2013 REPORT 7 2 11 51

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apy for the treatment of the treatment for apy of the effects reverse to apy ...... dicine that prompts the immunedicine that prompts ase Facts A me by affected neurons protect to system ALS. Gene ther . Alzheimer’s Gene ther Parkinson’s disease. Parkinson’s Medicines in Development Medicines Glossary Development/ Process Approval Contents Issues Key Dise

• • Other medicines in development target in development Other medicines (ALS), sclerosis lateral amyotrophic braindisease, injuries, Huntington’s and palsy, cerebral injury, new promising many Among the . are: in development medicines • by being developed medicines The new companies research biopharmaceutical understanding of the a growing reflect underlying mechanisms of neurological which fuels scientific progress disorders, - These medi research. and pharmaceutical - effec patients hope that more cines offer soon be available. may treatments tive

pinal Cord and Nerves pinal Cord S dicines for , multiple sclerosis, dicines for dicines for and sei- epilepsy dicines for dicines for , includ- headache, dicines for 2 medicines for brain tumors—nearly tumors—nearly brain for 2 medicines 2 medicines for Alzheimer’s disease, disease, Alzheimer’s for 2 medicines —100 million for 2 medicines 7 medicines for Parkinson’s disease, disease, Parkinson’s for 7 medicines 3 million Americans. zures, which impact more than which impact more zures, as 1 million as many which affects Americans. 25 me that affects a condition ing , million people. 37 than more 70,000 Americans are diagnosed Americans are 70,000 with a primary tumor. year brain each 38 me which afflicts 500,000 an estimated Americans. 28 me 2 8 than 5 million which afflicts more Americans. 8 pain. chronic adults experience U.S. 6

• • • • • • Neurological disorders—such as epi- disorders—such Neurological and Parkinson’s multiple sclerosis lepsy, and suffering pain disease—inflict great and every on patients and their families, billions economy the U.S. costs year research Biopharmaceutical of dollars. 444 new developing are companies neu- and treat prevent to medicines in The medicines disorders. rological either in human clinical are development and Food at the trials or under review include: They Drug Administration. • Biopharmaceutical Companies Researching and Researching Companies Biopharmaceutical for Medicines 450 Nearly Developing Disorders Neurological t n e m

27

Parkinson’s 82 Pain 38 Develop n

28

Multiple Sclerosis Multiple

es i Epilepsy n i 62 c i

Phase I Phase II Application Submitted Phase III

d s Brain Tumors Brain

82

Medicines in Development in Development Medicines Disorders Neurological For

presented by america’s biopharmaceutical research companies biopharmaceutical research america’s presented by Neurological Disorders Neurological A Report of the Brain, on Disorders Me Alzheimer’ Innovative Medicines in the Pipeline orders such as Duchenne muscular dystrophy (DMD). In DMD, DNA deletions cause mutations in important Of the 444 medicines in development in the United States genes that encode for dystrophin, a structural pro- listed in this report (see page 11), many present innovative tein found in normal muscle. The loss of this protein new ways to target . Some of them include: causes muscle fibers to disintegrate faster than they can be regenerated. One medicine in development • Gene Therapy to Restore Neuronal Function in targets restoration of dystrophin function and, as dys- Alzheimer’s—A gene therapy for the treatment trophin expression increases, there have been demon- of Alzheimer’s disease in clinical trials is designed strated improvements in patients’ ability to walk. to deliver nerve growth factor (NGF) to the brain. NGF is a naturally occurring protein important for • Gene Therapy as a Possible Approach for Parkinson’s neuron survival. The gene treatment is injected into Disease—Inserting genes into cells can alter the im- the brain region where neuron degeneration occurs pact the genes have on the proteins that are involved in Alzheimer’s disease. It is thought that the result- in a particular disease. These genes might alter or ing sustained expression of NGF in the neurons can replace a mutated gene or produce a new thera- restore their lost function, leading to memory and peutic protein entirely. In Parkinson’s disease, there cognition improvement. are a number of treatments addressing the disease’s symptoms, but none that replace the lost nerve cells • Targeted RNAi Therapy Approach for Duchenne resulting from Parkinson’s or that would stop disease Muscular Dystrophy—In clinical trials, RNAi therapies progression. More than one gene therapy in clinical have shown potential in treating neuromuscular dis- trials uses an adeno-associated virus (AAV) as a vector

Medicines in Development for Neurological Disorders By Disease and Phase

Some medicines are listed in more than one category

Alzheimer’s Disease 82 Application Submitted Amyotrophic Lateral Sclerosis (ALS) 8 Phase III Attention-Deficit/Hyperactivity Disorder 19 Phase II Brain Injury 8 Phase I Brain Tumors 62 Epilepsy 28

Genetic Disorders 14

Headache 25

Huntington’s Disease 7

Multiple Sclerosis 38

Muscular Dystrophy 7

Pain 82

Parkinson’s Disease 27

Spasticity 6

Spinal Cord Injury 9

Stroke 19

Other 33

2 Medicines in Development Neurological Disorders 2013 to deliver neurturin to restore cells damaged in Parkinson’s patients and to protect them from fur- ther degeneration; these inactivated viruses pres- OFALZHEIMER’S ent a safe way to get these important therapeutic IMPORTANCE TREATMENT options to patients.

• A LS: Fighting a Devastating Disease—ALS, or Lou Gehrig’s disease, is a progressive neurode- generative disease that causes the brain to lose 5 control over body movement, ultimately resulting MILLION in paralysis and death. The one drug approved to AMERICANS treat ALS can modestly slow progression of the disease, but new treatments are needed. As our scientific understanding of the disease has grown, ARE LIVING WITH ALZHEIMER’S DISEASE 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 15 by ALS. MILLION AMERICANS

BY 2050, THE NUMBER OF PATIENTS COULD TRIPLE Alzheimer’s: WITHOUT EFFECTIVE TREATMENT 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 2013 2050 growing. Existing medicines are able to treat the symptoms of the disease but cannot slow, $ $ prevent, or reverse the progressive . 203 1.2 Disease-modifying treatments that could BILLION TRILLION delay the onset of the disease could reduce the cost of care of Alzheimer’s patients in 2050 by $447 billion. Researchers continue ALZHEIMER’S COSTS SOCIETY $203 BILLION to unravel the mysteries of the disease AND COULD INCREASE TO $1.2 TRILLION BYBY 20502050 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 5 50 are thought to contribute to the death of 447 YEARS FEWER BILLION nerve cells. One medicine in development DELAYED = VICTIMS + SAVED has shown promise in reducing both brain ONSET plaques and tangles. A gene therapy also in clinical trials is being explored to restore lost DELAYING DISEASE ONSET BY 5 YEARS COULD RESULT IN neuron function. 50% FEWER PATIENTS/SAVEPATIENTS/SAVE $447 BILLION BYBY 20502050

Medicines in Development Neurological Disorders 2013 3 Advancing Biomedical Science Breakthrough Research in

Over the past decade, scientific advances and new technolo- Neurological Disorders gies have dramatically changed how medicines are discov- Early research discoveries often fuel the drug development ered. This new information is critical to the development of pathways that biopharmaceutical company researchers un- new treatments for neurological disorders. Greater knowl- dertake. These discoveries help researchers target a specific edge of how diseases work at the genetic and molecular level disease through certain mechanisms that may have been has allowed researchers to pursue new targets for therapy unknown before. Some noteworthy recent scientific discover- and better predict how certain biopharmaceuticals will affect ies in the field of include: specific subpopulations of patients. • Researchers at Mount Sinai Medical Center found • Bioinformatics —Bioinformatics use systems and 10 genes that account for half of the genetic risk for mathematical models to advance the scientific un- Alzheimer’s. derstanding of living systems. At its simplest level, bioinformatics involves the creation and maintenance • Research at the National Institutes of Health found of biological databases, including DNA sequences. that a protein linked with some early-onset Parkin- son’s disease cases regulates how the body processes • Biomarkers —Every disease leaves a signature of dietary fats. The study suggests there could be a link molecular “biomarkers” in our body—genes that turn between the defective protein and early-onset Parkin- on and off or proteins released into the bloodstream. son’s disease. Biomarkers measured in blood and other samples can tell us the state of our health and how we might • Scientists at the University of Chicago have uncovered respond to treatment. a previously unknown process of protein production where a single gene can create two separate proteins • Molecular Targeting—The idea behind molecular from the same messenger RNA simultaneously. They targeting is to design that specifically attack the believe this discovery will open the door for new molecular pathways that cause disease without dis- research into therapies for neurological disorders. rupting the normal functions in our cells and tissues. • Research at the University of Missouri suggests that • Nanotechnology —You can’t see it, but soon it will be two identical neurons can reach the same electrical everywhere. Nanotechnology is the science of build- activity in different ways and could help doctors in ing microscopic devices at the molecular and atomic treating patients with epilepsy. levels. In medicine, nanotechnology may also be used to help diagnose and treat diseases. • Two separate research groups have identified a muta- tion on the TREM2 gene that may increase a person’s • Personalized Medicine—The sequencing of the chance of developing late-stage Alzheimer’s disease human genome produced a “map” of the human by three to five times. genes in DNA. This new genetic knowledge opens up the possibility of developing “targeted” therapies • While studying at PennVet, a researcher discovered for people with specific gene sequences, and it can the gene responsible for Alexander disease, a rare, help physicians choose the best treatments based on genetic neurological disorder where the white matter individual genetic, lifestyle, and environmental factors. in the brain is destroyed and Rosenthal fibers form causing both mental and physical declines.

4 Medicines in Development Neurological Disorders 2013 • At the University of Notre Dame, researchers have created a prodrug (an inactive drug that is converted The BRAIN Initiative into its active form once it’s in the body) of an inhibi- Brain Research through Advancing Innovative tor of the gelatinase enzyme. Gelatinase is associated Neurotechnologies is a research effort launched with certain neurological disorders, such as , by the Obama Administration to map the human aneurysms and traumatic brain injury. brain and increase our understanding of how the • Researchers at the Manchester Institute of Biotech- human mind works. Approximately $100 million nology in the United Kingdom have identified an will be directed to government agencies, such as enzyme in the brain that interacts with a compound the National Institutes of Health, beginning in FY for Huntington’s disease to inhibit its activity. Animal 2014. The BRAIN Initiative aims to accelerate the studies have shown that by switching off the enzyme’s development and application of new technologies activity through drug-binding, the enzyme is effec- to help researchers understand the interworking’s tive in treating brain disorders such as Huntington’s, of the brain, leading to new ways to treat and Alzheimer’s, and Parkinson’s. maybe one day prevent or cure diseases, such as Alzheimer’s, epilepsy and traumatic brain injury.

Public/Private Partnerships Critical to Advancing Science

Collaboration among partners in the entire medical innovation trials. Data collected are made available at no cost to ecosystem is critical to help advance scientific understanding researchers when designing clinical trials and research of some of the most complex diseases facing patients. Federal projects. research institutions, academia, biopharmaceutical research companies and patient communities all play an important role • Another biopharmaceutical company is collaborating in furthering research in the neurological field. with a medical school’s neurodegenerative disease research center to screen for Alzheimer’s drug can- These evolving partnerships take many forms, for example: didates. The company is sharing their basic research with the research center’s screening assays and • One biopharmaceutical company recently formed a knowledge of the biology of the tau protein, which research consortium to bring together several lead- is thought to play a significant role in Alzheimer’s ing academic research centers to coordinate their disease. research and share results. Through this collaboration, researchers hope to accelerate their understanding of • The Coalition Against Major Diseases, a program of the disease and identify new approaches for targeting the Critical Path Institute, is a consortium of biophar- and treating amyotrophic lateral sclerosis (ALS). maceutical research companies, academic institu- tions, regulatory agencies, patient advocacy groups, • The Alzheimer’s Disease Neuroimaging Initiative is research foundations, scientific associations and a collaborative effort between several federal agen- consultants that work collaboratively through a pre- cies, non-profit organizations, and biopharmaceutical competitive partnership to accelerate development of industry members. The goal of the Initiative is to track therapeutics for neurodegenerative diseases. Alzheimer’s disease progression, establish quality stan- dards, and validate biomarkers to be used in clinical

Medicines in Development Neurological Disorders 2013 5 New Neurological Medicines Multiple Sclerosis (MS) Approved for Patients • Tecfidera ™ (dimethyl fumarate; BG-12) is a first-line The new medicines being developed today build on the medical oral treatment for relapsing forms of MS. It is be- progress seen over the last decade or so. Below are exam- lieved to treat the disease in a new way by stimulating ples of innovative medicines approved recently to treat some the Nrf2 transcriptional pathway that provides a way neurological conditions. for cells in the body to defend against inflamma- tion and neuronal death that is induced by oxidative Attention-Deficit/Hyperactivity Disorder (ADHD) stress. In clinical trials it was shown to reduce relapses and the development of brain lesions, as well as slow • Vyvanse® (lisdexamphetamine dimesylate) is the first disability progression. stimulant prodrug approved for the treatment of • Gilenya ® (fingolimod) is a first-in-class oral medicine ADHD. It is an oral biologic medicine that is thera- also approved to treat relapsing forms of MS. With peutically inactive until metabolized in the body. It is a different mechanism of action, it binds to the S1PR intended to provide a safer, abuse-resistant and effec- lipid and traps certain white blood cells in the lymph tive alternative to -based therapies for nodes, thereby reducing the immune system’s attack ADHD. on the central (CNS). By preventing the blood cells from reaching the CNS where they Alzheimer’s Disease can damage the covering around the nerve fibers, this medicine can reduce damage to the nerve cells. • Namenda ® () 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 antagonists to be approved for • Potiga ® (ezogabine) is a first-in-class potassium chan- the disease. Namenda interferes with the effects of nel blocker approved for the adjunctive treatment of excess glutamate release—glutamate plays a key role partial-onset seizures in adults. While the exact mech- in the neural pathways associated with learning and anism of action is unknown, it is believed to work by memory. opening the potassium channels, which are thought to stabilize the neurons and reduce brain excitability.

