2013 REPORT Neurological disorders—such as epi- lepsy, multiple sclerosis and Parkinson’s disease—inflict great pain and suffering on patients and their families, and every year costs the U.S. economy billions of dollars. Biopharmaceutical research companies are developing 444 new medicines to prevent and treat neu- rological disorders. The medicines in development are either in human clinical trials or under review at the Food and Drug Administration. They include: • 82 medicines for Alzheimer’s disease, which afflicts more than 5 million Americans. • 82 medicines for pain—100 million U.S. adults experience chronic pain. • 62 medicines for brain tumors—nearly 70,000 Americans are diagnosed each year with a primary brain tumor. • 38 medicines for multiple sclerosis, which afflicts an estimated 500,000 Americans. • 28 medicines for epilepsy and sei- zures, which impact more than 3 million Americans. • 27 medicines for Parkinson’s disease, which affects as many as 1 million Americans. • 25 medicines for headache, includ- ing migraine, a condition that affects more than 37 million people. Other medicines in development target amyotrophic lateral sclerosis (ALS), brain injuries, Huntington’s disease, spinal cord injury, cerebral palsy, and stroke. Among the many promising new medicines in development are: • A medicine that prompts the immune system to protect neurons affected by ALS. • Gene therapy for the treatment of Alzheimer’s disease. • Gene therapy to reverse the effects of Parkinson’s disease. The new medicines being developed by biopharmaceutical research companies reflect a growing understanding of the underlying mechanisms of neurological disorders, which fuels scientific progress and pharmaceutical research. These medi- cines offer patients hope that more effec- tive treatments may soon be available. Biopharmaceutical Companies Researching and Developing Nearly 450 Medicines for Neurological Disorders MEDICINES IN DEVELOPMENT Neurological Disorders A Report on Disorders of the Brain, Spinal Cord and Nerves PRESENTED BY AMERICA’S BIOPHARMACEUTICAL RESEARCH COMPANIES Multiple Sclerosis Pain Parkinson’s Brain Tumors Alzheimer’ s 82 82 62 28 27 Epilepsy 38 Application Submitted Phase III Phase II Phase I Medicines in Development For Neurological Disorders Contents Key Issues ......................................2 Disease Facts .................................. 7 Medicines in Development ............... 11 Glossary ...................................... 49 Drug Development/ Approval Process ....................... 51
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Medicines in Development Neurological Disorders 2013
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2013 R
EPORT
Neurological disorders—such as epi-lepsy, multiple sclerosis and Parkinson’s disease—inflict great pain and suffering on patients and their families, and every year costs the U.S. economy billions of dollars. Biopharmaceutical research companies are developing 444 new medicines to prevent and treat neu-rological disorders. The medicines in development are either in human clinical trials or under review at the Food and Drug Administration. They include:
• 82 medicines for Alzheimer’s disease, which afflicts more than 5 million Americans.
• 82 medicines for pain—100 million U.S. adults experience chronic pain.
• 62 medicines for brain tumors—nearly 70,000 Americans are diagnosed each year with a primary brain tumor.
• 38 medicines for multiple sclerosis, which afflicts an estimated 500,000 Americans.
• 28 medicines for epilepsy and sei-zures, which impact more than 3 million Americans.
• 27 medicines for Parkinson’s disease, which affects as many as 1 million Americans.
• 25 medicines for headache, includ-ing migraine, a condition that affects more than 37 million people.
Other medicines in development target amyotrophic lateral sclerosis (ALS), brain injuries, Huntington’s disease, spinal cord injury, cerebral palsy, and stroke. Among the many promising new medicines in development are:
• A medicine that prompts the immune system to protect neurons affected by ALS.
• Gene therapy for the treatment of Alzheimer’s disease.
• Gene therapy to reverse the effects of Parkinson’s disease.
The new medicines being developed by biopharmaceutical research companies reflect a growing understanding of the underlying mechanisms of neurological disorders, which fuels scientific progress and pharmaceutical research. These medi-cines offer patients hope that more effec-tive treatments may soon be available.
Biopharmaceutical Companies Researching and Developing Nearly 450 Medicines for Neurological Disorders
MeDiCiNes iN DevelopMeNt
Neurological DisordersA Report on Disorders of the Brain, spinal Cord and Nerves
presented by america’s biopharmaceutical research companies
Mul
tiple
Scler
osis
Pain
Park
inso
n’s
Brain
Tum
ors
Alzh
eimer
’s
82 82
62
28 27
Epile
psy
38
Application Submitted
Phase III
Phase II
Phase I
Medicines in Development For Neurological Disorders
Contents Key Issues ......................................2Disease Facts ..................................7Medicines in Development ...............11Glossary ...................................... 49Drug Development/ Approval Process ....................... 51
Medicines in Development neurological disorders 20132
innovative Medicines in the PipelineOf the 444 medicines in development in the United States listed in this report (see page 11), many present innovative new ways to target diseases. Some of them include:
• Gene Therapy to Restore Neuronal Function in Alzheimer’s—A gene therapy for the treatment of Alzheimer’s disease in clinical trials is designed to deliver nerve growth factor (NGF) to the brain. NGF is a naturally occurring protein important for neuron survival. The gene treatment is injected into the brain region where neuron degeneration occurs in Alzheimer’s disease. It is thought that the result-ing sustained expression of NGF in the neurons can restore their lost function, leading to memory and cognition improvement.
