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

RARE DISEASES

• T-cell acute lymphoblastic leukemia and T-cell 2005 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 2004 • acute lymphoblastic leukemia: clofarabine • pulmonary arterial hypertension: iloprost

• CD20-positive follicular non-Hodgkin’s lymphoma: 2003 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: 2002 nitazoxanide • cataplexy associated with narcolepsy: sodium oxybate • pulmonary arterial hypertension: treprostinil

• chronic myeloid leukemia: imatinib mesylate 2001 • pulmonary arterial hypertension: bosentan

• acute promyelocytic leukemia: arsenic trioxide • acute myeloid leukemia: gemtuzumab 2000

• hypoxic respiratory failure in newborns: nitric oxide 1999 • respiratory distress syndrome in premature infants: poractant alfa • anaplastic astrocytoma: temozolomide

• Crohn’s disease: infliximab • pulmonary tuberculosis: rifapentine 1998 • narcolepsy: modafinil • erythema nodosum leprosum: thalidomide • thrombocytopenia: lepirudin

• pediatric respiratory distress syndrome: calfactant 1997 • hemophilia B: recombinant human Factor IX

• interstitial cystitis: pentosan polysulfate sodium • neurocystericercosis and hydatid disease: 1996 albendazole • symptomatic orthostatic hypotension: midodrine hydrochloride

• amyotrophic lateral sclerosis: riluzole 1995 • primary pulmonary hypertension: epoprostenol 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. Advances in the Treatment of METABOLIC DISORDERS

The foods we eat every day are filled with the building blocks of life: carbohydrates, amino acids, and fats. But to use these materials, the body must break down complex foods into these simpler, usable forms. Any problems in this process, which is called metabolism, can cause a metabolic disorder, many of which are rare and difficult to treat.

Gaucher Disease

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.

Fabry Disease This rare genetic disorder is classified into three differ- ent types based on clinical severity and course, and by the presence or absence of Patients with Fabry disease are deficient in a particular neurological enzyme involved in the breakdown of fats, which causes a complications. buildup of fat in their blood vessels and organs. The symp- An estimated toms of this potentially fatal genetic disorder are diverse 6,000 individu- and can make diagnosis difficult.6 They include burning als in the sensations in the hands and feet, skin rash, excessive United States sweating, fever, severe gastrointestinal problems after eat- have Gaucher ing, and cloudiness of the eye. Fabry disease patients often disease.11,12 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 7,8 117,000 people, most of whom are male. PHARMACEUTICAL ADVANCES ■ Oral Treatment for Patients who Need Another Option PHARMACEUTICAL ADVANCES For patients who cannot receive the standard enzyme ■ The First to Attack Fabry Disease at Its Root treatment due to allergies, hypersensitivity, or poor venous Agalsidase beta, approved in 2003, is the first drug that access, miglustat, an oral treatment, was approved in 2003 treats the cause of Fabry disease rather than lessening its for treatment of mild to moderate disease.13 Miglustat symptoms. This enzyme replacement reduces the works by reducing the production of glucosylceramide so accumulated fat within the blood vessels and organs that the available glucocerebrosidase enzymes are not and decreases the symptoms of the disease.9 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

4 Mucopolysaccharidosis VI

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- Many Symptoms, One Disease glycan (GAG), a complex sugar. GAGs are used to provide Donna never expected an eye exam would structure for various tissues including bones, cartilage, change her family’s outlook on life. After an skin, and airways. When GAGs accumulate, however, they can cause a variety of symptoms including thickening of eye doctor noticed clouding in her 8-year-old the nose, lips, and tongue; breathing problems due to daughter’s eyes, Donna and her two sons narrowed airways; short stature; frequent ear infections were checked for similar symptoms. All four leading to hearing loss; heart disease as a result of mal- functioning heart valves, thickening of the heart muscle, had corneal opacities. Donna and her chil- and narrowed blood vessels; and stiff joints.16 Because the dren were sent to genetic counseling where signs and symptoms are so varied, diagnosis is often doctors confirmed that they had Fabry disease. difficult and delayed. The disease is also quite rare; approximately 1,100 people worldwide have MPS VI.17 Not all Fabry disease diagnoses are as fast as Donna’s due to the wide variety of symptoms PHARMACEUTICAL ADVANCES associated with the disease. Patients with the ■ First Therapy Targeted Toward Cause of Devastating disease experience problems ranging from Genetic Disorder stomach cramps and vomiting to body aches Approved in 2005, galsulfase is the first enzyme replace- ment therapy for MPS VI to treat the cause of the disorder and heat intolerance. Another patient, by breaking down the built-up stores of GAGs instead Adrian, had symptoms that baffled doctors 18,19 of improving symptoms related to the disease. Because for years before he was diagnosed. He of the problems associated with the disease, patients with MPS VI often become tired easily and cannot withstand eventually visited a rheumatologist who long periods of physical activity. In clinical trials, galsulfase was able to make sense of his symptoms, was shown to improve the walking and stair-climbing and get him proper medical treatment for 20 capacity of patients. the disease. Today, Fabry disease patients depend upon both enzyme replacement therapy (ERT) and symptom management to manage the Between 85 and 90 percent disease. While ERT does not cure Fabry of orphan diseases are serious disease, it can reduce the symptoms of or life-threatening.21 the disease, giving patients like Donna and Adrian a second chance at a normal life.22,23 5 Advances in the Treatment of RARE BLOOD PRESSURE DISORDERS

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 the body. It is determined by the force and amount of blood pumped, and the size and flexibility of the arteries. When any of these factors is compromised, disease may occur.