6 Medicines in Development Neurological Disorders 2013 Selected Facts about Neurological Disorders

Alzheimer’s Disease and Other Dementias1

• 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.

Amyotrophic Lateral Sclerosis2

• 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.

Brain Injury3

• 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.

Brain Tumors4

• 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.

Medicines in Development Neurological Disorders 2013 7 Selected Facts about Neurological Disorders

Epilepsy5

• E pilepsy 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.

• E pilepsy 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.

Genetic Disorders6

• 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.

Headache

• 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 ofheadache 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

Huntington’s Disease9

• 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.

8 Medicines in Development Neurological Disorders 2013 Selected Facts about Neurological Disorders

Muscular Dystrophy10

• 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.

Multiple Sclerosis11

• 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.

Pain12

• 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).

Parkinson’s Disease

• 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. 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

Spasticity15

• S pasticity 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.

Medicines in Development Neurological Disorders 2013 9 Selected Facts about Neurological Disorders

Spinal Cord Injury16

• 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.

Stroke17

• S troke 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.

Sources:

1. Alzheimer’s Association, www.alz.org 2. ALS Association, www.alsa.org 3. Brain Injury Association of America, www.biausa.org 4. American Brain Tumor Association, www.abta.org 5. Epilepsy Foundation, www.epilepsyfoundation.org 6. NetWellness from Case Western Reserve University, Ohio State University and University of Cincinnati, www.netwellness.org 7. International Association for the Study of Pain, www.iasp-pain.org 8. National Headache Foundation, www.headaches.org 9. National Institute of Neurological Disorders and Stroke, www.ninds.nih.gov 10. E-Medicine, www.emedicine.medscape.com 11. Multiple Sclerosis Foundation, www.msfocus.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

10 Medicines in Development Neurological Disorders 2013 Medicines in Development for Neurological Disorders

Alzheimer’s Disease

Product Name Sponsor Indication Development Phase*

AAB-003/PF-05236812 Janssen Alzheimer Immunotherapy Alzheimer’s disease Phase I (beta-amyloid protein inhibitor South San Francisco, CA www.janssenrnd.com mAB) Pfizer www.pfizer.com New York, NY

ABT-126 AbbVie Alzheimer’s disease Phase II (alpha-7-NNR antagonist) North Chicago, IL www.abbvie.com

ABT-288 AbbVie Alzheimer’s disease Phase II completed (neurotransmitter receptor North Chicago, IL www.abbvie.com modulator)

ABT-384 AbbVie Alzheimer’s disease Phase II completed North Chicago, IL (see also other) www.abbvie.com

ABT-957 AbbVie Alzheimer’s disease Phase I (calpain inhibitor) North Chicago, IL www.abbvie.com

AC-1204 Accera mild to moderate Alzheimer’s disease Phase II/III (glucose stimulant) Broomfield, CO www.accerapharma.com

AD02 vaccine Affiris Alzheimer’s disease Phase II (amyloid-beta protein inhibitor) Vienna, Austria www.affiris.com GlaxoSmithKline www.gsk.com Rsch. Triangle Park, NC

AD03 vaccine Affiris Alzheimer's disease Phase I (amyloid-beta protein inhibitor) Vienna, Austria www.affiris.com GlaxoSmithKline www.gsk.com Rsch. Triangle Park, NC

APH-0703 Aphios Corporation Alzheimer’s disease Phase I/II (protein kinase C stimulant) Woburn, MA www.aphios.com

ARC029 Archer Pharmaceuticals Alzheimer’s disease Phase I/II (nilvadipine) Sarasota, FL www.archerpharma.com

ARC031 Archer Pharmaceuticals Alzheimer’s disease Phase I (soluble amyloid reducing/clearing Sarasota, FL www.archerpharma.com agent)

ASP0777 Astellas Pharma US Alzheimer’s disease Phase I Northbrook, IL www.astellas.com

*For more information about a specific medicine or company in the report, please use the website provided.

Medicines in Development Neurological Disorders 2013 11 Medicines in Development for Neurological Disorders

Alzheimer’s Disease

Product Name Sponsor Indication Development Phase

AVN 101 Avineuro Pharmaceuticals Alzheimer’s disease Phase II ( 5-HT6 receptor San Diego, CA www.avineuro.com antagonist)

AVN 322 Avineuro Pharmaceuticals Alzheimer’s disease Phase I (serotonin 6 ) San Diego, CA www.avineuro.com

AVN 397 Avineuro Pharmaceuticals Alzheimer’s disease Phase II San Diego, CA www.avineuro.com

AVP-923 Avanir Pharmaceuticals agitation in Alzheimer’s disease Phase II (/ Aliso Viejo, CA (see also pain) www.avanir.com fixed-dose combination)

AZD1446 AstraZeneca Alzheimer’s disease Phase I (alpha4/beta2 neuronal nicotinic Wilmington, DE www.astrazeneca.com receptor ) Targacept www.targacept.com Winston-Salem, NC

AZD2184 Navidea Pharmaceuticals Alzheimer’s disease (diagnosis) Phase I (PET enhancer) Dublin, OH www.navidea.com

AZD2995 Navidea Pharmaceuticals Alzheimer’s disease (diagnosis) Phase I (PET enhancer) Dublin, OH www.navidea.com

AZD3293 Astex Pharmaceuticals Alzheimer’s disease Phase I (beta secretase) Dublin, CA www.astx.com AstraZeneca www.astrazeneca.com Wilmington, DE

AZD5213 AstraZeneca Alzheimer’s disease Phase II (histamine-3 receptor antagonist) Wilmington, DE www.astrazeneca.com

BACE inhibitor Janssen Pharmaceuticals Alzheimer’s disease Phase I Titusville, NJ www.janssenpharmaceuticalsinc.com Shionogi www.shionogi.com Florham Park, NJ

BAN2401 Eisai early stage Alzheimer’s disease Phase II (amyloid beta-protein inhibitor) Woodcliff Lake, NJ www.eisai.com

BIIB037 Biogen Idec Alzheimer’s disease Phase I (human anti-amyloid beta mAb) Weston, MA www.biogenidec.com

bisnorcymserine QR Pharma Alzheimer’s disease Phase I (BNC) Berwyn, PA www.qrpharma.com

BMS-241027 Bristol-Myers Squibb Alzheimer’s disease Phase I (microtubule stabilizer) Princeton, NJ www.bms.com

12 Medicines in Development Neurological Disorders 2013 Medicines in Development for Neurological Disorders

Alzheimer’s Disease

Product Name Sponsor Indication Development Phase

CAD106 Pharmaceuticals Alzheimer’s disease Phase II (amyloid beta-protein inhibitor) East Hanover, NJ www.novartis.com

CERE-110 Ceregene Alzheimer’s disease Phase II (AAV-NGF) San Diego, CA www.ceregene.com

crenezumab Genentech Alzheimer’s disease Phase II (anti-amyloid-beta mAb) South San Francisco, CA www.gene.com

davunetide intranasal Allon Therapeutics Alzheimer’s disease Phase II Vancouver, Canada (see also Parkinson’s, other) www.allontherapeutics.com

/memantine Adamas Pharmaceuticals moderate to severe Alzheimer’s Phase II extended release Emeryville, CA disease www.adamaspharma.com (fixed-dose combination) Forest Laboratories www.frx.com New York, NY

DSP-8658 Sunovion Pharmaceuticals Alzheimer’s disease Phase I (PPAR alpha/gamma agonist) Marlborough, MA www.sunovion.com

E2212 Eisai Alzheimer’s disease Phase I completed (amyloid precursor protein Woodcliff Lake, NJ www.eisai.com secretase modulator)

E2609 Eisai Alzheimer’s disease Phase I (BACE1 protein inhibitor) Woodcliff Lake, NJ www.eisai.com

ELND005 Speranza Therapeutics neuropsychiatric symptoms in Phase II Dublin, Ireland Alzheimer’s disease (Fast Track)

EVP-0962 EnVivo Pharmaceuticals Alzheimer’s disease Phase II (gamma secretase modulator) Watertown, MA www.envivopharma.com

EVP-6124 EnVivo Pharmaceuticals Alzheimer’s disease Phase II (alpha7 nicotinic acetylcholine Watertown, MA www.envivopharma.com receptor agonist)

Exebryl-1® ProteoTech Alzheimer’s disease Phase I amyloid-beta-protein/tau protein Kirkland, WA www.proteotech.com inhibitor

F-18 T808 Siemens Medical Solutions Alzheimer’s disease (diagnosis) Phase 0 (PET imaging) Malvern, PA www.usa.healthcare.siemens.com

F18-florbetaben IBA Molecular Alzheimer’s disease (diagnosis) application submitted (molecular imaging agent) Dulles, VA www.iba-molecular.com Piramal Healthcare www.piramal.com Mumbai, India

Medicines in Development Neurological Disorders 2013 13 Medicines in Development for Neurological Disorders

Alzheimer’s Disease

Product Name Sponsor Indication Development Phase

F18-flutemetamol GE Healthcare Alzheimer’s disease (diagnosis) application submitted (PET imaging agent) Waukesha, WI www.gehealthcare.com

gantenerumab Roche early stage Alzheimer’s disease Phase II/III (RG1450) Nutley, NJ www.roche.com

GM6 Genervon Biopharmaceuticals Alzheimer’s disease Phase I (peptide therapeutic) Pasadena, CA (see also amyotrophic lateral sclerosis, www.genervon.com multiple sclerosis, Parkinson’s, spinal cord injury, stroke)

GSK2647544 GlaxoSmithKline Alzheimer’s disease Phase I (Lp-PLA2 inhibitor) Rsch. Triangle Park, NC www.gsk.com

GSK2981710 GlaxoSmithKline Alzheimer’s disease Phase I (medium chain triglycerides) Rsch. Triangle Park, NC www.gsk.com

HPP-854 High Point Pharmaceuticals Alzheimer’s disease Phase I (BACE1 inhibitor) High Point, NC www.highpointpharma.com

JNJ-54861911 Janssen Research & Development Alzheimer’s disease Phase I Raritan, NJ www.janssenrnd.com

KU-046 Kareus Therapeutics Alzheimer’s disease Phase I (amyloid beta-protein modulator) La Chaux-de-Fonds, Switzerland www.kareustherapeutics.com

LMTX TauRx Pharmaceuticals Alzheimer’s disease, Phase III (TRx-0238) Singapore www.taurx.com

Lu AE58054 Lundbeck Alzheimer’s disease (cognition) Phase II (5-HT6 receptor antagonist) Deerfield, IL www.lundbeck.com Otsuka America Pharmaceutical www.otsuka.com Rockville, MD

LY2886721 Eli Lilly Alzheimer’s disease Phase I (beta secretase inhibitor) Indianapolis, IN (slow disease progression) www.lilly.com

LY3002813 Eli Lilly Alzheimer’s disease Phase I (biological) Indianapolis, IN www.lilly.com

Lym Pro® Amarantus BioSciences Alzheimer’s disease (diagnosis) Phase II neurotrophic factor companion Sunnyvale, CA www.amarantus.com diagnostic

MK-8931 Merck Alzheimer’s disease Phase II/III (BACE1 protein inhibitor) Whitehouse Station, NJ www.merck.com

14 Medicines in Development Neurological Disorders 2013 Medicines in Development for Neurological Disorders

Alzheimer’s Disease

Product Name Sponsor Indication Development Phase

MSDC-0160 Metabolic Solutions Development Alzheimer’s disease Phase II (mTOT modulator sensitizer) Company www.msdrx.com Kalamazoo, MI

NAV4694 Navidea Biopharmaceuticals Alzheimer’s disease (diagnosis) Phase II (fluorine-18 labeled precision Dublin, OH www.navidea.com radiopharmaceutical)

NAV5001 Navidea Biopharmaceuticals dementia with Lewy bodies Phase II (123I-labelled imaging agent) Dublin, OH (diagnosis) www.navidea.com (see also Parkinson’s)

NIC5-15 Humanetics Alzheimer’s disease Phase II (amyloid precursor protein Minneapolis, MN www.humaneticscorp.com secretase inhibitor)

PF-05212377 Pfizer Alzheimer’s disease Phase II (SAM-760) New York, NY www.pfizer.com

pioglitazone companion diagnostic Takeda Pharmaceuticals U.S.A. Alzheimer’s disease (diagnosis) Phase I Deerfield, IL www.takeda.com Zinfandel Pharmaceuticals Chapel Hill, NC

Posiphen® QR Pharma Alzheimer’s disease, Phase II R-phenserine Berwyn, PA mild cognitive impairment www.qrpharma.com (see also Parkinson’s)