• Targeted RNAi Therapy Approach for Duchenne Muscular Dystrophy—In clinical trials, RNAi therapies have shown potential in treating neuromuscular dis-
orders such as Duchenne muscular dystrophy (DMD). In DMD, DNA deletions cause mutations in important genes that encode for dystrophin, a structural pro-tein found in normal muscle. The loss of this protein causes muscle fibers to disintegrate faster than they can be regenerated. One medicine in development targets restoration of dystrophin function and, as dys-trophin expression increases, there have been demon-strated improvements in patients’ ability to walk.
• Gene Therapy as a Possible Approach for Parkinson’s Disease—Inserting genes into cells can alter the im-pact the genes have on the proteins that are involved in a particular disease. These genes might alter or replace a mutated gene or produce a new thera-peutic protein entirely. In Parkinson’s disease, there are a number of treatments addressing the disease’s symptoms, but none that replace the lost nerve cells resulting from Parkinson’s or that would stop disease progression. More than one gene therapy in clinical trials uses an adeno-associated virus (AAV) as a vector
82
28
8
19
8
62
14
82
25
7
7
38
27
6
9
19
Epilepsy
Genetic Disorders
Brain Tumors
Amyotrophic Lateral Sclerosis (ALS)
Brain Injury
Attention-Deficit/Hyperactivity Disorder
Alzheimer’s Disease
Parkinson’s Disease
Spasticity
Spinal Cord Injury
Stroke
33Other
Pain
Huntington’s Disease
Muscular Dystrophy
Multiple Sclerosis
Headache
Application Submitted
Phase III
Phase II
Phase I
Medicines in Development for Neurological Disorders By Disease and Phase
Some medicines are listed in more than one category
Medicines in Development neurological disorders 2013 3
to deliver neurturin to restore cells damaged in Parkinson’s patients and to protect them from fur-ther degeneration; these inactivated viruses pres-ent a safe way to get these important therapeutic options to patients.
• Als: Fighting a Devastating Disease—ALS, or Lou Gehrig’s disease, is a progressive neurode-generative disease that causes the brain to lose control over body movement, ultimately resulting in paralysis and death. The one drug approved to treat ALS can modestly slow progression of the disease, but new treatments are needed. As our scientific understanding of the disease has grown, researchers are pursuing many new approaches to halt or slow disease, including the use of the patient’s own bone marrow stem-cells to cre-ate healthy neuron-like cells to replace diseased neurons. Other trials are studying ways to prompt the immune system to protect neurons affected by ALS.
alzheimer’s: effective treatment is needed
Alzheimer’s is the 6th leading cause of death in the United States, and its impact on patients and the health care system is growing. Existing medicines are able to treat the symptoms of the disease but cannot slow, prevent, or reverse the progressive dementia. Disease-modifying treatments that could delay the onset of the disease could reduce the cost of care of Alzheimer’s patients in 2050 by $447 billion. Researchers continue to unravel the mysteries of the disease and are studying many new treatments in this area. Recent research has focused on the plaques and tangles which form in the brains of Alzheimer’s patients and are thought to contribute to the death of nerve cells. One medicine in development has shown promise in reducing both brain plaques and tangles. A gene therapy also in clinical trials is being explored to restore lost neuron function.
ALZHEIMER’S COSTS SOCIETY $203 BILLION AND COULD INCREASE TO $1.2 TRILLION BY 2050
ALZHEIMER’S COSTS SOCIETY $203 BILLION AND COULD INCREASE TO $1.2 TRILLION BY 2050
DELAYING DISEASE ONSET BY 5 YEARS COULD RESULT IN50% FEWER PATIENTS/SAVE $447 BILLION BY 2050DELAYING DISEASE ONSET BY 5 YEARS COULD RESULT IN50% FEWER PATIENTS/SAVE $447 BILLION BY 2050
ARE LIVING WITH ALZHEIMER’S DISEASEARE LIVING WITH ALZHEIMER’S DISEASE
BY 2050, THE NUMBER OF PATIENTS COULD TRIPLE WITHOUT EFFECTIVE TREATMENT
BY 2050, THE NUMBER OF PATIENTS COULD TRIPLE WITHOUT EFFECTIVE TREATMENT
5
5
$203
FEWERVICTIMS
YEARSDELAYEDONSET
AMERICANS
2013
SAVED
BILLION
$447 50%BILLION
$1.22050
TRILLION
+=
MILLION
AMERICANSMILLION15
IMPORTANCE TREATMENTALZHEIMER’SOF
Medicines in Development neurological disorders 20134
Advancing Biomedical science Over the past decade, scientific advances and new technolo-gies have dramatically changed how medicines are discov-ered. This new information is critical to the development of new treatments for neurological disorders. Greater knowl-edge of how diseases work at the genetic and molecular level has allowed researchers to pursue new targets for therapy and better predict how certain biopharmaceuticals will affect specific subpopulations of patients.