Pulmonary Hypertension 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- The pulmonary artery is the blood vessel that carries ing the stiffness of the blood vessels as well as widening blood from the heart to the lungs to be re-oxygenated. In them to allow blood to flow more easily.28 pulmonary arterial hypertension (PAH) there is continu- ous high blood pressure in the pulmonary artery. Possible Treprostinil was approved in 2002 for patients with the causes of the increased pressure may include tightened New York Heart Association (NYHA) Class II—IV pulmo- muscles within the artery walls, thickened walls of the nary arterial hypertension.29 Heart disease patients are clas- pulmonary arteries or scar tissue making the arteries sified according to the NYHA classification system, which narrower. Tiny blood clots may form within the smaller is based on the capacity of patients with heart diseases to arteries and cause blockages. The heart, as a result, must participate in physical activities, with Class IV disease work harder to supply the body with enough oxygen-rich resulting in discomfort blood, and over time the heart muscle weakens. with any activity and symptoms of the disease Shortness of breath is the primary symptom of PAH. occurring even at rest. People with PAH might also experience tiredness, In other words, trepros- dizziness, chest pain, or a racing pulse. As the disease tinil treats patients with progresses, energy level decreases, and these symptoms moderate to severe PAH, can occur even when resting.24 those who experience limitations on physical There are two types of pulmonary hypertension: primary activity as a result of the and secondary. Primary pulmonary hypertension is disease. Administered by inherited or occurs for no known reason. Secondary continuous infusion, tre- pulmonary hypertension is caused by another condition, prostinil works by dilating such as chronic heart or lung disease or blood clots in the the arteries and prevent- lungs.25 According to the American Heart Association, an ing blood clot formation.30 estimated 500 to 1,000 new cases of pulmonary hyperten- sion are diagnosed each year.26 Although this condition is Iloprost is the newest medicine for treatment of pulmo- very rare, four new orphan drugs have been approved to nary arterial hypertension and was approved in 2004 for treat it in the last decade. use by patients with NYHA Class III or IV pulmonary arterial hypertension to increase exercise ability and de- PHARMACEUTICAL ADVANCES crease symptoms.31 It is a novel treatment in that it is ■ Helping Blood Get to the Lungs inhaled by mouth using a special nebulizer. It works by Epoprostenol was approved in 1995 for treatment of dilating the arteries and prevents blood clot formation.32 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

6 Hypotension

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. Orthostatic hypotension results from Women with PAH Face a sudden change in body position, usually from Tough Decisions lying down to an upright While both men and women are at risk position.33 This condition for pulmonary arterial hypertension (PAH), affects 156,000 people34 it is more likely to affect women. Approxi- and can be caused by certain medicines, mately 60 percent of PAH patients hospital- dehydration, or heart ized between 1995 and 1998 were women. failure/attack.35 Among those women, 37 percent were younger than 65.

PHARMACEUTICAL ADVANCES Unfortunately, pregnancy aggravates the ■ Drug Makes Standing Up a Safe Activity condition, so for women with PAH, preg- Midodrine hydrochloride is used to treat symptomatic nancy can be life-threatening. Within 35 days orthostatic hypotension. It works by stimulating the of childbirth, the death rate for new mothers blood vessels to tighten, thereby raising blood pressure. with PAH is between 30 and 56 percent.37 Midodrine was approved in 1996 based on its ability to A woman with PAH often must choose 36 increase one-minute standing systolic blood pressure. between having a family and risking her own life to have a baby.

Despite the discouraging statistics, researchers are making progress. A 2001 case study in Chest reported that The Orphan Drug Act epoprostenol therapy combined with an was enacted in 1983 and anticoagulant can improve outcomes for mother and child when used before, dur- encourages companies to ing, and after delivery, without negative develop and manufacture side effects on the child.38 For nonpreg- drugs for rare conditions. nant patients, survival also appears to be increasing. Many people can manage the disorder for up to 20 years. Genetic studies and pharmaceutical research are providing hope for the development of new treatments of PAH and possi- bilities for a cure in the future.39 7 Advances in the Treatment of CROHN’S DISEASE & INTERSTITIAL CYSTITIS

Crohn’s Disease

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

PHARMACEUTICAL ADVANCES While scientists are deepening their understanding of the ■ Finally, Remission and Better Quality of Life for effects of Crohn’s disease, the cause remains a mystery. The most popular theory is that the body’s immune sys- Those with Painful Bowel Disease tem reacts to a virus or a bacterium by launching an attack Infliximab, the first therapy for Crohn’s disease, is a against the microbes and causing ongoing inflammation genetically engineered antibody that targets a protein that in the intestine. People with Crohn’s disease tend to have promotes inflammation in the body. Administered intra- abnormalities of the immune system, but doctors do not venously, infliximab decreases inflammation along the lin- know whether they are a cause or result of the disease.41 ing of the intestines and is effective in closing sores Crohn’s disease is characterized by chronic inflammation between the bowel and skin.42 In clinical trials, a clinical of the intestinal wall or any part of the gastrointestinal tract improvement or remission occurred in 65 percent of and causes symptoms of abdominal pain, chronic diarrhea, patients with severe to moderate Crohn’s disease after a loss of appetite, weight loss, joint aches, and fatigue. single dose.43 The FDA estimates that this drug can help about 175,000 people in the United States.44

Interstitial Cystitis

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 Two serious complications are abnormal enlargement of work full time.46 the colon and intestinal obstruction; the disease also can cause lesions, abscesses, and grooves in the intestinal wall These unpredictable symptoms may disappear without and surrounding area. 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,

8 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

A Decade-Long Struggle with Crohn’s: John’s Story

Diseases can seem especially devastating PHARMACEUTICAL ADVANCES ■ Soothing the Symptoms of Unpredictable Pelvic when they strike people in their youth. At Pain Disorder age 19, John was diagnosed with Crohn’s Pentosan polysulfate sodium was approved in 1996 and disease. A healthy, active teenager, John is the first and only orally administered medicine devel- found Crohn’s disease incredibly debilitat- oped specifically for relief of IC symptoms. It is believed ing. “My life was on hold—I was not able that it works by creating a buffer layer on the inside of the bladder to prevent urine from irritating the bladder wall.49 to work or go to college for four years.” In clinical trials, the drug was shown to bring relief of Eating became painfully difficult; he says bladder pain to 42 percent of patients who had been food felt like broken glass going through treated for up to six months, and 60 to 62 percent of those treated for 24 months.50 Patients also experienced his intestines. Within a month, he had reductions in frequency of urination.51 dropped from 165 to 115 pounds. “I felt like I was wearing my disease—a disease no one understood.” After 10 surgeries, In the decade after the Orphan John became “desperate for a solution Drug Act was passed, there were that did not include surgery.” That solu- tion came on his 29th birthday with his about 10 times as many drugs first treatment of infliximab. “It was the approved for rare diseases com- best birthday present I could have ever pared with the decade before.52 received.... I had just about given up hope, but with this treatment I felt like I had my life back.”53