RG1577 Roche Alzheimer’s disease Phase II (MAO-B inhibitor) Nutley, NJ www.roche.com

RG7129 Roche Alzheimer’s disease Phase I (BACE1 protein inhibitor) Nutley, NJ www.roche.com

rilapladib GlaxoSmithKline Alzheimer’s disease Phase II (Lp-PLA2 inhibitor) Rsch. Triangle Park, NC www.gsk.com

RVX-208 Resverlogix Alzheimer’s disease Phase I (BET protein inhibitor) Calgary, Canada www.resverlogix.com

SAR110894 Sanofi US Alzheimer’s disease Phase II (H3 antagonist) Bridgewater, NJ www.sanofi.com

SAR228810 Sanofi US Alzheimer’s disease Phase I (anti-protofibrillar AB mAb) Bridgewater, NJ www.sanofi.com

SB742457 GlaxoSmithKline Alzheimer’s disease Phase II (5HT6 antagonist) Rsch. Triangle Park, NC www.gsk.com

Medicines in Development Neurological Disorders 2013 15 Medicines in Development for Neurological Disorders

Alzheimer’s Disease

Product Name Sponsor Indication Development Phase

sGC 1061 sGC Pharma Alzheimer’s disease Phase I (nomethiazole) Wellesley, MA www.sgcpharma.com

solanezumab Eli Lilly mild Alzheimer’s disease Phase III (amyloid-beta protein inhibitor) Indianapolis, IN www.lilly.com

ST101 Sonexa Therapeutics Alzheimer’s disease Phase II San Diego, CA www.sonexa.com

T3D-959 T3D Therapeutics Alzheimer’s disease Phase I completed (dual PPAR agonist) Rsch. Triangle Park, NC www.t3dtherapeutics.com

T-817MA Toyama Chemical Alzheimer’s disease Phase II Tokyo, Japan www.toyama-chemical.co.jp

TC-1734 Targacept Alzheimer’s disease Phase II (ispronicline) Winston-Salem, NC www.targacept.com

TC-5619 Targacept Alzheimer’s disease Phase I (alpha7nAChR) Winston-Salem, NC www.targacept.com

TD-8954 Targacept Alzheimer’s disease Phase I (5-HT4 agonist) Winston-Salem, NC www.targacept.com

TTP488 Transtech Pharma Alzheimer’s disease Phase II High Point, NC (Fast Track) www.ttpharma.com

TTP4000 Transtech Pharma Alzheimer’s disease Phase I High Point, NC www.ttpharma.com

V950 vaccine Merck Alzheimer’s disease Phase I Whitehouse Station, NJ www.merck.com

vanutide cridificar Janssen Alzheimer Immunotherapy Alzheimer’s disease Phase II (ACC-001/PF-05236806) South San Francisco, CA www.janimm.com Pfizer www.pfizer.com New York, NY

VI-1121 VIVUS Alzheimer’s disease Phase II Mountain View, CA www.vivus.com

XEL 001HP Xel Pharmaceuticals Alzheimer’s disease Phase I (transdermal patch) Draper, UT www.xelpharmaceuticals.com

16 Medicines in Development Neurological Disorders 2013 Medicines in Development for Neurological Disorders

Amyotrophic Lateral Sclerosis

Product Name Sponsor Indication Development Phase

arimoclomol ALS Association amyotrophic lateral sclerosis (ALS) Phase II/III (Orphan Drug) Washington, DC (Fast Track) www.orphazyme.com Orphazyme Copenhagen, Denmark University of Miami Miami, FL

GM6 Genervon Biopharmaceuticals ALS (Fast Track) Phase II (peptide therapeutic) Pasadena, CA (see also Alzheimer’s, multiple www.genervon.com sclerosis, Parkinson’s, spinal cord injury, stroke)

NP001 Neuraltus Pharmaceuticals ALS Phase II (macrophage regulator) Palo Alto, CA www.neuraltus.com

NSI-566 Neuralstem ALS Phase II (stem cell therapy) Rockville, MD www.neuralstem.com (Orphan Drug)

NurOwn™ BrainStorm Cell Therapeutics ALS Phase II GDNF-producing adult New York, NY www.brainstorm-cell.com stem cell therapy (Orphan Drug)

ozanezumab GlaxoSmithKline ALS Phase II (NOGO-A mAb) Rsch. Triangle Park, NC www.gsk.com

stem cell therapy TCA Cellular Therapy ALS Phase I Covington, LA (see also spinal cord injury) www.tcacellulartherapy.com

tirasemtiv Cytokinetics ALS Phase II (Orphan Drug) South San Francisco, CA (Fast Track) www.cytokinetics.com

Attention-Deficit/Hyperactivity Disorder

Product Name Sponsor Indication Development Phase

AR08 Arbor Pharmaceuticals attention-deficit/hyperactivity Phase II (adrenergic receptor agonist) Atlanta, GA disorder (ADHD) www.arborpharma.com

COL-171 Collegium Pharmaceuticals ADHD in clinical trials (sustained release) Cumberland, RI www.collegiumpharma.com

Medicines in Development Neurological Disorders 2013 17 Medicines in Development for Neurological Disorders

Attention-Deficit/Hyperactivity Disorder

Product Name Sponsor Indication Development Phase

d-amphetamine transdermal Noven Pharmaceuticals ADHD Phase II (ATS) Miami, FL www.noven.com

EB-1020 Neurovance (Euthymics) ADHD Phase I (triple reuptake inhibitor) Cambridge, MA www.euthymics.com

edivoxetine Eli Lilly ADHD (pediatric) Phase II/III (norepinephrine reuptake Indianapolis, IN www.lilly.com inhibitor)

PsychoGenics ADHD (adults) Phase II (serotonin 1A/1B ) Tarrytown, NY www.psychogenics.com

HDL-100 Highland Therapeutics ADHD Phase I (amphetamine modified release) Toronto, Canada www.highlandtherapeutics.com

HDL-200 Highland Therapeutics ADHD Phase I ( Toronto, Canada www.highlandtherapeutics.com modified-release)

KP106 KemPharm ADHD Phase I completed (d-amphetamine prodrug) North Liberty, IA www.kempharm.com

KRL-401 Krele Pharmaceuticals ADHD in clinical trials (TONIX Pharmaceuticals) www.krele.com New York, NY

methylphenidate Purdue Pharma ADHD Phase III extended release Stamford, CT www.purduepharma.com Rhodes Pharma www.rhodespharma.com Coventry, RI

NT0202 Neos Therapeutics ADHD application submitted (amphetamine controlled release) Grand Prairie, TX www.neostx.com

NWP09 Pfizer ADHD Phase III completed (methylphenidate New York, NY www.pfizer.com extended-release chewable tablets)

OPC-34712 Lundbeck ADHD (adults) Phase II () Deerfield, IL www.lundbeck.com Otsuka America Pharmaceutical www.otsuka.com Rockville, MD

18 Medicines in Development Neurological Disorders 2013 Medicines in Development for Neurological Disorders

Attention-Deficit/Hyperactivity Disorder

Product Name Sponsor Indication Development Phase

ORADUR®-ADHD DURECT ADHD Phase I (sustained-release oral gel) Cupertino, CA www.durect.com

SEP-225289 Sunovion Pharmaceuticals ADHD Phase II (triple reuptake inhibitor) Marlborough, MA www.sunovion.com

SPN-810 Supernus Pharmaceuticals impulsive aggression in ADHD Phase II completed () Rockville, MD (pediatric) www.supernus.com

SPN-812 Supernus Pharmaceuticals ADHD Phase II completed (norepinephrine uptake inhibitor) Rockville, MD www.supernus.com

TD-9855 Theravance ADHD Phase II (monoamine reuptake inhibitor) South San Francisco, CA www.theravance.com

Brain Injury

Product Name Sponsor Indication Development Phase

BHR-100 BHR Pharma traumatic brain injury Phase III (intravenous Herndon, VA (Fast Track) www.bhr-pharma.com infusion) (Orphan Drug)

ciclosporin intravenous Maas Biolab traumatic brain injury Phase I (Orphan Drug) Albuquerque, NM www.maasbiolab.com NeuroVive Pharmaceutical www.neurovive.com Lund, Sweden

intravenous Sinapis Pharma traumatic brain injury Phase I completed Jacksonville, FL (see also stroke) www.sinapispharma.com

NNZ-2566 Neuren Pharmaceuticals traumatic brain injury Phase II (cytokine inhibitors/neuropeptide Bethesda, MD (Fast Track) www.neurenpharma.com ) (see also other)

NTx-428® Stem Cell Therapeutics traumatic brain injury Phase II cell differentiation, nerve growth Toronto, Canada www.stemcellthera.com factor and stem cell stimulant

Oxycyte® Oxygen Biotherapeutics traumatic brain injury Phase II perfluorocarbon oxygen carrier Morrisville, NC www.oxybiomed.com

Medicines in Development Neurological Disorders 2013 19 Medicines in Development for Neurological Disorders

Brain Injury

Product Name Sponsor Indication Development Phase

RP-1127 Remedy Pharmaceuticals moderate to severe traumatic brain Phase II (glibenclamide) New York, NY injury www.remedypharmaceuticals.com (see also stroke)

SAR127963 Sanofi US traumatic brain injury Phase I (P75 receptor antagonist) Bridgewater, NJ www.sanofi.com

Brain Tumors

Product Name Sponsor Indication Development Phase

8H9 mAb United Therapeutics metastatic brain cancer Phase I Silver Spring, MD www.unither.com

ABT-414 AbbVie glioblastoma Phase I (EGFR antagonist) North Chicago, IL www.abbvie.com

AEE788 Novartis Pharmaceuticals glioblastoma Phase I/II (multiple tyrosine kinase inhibitor) East Hanover, NJ www.novartis.com

afatinib Boehringer Ingelheim Pharmaceuticals glioblastoma Phase I/II (ErbB tyrosine kinase inhibitor) Ridgefield, CT www.boehringer-ingelheim.com

AMG 595 Amgen anaplastic astrocytoma, Phase I (anti-EGFRvIII antibody-drug Thousand Oaks, CA glioblastoma www.amgen.com conjugate)

ANG1005 AngioChem glioma Phase I ( prodrug) Montreal, Canada www.angiochem.com

ARC 100 Archer Biosciences recurrent glioblastoma Phase II (tubulin polymerisation inhibitor) New York, NY www.archerbiosciences.com ------medulloblastoma, Phase I/II recurrent neuroblastoma www.archerbiosciences.com

AT-101 Ascenta Therapeutics glioblastoma Phase II (Bcl-2 inhibitor) Malvern, PA www.ascenta.com

Avastin® Genentech first-line glioblastoma Phase III bevacizumab South San Francisco, CA www.gene.com

Azedra™ Progenics Pharmaceuticals neuroblastoma (pediatric) Phase II iobenguane I-131 Tarrytown, NY (Fast Track) www.progenics.com (Orphan Drug)

20 Medicines in Development Neurological Disorders 2013 Medicines in Development for Neurological Disorders

Brain Tumors

Product Name Sponsor Indication Development Phase

BKM120 Novartis Pharmaceuticals glioblastoma Phase I (PI3K inhibitor) East Hanover, NJ www.novartis.com

ch14.18 mAb United Therapeutics neuroblastoma Phase III (Orphan Drug) Silver Spring, MD www.unither.com

cilengitide EMD Serono glioblastoma Phase III (Orphan Drug) Rockland, MA www.emdserono.com

cilengitide companion diagnostic EMD Serono glioblastoma (diagnosis) Phase III Rockland, MA www.emdserono.com MDxHealth www.mdxhealth.com Irvine, CA

cintredekin besudotox INSYS Therapeutics glioma Phase I (IL13-PE38QQR) Chandler, AZ (Fast Track) www.insysrx.com (Orphan Drug) National Institute of Neurological Disorders and Stroke Bethesda, MD

CLR 1404 I-124 Novelos Therapeutics brain tumor (diagnosis) Phase I/II (PET imaging) Madison, WI www.novelos.com

Cotara® Peregrine Pharmaceuticals recurrent glioblastoma Phase II (iodine-131 radiolabeled TNT mAb) Tustin, CA (Fast Track) www.peregrineinc.com (Orphan Drug)

crenolanib AROG Pharmaceuticals glioma (pediatric) Phase I (receptor tyrosine kinase inhibitor) Dallas, TX www.arogpharma.com (Orphan Drug)

dacomitinib Pfizer glioblastoma Phase II (PF-00299804) New York, NY www.pfizer.com

DCVax®-Brain Northwest Biotherapeutics glioblastoma Phase III dendritic cell vaccine Bethesda, MD www.nwbio.com (Orphan Drug)

DNX-2401 DNAtrix glioblastoma Phase I (cell death stimulant) Houston, TX www.dnatrix.com

E7080 Eisai glioma Phase II (lenvatinib) Woodcliff Lake, NJ www.eisai.com

Medicines in Development Neurological Disorders 2013 21 Medicines in Development for Neurological Disorders

Brain Tumors

Product Name Sponsor Indication Development Phase

eflornithine Cancer Prevention Pharmaceuticals neuroblastoma Phase II (CPP-1X) Tucson, AZ www.canprevent.com