• Bioinformatics—Bioinformatics use systems and mathematical models to advance the scientific un-derstanding of living systems. At its simplest level, bioinformatics involves the creation and maintenance of biological databases, including DNA sequences.
• Biomarkers—Every disease leaves a signature of molecular “biomarkers” in our body—genes that turn on and off or proteins released into the bloodstream. Biomarkers measured in blood and other samples can tell us the state of our health and how we might respond to treatment.
• Molecular Targeting—The idea behind molecular targeting is to design drugs that specifically attack the molecular pathways that cause disease without dis-rupting the normal functions in our cells and tissues.
• Nanotechnology—You can’t see it, but soon it will be everywhere. Nanotechnology is the science of build-ing microscopic devices at the molecular and atomic levels. In medicine, nanotechnology may also be used to help diagnose and treat diseases.
• Personalized Medicine—The sequencing of the human genome produced a “map” of the human genes in DNA. This new genetic knowledge opens up the possibility of developing “targeted” therapies for people with specific gene sequences, and it can help physicians choose the best treatments based on individual genetic, lifestyle, and environmental factors.
Breakthrough Research in Neurological DisordersEarly research discoveries often fuel the drug development pathways that biopharmaceutical company researchers un-dertake. These discoveries help researchers target a specific disease through certain mechanisms that may have been unknown before. Some noteworthy recent scientific discover-ies in the field of neurology include:
• Researchers at Mount Sinai Medical Center found 10 genes that account for half of the genetic risk for Alzheimer’s.
• Research at the National Institutes of Health found that a protein linked with some early-onset Parkin-son’s disease cases regulates how the body processes dietary fats. The study suggests there could be a link between the defective protein and early-onset Parkin-son’s disease.
• Scientists at the University of Chicago have uncovered a previously unknown process of protein production where a single gene can create two separate proteins from the same messenger RNA simultaneously. They believe this discovery will open the door for new research into therapies for neurological disorders.
• Research at the University of Missouri suggests that two identical neurons can reach the same electrical activity in different ways and could help doctors in treating patients with epilepsy.
• Two separate research groups have identified a muta-tion on the TREM2 gene that may increase a person’s chance of developing late-stage Alzheimer’s disease by three to five times.
• While studying at PennVet, a researcher discovered the gene responsible for Alexander disease, a rare, genetic neurological disorder where the white matter in the brain is destroyed and Rosenthal fibers form causing both mental and physical declines.
Medicines in Development neurological disorders 2013 5
• At the University of Notre Dame, researchers have created a prodrug (an inactive drug that is converted into its active form once it’s in the body) of an inhibi-tor of the gelatinase enzyme. Gelatinase is associated with certain neurological disorders, such as strokes, aneurysms and traumatic brain injury.
• Researchers at the Manchester Institute of Biotech-nology in the United Kingdom have identified an enzyme in the brain that interacts with a compound for Huntington’s disease to inhibit its activity. Animal studies have shown that by switching off the enzyme’s activity through drug-binding, the enzyme is effec-tive in treating brain disorders such as Huntington’s, Alzheimer’s, and Parkinson’s.
the brain initiative
Brain Research through Advancing Innovative Neurotechnologies is a research effort launched by the Obama Administration to map the human brain and increase our understanding of how the human mind works. Approximately $100 million will be directed to government agencies, such as the National Institutes of Health, beginning in FY 2014. The BRAIN Initiative aims to accelerate the development and application of new technologies to help researchers understand the interworking’s of the brain, leading to new ways to treat and maybe one day prevent or cure diseases, such as Alzheimer’s, epilepsy and traumatic brain injury.
Public/Private Partnerships Critical to Advancing scienceCollaboration among partners in the entire medical innovation ecosystem is critical to help advance scientific understanding of some of the most complex diseases facing patients. Federal research institutions, academia, biopharmaceutical research companies and patient communities all play an important role in furthering research in the neurological field.
These evolving partnerships take many forms, for example:
• One biopharmaceutical company recently formed a research consortium to bring together several lead-ing academic research centers to coordinate their research and share results. Through this collaboration, researchers hope to accelerate their understanding of the disease and identify new approaches for targeting and treating amyotrophic lateral sclerosis (ALS).