9 Advances in the Treatment of HYPERPARATHYROIDISM &

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- PHARMACEUTICAL ADVANCES ed with bone pain, fractures, kidney stones, and risk of ■ cardiovascular death.54 According to the FDA, about First-In-Class Treatment Counteracts Overactive Parathyroid Glands 37,000 people in the United States have hypercalcemia as a result of parathyroid cancer.55 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.

Acromegaly

When a manufactured protein became available in 2003 for 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

10 ACROMEGALY

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 The “Gentle Giant” with adults, can lead to serious health complications such as the Devastating Disease arthritis, diabetes, high blood pressure, and increased risk of cardiovascular disease. It affects at least 40 to 60 out of Andre the Giant (born Andres Roussimoff) every million people at any time.61 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 In the pipeline are potential Today, acromegaly is treatable with treatments for anthrax, cystic surgery, radiation, and medicines, which fibrosis, and West Nile Virus, can help normalize levels of growth hormone and insulin-like growth which have been granted orphan factor-1 (IGF-1) in the bloodstream. 62 status by the FDA. There are three drugs available among three different classes to treat the condition.64

11 Advances in the Treatment of DISEASES OF THE DEVELOPING WORLD

Some diseases considered rare in the United States are actually very common around the world. For these diseases, new treatments being developed in the United States are helping millions of men, women, and children in the developing nations. Even before the horrors of Hurricane 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 leading causes of death in developing countries.

Cryptosporidiosis and Neurocysticercosis and Giardiasis Hydatid

Cryptosporidiosis and giardiasis, parasitic infections that Both neurocysticercosis and hydatid disease are parasitic cause diarrhea, mainly affect people living in developing diseases from worms and affect approximately 300 countries around the world, but even in the United States Americans annually.71 Neuro- there are cases every year.65 cysticercosis, caused by pork tapeworm larvae (eggs), is The parasite cryptosporidium can be found in drinking or usually spread through con- recreational water and contaminated food. Once it enters taminated water or food. the body it lives in the intestinal tract, but outside the body It causes cysts to develop it can survive for long periods because of a tough outer throughout the body and can shell. The parasite causes vomiting and nausea, dehydra- cause headaches and seizures tion, stomach pain, and weight loss.66 Giardiasis is an if they develop in the brain infection caused by a single-celled parasite called Giardia tissue.72 It is the most common lamblia or, simply, infectious cause of seizures Giardia. If left worldwide.73 untreated in children, complications from People can contract hydatid disease, also known as these parasites Echinoccocus, by eating contaminated food containing include malnutrition, Echinococcus granulosus worm eggs. The infection causes impaired growth, cysts in the liver first but they can also develop in the and death.67 lungs, brain, bones, and other organs. If the cysts rupture, severe illness results, including fever, low blood pressure, and shock.74,75 PHARMACEUTICAL ADVANCES ■ Killing Parasites That Cause Dangerous PHARMACEUTICAL ADVANCES Waterborne Illnesses ■ First Treatment for Two Kinds of Cyst-Causing Worms Nitazoxanide, an antiprotozoal approved in 2002, is used In 1996, albendazole became the first treatment approved to treat children up to 11 years of age with diarrhea caused to treat both neurocysticercosis and hydatid.76 Albendazole by cryptosporidiosis and giardiasis. It is the first new drug kills the worm by preventing it from absorbing sugar (glu- approved for giardiasis in over 40 years.68 Nitazoxanide is cose), which it needs to survive.77 This drug was found to the only drug approved for treating cryptosporidiosis and destroy cysts in 40 to 70 percent of patients with neurocys- the only drug approved for giardiasis for children one to 11 ticercosis. Among patients with hydatid disease, albenda- years of age. Nitazoxanide works by stopping the growth of zole eliminates the cysts in about 30 percent of patients the infecting organisms.69 The FDA estimates that nitazox- and reduces their size in an additional 40 percent anide could help 2,500 people in the United States.70 of patients.78

12 Tuberculosis

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, Tuberculosis— rifapentine, was approved for treatment of pulmonary A Disease from Antiquity tuberculosis. It works by stopping the cell multiplication process of the bacteria and is used in combination with Tuberculosis has ravaged human culture other anti-tuberculosis drugs to treat pulmonary tuberculo- since ancient times. Egyptian mummies sis.81 Before rifapentine was approved, the health care com- munity was worried about resistance to older drugs that tell the story of deadly tuberculosis infec- was developing over time. This treatment offers another tions thousands of years ago. Fragments tool to fight tuberculosis. Also, the dosing regimen for this of the spinal columns of mummies drug is simpler than other drugs, so patients are more dating back to 2400 B.C. show evidence likely to take it.82 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, In the last decade (1995–2005), tuberculosis infections still occur in over 160 orphan drugs were all parts of the world, but mankind is approved, compared with 108 fighting back. Scientists are using the from 1984 to 1994 and only 10 in vast knowledge and powerful tools the decade prior to the passage of that the Egyptians could not have the Orphan Drug Act in 1983.83 dreamed of to develop new treat- ments for this age-old foe.

13 Advances in the Treatment of BLOOD DISORDERS &

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 few specific cells can cause illnesses. Today’s pharmaceutical innovations, however, are revolu- tionizing treatments for people with rare blood diseases.