ETS2101 e-Therapeutics glioma Phase I (synthetic terpene-based Oxfordshire, United Kingdom www.etherapeutics.co.uk cannabinoid) University of California San Diego, CA

F18-ML-10 IBA Molecular brain tumors (diagnosis) Phase II (molecular imaging agent) Dulles, VA www.iba-molecular.com Aposense www.aposense.com Petach-Tikva, Israel

firtecan pegol Belrose Pharma neuroblastoma Phase I/II (Orphan Drug) Princeton, NJ www.belrosepharma.com

galunisertib Eli Lilly glioblastoma Phase II (LY2157299) Indianapolis, IN www.lilly.com ------newly diagnosed glioma Phase I/II www.lilly.com

GDC-0084/RG7666 Genentech glioma Phase I (PI3K inhibitor) South San Francisco, CA www.gene.com

GliAtak™ Advantagene malignant glioma Phase II cancer gene therapy Auburndale, MA www.advantagene.com (Orphan Drug)

Glionix™ NovaRx glioma Phase I belagenpumatucel-L San Diego, CA www.novarx.com subcutaneous

Hiltonol® Oncovir glioblastoma Phase II poly-ICLC Washington, DC www.oncovir.com (Orphan Drug)

ICT-107 ImmunoCellular Therapeutics glioblastoma Phase II (autologous dendritic cell-based Woodland Hills, CA www.imuc.com vaccine) (Orphan Drug)

IMA950 Immatics Biotechnologies glioblastoma Phase I (tumor-associated peptide vaccine) Tuebingen, Germany www.immatics.com

LDE225 Novartis Pharmaceuticals medulloblastoma Phase III (SMO protein inhibitor) East Hanover, NJ www.novartis.com

22 Medicines in Development Neurological Disorders 2013 Medicines in Development for Neurological Disorders

Brain Tumors

Product Name Sponsor Indication Development Phase

LEE011 Novartis Pharmaceuticals neuroblastoma Phase I (cyclin-dependent kinase-4/6 East Hanover, NJ www.novartis.com inhibitor)

Actelion Pharmaceuticals recurrent glioblastoma Phase I South San Francisco, CA www.actelion.us

mibefradil Tau Therapeutics recurrent glioma Phase I Charlottesville, VA www.tautherapeutics.com

NEO100 NEONC Technologies glioblastoma in clinical trials (perillyl intranasal) Woodland Hills, CA www.neonctech.com (Orphan Drug)

neuroblastoma vaccine MabVax neuroblastoma Phase I San Diego, CA www.mabvax.com

onartuzumab Genentech recurrent glioblastoma Phase II (anti-c-Met mAb) South San Francisco, CA www.gene.com

Opaxio® Cell Therapeutics glioblastoma Phase II paclitaxel poliglumex Seattle, WA www.celltherapeutics.com (Orphan Drug)

palbociclib Pfizer Rb-positive glioblastoma Phase II (PD-0332991/CDK4-6 kinase New York, NY www.pfizer.com inhibitor)

perifosine AEterna Zentaris glioma Phase II Basking Ridge, NJ www.aezsinc.com

PLX3397 Plexxikon glioblastoma Phase II Berkeley, CA www.plexxikon.com

PX-866 Oncothyreon glioblastoma Phase II (PI-3 kinase inhibitor) Seattle, WA www.oncothyreon.com

Reolysin® Oncolytics Biotech glioma Phase I/II completed pelareorep Calgary, Canada www.oncolyticsbiotech.com

rindopepimut Celldex Therapeutics first-line glioblastoma Phase III (EGFR varient III vaccine) Needham, MA (Fast Track) www.celldextherapeutics.com (Orphan Drug) ------recurrent glioblastoma Phase II (Fast Track) www.celldextheraputics.com

SB-313 Sangamo Biosciences glioblastoma Phase I (T-cell receptor gene stimulant) Richmond, CA www.sangamo.com City of Hope National Medical Center Duarte, CA

Medicines in Development Neurological Disorders 2013 23 Medicines in Development for Neurological Disorders

Brain Tumors

Product Name Sponsor Indication Development Phase

SL-701 Stemline Therapeutics glioma Phase I/II (dendritic cell vaccine) New York, NY www.stemline.com

Tarceva® Astellas Pharma US recurrent ependymoma (pediatric) Phase III erlotinib Northbrook, IL www.astellas.com

terameprocol Erimos Pharmaceuticals glioma Phase I/II (intravenous) Raleigh, NC www.erimos.com

Toca 511/Toca FC Tocagen recurrent glioblastoma Phase I/II (fluorouracil prodrug gene therapy) San Diego, CA www.tocagen.com ------late-stage glioma Phase I www.tocagen.com

TRC105 Tracon Pharmaceuticals glioblastoma Phase II (ENG protein inhibitor) San Diego, CA www.traconpharma.com

TSC Diffusion Pharmaceuticals glioblastoma Phase I/II (trans-sodium crocetinate) Charlottesville, VA www.diffusionpharma.com

TVI-Brain-1 TVAX Biomedical glioma Phase II (cancer vaccine) Lenexa, KS www.tvaxbiomedical.com

Tykerb® GlaxoSmithKline glioblastoma Phase II lapatinib Rsch. Triangle Park, NC www.gsk.com Jonsson Comprehensive Cancer Center Los Angeles, CA

VAL-083 Del Mar Pharmaceuticals glioblastoma Phase I/II (Orphan Drug) Vancouver, Canada www.delmarpharma.com

VB-111 VBL Therapeutics glioblastoma Phase I/II (gene therapy) Or Yehuda, Israel www.vblrx.com

veliparib AbbVie brain metastases Phase II North Chicago, IL www.abbvie.com

vemurafenib Roche brain metastases Phase II Nutley, NJ www.roche.com

vitespen Agenus glioma Phase II (G-100 prophage) Lexington, MA www.agenusbio.com

Xeloda® Roche glioma (pediatric) Phase II capecitabine Nutley, NJ www.roche.com

24 Medicines in Development Neurological Disorders 2013 Medicines in Development for Neurological Disorders

Epilepsy

Product Name Sponsor Indication Development Phase

Banzel® Eisai Lennox-Gastaut syndrome (pediatric) Phase III Woodcliff Lake, NJ www.eisai.com (Orphan Drug)

BGG492 Novartis Pharmaceuticals partial seizures Phase II completed (selurampanel) East Hanover, NJ (see also headache) www.novartis.com

UCB epilepsy Phase III Smyrna, GA www.ucb.com

CPP -15 Catalyst Pharmaceutical Partners complex partial seizures, Phase I (GABA-aminotransferase inhibitor) Coral Gables, FL infantile spasms www.catalystpharma.com (Orphan Drug)

intranasal spray Acorda Therapeutics acute repetitive seizures Phase III (Orphan Drug) Ardsley, NY www.acorda.com

DSP-0565 Sunovion Pharmaceuticals epilepsy Phase I (sodium/) Marlborough, MA www.sunovion.com

ezogabine extended release GlaxoSmithKline partial onset seizures Phase III Rsch. Triangle Park, NC www.gsk.com Valeant Pharmaceuticals North America www.valeant.com Bridgewater, NJ

Fycompa® Eisai generalized seizures Phase III Woodcliff Lake, NJ www.eisai.com ------partial-onset seizures (pediatric) Phase II www.eisai.com

ganaxolone Marinus Pharmaceuticals infantile spasms (infants), Phase II (Orphan Drug) New Haven, CT partial-onset seizures (adults) www.marinuspharma.com

INS-001 Insero Health epilepsy Phase I () Miami, FL www.insero.com

I.V. Lundbeck epilepsy Phase III Deerfield, IL www.lundbeck.com

JZP8 Jazz Pharmaceuticals recurrent acute repetitive seizures Phase II ( intranasal) Palo Alto, CA www.jazzpharma.com

Lyrica® Pfizer generalized tonic clonic seizures Phase III New York, NY (see also pain) www.pfizer.com

intranasal Upsher-Smith Laboratories acute repetitive seizures Phase III (USL261) Maple Grove, MN (Fast Track) www.upsher-smith.com

Medicines in Development Neurological Disorders 2013 25 Medicines in Development for Neurological Disorders

Epilepsy

Product Name Sponsor Indication Development Phase

naluzotan Proximagen epilepsy Phase II (serotonin 1A receptor agonist/ London, United Kingdom www.proximagen.com sigma-1 receptor antagonist)

NRL-1 Biotie Therapies epilepsy Phase I (diazepam intranasal) Turku, Finland www.biotie.com Neuralis San Diego, CA

PF-04895162 Pfizer epilepsy Phase I completed New York, NY www.pfizer.com

Potiga™ GlaxoSmithKline Lennox-Gastaut syndrome, Phase III ezogabine Rsch. Triangle Park, NC partial onset seizures www.gsk.com Valeant Pharmaceuticals North America (patients age 12 and older) www.valeant.com Bridgewater, NJ

pregabalin controlled release Pfizer epilepsy (adjunctive treatment) Phase III New York, NY (see also pain) www.pfizer.com

Stedesa® Sunovion Pharmaceuticals partial seizures in adults application submitted Marlborough, MA (adjunctive therapy) www.sunovion.com ------partial seizures (monotherapy) Phase III www.sunovion.com

tonabersat Upsher-Smith Laboratories epilepsy Phase I (USL260) Maple Grove, MN www.upsher-smith.com

extended release Upsher-Smith Laboratories partial-onset seizures application submitted (USL255) Maple Grove, MN www.upsher-smith.com

topiramate intravenous CyDex Pharmaceuticals epilepsy Phase I (Captisol®-enabled) (Ligand Pharmaceuticals) www.ligand.com Lenexa, KS

Trokendi XR™ Supernus Pharmaceuticals epilepsy application submitted topiramate controlled release Rockville, MD www.supernus.com

Vanquix® Auto-Injector Pfizer acute repetitive seizures Phase III diazepam injection New York, NY (intermittent therapy) www.pfizer.com

Vimpat® UCB epilepsy (monotherapy) Phase III Smyrna, GA www.ucb.com ------epilepsy in patients 2-17 years of age Phase II (adjunctive therapy), primary gener- www.ucb.com alized tonic clonic seizures (adjunctive therapy)

26 Medicines in Development Neurological Disorders 2013 Medicines in Development for Neurological Disorders

Epilepsy

Product Name Sponsor Indication Development Phase

VX-765 Vertex Pharmaceuticals treatment-resistant partial epilepsy Phase II (caspase 1 inhibitor) Cambridge, MA www.vrtx.com

YKP-3089 SK biopharmaceuticals epilepsy Phase II Fair Lawn, NJ (see also pain) www.skbp.com

Genetic Disorders

Product Name Sponsor Indication Development Phase

Afinitor® Novartis Pharmaceuticals seizures associated with tuberous Phase III everlimus East Hanover, NJ sclerosis complex (TSC) www.novartis.com

deferiprone ApoPharma pantothenate kinase-associated Phase III Toronto, Canada www.apotex.com

ecopipam Psyadon Pharmaceuticals Lesch-Nyhan syndrome Phase III (D1 receptor antagonist) Germantown, MD (see also other) www.psyadonrx.com (Orphan Drug)

Gammagard Liquid™ Baxter Healthcare Friedreich’s ataxia Phase II immune globulin Deerfield, IL www.baxter.com

HuCNS-SC® StemCells Pelizaeus-Merzbacher disease Phase I adult neural stem cell therapy Newark, CA (see also spinal cord injury) www.stemcellsinc.com

ISIS-SMNRx Biogen Idec Phase II (antisense oligonucleotide) Weston, MA (Fast Track) www.biogenidec.com (Orphan Drug) Isis Pharmaceuticals www.isispharm.com Carlsbad, CA

ISIS-TTRRx Isis Pharmaceuticals familial amyloid polyneuropathy Phase II/III (antisense RNA modulator) Carlsbad, CA (Fast Track) www.isispharm.com (Orphan Drug)

Lenti-D™ Bluebird Bio childhood cerebral Phase I/II adrenoleukodystrophy Cambridge, MA adrenoleukodystrophy www.bluebirdbio.com gene therapy (Orphan Drug)

PF-06687859 Pfizer spinal muscular atrophy Phase I (DcpS protein inhibitor) New York, NY www.pfizer.com (Orphan Drug)

RG2833 Repligen Friedreich’s ataxia Phase I completed (HDAC inhibitor) Waltham, MA www.repligen.com (Orphan Drug)

Medicines in Development Neurological Disorders 2013 27 Medicines in Development for Neurological Disorders

Genetic Disorders

Product Name Sponsor Indication Development Phase

tafamidis meglumine Pfizer transthyretin familial amyloid poly- application submitted (transthyretin dissociation New York, NY neuropathy www.pfizer.com inhibitor) (Fast Track) (Orphan Drug)

vatiquinone Edison Pharmaceuticals mitochondrial myopathies Phase II/III (EPI-743) Mountain View, CA www.edisonpharma.com (Orphan Drug) ------Friedreich’s ataxia, Phase II Leigh’s disease www.edisonpharma.com

VP20629 ViroPharma Friedreich’s ataxia Phase I Exton, PA www.viropharma.com

UX001 sialic acid Ultragenyx Pharmaceuticals hereditary inclusion body myositis Phase II (sialic acid extended release) Novato, CA www.ultragenyx.com