• The Alzheimer’s Disease Neuroimaging Initiative is a collaborative effort between several federal agen-cies, non-profit organizations, and biopharmaceutical industry members. The goal of the Initiative is to track Alzheimer’s disease progression, establish quality stan-dards, and validate biomarkers to be used in clinical
trials. Data collected are made available at no cost to researchers when designing clinical trials and research projects.
• Another biopharmaceutical company is collaborating with a medical school’s neurodegenerative disease research center to screen for Alzheimer’s drug can-didates. The company is sharing their basic research with the research center’s screening assays and knowledge of the biology of the tau protein, which is thought to play a significant role in Alzheimer’s disease.
• The Coalition Against Major Diseases, a program of the Critical Path Institute, is a consortium of biophar-maceutical research companies, academic institu-tions, regulatory agencies, patient advocacy groups, research foundations, scientific associations and consultants that work collaboratively through a pre-competitive partnership to accelerate development of therapeutics for neurodegenerative diseases.
Medicines in Development neurological disorders 20136
New Neurological Medicines Approved for PatientsThe new medicines being developed today build on the medical progress seen over the last decade or so. Below are exam-ples of innovative medicines approved recently to treat some neurological conditions.
Attention-Deficit/Hyperactivity Disorder (ADHD)
• vyvanse® (lisdexamphetamine dimesylate) is the first stimulant prodrug approved for the treatment of ADHD. It is an oral biologic medicine that is thera-peutically inactive until metabolized in the body. It is intended to provide a safer, abuse-resistant and effec-tive alternative to amphetamine-based therapies for ADHD.
Alzheimer’s Disease
• Namenda® (memantine) is the first treatment ap-proved for moderate to severe Alzheimer’s disease. It was also the first in a new class of medicines called NMDA receptor antagonists to be approved for the disease. Namenda interferes with the effects of excess glutamate release—glutamate plays a key role in the neural pathways associated with learning and memory.
Multiple Sclerosis (MS)
• Tecfidera™ (dimethyl fumarate; BG-12) is a first-line oral treatment for relapsing forms of MS. It is be-lieved to treat the disease in a new way by stimulating the Nrf2 transcriptional pathway that provides a way for cells in the body to defend against inflamma-tion and neuronal death that is induced by oxidative stress. In clinical trials it was shown to reduce relapses and the development of brain lesions, as well as slow disability progression.
• Gilenya® (fingolimod) is a first-in-class oral medicine also approved to treat relapsing forms of MS. With a different mechanism of action, it binds to the S1PR lipid and traps certain white blood cells in the lymph nodes, thereby reducing the immune system’s attack on the central nervous system (CNS). By preventing the blood cells from reaching the CNS where they can damage the covering around the nerve fibers, this medicine can reduce damage to the nerve cells.
Seizures
• Potiga® (ezogabine) is a first-in-class potassium chan-nel blocker approved for the adjunctive treatment of partial-onset seizures in adults. While the exact mech-anism of action is unknown, it is believed to work by opening the potassium channels, which are thought to stabilize the neurons and reduce brain excitability.
Medicines in Development neurological disorders 2013 7
Brain Tumors4
Amyotrophic Lateral Sclerosis2
Brain Injury3
Alzheimer’s Disease and Other Dementias1
• An estimated 69,720 new cases of primary brain tumors (those that begin and tend to stay in the brain) are expected to be diagnosed in 2013, including both malignant (24,620) and non-malignant (45,100) brain tumors.
• In 2010, more than 688,096 people in the United States were living with the diagnosis of a primary brain or central ner-vous system tumor—more than 138,054 were malignant tumors and more than 550,042 were non-malignant.
• Gliomas, a broad term which includes all tumors arising from the gluey or supportive tissue of the brain, represent 30 percent of all brain tumors and 80 percent of all malignant tumors. Glioblastomas represent 17 percent of all primary brain tumors and 54 percent of all gliomas.
• An estimated 30,000 Americans may have amyotrophic lateral sclerosis (Als) at any given time, and some 5,600 people in the United States are diagnosed with ALS each year. It is estimated that ALS is responsible for nearly 2 deaths per 100,000 population annually.
• According to the U.S. Centers for Disease Control (CDC) Injury Prevention Center, the leading causes of traumatic brain in-jury (TBi) are: falls, 35.2 percent; unknown/other, 21 percent; motor vehicle, 17.3 percent; head strikes, 16.5 percent; assault, 10 percent.
• Traumatic brain injury is the leading cause of disability and death in children and adolescents in the United States. According to the CDC, the two age groups at greatest risk for TBI are ages 0-4 and 15-19. Among children ages 0 to 14 years, each year TBI results in an estimated: 2,685 deaths; 37,000 hospitalizations; and 435,000 emergency department visits.
• Approximately 1,300 U.S. children experience severe or fatal brain trauma from child abuse every year.