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

Hemophilia B

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 PHARMACEUTICAL ADVANCES ■ DNA-Derived Clotting Factor: A Better Treatment ■ Alternative Blood-Thinning Treatment Option for Patients In 1998, lepirudin was introduced as the first alternative Recombinant human Factor IX was approved in 1997 to heparin for patients who experience heparin-induced for the prevention and control of excessive, potentially thrombocytopenia. Lepirudin is a derivative of the saliva life-threatening bleeding in hemophilia B patients. of a medicinal leech, a bloodsucking aquatic worm that Recombinant DNA-derived clotting factors are lab- is sometimes used in blood withdrawal. Lepirudin produced using Chinese hamster ovary cells that have blocks thrombin, which is an enzyme that aids in clot been modified to express the human Factor IX gene.90 The formation. Lepirudin also promotes a rapid increase of advantage of recombinant human Factor IX over other platelets.87 The FDA estimates that 180,000 people sources of Factor IX is that it is free from the risk of could benefit from this new drug.88 transmitting human viruses.

14 LEPROSY

Leprosy

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- Leprosy—Reason for Exile in matory complication of leprosy that can include severe the Old World skin lesions, nerve pain, loss of nerve function, joint 94 swelling and high fever. Tales of leprosy date back to biblical times. During those times, leprosy was thought to PHARMACEUTICAL ADVANCES be transmitted by contact with infected ■ Ancient, “Incurable” Disease Now Treated with “Second Chance” Drug people. To decrease the possibility of catch- Nearly 40 years after thalidomide was first found to pro- ing the disease, leprosy sufferers were duce severe birth defects when used as a treatment for often shunned. “…[I]n Europe during the morning sickness associated with pregnancy in coun- Middle Ages, leprosy sufferers had to wear tries around the world, it was approved for the first time special clothing, ring bells to warn others by the FDA in 1998. With tight restrictions, it is now used to treat debilitating skin sores that result from that they were close, and even walk on a ENL.95 In clinical trials, treatment with thalidomide particular side of the road, depending on caused improvement in at least 70 to 80 percent of the direction of the wind. Even in mod- patients with ENL, compared to approximately 25 percent of patients given placebo.96 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, Since the Orphan Drug Act, new medicines continue to combat over 1,450 drugs in development leprosy infections, and the number of have been designated as orphan known cases is falling. products.97

15 Advances in the Treatment of CHILDHOOD DISEASES

Respiratory Distress Poractant alfa, approved in 1999, treats RDS in premature Syndrome 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 Premature babies face an uphill battle as their fragile, thus improving expansion and ventilation.104 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 Tyrosinemia 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- Children with the genetic, metabolic disorder tyrosinemia ment may include medicines, supplemental oxygen, and gradually develop liver failure and liver cancer, but a new use of a ventilator.100 drug, nitisinone, approved in 2002, can extend their lives. These children lack the enzyme that breaks down the Of the 250,000 infants born prematurely each year, up to amino acid tyrosine. Normally, the liver is where tyrosine 50,000 will suffer from infant RDS, and 5,000 will die is broken down; when it accumulates in the blood, it can 101 from it. RDS usually occurs right after birth. lead to progressive liver failure and, often, cancer. Tyrosinemia may also cause damage to the kidneys, eyes, Three new medicines have been approved in the last decade skin, and nervous system. for this one rare condition, advancing the way that The most common and severe form of the disease is acute neonates with immature tyrosinemia, with which children are born or develop soon lungs are treated. With after birth. Infants with acute tyrosinemia exhibit rapid these medicines, prema- onset of symptoms, and they often fail to gain weight and ture infants have a better grow. Infants with the less prevalent chronic tyrosinemia chance of surviving this have a more gradual and less severe onset of symptoms. life-threatening disorder. Children who experience liver failure or are diagnosed PHARMACEUTICAL ADVANCES with liver cancer as a result of tyrosinemia rarely make it ■ Rescuing the Tiniest Lungs into their twenties without a liver transplant. According Calfactant, approved in 1997, is used to treat babies with to the FDA, this disorder affects 2,500 children in the RDS, and also to prevent premature babies from develop- United States.105 ing RDS.102 A natural bovine-derived surfactant, calfactant attaches rapidly to the surface of the air-to-liquid inter- PHARMACEUTICAL ADVANCES face within the lung’s air sacs and modifies surface ■ Patients’ Pathway to Longer Life tension similarly to natural lung surfactant, thereby allowing the air sacs to expand and improving newborns’ Nitisinone opens the door to an extended lifespan for chil- breathing ability. 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- Nitric oxide, approved in 1999, reduces the common com- ed in the amino acids tyrosine and phenylalanine, this plications of lung hypertension in newborns by expanding drug has been shown to increase the four-year survival 103 blood vessels in the lungs. Nitric oxide reduces the need rate of children who were diagnosed at less than two for ventilator support and helps regulate the muscle tone months of age to 88 percent. Historical data for children in the arteries of the lungs. treated with dietary restrictions alone shows a survival rate of 29 percent for the same time period.106 16 Primary IGF-1 Deficiency

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 Hope is in the Pipeline for Children with Progeria PHARMACEUTICAL ADVANCES ■ First Medicine to Treat Primary IGFD Medical researchers are racing to beat the In 2005, the FDA approved mecasermin, the first treat- clock in search of a cure for progeria, a ment for approximately 6,000 children in the United premature aging condition that afflicts just States with severe Primary IGFD.109 Mecasermin is a manufactured protein that functions like the natural 14 children in the United States and human protein as a growth catalyst. This protein must usually leads to death near age 13. In 2003, be present for children’s bones, cartilage, and organs to scientists were able to isolate the gene grow properly. An eight-year clinical trial demonstrated mutation that causes this rare disease. In that, on average, children grew one inch per year for each year of therapy using this new medicine.110 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- The number of orphan drugs maceutical companies. These drugs is expected to rise in the coming appear to repair cells damaged due to the disease. By halting the rapid aging years as more new medicines are process associated with the disease and developed that target specific restoring damaged cells, medical 111 genetic disorders. research gives children living with progeria hope that their time will not run out before they reach adulthood.113