Headache

Product Name Sponsor Indication Development Phase

ALD403 Alder Biopharmaceuticals prevention of migraine Phase II (CGRP inhibitor mAb) Bothell, WA (subcutaneous) www.alderbio.com ------prevention of migraine Phase I (intravenous) www.alderbio.com

AMG 334 Amgen migraine Phase I (CGRP receptor antagonist mAb) Thousand Oaks, CA www.amgen.com

Amrix® Cephalon (Teva) migraine Phase III extended release Frazer, PA www.tevapharm.com

AP-1531 Ariel Pharmaceuticals migraine Phase I (EPH receptor antagonist) Broomfield, CO

AVP-825 Avanir Pharmaceuticals migraine Phase III ( intranasal) Aliso Viejo, CA www.avanir.com

AZ-104 Alexza Pharmaceuticals migraine Phase II completed (Staccato® low dose) Mountain View, CA www.alexza.com

28 Medicines in Development Neurological Disorders 2013 Medicines in Development for Neurological Disorders

Headache

Product Name Sponsor Indication Development Phase

BGG492 Novartis Pharmaceuticals migraine Phase II (selurampanel) East Hanover, NJ (see also epilepsy) www.novartis.com

Botox® Allergan prevention of migraine Phase III onabotulinumtoxinA Irvine, CA (adolescents) www.allergan.com (see also pain, other)

CL-H1T Charleston Laboratories migraine Phase II (sumatriptan) Charleston, SC www.charlestonlabs.com

intranasal Winston Pharmaceuticals chronic daily headache Phase II Vernon Hills, IL www.winstonlabs.com

DR-105 Duramed Pharmaceuticals (Teva) menstrual migraine Phase II completed (ethinylestradiol/levonorgestrel) North Wales, PA www.tevapharm.com

CoLucid Pharmaceuticals migraine Phase II (serotonin 1F receptor agonist) Durham, NC www.colucid.com

LBR-101 Labrys Biologics prevention of chronic migraine Phase I (CGRP mAb) San Mateo, CA www.labrysbiologics.com

Levadex® Allergan migraine (adults) application submitted mesilate Irvine, CA www.allergan.com inhalation MAP Pharmaceuticals Mountain View, CA

LY2951742 Arteaus Therapeutics prevention of migraine Phase II ( gene-related peptide Cambridge, MA www.arteaus.com antagonist mAb) Eli Lilly www.lilly.com Indianapolis, IN

NVD-201 NovaDel migraine Phase II (sumatriptan oral spray) Bridgewater, NJ www.novadel.com

NXN-188 NeurAxon acute migraine Phase II completed (nNOS inhibitor/5-HT agonist) Mississauga, Canada www.neuraxon.com

odansetron/rizatriptan MonoSol Rx migraine Phase I fixed-dose combination Warren, NJ www.monosolrx.com

oral film IntelGenx migraine application submitted Ville St-Laurent, Canada www.intelgenx.com RedHill Biopharma www.redhillbio.com Tel Aviv, Israel

RT001 Revance Therapeutics migraine Phase II (botulinum toxin A topical) Newark, CA www.revance.com

Medicines in Development Neurological Disorders 2013 29 Medicines in Development for Neurological Disorders

Headache

Product Name Sponsor Indication Development Phase

SPRIX® Regency Therapeutics migraine Phase III ketorolac intranasal Shirley, NY www.regencytherapeutics.com

TI-001 Trigemina chronic migraine, daily headache Phase II (oxytocin intranasal) Moraga, CA www.trigemina.com

Merck migraine Phase II (MK-1602) Whitehouse Station, NJ www.merck.com

intranasal Shin Nippon Biomedical Laboratories USA migraine Phase I Everett, WA www.snblusa.com

Winston Pharmaceuticals Phase III (TRPV-1 agonist) Vernon Hills, IL (see also pain) www.winstonlabs.com

Huntington’s Disease

Product Name Sponsor Indication Development Phase

EX-527 Siena Biotech Huntington’s disease Phase I completed (SIRT1 protein inhibitor) Siena, Italy www.sienabiotech.com

GSK356278 GlaxoSmithKline Huntington’s disease Phase I (PDE4 inhibitor) Rsch. Triangle Park, NC www.gsk.com

OMS-824 Omeros Huntington’s disease Phase I (PDE10 inhibitor) Seattle, WA www.omeros.com

PBT2 Prana Biotechnology Huntington’s disease Phase II (metal protein-attenuating Parkville, Australia www.pranabio.com compound)

Teva Pharmaceutical Huntington’s disease Phase III (Orphan Drug) North Wales, PA www.tevapharm.com

RP103 Raptor Pharmaceuticals Huntington’s disease Phase II/III (mercaptamine bitartrate Novato, CA www.raptorpharma.com delayed release)

SD-809 Auspex Pharmaceuticals Huntington’s disease Phase I (VMAT inhibitor) La Jolla, CA (see also other) www.auspexpharma.com

30 Medicines in Development Neurological Disorders 2013 Medicines in Development for Neurological Disorders

Multiple Sclerosis

Product Name Sponsor Indication Development Phase

ABT-413 AbbVie multiple sclerosis Phase I (sphingosine-1 phosphate North Chicago, IL www.abbvie.com receptor modulator)

anti-LINGO Biogen Idec multiple sclerosis Phase II (LINGO-1-protein-inhibitor) Weston, MA www.biogenidec.com

ARX424 Ambrx multiple sclerosis Phase I (peginterferon beta-1a) La Jolla, CA www.ambrx.com

ATX-MS-1467 EMD Serono multiple sclerosis Phase I (immune tolerizing agent) Rockland, MA www.emdserono.com

AZ01 Allozyne multiple sclerosis Phase I (peginterferon beta) Seattle, WA www.allozyne.com

BHT-3009 Bayhill Therapeutics relapsing-remitting Phase II completed (DNA vaccine) Palo Alto, CA multiple sclerosis www.bayhilltx.com

Copaxone® Teva Pharmaceutical multiple sclerosis application submitted glatiramer acetate for injection North Wales, PA www.tevapharm.com (20 mg)

daclizumab AbbVie multiple sclerosis, relapsing forms Phase III North Chicago, IL www.abbvie.com Biogen Idec www.biogenidec.com Weston, MA

firategrast GlaxoSmithKline multiple sclerosis Phase II (dual alpha4- antagonist) Rsch. Triangle Park, NC www.gsk.com

GEH-120714 GE Healthcare multiple sclerosis (diagnosis) Phase I (18F-labeled imaging agent) Waukesha, WI www.gehealthcare.com

GM6 Genervon Biopharmaceuticals multiple sclerosis Phase I (peptide therapeutic) Pasadena, CA (see also Alzheimer’s, amyotrophic www.genervon.com lateral sclerosis, Parkinson’s, spinal cord injury, stroke)

GSK239512 GlaxoSmithKline multiple sclerosis Phase II (H3 receptor inhibitor) Rsch. Triangle Park, NC www.gsk.com

GSK2618960 GlaxoSmithKline multiple sclerosis Phase I (IL-7 modulator mAb) Rsch. Triangle Park, NC www.gsk.com

idebenone Santhera Pharmaceuticals primary progressive multiple sclerosis Phase I/II Liestal, Switzerland (see also other) www.santhera.com U.S. National Institutes of Health Bethesda, MD

Medicines in Development Neurological Disorders 2013 31 Medicines in Development for Neurological Disorders

Multiple Sclerosis

Product Name Sponsor Indication Development Phase

imilecleucel-T Opexa Therapeutics secondary progressive multiple Phase II The Woodlands, TX sclerosis www.opexatherapeutics.com (Fast Track)

IR208 Immune Response BioPharma multiple sclerosis Phase II (immunostimulant vaccine) New York, NY www.immuneresponsebiopharma. com

laquinimod Teva Pharmaceutical multiple sclerosis Phase III North Wales, PA (Fast Track) www.tevapharm.com

Lemtrada™ Bayer HealthCare Pharmaceuticals multiple sclerosis application submitted alemtuzumab Wayne, NJ (Fast Track) www.bayerpharma.com Genzyme www.genzyme.com Cambridge, MA

masitinib AB Science USA multiple sclerosis, primary Phase II/III Short Hills, NJ progressive multiple sclerosis, www.ab-science.com secondary progressive multiple sclerosis

MEDI-551 MedImmune multiple sclerosis Phase I (anti-CD19 mAb) Gaithersburg, MD www.medimmune.com

MOR103 GlaxoSmithKline multiple sclerosis Phase I/II completed (GM-CSF antagonist mAb) Rsch. Triangle Park, NC www.gsk.com

ocrelizumab Biogen Idec primary progressive multiple Phase III (humanized anti-CD20 mAb) Weston, MA sclerosis, relapsing-remitting multiple www.biogenidec.com Genentech sclerosis www.gene.com South San Francisco, CA

ofatumumab Genmab US relapsing-remitting multiple sclerosis Phase II subcutaneous Princeton, NJ www.genmab.com (CD20 human mAb) GlaxoSmithKline www.gsk.com Rsch. Triangle Park, NC

ONO-4641 EMD Serono multiple sclerosis Phase II (oral S1P receptor modulator) Rockland, MA www.emdserono.com

Plegridy™ Biogen Idec multiple sclerosis, relapsing forms application submitted peginterferon beta-1a Weston, MA (Fast Track) www.biogenidec.com

plovamer acetate EMD Serono multiple sclerosis Phase I (second-generation peptide Rockland, MA www.emdserono.com copolymer)

32 Medicines in Development Neurological Disorders 2013 Medicines in Development for Neurological Disorders

Multiple Sclerosis

Product Name Sponsor Indication Development Phase

ponesimod Actelion Pharmaceuticals multiple sclerosis Phase II completed South San Francisco, CA www.actelion.com

rHIgM22 Acorda Therapeutics multiple sclerosis Phase I (myelin protein stimulant mAb) Ardsley, NY www.acorda.com

RPC1063 Receptos relapsing multiple sclerosis Phase II/III (S1P1 receptor agonist) San Diego, CA www.receptos.com

RTL1000 Artielle ImmunoTherapeutics multiple sclerosis Phase I (T-lymphocyte modulator) San Mateo, CA www.artielle.com

Sativex® GW Pharmaceutical muscle spasticity in multiple sclerosis Phase II nabiximols Wiltshire, United Kingdom www.gwpharm.com

secukinumab Novartis Pharmaceuticals multiple sclerosis Phase II (AIN457) East Hanover, NJ www.novartis.com

siponimod Novartis Pharmaceuticals multiple sclerosis Phase III (BAF312) East Hanover, NJ www.novartis.com

Trimesta™ Synthetic Biologics multiple sclerosis Phase II estriol succinate Rockville, MD www.syntheticbiologics.com

TSO Coronado Biosciences multiple sclerosis Phase II (trichuris suis ova/CNDO-201) Burlington, MA www.coronadobiosciences.com

Tysarbi® Biogen Idec multiple sclerosis (first-line therapy) application submitted natalizumab Weston, MA in patients negative for JCV antibodies www.biogenidec.com ------secondary-progressive Phase III multiple sclerosis www.biogenidec.com

VX15 Teva Pharmaceutical multiple sclerosis Phase I (SEMA-4D mAb) North Wales, PA www.tevapharm.com Vaccinex www.vaccinex.com Rochester, NY

XP23829 Xenoport multiple sclerosis Phase I (NF-kappa B inhibitor) Santa Clara, CA www.xenoport.com

Medicines in Development Neurological Disorders 2013 33 Medicines in Development for Neurological Disorders

Muscular Dystrophy

Product Name Sponsor Indication Development Phase

AAV1-FS344 Milo Biotechnology Duchenne muscular dystrophy Phase I/II (gene therapy-delivered myostatin Cleveland, OH www.milobiotechnology.com inhibitor) (Orphan Drug)

ataluren PTC Therapeutics Duchenne muscular dystrophy Phase III (Orphan Drug) South Plainfield, NJ (Fast Track) www.ptcbio.com

drisapersen GlaxoSmithKline Duchenne muscular dystrophy Phase III (antisense oligonucleotide) Rsch. Triangle Park, NC www.gsk.com (Orphan Drug) Prosensa Leiden, Netherlands

eteplirsen Sarepta Therapeutics Duchenne muscular dystrophy Phase II (RNA interference) Cambridge, MA (Fast Track) www.sareptatherapeutics.com

GNE lipoplex Gradalis hereditary inclusion body Phase I (muscular dystrophy gene therapy) Carrollton, TX myopathy www.gradalisinc.com

HT-100 Halo Therapeutics Duchenne muscular dystrophy Phase I/II (halofunginone) Newton, MA www.halotherapeutics.com (Orphan Drug)

PF-06252616 Pfizer muscular dystrophy Phase I New York, NY www.pfizer.com

Pain

Product Name Sponsor Indication Development Phase

ABT-639 AbbVie diabetic neuropathy Phase II (T-type calcium channel North Chicago, IL www.abbvie.com antagonist)

ABT-652 AbbVie diabetic neuropathy Phase II (histamine H3 receptor modulator) North Chicago, IL www.abbvie.com

AF-219 Afferent Pharmaceuticals osteoarthritis pain Phase II (purinergic P2 receptor antagonist) San Mateo, CA www.afferentpharma.com