• An estimated 5.4 million Americans have Alzheimer’s disease (AD). Today, someone in America develops AD every 68 sec-onds. By 2050, there is expected to be one new case of AD every 33 seconds, or nearly a million new cases per year, and AD prevalence is projected to be 11 million to 16 million.
• AD is the sixth leading cause of death in the United States and the fifth leading cause of death in Americans age 65 and older.
selected facts about neurological disorders
Medicines in Development neurological disorders 20138
Epilepsy5
Headache
Huntington’s Disease9
Genetic Disorders6
• epilepsy affects nearly 3 million Americans. Epilepsy is the fourth most common neurological disorder in the United States after migraine, stroke, and Alzheimer’s disease. And it costs society $17.6 billion in direct and indirect costs.
• epilepsy strikes most often among the very young and the very old, although anyone can develop the disorder at any age. In this country, it affects more than 300,000 children under the age of 15—more than 90,000 of whom have seizures that cannot be adequately treated.
• The number of epilepsy cases in the elderly is climbing as the baby boom generation reaches retirement age. More than 300,000 adults age 65 and above have the condition.
• Headaches are the most prevalent neurological disorders and among the most frequent symptoms seen in general practice—50 percent of the general population have headaches during any given year, and more than 90 percent report a lifetime history of headache.7
• Chronic headache (a headache that occurs 15 or more days per month) affects 3 percent of the general population, and those people are the most severely disabled.7
• More than 37 million Americans suffer from migraine, with women being affected three times more often than men. This vascular headache is most commonly experienced between the ages of 15 and 55, and 70 percent to 80 percent of suffer-ers have a family history of migraine.8
• The financial cost of headache arises partly from direct treatment costs, but much more from loss of work time and produc-tivity. The annual U.S. direct medical costs attributable to migraine were estimated at $1 billion in 1999.7
• More than 15,000 Americans have Huntington’s disease (HD). At least 150,000 others have a 50 percent risk of develop-ing the disease, and thousands more of their relatives live with the possibility that they, too, might develop HD.
• More than 6,000 known genetic disorders account for a significant portion of human disease and conditions and can present themselves in several different ways, such as Down syndrome, spina bifida, and sickle cell anemia.
• Up to 4 percent of the approximately 4 millon babies born each year have a genetic disease or major birth defect. More than 20 percent of infant deaths are caused by birth defects or genetic conditions (e.g., congenital heart defects, abnormalities of the nervous system, or chromosomal abnormalities).
• Approximately 10 percent of all adults and 30 percent of children in hospitals are there due to genetically-related problems.
selected facts about neurological disorders
Medicines in Development neurological disorders 2013 9
selected facts about neurological disorders
Spasticity15
Parkinson’s Disease
Pain12
• spasticity is a common finding in multiple sclerosis (MS), stroke, traumatic brain injury (TBI), cerebral palsy (CP), and spinal cord injury (SCI). Within those patient populations, spasticity occurs at a variable rate. Studies have shown that spasticity affects between 37 percent and 78 percent of people with MS, 40 percent of those with SCI, approximately 35 percent of those with stroke, more than 90 percent with CP, and approximately 50 percent of patients with TBI.
• In the United States, 50,000-60,000 new cases of Parkinson’s disease (PD) are diagnosed each year, adding to the 1 million people who currently have PD. The U.S. Centers for Disease Control and Prevention rated complications from Parkinson’s disease as the 14th leading cause of death in the United States.13
• Men are one and a half times more likely to have Parkinson’s than women.14
• The combined direct and indirect costs of Parkinson’s, including treatment, Social Security payments and lost income from inability to work, is estimated to be nearly $25 billion per year in the United States. Medication costs for an individual person with PD average $2,500 a year, and therapeutic surgery can cost up to $100,000 dollars per patient.14
• In 2011, at least 100 million adult Americans had common chronic pain conditions.
• Recent Centers for Disease Control and Prevention (CDC) and National Center for Health Statistics (NCHS) data suggest sub-stantial rates of pain from various causes and that most people in chronic pain have multiple sites of pain. For U.S. adults report-ing pain, causes include: severe headache or migraine (16.1 percent), low back pain (28.1 percent), neck pain (15.1 percent), knee pain (19.5 percent), shoulder pain (9.0 percent), finger pain (7.6 percent), and hip pain (7.1 percent).
• Pain is a significant public health problem that costs society at least $560-$635 billion annually (an amount equal to about $2,000.00 for everyone living in the United States).
Muscular Dystrophy10
Multiple Sclerosis11
• The incidence rates of muscular dystrophies (MD) vary depending on the specific type. Duchenne MD is the most com-mon MD and is sex-linked, with an inheritance pattern of 1 case per 3,500 live male births. Becker MD is the second most common form, with an incidence of 1 case per 30,000 live male births. Other types of MD are rare. For example, limb-girdle dystrophy occurs in only 1.3 percent of patients with MDs.