17 Advances in the Treatment of NARCOLEPSY &

Narcolepsy 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 In people with narcolepsy the brain does not properly medications.118 The cause of narcolepsy remains unknown, regulate sleep and wake cycles, so they experience episodes but genetic factors may play a role.119 of frequent, uncontrollable daytime sleeping. It is estimated that narcolepsy, which is generally a lifelong PHARMACEUTICAL ADVANCES condition, affects 135,000 people in the United States.114,115 ■ Easing Worst Symptoms of Sleep Disorder For these patients, falling asleep in unlikely situations is much more than an inconvenience; it can jeopardize Modafinil was approved in 1998 for the treatment of their education, ruin relationships, or endanger their narcolepsy and is the first new stimulant for treatment in lives when driving. 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 Excessive Daytime Sleepiness (EDS) is the most common 121 symptom of narcolepsy patients, but they can also have are often used for treatment of narcolepsy. In clinical trials, modafinil proved to be effective in alleviating EDS cataplexy (sudden loss of muscle tone), sleep paralysis while producing fewer, less serious side effects than (temporary inability to use muscles), and hallucinations 122 before and/or after sleep episodes.116 A cataplexy episode is other medications. often triggered by emotions such as surprise or anger, causing a range of effects, from a simple slumping of Sodium oxybate is the first approved treatment for cata- the head or a more dramatic collapse of the body. An plexy. Available since 2002, it reduces the number of estimated 20,000 to 50,000 narcolepsy patients cataplexy attacks,123 which can cause a patient’s muscles experience cataplexy.117 to feel weak or paralyzed.

ALS/Lou Gehrig’s Disease

Amyotrophic lateral sclerosis (ALS), also known as Lou Gehrig’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

18 AMYOTROPHIC LATERAL SCLEROSIS

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 A Pitch for ALS been found at abnormally high levels in the cerebrospinal fluid of some ALS patients. Scientists theorize that gluta- Sixty-five years after baseball legend Lou mate toxicity might be killing motor neurons, leading to Gehrig announced his battle with ALS to progressive muscle degeneration in people with ALS. Riluzole, however, inhibits the release of glutamate in the world, Red Sox pitcher Curt Schilling the brain. brought the disease back to international attention. During game two of the 2004 According to Dr. Jeffrey Rothstein of Johns Hopkins World Series, Schilling, pitching with an University School of Medicine, this medicine offers great hope despite the fact that the improvement is not dramatic: injured ankle, wrote “K ALS,” meaning “This is against the background of decades when no drug strikeout ALS, on his shoe, just below his ever did anything for the disease. Initial therapies for blood-stained sock. Photographers looking many diseases, like leukemia and other cancers, had the same kind of effect... a modest increase in survival. But to capture images of an athlete persever- they were followed by better therapies that, over time, ing through pain instead told the story of increased patients’ survival…. It’s a daunting task, but I a man fighting for the 30,000 Americans envision that someday it will be possible to develop drugs living with ALS. that will not only stop motor neurons from dying but replace them and reverse the course of ALS.”130 Curt Schilling is the pitcher for the 2004 World Series Champion Boston Red Sox. He and his wife, Shonda, became involved in the fight against ALS after An “orphan” or rare disease meeting Dick Bergeron, an ALS patient, affects fewer than 200,000 in 1992. people in the United States.131

19 Advances in the Treatment of CANCER

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.

Cancer medication in the comfort of their own homes rather than having to receive intravenous treatments at a physi- cian’s office or hospital.

Cancer is a group of diseases in which abnormal cells ■ Dual-Action Therapy Initiates Immune Response develop and spread through parts of the body. Anyone can and Attacks Tumor Cells Directly develop cancer. The National Cancer Institute estimates Non-Hodgkin’s lymphoma is a cancer of lymphatic that 9.8 million Americans with a history of cancer were tissues, such as lymph nodes, spleen, and other immune alive in 2001. Some were cancer-free; others were continu- system organs. There are several different types of non- ing to undergo treatment.132 Hodgkin’s lymphomas. One of those types, follicular lymphoma, makes up 22 percent of all non-Hodgkin’s PHARMACEUTICAL ADVANCES lymphomas. Follicular lymphoma is not curable, but ■ Disrupting DNA Adds Months for Severe due to its slow growth, 60 to 70 percent of patients live Brain Cancer Patients at least five years; it occurs mainly in adults, with an average age of 60.141 People with follicular non-Hodgkin’s In the two most aggressive forms of astrocytoma, brain lymphoma usually have lymphoma in many parts of the tumors grow rapidly and spread to other parts of the body. body. According to the FDA Office of Orphan Products, Astrocytoma is classified into four grades (Grade I being the condition affects 193,500 people in the United States. 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. With the 2003 approval of tositumomab and Iodine-131 Grade IV is glioblastoma multiforme, which affects tositumomab, patients with a subset of follicular non- 8,000–10,000 people each year and is usually fatal within Hodgkin’s lymphoma—CD20 positive follicular non- one year.133 Hodgkin’s lymphoma—gained a new treatment option with an innovative therapeutic twist. The drug is made up Temozolomide can add an average of two and a half addi- of an immune system protein, called an antibody, attached tional months—an enormous amount of time in the world to radioactive Iodine-131. Combined, they form a “radiola- of cancer treatment—for patients with glioblastoma beled” monoclonal antibody that is able to bind to a multiforme.134,135 “It doesn’t sound like much… but if you protein found only on the cancer cells, thus targeting the can demonstrate that you can extend life for two or three radioactivity directly months for the average patient, that’s a significant to the cancer cell, 142,143 advance,” says Dr. Warren Mason, the co-author of a killing it. New England Journal of Medicine study about the drug.136 Patients taking temozolomide for treatment of anaplastic This new medicine is astrocytoma experienced an average survival time of nearly used for patients with 16 months.137 CD20 positive follicu- lar non-Hodgkin’s Approved in 1999, temozolomide is the first major new lymphoma who have treatment for anaplastic astrocytoma in 20 years, and with not responded to a second indication approved in 2005, it is the first in over other treatments or 30 years for glioblastoma.138,139 It works by disrupting DNA whose cancer has to prevent cancer cells from multiplying and prolongs returned after 144 survival when combined with standard radiation.140 chemotherapy. For Additionally, it is a more convenient therapy for patients; more than two years, it is an oral treatment allowing patients to take their

