Acromegaly 2
Tuberculosis 5
Thrombocytopenia 5
Mesothelioma 9
Acute myeloid leukemia 31
New Medicinein Clinical Trialsor FDA Review
Disease
Medicines in Development forSelected Rare Diseases174
26
1 Food and Drug Administration, Office of Orphan Products
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2 National Institutes of Health, Office of Rare Diseases, Biennialand Annual Report on the Rare Diseases Research Activities at theNational Institutes of Health FY 2004, Executive Summary
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3 National Institutes of Health, Office of Rare Diseases, Access toQuality Testing for Rare Diseases: A National Conference,Overview (Rockville, MD: NIH, 26 September 2005),http://rarediseases.info.nih.gov/QTRD/overview.html.
4 National Organization for Rare Disorders, http://www.
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6 Fabry Community, Health Care Professionals, http://www.
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7 National Institute of Neurological Disorders and Stroke, “NINDS
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11 National Tay-Sachs and Allied Diseases Association, Inc.,
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24 National Heart, Lung, and Blood Institute, What Is PulmonaryArterial Hypertension?, http://www.nhlbi.nih.gov/health/dci/
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25 Ibid.26 American Heart Association, Primary or Unexplained Pulmonary
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27 S. Reents et al., Clinical Pharmacology, Gold Standard Multi-
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29 S. Reents et al., Clinical Pharmacology, Gold Standard Multi-
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30 Ibid.31 Food and Drug Administration, Patient Information Sheet:
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32 S. Reents et al., Clinical Pharmacology, Gold Standard Multi-
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33 National Library of Medicine, MedlinePlus Medical Encyclo-
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Endnotes
27
34 Food and Drug Administration, Office of Orphan Products
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available upon request from OOPD.
35 National Library of Medicine, MedlinePlus Medical Encyclopedia,
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37 Women and Pulmonary Hypertension, fact sheet, http://www.
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38 R. Stewart et al., “Pregnancy and Primary Pulmonary
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39 Women and Pulmonary Hypertension, op. cit.40 Food and Drug Administration, “First Treatment for Crohn’s
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44 Food and Drug Administration, Office of Orphan Products
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51 Ibid.52 Food and Drug Administration, Office of Orphan Products
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55 Food and Drug Administration, Office of Orphan Products
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57 National Institute of Diabetes and Digestive and Kidney Diseases,
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58 National Library of Medicine, MedlinePlus Drug Information,
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60 Food and Drug Administration, “FDA Approves First in a New
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61 University of Maryland Medical Center, “Endocrinology Health
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67 Centers for Disease Control and Prevention, http://www.cdc.gov/
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69 National Library of Medicine, MedlinePlus Drug Information,
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28
71 Food and Drug Administration, “First Treatment Approved for
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90 Food and Drug Administration, “New Recombinant Product for
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106 Ibid.
29
107 Tercica, Understanding Short Stature, http://investor.tercica.
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108 Drugs.com, “Increlex,” Drugs.com, http://www.drugs.com/
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116 National Library of Medicine, MedlinePlus Medical Encyclo-
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117 Food and Drug Administration, “FDA Approves Xyren for
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118 National Institute of Neurological Disorders and Stroke,
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NOTES
Much has been done…
...but the work continues.
The number of orphan drugs being
developed is going up: In 2004, there
were a record 160 applications for
orphan status, representing a 30 percent
increase over the average (124 per year)
of the prior four years.
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www.phrma.org
April 2006