Nectid neuropathic pain, pain Phase II (NRT-31/36) Princeton, NJ associated with multiple sclerosis www.nectid.com

34 Medicines in Development Neurological Disorders 2013 Medicines in Development for Neurological Disorders

Pain

Product Name Sponsor Indication Development Phase

ALO-02 Pfizer moderate to severe chronic pain Phase III (oxycodone/naltrexone core/ New York, NY www.pfizer.com abuse resistant)

AmiKet™ EpiCept neuropathic pain Phase II / Tarrytown, NY (Fast Track) www.epicept.com

ARA 290 Araim Pharmaceuticals diabetic neuropathy Phase II (erythropoietin receptor agonist) Yorktown, NY www.araim.org

ARC-2022 Arcion Therapeutics Phase I/II (lidocaine topical gel) Baltimore, MD www.arciontherapeutics.com

ARRY-797 Array BioPharma osteoarthritis pain Phase II (p38 MAP kinase inhibitor) Boulder, CO www.arraybiopharma.com

AS-3201 Eisai diabetic neuropathy Phase III (ranirestat) Woodcliff Lake, NJ www.eisai.com

ATx08 001 Aestus Therapeutics postherpetic neuralgia Phase II (PPAR-gamma agonist) East Windsor, NJ www.aestustherapeutics.com

AV-101 VistaGen Therapeutics neuropathic pain Phase I (NMDA receptor antagonist) South San Francisco, CA www.vistagen.com

AVP-786 Avanir Pharmaceuticals chronic pain Phase I (deuterated dextromethorphan) Aliso Viejo, CA www.avanir.com

AVP-923 Avanir Pharmaceuticals diabetic neuropathy Phase III (dextromethorphan/quinidine Aliso Viejo, CA (see also Alzheimer’s) www.avanir.com fixed-dose combination) ------central neuropathic pain in Phase III multiple sclerosis www.avanir.com

BEMA buprenorphine transmucosal BioDelivery Sciences International neuropathic pain Phase III Raleigh, NC www.bdsi.com

Botox® Allergan osteoarthritis pain Phase II onabotulinumtoxinA Irvine, CA (see also headache, other) www.allergan.com

Butrans™ Transdermal Purdue Pharma chronic pain (adolescents) Phase III System CIII Stamford, CT www.purduepharma.com buprenorphine transdermal

Celebrex® Pfizer chronic pain application submitted celecoxib New York, NY www.pfizer.com

Medicines in Development Neurological Disorders 2013 35 Medicines in Development for Neurological Disorders

Pain

Product Name Sponsor Indication Development Phase

topical gel BioDelivery Sciences diabetic neuropathy Phase II Raleigh, NC (Fast Track) www.bdsi.com

CNSB015 Relevare Pharmaceuticals neuropathic pain Phase I/II (-based pain therapy) Melbourne, Australia www.relevarepharma.com

COL-003 Collegium Pharmaceuticals chronic lower back pain Phase III (oxycodone extended release/ Canton, MA www.collegiumpharma.com abuse-resistant formulation)

COL-172 Collegium Pharmaceuticals chronic lower back pain Phase I (oxymorphone extended release/ Canton, MA (Fast Track) www.collegiumpharma.com abuse resistant)

C-peptide long-acting Cebix diabetic neuropathy Phase II (CBX129801) La Jolla, CA (Fast Track) www.cebix.com

CR845 Cara Therapeutics chronic pain Phase I (opioid kappa receptor agonist) Shelton, CT www.caratherapeutics.com

CTP-354 Concert Pharmaceuticals neuropathic pain Phase I (GABA-A receptor modulator) Lexington, MA (see also spasticity) www.concertpharma.com

diclofenac nano-formulation Iroko Pharmaceuticals osteoarthritis pain Phase III Philadelphia, PA www.iroko.com

DS-5565 Daiichi Sankyo chronic pain Phase II (CACNA2D1 protein modulator) Parsippany, NJ www.dsi.com

Eladur® DURECT post-herpetic neuralgia Phase II bupivacaine transdermal Cupertino, CA www.durect.com (Orphan Drug)

ELI-154 Elite Pharmaceuticals chronic pain Phase II (oxycodone controlled release) Northvale, NJ www.elitepharma.com

ELI-216 Elite Pharmaceuticals moderate to severe chronic pain Phase II (oxycodone/naltrexone Northvale, NJ www.elitepharma.com fixed-dose combination)

EMA401 Spinifex Pharmaceuticals postherpetic neuralgia Phase I (-type-2 receptor South Yarra, Australia www.spinifexpharma.com.au antagonist)

Fentora® Cephalon (Teva) chronic pain application submitted fentanyl buccal Frazer, PA www.tevapharm.com

36 Medicines in Development Neurological Disorders 2013 Medicines in Development for Neurological Disorders

Pain

Product Name Sponsor Indication Development Phase

Merck diabetic neuropathy Phase II (dual receptor antagonist) Whitehouse Station, NJ www.merck.com

fulranumab Janssen Research & Development neuropathic pain Phase II (nerve growth factor inhibitor) Raritan, NJ www.janssenrnd.com

GRT6005 Forest Laboratories pain due to osteoarthritis of the knee Phase II (ORL-1 receptor agonist) New York, NY www.frx.com

hydrocodone extended release Cephalon (Teva) chronic pain Phase III (CEP-33237) Frazer, PA www.tevapharm.com

hydromorphone intrathecal Mallinckrodt chronic pain Phase III Hazelwood, MO www.mallinckrodt.com

K-103-IP Kowa Research Institute arthritis pain Phase I (COX inhibitor) Morrisville, NC www.kowaus.com

KRN5500 DARA Biosciences peripheral neuropathy Phase II (protein synthesis inhibitor) Raleigh, NC (Fast Track) www.darabio.com

extended release Relmada Therapeutics moderate to severe chronic pain Phase I (abuse-deterrent drug delivery Blue Bell, PA www.relmada.com system)

Lyrica® Pfizer peripheral neuropathic pain Phase III pregabalin New York, NY (see also epilepsy) www.pfizer.com

mavatrep Janssen Research & Development chronic pain Phase I Raritan, NJ www.janssenrnd.com

meloxicam nano-formulation Iroko Pharmaceuticals osteoarthritis pain Phase III Philadelphia, PA www.iroko.com

NCE Eli Lilly osteoarthritis pain Phase I Indianapolis, IN www.lilly.com

neublastin Biogen Idec neuropathic pain Phase I Weston, MA www.biogenidec.com NsGene Ballerup, Denmark

NKTR-181 Nektar Therapeutics moderate to severe chronic pain Phase II (mu-opioid agonist) San Francisco, CA (Fast Track) www.nektar.com

Medicines in Development Neurological Disorders 2013 37 Medicines in Development for Neurological Disorders

Pain

Product Name Sponsor Indication Development Phase

NP-1998 Acorda Therapeutics neuropathic pain Phase II ( topical liquid) Ardsley, NY www.acorda.com

NXN-462 NeurAxon postherpetic neuralgia Phase II (nNOS inhibitor) Mississauga, Canada www.neuraxon.com

oxycodone/naloxone Purdue Pharma severe chronic lower back pain Phase II controlled release Stamford, CT www.purduepharma.com (OXN)

PA65020 POZEN chronic pain Phase I (aspirin 650mg/omeprazole 20mg Chapel Hill, NC www.pozen.com fixed-dose combination)

Pennsaid® 2% Nuvo Research osteoarthritis pain application submitted diclofenac transdermal Mississauga, Canada www.nuvoresearch.com second-generation

PF-05089771 Pfizer chronic pain Phase I (Nav1.7 sodium channel inhibitor) New York, NY www.pfizer.com

PF-06273340 Pfizer chronic pain Phase I New York, NY www.pfizer.com

PF-06305591 Pfizer chronic pain Phase I New York, NY www.pfizer.com

PLX1100 PLx Pharma osteoarthritis pain Phase II (ibuprofen/phosphatidylcholine) Houston, TX www.plxpharma.com

pregabalin controlled release Pfizer postherpetic neuralgia Phase III New York, NY (see also epilepsy) www.pfizer.com

PTI-202 Pain Therapeutics moderate to severe chronic pain Phase I completed (abuse-resistant opioid) Austin, TX www.paintrials.com

PTI-721 Pain Therapeutics moderate to severe chronic pain Phase I completed (abuse-resistant opioid) Austin, TX www.paintrials.com

Qutenza® Astellas Pharma HIV-associated neuropathy application submitted capsaicin 8% patch Tokyo, Japan (Fast Track) www.astellas.com NeurogesX www.neurogesx.com San Mateo, CA ------diabetic neuropathy Phase III www.astellas.com www.neurogesx.com

38 Medicines in Development Neurological Disorders 2013 Medicines in Development for Neurological Disorders

Pain

Product Name Sponsor Indication Development Phase

Remoxy™ Pain Therapeutics moderate to severe chronic pain application submitted oxycodone controlled release Austin, TX www.pfizer.com (Mu-type agonist/ Pfizer abuse resistant) New York, NY

rezatomidine ACADIA Pharmaceuticals diabetic neuropathy Phase II (alpha adrenergic receptor agonist) San Diego, CA www.acadia-pharm.com Allergan www.allergan.com Irvine, CA

S-117957 Purdue Pharma neuropathic pain Phase I Stamford, CT www.purduepharma.com Shionogi www.shionogi.com Florham Park, NJ

SAR292833/GRC15300 Glenmark Pharmaceuticals neuropathic pain, osteoarthritis pain Phase II (TRVP3 antagonist) Mumbai, India www.sanofi.com Sanofi US Bridgewater, NJ

SD-254 Auspex Pharmaceuticals neuropathic pain Phase I (deuterium-substituted La Jolla, CA www.auspexpharma.com analogue)

SEP-228432 Sunovion Pharmaceuticals neuropathic pain Phase I (SRNDI inhibitor) Marlborough, MA www.sunovion.com

SKL-NP SK biopharmaceuticals neuropathic pain Phase II Fair Lawn, NJ www.skbp.com

sufentanil DURECT chronic pain Phase II (transdermal delivery system) Cupertino, CA www.durect.com

TAK-428 Takeda Pharmaceuticals International diabetic neuropathy Phase II (neurotrophic factor production Deerfield, IL www.takeda.com accelerator)

TEM Allergan postherpetic neuralgia Phase II (senrebotase) Irvine, CA www.allergan.com

V116517 Purdue Pharma pain due to osteoarthritis of the knee, Phase II Stamford, CT postherpetic neuralgia www.purduepharma.com

V158866 Vernalis neuropathic pain Phase II (FAAH inhibitor) Winnersh, United Kingdom www.vernalis.com

Medicines in Development Neurological Disorders 2013 39 Medicines in Development for Neurological Disorders

Pain

Product Name Sponsor Indication Development Phase

VBY-036 Virobay neuropathic pain Phase I (protease inhibitor) Menlo Park, CA www.virobayinc.com

Calosyn Pharma osteoarthritis pain Phase I/II Sharon, MA www.calosynpharma.com

Vicodin® CR AbbVie back pain, osteoarthritis pain application submitted hydrocodone/ North Chicago, IL www.abbvie.com controlled release

VM202 ViroMed diabetic neuropathy Phase II (modified hepatocyte growth Seoul, South Korea www.viromed.co.kr factor gene therapy)

XEN402 Teva Pharmaceutical postherpetic neuralgia Phase II North Wales, PA www.tevapharm.com Pharmaceuticals www.xenon-pharma.com Burnaby, Canada

YKP-509 SK biopharmaceuticals neuropathic pain Phase II (carisbamate) Fair Lawn, NJ www.skbp.com

YKP-3089 SK biopharmaceuticals neuropathic pain Phase II Fair Lawn, NJ (see also epilepsy) www.skbp.com

Z160 Zalicus neuropathic pain, Phase II (N-type calcium channel Cambridge, MA postherpetic neuralgia www.zalicus.com antagonist)

Z944 Zalicus neuropathic pain Phase I (T-type calcium channel Cambridge, MA www.zalicus.com antagonist)

Zohydro ER™ Zogenix moderate to severe chronic pain application submitted hydrocodone extended-release San Diego, CA www.zogenix.com

zucapsaicin Winston Pharmaceuticals chronic pain, postherpetic neuralgia application submitted (TRPV-1 agonist) Vernon Hills, IL (see also headache) www.winstonlabs.com (Orphan Drug)

40 Medicines in Development Neurological Disorders 2013 Medicines in Development for Neurological Disorders

Parkinson’s Disease

Product Name Sponsor Indication Development Phase

AFQ056 Novartis Pharmaceuticals drug-induced in Phase II (mavoglurant) East Hanover, NJ Parkinson’s disease www.novartis.com

AQW051 Novartis Pharmaceuticals drug-induced dyskinesia Phase II completed (alpha7 nicotinic acetylcholine East Hanover, NJ in Parkinson’s disease www.novartis.com receptor agonist)

autologous stem cell therapy NeuroGeneration Parkinson’s disease Phase I Los Angeles, CA www.neurogeneration.com

AVE-8112 Sanofi US Parkinson’s disease Phase I (PDE4 inhibitor) Bridgewater, NJ www.sanofi.com The Michael J. Fox Foundation www.michaeljfox.org for Parkinson’s Research New York, NY