• Some 350,000 to 500,000 patients suffer from multiple sclerosis (Ms) in the United States. Most cases are diagnosed between 20 and 50 years.
Medicines in Development neurological disorders 201310
selected facts about neurological disorders
Sources:
1. Alzheimer’s Association, www.alz.org
2. ALS Association, www.alsa.org
3. Brain Injury Association of America, www.biausa.org
12. The American Academy of Pain Medicine, www.painmed.org
13. National Parkinson Foundation, www.parkinson.org
14. Parkinson Disease Foundation, www.pdf.org
15. Medscape, www.medscape.org
16. National Spinal Cord Injury Statistical Center, www.nscisc.uab.edu
17. American Heart Association, www.heart.org/advocacy
Spinal Cord Injury16
Stroke17
• The estimated annual incidence of spinal cord injury (sCi), not including those who die at an accident scene, is approximate-ly 12,000 new cases each year. The estimated number of people living today with SCI ranges from 238,000 to 332,000.
• The costs for those living with sCi vary greatly according to injury severity. For example, the lifetime direct medical costs are more than $4.6 million for someone with high quadriplegia injured at age 25, compared with the more than $1.5 million it will cost someone injured at the same age who has incomplete motor functions.
• stroke is the nation’s fourth leading killer and a leading cause of long-term disability. Each year, about 795,000 people suf-fer a stroke. On average, someone in the United States has a stroke every 40 seconds, and every 4 minutes someone dies from one.
• Deaths from ischemic stroke, the most common type, are predicted to nearly double between 2000 and 2032. Conserva-tive estimates forecast that ischemic stroke alone will cost the United States $2.2 trillion from 2005 to 2050.
• The direct and indirect costs of stroke in the United States for 2009 were $38.6 billion, with an average per person expen-diture of $6,018.
Medicines in Development neurological disorders 2013 11
medicines in development for neurological disorders
*For more information about a specific medicine or company in the report, please use the website provided.
Alzheimer’s Disease
Product Name Sponsor Indication Development Phase*
AAB-003/PF-05236812(beta-amyloid protein inhibitor mAB)
Janssen Alzheimer ImmunotherapySouth San Francisco, CAPfizerNew York, NY
--------------------------------------epilepsy in patients 2-17 years of age (adjunctive therapy), primary gener-alized tonic clonic seizures (adjunctive therapy)
Medicines in Development neurological disorders 2013 49
Glossary
Alzheimer’s disease—The most com-mon form of dementia, characterized by progressive and chronic deterioration of cognitive functions, including memory, thinking and reasoning. Early manifes-tations include forgetfulness, impaired ability to focus, and changes in mood and personality. As the disease progresses, there is a loss of computational ability, in addition to word-finding problems and dif-ficulty with ordinary activities. Ultimately, the disease leads to severe memory loss, complete disorientation, social withdrawal, loss of independence, and is fatal.
amyotrophic lateral sclerosis (Als)—Also known as Lou Gehrig’s disease, the most common of the motor neuron dis-eases, a group of rare disorders in which the nerves that control muscular activity degenerate within the brain and spinal cord causing weakness and wasting of the muscles.
application submitted—An application for marketing has been submitted by the company to the Food and Drug Admin-istration (FDA).
attention deficit/hyperactivity disorder (ADHD)—ADHD is a complex neurologi-cal impairment that results in an over-active behavior pattern and a difficulty concentrating. While it primarily affects children, a growing number of adults are being diagnosed with the disorder. Boys are affected about three times as often as girls. Children with ADHD are fidgety, impulsive, reckless, irritable, emotionally immature and sometimes aggressive. Because their attention span is short, they do not conform to orderly routine. ADHD often leads to anti-social acts and difficulty learning, although IQ is normal. No definite cause has been established, but some researchers now believe genet-ics plays a role.
cerebral palsy—A general term for disor-ders of movement and posture resulting from damage to the brain in pregnancy, during birth, in the newborn period or in early childhood.
dementia—Degeneration of central nervous functions, such as memory and
learning capacity. The natural decline of these functions with age is grossly exag-gerated in dementia.
Duchenne muscular dystrophy—An inherited disorder that involves rapidly worsening muscle weakness. Other muscular dystrophies get worse much more slowly. Duchenne’s is caused by a defective gene. Because of the way the disease is inherited, males are more likely to develop symptoms than are women.
epilepsy—Recurrent seizures—transient neurological abnormalities caused by abnormal electrical activity in the brain—or temporary alteration in one or more brain functions. Seizures are a symptom of brain dysfunction and can result from a wide variety of diseases or injury.