20 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. Thankful for Another Day Now the first drug approved for this rare cancer, pemetrexed, combined with other treatments, gives Karl, like many people, was not one to visit patients 40 percent longer survival time compared with current treatment alone. “Before [pemetrexed] was his doctor often, even if he was feeling available, patients suffering from mesothelioma had no under the weather. However, after days and hope—rarely living a year after diagnosis,” said days of feeling tired and eventually having Nicholas J. Vogelzang, MD, Director of the Nevada difficulty just getting in and out of the car, Cancer Institute in Las Vegas. “At 18 months, there is still a statistically significant difference in survival, which Karl decided it was time to see a doctor. demonstrates patients are living longer when treated with After an x-ray and other tests, he was diag- this [pemetrexed] combination,” Volgelzang said.147 nosed with mesothelioma. Karl’s daughter, who works in a hospital, was familiar with Approved in 2004, pemetrexed is a novel antifolate, a class the disease and understood the prognosis of drugs that targets the folic acid metabolic pathway, which affects availability of certain B complex vitamins.148 was poor. Fortunately, after several chemo- It is indicated for patients with the advanced form of the therapy treatments with pemetrexed, disease who have already had chemotherapy. Pemetrexed Karl’s condition began to improve. Karl’s was found in clinical trials to be as effective as other can- wife is thankful, noting, “Every day, we cer drugs, but with fewer side effects, such as hair loss and subsequent infections. 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 There are approximately drive in town together. He could not 6,000–7,000 rare diseases.149 drive before. Now, little by little, it’s getting better and better and we are very grateful for that.”150

21 Advances in the Treatment of LEUKEMIA

Thanks to advances in pharmaceutical treatment and other research, the survival rate of people with leukemia has tripled in the last 40 years.

Leukemia ■ 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 In leukemia, the bone marrow produces abnormal white drugs, “antibody-targeted chemotherapy.” Scientists study- blood cells—the leukemia cells, which in time may crowd ing the soil discovered a powerful cancer-fighting substance, out normal white blood cells, red blood cells, and platelets. calicheamicin, which destroyed the DNA of cancer cells Types of leukemia vary according to which type of blood and proved to be stronger cells are affected, how developed the cancer cells are at the than any anticancer drugs time of diagnosis, and how different they are from normal at the time. But it was up cells.151 According to the National Cancer Institute, there to 10,000 times more toxic were 30,600 new cases of leukemia in the United States to normal cells than other in 2003.152 anticancer drugs. Research- ers discovered that by PHARMACEUTICAL ADVANCES attaching calicheamicin to ■ an antibody (immune Ancient Medicinal Offers New Hope to Young Adults system protein), they could Contrary to images people may conjure up when hearing safely bring it directly to “arsenic,” it actually has given new hope to patients with the tumor, bypassing most acute promyelocytic leukemia (APL), which is most com- normal cells. In May 2000, the FDA approved the first mon in young adults and causes fatigue and tendency antibody-targeted chemotherapy, gemtuzumab, for use to bleed. Arsenic-containing preparations, dating back in patients over age 60 with relapsed acute myeloid more than 2,000 years, were used more than 100 years leukemia (AML). ago for leukemia therapy but were replaced by modern chemotherapy. Because some Chinese arsenic- In patients with AML, unhealthy white and red blood cells containing treatments and platelets build up in the bone marrow, blood, and showed effectiveness other parts of the body leading to infections, easy bleeding, 156 against leukemia, and anemia. AML quickly worsens if not treated. It is attention again turned estimated that in 2005, 11,960 cases of AML will be diag- 157 to arsenic.”153 nosed and will cause 9,000 deaths. Gemtuzumab was found to cause remission in about 30 percent of AML Arsenic trioxide was sufferers and produces fewer side effects than traditional approved in 2000 to chemotherapies.158 treat APL patients whose disease has recurred or ■ failed to respond to stan- A Powerful Attack and a True Trailblazer dard treatment (about The approval of imatinib mesylate in 2001 proved that a 400 of the 1,500 diagnosed cases per year).154 About 75 targeted therapy—one that directly turns off the signal of a percent of APL patients can be cured with other combina- protein known to cause cancer—could powerfully attack tion therapies, but those who do not achieve remission or cancer with few side effects.159 Imatinib not only benefits who relapse can now be treated with arsenic trioxide.155 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 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 The Wave of the Future occurs in middle-aged or older adults.161 It is estimated Brings Hope that 4,600 new cases of chronic myeloid leukemia will be diagnosed this year, and 850 people will die from A new generation of precise and powerful the disease.162 drugs known as “targeted therapies” may represent a better way to treat many cancers, ■ First For-Kids-Only Leukemia Drug in 10 Years bringing hope for patients with rare cancers. For 10 years, oncologists treating pediatric patients with Leukemia treatments are blazing the trail. acute lymphoblastic leukemia (ALL) treaded water as ther- “Slowly, many scientists believe, the drugs are apy for the most common childhood leukemia had hit a plateau.163 Finally, the 2004 approval of clofarabine pre- transforming cancer treatment. But for now, sented a new option for children aged 1 to 21 with ALL the drugs are still only a whisper of hope. who had relapsed or were unresponsive to other treat- They are not a miracle cure and not fully ments. Clofarabine produces remissions and allows some understood. Many are still in clinical trials. patients to proceed to bone marrow transplant, the best chance for long-term survival.164 Those that work often help patients in sub- sets of disease—one kind of leukemia, one About 3,830 Americans are diagnosed with ALL, the most type of breast cancer… common type of leukemia in patients under age 19, each year.165 In ALL, abnormal blood cells called lymphoblasts “Yet for all they are not, it is what the drugs accumulate, while fewer normal red and white blood cells achieve for the lucky few that captures the are produced. imagination: the stories that patients tell of teetering near death, only to see a stunning Clofarabine is an antimetabolite, a drug that prevents can- comeback, at least for a while. They can cer cells from growing by disrupting the synthesis of nucleic acids, which are needed to produce DNA and RNA. 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 One in every 10 individuals in child. Side effects, the bane of cancer this country has received a treatment, are comparatively few.”167 diagnosis of a rare disease.166 — Donna St. George, The Washington Post