AZD3241 AstraZeneca Parkinson’s disease Phase II (myeloperoxidase inhibitor) Wilmington, DE www.astrazeneca.com

CERE-120 Ceregene Parkinson’s disease Phase II (AAV-NTN) San Diego, CA www.ceregene.com

CVT-301 Civitas Therapeutics Parkinson’s disease Phase II (levodopa inhalation) Chelsea, MA www.civitastherapeutics.com

davunetide intranasal Allon Therapeutics Parkinson’s disease Phase I Vancouver, Canada (see also Alzheimer’s, other) www.allontherapeutics.com

dipraglurant Addex Therapeutics levodopa-induced dyskinesia in Phase II (ADX48621) Geneva, Switzerland Parkinson’s disease www.addextherapeutics.com (immediate release)

DM-1992 Depomed, Inc. Parkinson’s disease Phase II (carbidopa/levodopa Newark, CA www.depomed.com controlled-release)

Duopa® AbbVie advanced Parkinson’s disease application submitted levodopa/carbidopa North Chicago, IL (Fast Track) www.abbvie.com intestinal gel (LCIG) (Orphan Drug)

fipamezole Santhera Pharmaceuticals Parkinson’s disease Phase II completed (alpha-2 adrenergic receptor Liestal, Switzerland (Fast Track) www.santhera.com antagonist)

Medicines in Development Neurological Disorders 2013 41 Medicines in Development for Neurological Disorders

Parkinson’s Disease

Product Name Sponsor Indication Development Phase

GM6 Genervon Biopharmaceuticals Parkinson’s disease Phase II (peptide therapeutic) Pasadena, CA (see also Alzheimer’s, amyotrophic www.genervon.com lateral sclerosis, multiple sclerosis, spinal cord injury, stroke)

GZ404477 Genzyme Parkinson’s disease Phase I (AAV-hAADC gene therapy) Cambridge, MA www.genzyme.com

HT-1067 Dart NeuroScience Parkinson’s disease Phase I (MOA-B reversible inhibitor) San Diego, CA www.dartneuroscience.com

KW-6002 Kyowa Hakko Kirin America Parkinson’s disease application submitted (istradefylline) Princeton, NJ www.kyowa-kirin.com

levodopa/carbidopa IMPAX Laboratories Parkinson’s disease application submitted extended release Hayward, CA www.impaxlabs.com

NAV5001 Navidea Biopharmaceuticals Parkinsonian disorder (diagnosis) Phase III (123I-labelled imaging agent) Dublin, OH (see also Alzheimer’s) www.navidea.com

Nurelin™ Adamas Pharmaceuticals levodopa-induced dyskinesia Phase III ADS-5102/ ER Emeryville, CA in Parkinson’s disease www.adamaspharma.com

NuroPro® Amarantus BioSciences Parkinson’s disease (diagnosis) Phase II neurotrophic factor companion Sunnyvale, CA www.amarantus.com diagnostic

opicapone Bial Parkinson’s disease Phase I (COMT inhibitor) Lisbon, Portugal www.bial.com

OS-320 Osmotica Pharmaceutical Parkinson’s disease Phase III (levodopa/carbidopa) Wilmington, NC www.osmoticausa.com

Posiphen® QR Pharma Parkinson’s disease Phase II R-phenserine Berwyn, PA (see also Alzheimer's) www.qrpharma.com

PYM-50028 Phytopharm early stage Parkinson’s disease Phase II Huntingdon, United Kingdom www.phytopharm.com

Newron Pharmaceuticals Parkinson’s disease Phase III Bresso, Italy www.newron.com Zambon www.zambonpharma.com Bresso, Italy

tozadenant Biotie Therapies Parkinson’s disease Phase II/III (adenosine A2A receptor South San Francisco, CA www.biotie.com antagonist) UCB www.ucb.com Brussels, Belgium

42 Medicines in Development Neurological Disorders 2013 Medicines in Development for Neurological Disorders

Parkinson’s Disease

Product Name Sponsor Indication Development Phase

XP21279 Xenoport Parkinson’s disease Phase II (dopamine receptor agonist) Santa Clara, CA www.xenoport.com

Spasticity

Product Name Sponsor Indication Development Phase

CK-2127107 Cytokinetics muscular atrophy associated with Phase I South San Francisco, CA neuromuscular dysfunction, www.cytokinetics.com muscular weakness, and/or muscle fatigue

CTP-354 Concert Pharmaceuticals muscle spasticity Phase I (GABA-A receptor modulator) Lexington, MA (see also pain) www.concertpharma.com

Dysport® Ipsen Biopharmaceuticals focal spasticity of upper and lower Phase III abobotulinumtoxinA Basking Ridge, NJ limb in adults, adolescents and www.ipsen.com children

OS-440 Osmotica Pharmaceutical muscle spasticity due to Phase III (arbaclofen extended release) Marietta, GA multiple sclerosis www.osmotica.com

SUN 09 Sun Pharma Advanced Research muscle spasticity due to Phase III (baclofen extended release) Mumbai, India multiple sclerosis www.sunpharma.in

Xeomin® Merz Pharmaceuticals post-stroke spasticity Phase III incobotulinumtoxinA Greensboro, NC www.merzusa.com

Spinal Cord Injury

Product Name Sponsor Indication Development Phase

AC105 Acorda Therapeutics spinal cord injury Phase II (nervous system modulator) Ardsley, NY (Fast Track) www.acorda.com

ATI355 Novartis Pharmaceuticals spinal cord injury Phase I (anti-NOGO-A mAb) East Hanover, NJ www.novartis.com (Orphan Drug)

Medicines in Development Neurological Disorders 2013 43 Medicines in Development for Neurological Disorders

Spinal Cord Injury

Product Name Sponsor Indication Development Phase

autologous stem cell therapy DaVinci Biosciences spinal cord injury in clinical trials Costa Mesa, CA www.dvbiosciences.com

BA-210 BioAxone BioSciences spinal cord injury Phase II (Rho GTP-binding Ft. Lauderdale, FL www.bioaxonebio.com protein-inhibitor) (Orphan Drug)

GM6 Genervon Biopharmaceuticals spinal cord injury Phase I (peptide therapeutic) Pasadena, CA (see also Alzheimer’s, amyotrophic www.genervon.com lateral sclerosis, multiple sclerosis, Parkinson’s, stroke)

HuCNS-SC® StemCells chronic spinal cord injury Phase I/II adult neural stem cell therapy Newark, CA (see also genetic) www.stemcellsinc.com

NEU2000 GNT Pharma spinal cord injury Phase I completed Yongin, South Korea (see also stroke) www.gntpharma.com

stem cell therapy TCA Cellular Therapy spinal cord injury Phase I Covington, LA (see also amyotrophic lateral www.tcacellulartherapy.com sclerosis)

SUN13837 Daiichi Sankyo spinal cord injury Phase II (FGF-receptor agonist) Parsippany, NJ www.dsi.com

Stroke

Product Name Sponsor Indication Development Phase

3K3A-APC ZZ Biotech stroke Phase I (recombinant human Houston, TX www.zzbiotech.com activated protein C)

ALD-401 Cytomedix stroke Phase II (bone marrow-derived adult Gaithersburg, MD www.cytomedix.com stem cell therapy)

allogeneic mesenchymal Stemedica Cell Technologies ischemic stroke Phase I/II bone marrow cell therapy San Diego, CA www.stemedica.com

Ampyra® Acorda Therapeutics post-stroke deficits Phase II fampridine sustained-release Ardsley, NY (see also other) www.acorda.com

44 Medicines in Development Neurological Disorders 2013 Medicines in Development for Neurological Disorders

Stroke

Product Name Sponsor Indication Development Phase

betrixaban Portola Pharmaceuticals prevention of stroke in patients with Phase II South San Francisco, CA atrial fibrillation www.portola.com

CNTO-0007 Janssen Research & Development stroke Phase I/II (cell therapy) Raritan, NJ www.janssenrnd.com

desmoteplase Lundbeck stroke Phase III Deerfield, IL (Fast Track) www.lundbeck.com

GM6 Genervon Biopharmaceuticals stroke Phase II (peptide therapeutic) Pasadena, CA (see also Alzheimer’s, amyotrophic www.genervon.com lateral sclerosis, multiple sclerosis, Parkinson’s, spinal cord injury)

GSK249320 GlaxoSmithKline stroke Phase II (myelin-associated glycoprotein Rsch. Triangle Park, NC www.gsk.com mAb)

methamphetamine intravenous Sinapis Pharma stroke Phase I completed Jacksonville, FL (see also brain injury) www.sinapispharma.com

MP-124 Mitsubishi Tanabe Pharma America acute ischemic stroke Phase I (PARP inhibitor) Jersey City, NJ www.mt-pharma.co.jp

MultiStem® Athersys stroke Phase II stem cell therapy Cleveland, OH www.athersys.com

NA-1 NoNO acute ischemic stroke Phase II completed (signal transduction Toronto, Canada www.nonoinc.ca pathway inhibitor)

NEU2000 GNT Pharma stroke Phase I completed Yongin, South Korea (see also spinal cord injury) www.gntpharma.com

PF-03049423 Pfizer stroke recovery Phase II New York, NY www.pfizer.com

RP-1127 Remedy Pharmaceuticals stroke Phase II (glibenclamide) New York, NY (see also brain injury) www.remedypharmaceuticals.com

SAR126119 Sanofi US acute ischemic stroke Phase I (TAFIa inhibitor) Bridgewater, NJ www.sanofi.com

SB623 SanBio stroke Phase I/II (stem cell therapy) Mountain View, CA www.san-bio.com

Medicines in Development Neurological Disorders 2013 45 Medicines in Development for Neurological Disorders

Stroke

Product Name Sponsor Indication Development Phase

TS01 Thrombolytic Science International stroke Phase I (recombinant complement Cambridge, MA www.tsillc.com C1-inactivator-protein)

Other

Product Name Sponsor Indication Development Phase

18F-AV-133 Avid Radiopharmaceuticals neurodegenerative disorders Phase I/II imaging agent Philadelphia, PA (diagnosis) www.avidrp.com

Abilify® Otsuka America Pharmaceutical Tourette’s syndrome Phase III Rockville, MD www.otsuka.com (once-weekly)

ABT-354 AbbVie neurological disorders Phase I (serotonin-6 receptor antagonist) North Chicago, IL www.abbvie.com

ABT-384 AbbVie neurological disorders Phase I completed North Chicago, IL (see also Alzheimer’s) www.abbvie.com

Ampyra® Acorda Therapeutics cerebral palsy Phase II fampridine sustained release Ardsley, NY (see also stroke) www.acorda.com

AP-1101 Ariel Pharmaceuticals neuroprotection against Phase II Broomfield, CO postoperative cognitive decline and memory loss in patients undergoing extracorporeal cardiopulmonary bypass

Botox® Allergan juvenile cerebral palsy Phase III onabotulinumtoxinA Irvine, CA (see also headache, pain) www.allergan.com

BYM338 Novartis Pharmaceuticals inclusion body myositis Phase II (type II-B activin receptor East Hanover, NJ www.novartis.com modulator mAb)

CX1739 Cortex Pharmaceuticals central sleep apnea Phase I (AMPA receptor agonist) Glen Rock, NJ www.cortexpharm.com

davunetide intranasal Allon Therapeutics progressive supranuclear palsy Phase II/III (Orphan Drug) Vancouver, Canada (Fast Track) www.allontherapeutics.com (see also Alzheimer’s, Parkinson’s)

46 Medicines in Development Neurological Disorders 2013 Medicines in Development for Neurological Disorders

Other

Product Name Sponsor Indication Development Phase

ecopipam Psyadon Pharmaceuticals Tourette’s syndrome Phase I/II (D1 dopamine receptor antagonist) Germantown, MD (see also genetic) www.psyadonrx.com

EVP-0334 EnVivo Pharmaceuticals neurodegenerative disorders Phase I (HDAC inhibitor) Watertown, MA www.envivopharma.com

Firdapse™ Catalyst Pharmaceutical Partners Lambert-Eaton myasthenic syndrome Phase III amifampridine Coral Gables, FL www.catalystpharma.com (Orphan Drug)

Gilenya® Novartis Pharmaceuticals chronic inflammatory Phase III fingolimod East Hanover, NJ demyelinating www.novartis.com polyradiculoneuropathy

glycerol phenylbutyrate Hyperion Therapeutics hepatic Phase II completed (Orphan Drug) South San Francisco, CA www.hyperiontx.com

human immune globulin CSL Behring chronic inflammatory Phase III (subcutaneous) King of Prussia, PA demyelinating www.cslbehring.com polyradiculoneuropathy

idebenone Columbia University MELAS syndrome Phase II (Orphan Drug) New York, NY (see also multiple sclerosis) www.santhera.com Santhera Pharmaceuticals Liestal, Switzerland

interleukin-7 Cytheris progressive multifocal Phase II Rockville, MD leukoencephalopathy www.cytheris.com

IPX159 IMPAX Pharmaceuticals Phase II Hayward, CA www.impaxpharma.com

MK-8616 Merck neuromuscular blockade application submitted (sugammadex) Whitehouse Station, NJ www.merck.com

NBI-98854 Neurocrine Biosciences drug-induced dyskinesia Phase II (VMAT2 inhibitor) San Diego, CA (Fast Track) www.neurocrine.com