Fast Track—A process designed to facilitate the development and expedite the review of drugs to treat serious diseases and fill an unmet medical need. The status is assigned by the U.S. Food and Drug Administration. The purpose is to get important new drugs to the patient earlier. Fast Track addresses a broad range of serious diseases. Gener-ally, determining factors include whether the drug will have an impact on such factors as survival, day-to-day function-ing, or the likelihood that the disease, if left untreated, will progress from a less severe condition to a more serious one. Filling an unmet medical need is defined as providing a therapy where none exists or providing a therapy which may be potentially superior to existing therapy. Once a drug receives Fast Track designa-tion, early and frequent communication between the FDA and a drug company is encouraged throughout the entire drug development and review process. The frequency of communication assures that questions and issues are resolved quickly, often leading to earlier drug approval and access by patients.
Friedreich’s ataxia—An inherited disease that causes progressive dam-age to the nervous system resulting in symptoms ranging from gait disturbance and speech problems to heart disease. “Ataxia,” which refers to coordination
problems such as clumsy or awkward movements and unsteadiness, occurs in many different diseases and conditions.
glioblastoma multiforme—The most common and most malignant of the as-trocytomas. The tumor grows so fast that it increases pressure in the brain, produc-ing headaches, slowed thinking, and if severe enough, sleepiness and coma.
glioma—A type of brain tumor arising from the supporting glial cells within the brain. Gliomas make up about 60 percent of all primary brain tumors.
Huntington’s disease—Huntington’s chorea is an uncommon, inherited dis-ease in which degeneration of the basal ganglia (structures deep in the brain) results in chorea (rapid, jerky, involuntary movements) and dementia (progressive mental impairment).
lennox-Gastaut syndrome—Character-ized by seizures and mental retardation in infants and young children.
metastases/metastatic—Areas of sec-ondary cancer that have spread from the primary or original cancer site.
migraine—Severe headache result-ing from an abnormal dilation of blood vessels deep within the brain. It can last from two hours to several days and is often accompanied by nausea, vomiting and sensitivity to noise and/or light.
multiple sclerosis (Ms)—Progressive disease of the central nervous system in which scattered patches of the covering of nerve fibers (myelin) in the brain and spinal cord are destroyed. Symptoms range from numbness and tingling to paralysis and incontinence.
muscular dystrophy—Inherited muscu-lar disorder of unknown cause in which muscle fibers slowly degenerate. Duch-enne MD is the most common type.
myasthenia gravis—A chronic autoim-mune neuromuscular disease character-ized by varying degrees of weakness of the skeletal (voluntary) muscles of the body. The hallmark of myasthenia gravis
Medicines in Development Neurological Disorders 201350
Glossary
is muscle weakness that increases during periods of activity and improves after periods of rest.
neuroblastoma—A tumor of the adrenal glands or sympathetic nervous system (the part of the nervous system respon-sible for certain automatic body func-tions, such as the control of heart rate). Neuroblastomas are the most common extracranial (outside the skull) solid tumors of childhood.
neuropathic pain—Caused by disease, inflammation, or damage to the periph-eral nerves, which connect the central nervous system (brain and spinal cord) to the sense organs, muscles, glands, and internal organs.
neuropathy—Disease, inflammation, or damage to the peripheral nerves, which connect the central nervous system to the sense organs, muscles, glands, and internal organs.
Orphan Drug—A drug to treat a disease that has a patient population of 200,000 or less, or a disease that has a patient population of more than 200,000 and a developmental cost that will not be re-covered from sales in the United States.
Parkinson’s disease—Chronic neurologic disease of unknown cause, characterized by tremors, rigidity and an abnormal gait.
Phase 0—First-in-human trials conduct-ed in accordance with FDA’s 2006 guid-ance on exploratory Investigational New Drug (IND) studies designed to speed up development of promising drugs by es-tablishing very early whether the tested compound behaves in human subjects as was anticipated from preclinical studies.
Phase I—Safety testing and pharmaco-logical profiling in humans.
Phase II—Effectiveness testing in humans.
Phase III—Extensive clinical trials in humans.
postherpetic neuralgia—A burning pain that may recur at the site of an attack of shingles months or even years after the illness.
prodrug—An inactive medicine that becomes active inside the body through metabolic processes. Prodrugs can be used to improve how a specific medi-cine is absorbed, distributed, metabo-lized or excreted.
restless legs syndrome—Restless legs syndrome is an overwhelming urge to move the legs usually caused by uncomfortable or unpleasant sensations in the legs.
spinal cord injury—Damage to the spinal cord which can cause loss of sensation, muscle weakness or paralysis.
stroke—Usually caused by atheroscle-rosis. It results in death or serious brain damage, such as paralysis or loss of speech. An ischemic stroke is caused by blocked or narrowed arteries that prevent sufficient blood and oxygen from reaching the brain.