23 Conclusion

Looking back over the last decade, we have clearly made for orphan status among drugs in development. That much progress and because of these new treatments many number represented a 30 percent increase over the average lives have changed. These facts offer hope to the many of 124 per year in the previous four years.168 patients with rare diseases who are still waiting for treat- ments. Looking forward, the future holds great promise. Pharmaceutical discovery is entering a new era. Our new understanding of the genome and powerful scientific Just as the number of new orphan drugs being approved research tools are opening new doors to discovery of has grown, the number currently being studied continues breakthrough medicines. The number of orphan drugs to rise. According to the FDA’s Office of Orphan Products is expected to rise in the coming years as more new medi- Development, in 2004 there were a record 160 applications 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.

24 LOOKING BACK… Medicines in Development for In the past year alone, nine new orphan drugs were 174 approved. These new medicines that provide additional Selected Rare Diseases treatment options for a variety of diseases include: New Medicine For patients with T-cell acute lympho- • Nelarabine— Disease in Clinical Trials blastic leukemia and T-cell lymphoblastic lymphoma, or FDA Review this new treatment resulted in complete disappear- ance of cancer cells in some patients during clinical Amyotrophic Lateral Sclerosis (ALS) 5 170 trials. Pulmonary Hypertension 6 • Deferasirox—The first oral therapy for chronic iron overload, it allows patients to drink their medicine Interstitial Cystitis 3 rather than endure multi-hour nightly infusions to Acromegaly 2 remove excess iron.171 • Sorafenib tosylate—The first new treatment for kid- Tuberculosis 5 ney cancer in 12 years, it extended time until tumor Thrombocytopenia 5 progression and until death in patients with this rare cancer.172 Mesothelioma 9 • Lenalidomide—This is an oral treatment for patients Acute myeloid leukemia 31 requiring blood transfusions as a result of anemia caused by myelodysplastic syndrome, which causes LOOKING AHEAD… low red blood cell counts. Patients who received this medicine during clinical trials no longer needed Every day researchers continue to search for and develop new medicines for rare diseases. Here are examples of the blood transfusions.173 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 25 15 Actelion Pharmaceuticals US Inc., “Balance at Work in Patients Endnotes Naive to ERT,” Zavesca, http://www.zavesca.com/HP_PNE.html (accessed 12 May 2005). 16 The National MPS Society, A Guide to Understanding Maroteaux- Lamy Syndrome, http://www.mpssociety.org/images/pdfs/ 1 Food and Drug Administration, Office of Orphan Products booklets/MPS%20VI%20final.pdf (accessed 29 September Development, “List of All Approved Orphan Products Through 2005). the Year 2005,” 13 May 2005, http://www.fda.gov/orphan/ 17 MPSVI.COM, http://www.maroteauxlamy.com/pc/faq/faqs.asp designat/allap.rtf (accessed 7 September 2005). (accessed 29 September 2005). 2 National Institutes of Health, Office of Rare Diseases, Biennial 18 CenterWatch, Naglazyme, http://www.centerwatch.com/cgi-bin/ and Annual Report on the Rare Diseases Research Activities at the cl.pl?p=patient/drugs/dru885.html&h=wbmdhd.txt&f=wbmdft. National Institutes of Health FY 2004, Executive Summary txt (accessed 29 September 2005). (Bethesda, MD: NIH, 22 July 2005), http://rarediseases.info. 19 BioMarin Pharmaceutical Inc., Naglazyme Dosing and nih.gov/html/reports/fy2004/summary04.html. Administration Guide, http://www.naglazyme.com/includes/ 3 National Institutes of Health, Office of Rare Diseases, Access to DoseAdminBroch.pdf (accessed 29 September 2005). Quality Testing for Rare Diseases: A National Conference, 20 BioMarin Pharmaceutical Inc., “Clinical Support Materials,” Overview (Rockville, MD: NIH, 26 September 2005), Naglazyme, http://www.naglazyme.com/csm.asp (accessed 29 http://rarediseases.info.nih.gov/QTRD/overview.html. September 2005). 4 National Organization for Rare Disorders, http://www. 21 Food and Drug Administration, “Office of Orphan Products rarediseases.org (accessed 11 August 2005). Development,” op. cit. 5 Food and Drug Administration, “Office of Orphan Products 22 Genzyme Therapeutics, “Living with Fabry Disease,” Fabrazyme, Development,” Budget 2006, http://www.fda.gov/oc/oms/ http://www.fabrazyme.com/patient/disease/fz_us_pt_ds_living. ofm/budget/2006/PDFs/Summary/Pages194thru199.pdf asp (accessed 20 September 2005). (accessed 7 September 2005). 23 Genzyme Therapeutics, “Treatment,” Fabrazyme, http://www. 6 Fabry Community, Health Care Professionals, http://www. fabrazyme.com/patient/treat/fz_us_pt_tr_overview.asp (accessed fabrycommunity.com/healthcare/fc_p_hc_overview.asp 20 September 2005). (accessed 13 September 2005). 24 National Heart, Lung, and Blood Institute, What Is Pulmonary 7 National Institute of Neurological Disorders and Stroke, “NINDS Arterial Hypertension?, http://www.nhlbi.nih.gov/health/dci/ Fabry’s Disease Information Page,” National Institute of Neurolo- Diseases/pah/pah_what.html (accessed 12 September 2005). gical Disorders and Stroke, http://www.ninds.nih.gov/disorders/ 25 Ibid. fabrys/fabrys.htm (accessed 12 May 2005). 26 American Heart Association, Primary or Unexplained Pulmonary 8 Fabry Community, Fabry Disease Overview, http://www. Hypertension, http://www.americanheart.org/presenter.jhtml? fabrycommunity.com/patient/about/fc_p_pt_fabry-disease.asp identifier=4752 (accessed 16 May 2005). (accessed 12 May 2005). 27 S. Reents et al., Clinical Pharmacology, Gold Standard Multi- 9 S. Reents et al., Clinical Pharmacology, Gold Standard Multi- media, Inc., Flolan®, http://cp.gsm.com (accessed 16 May 2005). media, Inc., Fabrazyme®, http://cp.gsm.com (accessed 10 May 28 2005). S. Reents et al., Clinical Pharmacology, Gold Standard Multi- media, Inc., Tracleer®, http://cp.gsm.com (accessed 16 May 10 National Institute of Neurological Disorders and Stroke, “NINDS 2005). Gaucher’s Disease Information Page,” National Institute of 29 Neurological Disorders and Stroke, http://www.ninds.nih.gov/ S. Reents et al., Clinical Pharmacology, Gold Standard Multi- ® disorders/gauchers/gauchers.htm (accessed 12 May 2005). media, Inc., Remodulin , http://cp.gsm.com (accessed 16 May 2005). 11 National Tay-Sachs and Allied Diseases Association, Inc., 30 Gaucher Disease, http://www.ntsad.org/pages/gaucher.htm Ibid. (accessed 12 May 2005). 31 Food and Drug Administration, Patient Information Sheet: 12 National Organization for Rare Disorders, Gaucher Disease, Iloprost, http://www.fda.gov/cder/drug/InfoSheets/ http://www.rarediseases.org/search/rdbdetail_fullreport_pf patient/iloprostPIS.htm (accessed 12 September 2005). (accessed 30 August 2005). 32 S. Reents et al., Clinical Pharmacology, Gold Standard Multi- ® 13 National Gaucher Foundation, Prevention and Treatment of media, Inc., Ventavis , http://cp.gsm.com (accessed 16 May Gaucher Disease, http://www.gaucherdisease.org (accessed 12 2005). May 2005). 33 National Library of Medicine, MedlinePlus Medical Encyclo- 14 S. Reents et al., Clinical Pharmacology, Gold Standard Multi- pedia, Hypotension, http://www.nlm.nih.gov/medlineplus/ media., Inc., Zavesca®, http://cp.gsm.com (accessed 10 May ency/article/003083.htm (accessed 12 September 2005). 2005).