NH001 NeuroHealing Pharmaceuticals coma Phase II ( subcutaneous) Waban, MA (Fast Track) www.neurohealing.com (Orphan Drug)

Medicines in Development Neurological Disorders 2013 47 Other

Product Name Sponsor Indication Development Phase

NNZ-2566 Neuren Pharmaceuticals Rett syndrome Phase I (cytokine inhibitors/neuropeptide Bethesda, MD (Fast Track) www.neurenpharma.com receptor modulator) (see also brain injury)

OCR-002 Ocera Therapeutics in patients Phase II (ornithine phenylacetate) San Diego, CA with acute liver failure (iv) www.ocerainc.com (Orphan Drug) (Fast Track) ------hepatic encephalopathy in patients Phase I with liver cirrhosis (oral) www.ocerainc.com (Fast Track)

placulumab Cephalon (Teva) sciatica Phase I/II Frazer, PA www.tevapharm.com

pomaglumetad Eli Lilly CNS disorders Phase I (LY2140023 monohydrate) Indianapolis, IN www.lilly.com

SD-809 Auspex Pharmaceuticals drug-induced , Phase I (VMAT inhibitor) La Jolla, CA Tourette’s syndrome www.auspexpharma.com (see also Huntington’s)

Soliris® Alexion Pharmaceuticals myasthenia gravis, severe and relaps- Phase II eculizumab Cheshire, CT ing neuromyelitis optica www.alxn.com (Orphan Drug)

SPI-017 Sucampo Pharmaceuticals lumbar spinal stenosis Phase II Bethesda, MD www.sucampo.com

SPI-3608 Sucampo Pharmaceuticals spinal stenosis Phase I Bethesda, MD www.sucampo.com

Tardoxyl™ Medicure Pharma drug-induced dyskinesia Phase II pyridoxal phosphate Somerset, NJ (Fast Track) www.medicure.com

uridine triacetate Wellstat Therapeutics neurodegenerative disorders Phase I (PN401) Gaithersburg, MD www.wellstattherapeutics.com

Catalyst Pharmaceutical Partners Tourette’s syndrome Phase I/II (GABA-AT inhibitor) Coral Gables, FL www.catalystpharma.com

48 Medicines in Development Neurological Disorders 2013 Glossary

Alzheimer’s disease—The most com- learning capacity. The natural decline of problems such as clumsy or awkward mon form of dementia, characterized by these functions with age is grossly exag- movements and unsteadiness, occurs in progressive and chronic deterioration of gerated in dementia. many different diseases and conditions. cognitive functions, including memory, thinking and reasoning. Early manifes- Duchenne muscular dystrophy—An glioblastoma multiforme—The most tations include forgetfulness, impaired inherited disorder that involves rapidly common and most malignant of the as- ability to focus, and changes in mood and worsening muscle weakness. Other trocytomas. The tumor grows so fast that personality. As the disease progresses, muscular dystrophies get worse much it increases pressure in the brain, produc- there is a loss of computational ability, in more slowly. Duchenne’s is caused by a ing headaches, slowed thinking, and if addition to word-finding problems and dif- defective gene. Because of the way the severe enough, sleepiness and coma. ficulty with ordinary activities. Ultimately, disease is inherited, males are more likely glioma—A type of brain tumor arising the disease leads to severe memory loss, to develop symptoms than are women. from the supporting glial cells within complete disorientation, social withdrawal, epilepsy—Recurrent seizures—transient the brain. Gliomas make up about 60 loss of independence, and is fatal. neurological abnormalities caused by percent of all primary brain tumors. amyotrophic lateral sclerosis (ALS)— abnormal electrical activity in the brain— Huntington’s disease—Huntington’s Also known as Lou Gehrig’s disease, the or temporary alteration in one or more is an uncommon, inherited dis- most common of the motor neuron dis- brain functions. Seizures are a symptom ease in which degeneration of the basal eases, a group of rare disorders in which of brain dysfunction and can result from ganglia (structures deep in the brain) the nerves that control muscular activity a wide variety of diseases or injury. results in chorea (rapid, jerky, involuntary degenerate within the brain and spinal Fast Track—A process designed to movements) and dementia (progressive cord causing weakness and wasting of facilitate the development and expedite mental impairment). the muscles. the review of drugs to treat serious Lennox-Gastaut syndrome—Character- application submitted—An application diseases and fill an unmet medical need. ized by seizures and mental retardation for marketing has been submitted by the The status is assigned by the U.S. Food in infants and young children. company to the Food and Drug Admin- and Drug Administration. The purpose is to get important new drugs to the istration (FDA). metastases/metastatic—Areas of sec- patient earlier. Fast Track addresses a ondary cancer that have spread from the attention deficit/hyperactivity disorder broad range of serious diseases. Gener- primary or original cancer site. (ADHD)—ADHD is a complex neurologi- ally, determining factors include whether cal impairment that results in an over- the drug will have an impact on such migraine—Severe headache result- active behavior pattern and a difficulty factors as survival, day-to-day function- ing from an abnormal dilation of blood concentrating. While it primarily affects ing, or the likelihood that the disease, if vessels deep within the brain. It can last children, a growing number of adults are left untreated, will progress from a less from two hours to several days and is being diagnosed with the disorder. Boys severe condition to a more serious one. often accompanied by nausea, vomiting are affected about three times as often Filling an unmet medical need is defined and sensitivity to noise and/or light. as girls. Children with ADHD are fidgety, as providing a therapy where none exists impulsive, reckless, irritable, emotionally or providing a therapy which may be multiple sclerosis (MS)—Progressive immature and sometimes aggressive. potentially superior to existing therapy. disease of the central nervous system in Because their attention span is short, Once a drug receives Fast Track designa- which scattered patches of the covering they do not conform to orderly routine. tion, early and frequent communication of nerve fibers (myelin) in the brain and ADHD often leads to anti-social acts and between the FDA and a drug company is spinal cord are destroyed. Symptoms difficulty learning, although IQ is normal. encouraged throughout the entire drug range from numbness and tingling to No definite cause has been established, development and review process. The paralysis and incontinence. but some researchers now believe genet- frequency of communication assures that ics plays a role. questions and issues are resolved quickly, muscular dystrophy—Inherited muscu- often leading to earlier drug approval lar disorder of unknown cause in which cerebral palsy—A general term for disor- and access by patients. muscle fibers slowly degenerate.Duch- ders of movement and posture resulting enne MD is the most common type. from damage to the brain in pregnancy, Friedreich’s ataxia—An inherited during birth, in the newborn period or in disease that causes progressive dam- myasthenia gravis—A chronic autoim- early childhood. age to the nervous system resulting in mune neuromuscular disease character- symptoms ranging from gait disturbance ized by varying degrees of weakness of dementia—Degeneration of central and speech problems to heart disease. the skeletal (voluntary) muscles of the nervous functions, such as memory and “Ataxia,” which refers to coordination body. The hallmark of myasthenia gravis

Medicines in Development Neurological Disorders 2013 49 Glossary

is muscle weakness that increases during Phase 0—First-in-human trials conduct- spinal cord injury—Damage to the spinal periods of activity and improves after ed in accordance with FDA’s 2006 guid- cord which can cause loss of sensation, periods of rest. ance on exploratory Investigational New muscle weakness or paralysis. Drug (IND) studies designed to speed up neuroblastoma—A tumor of the adrenal development of promising drugs by es- stroke—Usually caused by atheroscle- glands or sympathetic nervous system tablishing very early whether the tested rosis. It results in death or serious brain (the part of the nervous system respon- compound behaves in human subjects as damage, such as paralysis or loss of sible for certain automatic body func- was anticipated from preclinical studies. speech. An ischemic stroke is caused tions, such as the control of heart rate). by blocked or narrowed arteries that Neuroblastomas are the most common Phase I—Safety testing and pharmaco- prevent sufficient blood and oxygen from extracranial (outside the skull) solid logical profiling in humans. reaching the brain. tumors of childhood. Phase II—Effectiveness testing in Tourette syndrome (TS)—A neurologi- neuropathic pain—Caused by disease, humans. cal disorder characterized by repetitive, , or damage to the periph- involuntary movements and vocalizations eral nerves, which connect the central Phase III—Extensive clinical trials in called tics. The early symptoms of TS are nervous system (brain and spinal cord) to humans. typically noticed first in childhood, with the sense organs, muscles, glands, and the average onset between the ages of postherpetic neuralgia—A burning pain internal organs. 3 and 9. TS occurs in people from all that may recur at the site of an attack ethnic groups; males are affected about of shingles months or even years after neuropathy—Disease, inflammation, or three to four times more often than the illness. damage to the peripheral nerves, which females. It is estimated that 200,000 connect the central nervous system to prodrug—An inactive medicine that Americans have the most severe form the sense organs, muscles, glands, and becomes active inside the body through of TS, and as many as 1 in 100 exhibit internal organs. metabolic processes. Prodrugs can be milder and less complex symptoms such as chronic motor or vocal tics. Although Orphan Drug—A drug to treat a disease used to improve how a specific medi- TS can be a chronic condition with that has a patient population of 200,000 cine is absorbed, distributed, metabo- symptoms lasting a lifetime, most people or less, or a disease that has a patient lized or excreted. with the condition experience their worst population of more than 200,000 and a restless legs syndrome—Restless legs tic symptoms in their early teens, with developmental cost that will not be re- syndrome is an overwhelming urge improvement occurring in the late teens covered from sales in the United States. to move the legs usually caused by and continuing into adulthood. Parkinson’s disease—Chronic neurologic uncomfortable or unpleasant sensations disease of unknown cause, characterized in the legs. by , rigidity and an abnormal gait.

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 www.phrma.org | www.innovation.org | www.pparx.org Provided as a Public Service by PhRMA. Founded in 1958 as the Pharmaceutical Manufacturers Association. Copyright © 2013 by the Pharmaceutical Research and Manufacturers of America. Permission to reprint is awarded if proper credit is given.

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50 Medicines in Development Neurological Disorders 2013 The Drug Discovery, Development and Approval Process

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. Drug Discovery and Development: A LONG, RISKY ROAD

DRUG DISCOVERY PRECLINICAL CLINICAL TRIALS FDA REVIEW LG-SCALE MFG Y

5,000–10,000 250 5 VEILLANCE ONE FDA-

VER COMPOUNDS APPROVED O DRUG

PHASE PHASE PHASE ARKETING SUR 1 2 3 -M ST NUMBER OF VOLUNTEERS PRE-DISC 20–80 100–300 1,000–3,000 A SUBMITTED 0.5–2 IND SUBMITTE D 3–6 YEARS6–7 YEARS ND

YEARS PHASE 4: PO The Drug Development and Approval Process The U.S. system of new drug approvals is in people. The IND shows results of previous ate statistically significant evidence to confirm perhaps the most rigorous in the world. experiments; how, where and by whom the new its safety and effectiveness. They are the lon- studies will be conducted; the chemical structure gest studies, and usually take place in multiple It takes 10-15 years, on average, for an experi- of the compound; how it is thought to work in sites around the world. mental drug to travel from lab to U.S. patients, the body; any toxic effects found in the animal according to the Tufts Center for the Study of New Drug Application (NDA)/Biologic License studies; and how the compound is manufac- Drug Development. Only five in 5,000 com- Application (BLA). Following the completion tured. All clinical trials must be reviewed and ap- pounds that enter preclinical testing make it to of all three phases of clinical trials, a company proved by the Institutional Review Board (IRB) human testing. And only one of those five is analyzes all of the data and files an NDA or BLA where the trials will be conducted. Progress approved for sale. with FDA if the data successfully demonstrate reports on clinical trials must be submitted at both safety and effectiveness. The applications On average, it costs a company $1.2 billion, least annually to FDA and the IRB. contain all of the scientific information that the including the cost of failures, to get one new Clinical Trials, Phase I—Researchers test the company has gathered. Applications typically medicine from the laboratory to U.S. patients, drug in a small group of people, usually between run 100,000 pages or more. according to a recent study by the Tufts Center 20 and 80 healthy adult volunteers, to evaluate for the Study of Drug Development. Approval. Once FDA approves an NDA or BLA, its initial safety and tolerability profile, deter- the new medicine becomes available for physi- Once a new compound has been identified in mine a safe dosage range, and identify potential cians to prescribe. A company must continue the laboratory, medicines are usually developed side effects. to submit periodic reports to FDA, including as follows: Clinical Trials, Phase II—The drug is given any cases of adverse reactions and appropriate Preclinical Testing. A pharmaceutical company to volunteer patients, usually between 100 and quality-control records. For some medicines, conducts laboratory and animal studies to show 300, to see if it is effective, identify an optimal FDA requires additional trials (Phase IV) to biological activity of the compound against the dose, and to further evaluate its short-term evaluate long-term effects. targeted disease, and the compound is evalu- safety. Discovering and developing safe and effective ated for safety. Clinical Trials, Phase III—The drug is given to a new medicines is a long, difficult, and expensive Investigational New Drug Application (IND). larger, more diverse patient population, often process. PhRMA member companies invested an After completing preclinical testing, a com- involving between 1,000 and 3,000 patients estimated $48.5 billion in research and develop- pany files an IND with the U.S. Food and Drug (but sometime many more thousands), to gener- ment in 2012. Administration (FDA) to begin to test the drug