Tourette syndrome (TS)—A neurologi-cal disorder characterized by repetitive, involuntary movements and vocalizations called tics. The early symptoms of TS are typically noticed first in childhood, with the average onset between the ages of 3 and 9. TS occurs in people from all ethnic groups; males are affected about three to four times more often than females. It is estimated that 200,000 Americans have the most severe form of TS, and as many as 1 in 100 exhibit milder and less complex symptoms such as chronic motor or vocal tics. Although TS can be a chronic condition with symptoms lasting a lifetime, most people with the condition experience their worst tic symptoms in their early teens, with improvement occurring in the late teens and continuing into adulthood.
The content of this report has been obtained through public, government and industry sources, and the Adis “R&D Insight” data-base based on the latest information. Report current as of July 18, 2013. The medicines in this report include medicines being developed by U.S. based companies conducting trials in the United States and abroad, PhRMA-member companies conducting trials in the United States and abroad, and foreign companies conducting clinical trials in the United States. The information in this report may not be comprehensive. For more specific information about a particular product, contact the individual company directly or go to www.clinicaltrials.gov. The entire series of Medicines in Development is available on PhRMA’s website.
A publication of PhRMA’s Communications & Public Affairs Department. (202) 835-3460
Pharmaceutical Research and Manufacturers of America • 950 F Street, NW, Washington, DC 20004
the drug discovery, development and approval process
The U.S. system of new drug approvals is perhaps the most rigorous in the world.
It takes 10-15 years, on average, for an experi-mental drug to travel from lab to U.S. patients, according to the Tufts Center for the Study of Drug Development. Only five in 5,000 com-pounds that enter preclinical testing make it to human testing. And only one of those five is approved for sale.
On average, it costs a company $1.2 billion, including the cost of failures, to get one new medicine from the laboratory to U.S. patients, according to a recent study by the Tufts Center for the Study of Drug Development.
Once a new compound has been identified in the laboratory, medicines are usually developed as follows:
Preclinical Testing. A pharmaceutical company conducts laboratory and animal studies to show biological activity of the compound against the targeted disease, and the compound is evalu-ated for safety.
Investigational New Drug Application (IND). After completing preclinical testing, a com-pany files an IND with the U.S. Food and Drug Administration (FDA) to begin to test the drug
in people. The IND shows results of previous experiments; how, where and by whom the new studies will be conducted; the chemical structure of the compound; how it is thought to work in the body; any toxic effects found in the animal studies; and how the compound is manufac-tured. All clinical trials must be reviewed and ap-proved by the Institutional Review Board (IRB) where the trials will be conducted. Progress reports on clinical trials must be submitted at least annually to FDA and the IRB.
Clinical Trials, Phase I—Researchers test the drug in a small group of people, usually between 20 and 80 healthy adult volunteers, to evaluate its initial safety and tolerability profile, deter-mine a safe dosage range, and identify potential side effects.
Clinical Trials, Phase II—The drug is given to volunteer patients, usually between 100 and 300, to see if it is effective, identify an optimal dose, and to further evaluate its short-term safety.
Clinical Trials, Phase III—The drug is given to a larger, more diverse patient population, often involving between 1,000 and 3,000 patients (but sometime many more thousands), to gener-
ate statistically significant evidence to confirm its safety and effectiveness. They are the lon-gest studies, and usually take place in multiple sites around the world.
New Drug Application (NDA)/Biologic License Application (BLA). Following the completion of all three phases of clinical trials, a company analyzes all of the data and files an NDA or BLA with FDA if the data successfully demonstrate both safety and effectiveness. The applications contain all of the scientific information that the company has gathered. Applications typically run 100,000 pages or more.
Approval. Once FDA approves an NDA or BLA, the new medicine becomes available for physi-cians to prescribe. A company must continue to submit periodic reports to FDA, including any cases of adverse reactions and appropriate quality-control records. For some medicines, FDA requires additional trials (Phase IV) to evaluate long-term effects.
Discovering and developing safe and effective new medicines is a long, difficult, and expensive process. PhRMA member companies invested an estimated $48.5 billion in research and develop-ment in 2012.
Developing a new medicine takes an average of 10-15 years; For every 5,000-10,000 compounds in the pipeline, only 1 is approved.
The Drug Development and Approval Process
PRE-
DIS
COV
ERY
DRUG DISCOVERY PRECLINICAL CLINICAL TRIALS FDA REVIEW LG-SCALE MFG
3 – 6 Y E A RS 6 – 7 Y E A RS 0. 5 – 2 Y E A RS
100 – 300 1,000 – 3,00020 –80
PHASE 2
PHASE 3
PHASE 1
IND
SU
BM
ITTE
D
ND
A S
UB
MIT
TED
PHA
SE 4
: PO
ST-M
AR
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ING
SU
RVEI
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NUMBER OF VOLUNTEERS
ONE FDA-APPROVED
DRUG
5,000 – 10,000
COMPOUNDS
250 5
Drug Discovery and Development: A LONG, RISKY ROAD