26 34 Food and Drug Administration, Office of Orphan Products 54 Food and Drug Administration, “FDA Approves First in a New Development (OOPD), Approved Orphan Drug Spreadsheet, Class of Drugs to Treat Hyperparathyroidism Associated with available upon request from OOPD. Renal Failure and in Patients with Parathyroid Cancer,” 8 March 35 National Library of Medicine, MedlinePlus Medical Encyclopedia, 2004, http://www.fda.gov/bbs/topics/ANSWERS/2004/ Hypotension, op. cit. ANS01282.html (accessed 29 July 2005). 55 36 S. Reents et al., Clinical Pharmacology, Gold Standard Multi- Food and Drug Administration, Office of Orphan Products media, Inc., Midodrine, http://cp.gsm.com (accessed 3 August Development (OOPD), Approved Orphan Drug Spreadsheet, 2005). op. cit. 56 37 Women and Pulmonary Hypertension, fact sheet, http://www. S. 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28 107 Tercica, Understanding Short Stature, http://investor.tercica. 126 National Library of Medicine, MedlinePlus Medical com/releases.cfm (accessed 29 September 2005). Encyclopedia, Amyotrophic Lateral Sclerosis, http://www.nlm. 108 Drugs.com, “Increlex,” Drugs.com, http://www.drugs.com/ nih.gov/medlineplus/ency/article/000688.htm (accessed 12 increlex.html (accessed 29 September 2005). September 2005). 127 109 M. Herper, “FDA Approves Tercica’s Increlex,” Forbes.com, National Organization for Rare Disorders, “Amyotrophic Lateral 31 August 2005, http://www.forbes.com/markets/2005/08/ Sclerosis,” op. cit. 31/fda-increlex-tercica-0830markets01.html?partner=yahootix 128 Food and Drug Administration, “FDA Approves First Drug for (accessed 29 September 2005). 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30 175 T. Hampton, “Looking Beyond Imatinib: Next Line of Targeted Drugs for CML Shows Promise,” The Journal of the American Medical Association 295, no. 4 (2006): 369–370. 176 Cambridge Antibody Technology, “MYO-029,” http://www.cam- bridgeantibody.com/html/products/licensed_products/wyeth/ myo30 (accessed 13 February 2006). 177 Medical News Today, “Wyeth Initiates Clinical Trial with Investigational Muscular Dystrophy Therapy MYO-029,” 28 February 2005, http://www.medicalnewstoday.com/medicalnews. php?newsid=20441 (accessed 13 February 2006). 178 Muscular Dystrophy Campaign, “Myostatin Inhibitor (MYO-029) Trial Announced By Wyeth,” 24 February 2005, http://www.muscular-dystrophy.org/news/myostatin.html (accessed 13 February 2006). 179 Astellas US LLC, “Business Development: Immunology,” http://www.astellas.us/bd/immunology.php (accessed 14 February 2006). 180 PR Newswire Europe Ltd., news release, “FK778, a novel com- pound with multiple modes of action—a breakthrough in transplant immunosuppression?,” 23 September 2003, http://www.prnewswire.co.uk/cgi/news/release?id=108689 (accessed 14 February 2006).

31 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. Pharmaceutical Research and Manufacturers of America 950 F Street, NW, Suite 300 • Washington, DC 20004 www.phrma.org

April 2006