2014 REPORT 2 5 3 6 8 11 24 28 provide a broader spectrum of thera- a broader provide cit/ attention-defi peutic activity for . (ADHD) hyperactivity disorder ...... c Discoveries Scientifi Early in the About Mental Health Facts States ...... United Chart in Development Medicines ...... Glossary ...... Drug Development/ ...... Process Approval Contents Challenges in Mental Health ...... Research ...... in the Pipeline Medicines Research Collaborative Partnerships ...... dependent a better un- on developing how current treatments of derstanding identifying that can work, biomarkers be used to and as- diagnosis improve nding and fi therapies, to sess responses - identifi through targets therapeutic new cation of the pathologies or mechanisms mental disorders. to contributing being now of some medicines Examples c mental disorders specifi treat to tested include: • that may inhibitor A triple reuptake

Mental health conditions exact a heavy a heavy exact conditions Mental health in the United toll human and economic of Mental Institute The National States. (NIMH) estimates that 1 in 4 Health been million—have American adults—61.5 disorder. a mental health with diagnosed mental the NIMH, serious to According than States more the United illnesses cost health billion annually in lost wages, $317 ts. benefi and disability expenditures care companies research Biopharmaceutical 119 medicines developing currently are some type of help people who have to depres- such as anxiety, mental disorder, use or substance sion, schizophrenia, either are Those medicines disorders. by review in clinical trials or awaiting and Drug Administration Food the U.S. of than 75 percent with more (FDA), phases in the earliest the medicines time and development—a of research often face when potential treatments and setbacks. cult hurdles diffi biopharma- the past half century, Over the alleviate has helped research ceutical the quality of life improve and burden individuals living with a mental many for are advances But therapeutic disorder. current by people not helped for needed those who experience or for treatments Further research side effects. negative is treatments or improved new into Biopharmaceutical Research Companies Companies Research Biopharmaceutical Than 100 to Medicines More Developing Are and Addictive Mental Disorders Treat

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Medicines in Development in Development Medicines Mental Health For

PRESENTED BY AMERICA’S BIOPHARMACEUTICAL RESEARCH COMPANIES BIOPHARMACEUTICALRESEARCH AMERICA’S BY PRESENTED Mental Health Mental MEDICINES IN DEVELOPMENT FOR IN DEVELOPMENT MEDICINES ADHD Some medicines are listed in more than one in more listed are Some medicines category. Key Issues

the brain; a lack of biomarkers that help clinicians’ diagnose MENTAL HEALTH accurately, measure disease progression and assess treatment response; and the complexity of mental disorders them- selves. In fact, most medicines that are in use today for the treatment of mental disorders have stemmed from and built on compounds that were initially developed many years ago. NIMH’s practical guidelines have documented the sometimes 61.5 MILLION limited benefi ts of current treatments and the need for a new AMERICANS generation of mental health medicines.

Specifi c challenges associated with developing new treat- 1 in 4 ments for mental disorders include diagnosis based on has a symptoms rather than underlying pathology. This can make it diffi cult to ensure that the appropriate participants MENTAL ILLNESS are included in a clinical trial. For some disorders, such as schizophrenia or autism spectrum disorder (ASD), individu- als meeting the diagnostic criteria, may in reality comprise

Source: National Institute of Mental Health (NIMH). several subgroups, each with different underlying pathologies even though they have similar symptoms. Therefore, the medication under study may be targeting the appropriate • An intranasal medicine for treatment-resistant depres- mechanism or pathology in only a subset of the clinical trial sion that targets a receptor in the brain resulting in a participants. Even if the medicine is effective in that portion rapid onset of antidepressant effects. of participants, it may appear to be ineffective because statisti- cal tests assess the entire group. A greater understanding of • A medicine for schizophrenia that targets a known treat- ment pathway but with potentially fewer negative side effects than existing treatments. MENTAL HEALTH Researching and developing new medicines is a risky invest- ment and lengthy process—only one in 5,000-10,000 tar- gets are ever approved for patients. And although advances in our understanding of mental disorders and how to treat MENTAL them have allowed America’s biopharmaceutical companies ILLNESSES and other partners in the collaborative ecosystem to con- duct cutting-edge research, additional scientifi c research is needed to reduce the destructive toll of these disorders and allow more people to lead healthier, more productive lives.

Challenges in Mental COST THE BILLION U.S.$317 ANNUALL Y Health Research in lost wages, health care and disability Development of new and effective treatments for mental disorders has been hindered by many factors, including a Source: NIMH. limited understanding of how current treatments work in

2 Medicines in Development for Mental Health 2014 Key Issues

tiple mental disorders. Further research is needed to support MENTAL HEALTH the research and development efforts of the biopharmaceuti- cal industry.

Medicines in the Pipeline

Although research into mental disorders can be very diffi - cult, there are some promising medicines in the pipeline that MENTAL are looking at new ways to treat many of these disorders. DISORDERS Examples of some current research include: are the leading cause of Attention-Defi cit/Hyperactivity Disorder (ADHD) U.S. DISABILITY A triple reuptake inhibitor that targets three chemical pathways in brain—serotonin, norepinephrine and dopamine—is being tested for the once-daily treatment of ADHD. By targeting all three pathways at the same time, the compound may poten-

Source: NIMH. tially provide a broad spectrum of activity. Because of its ability to maintain therapeutic levels in the blood for a long period of time, it is being developed as a once-daily treatment. mental disorders will help with diagnosis accuracy and ensure clinical trial participants are grouped appropriately. Cocaine Addiction Currently, there are no medications that explicitly address At NIMH, several initiatives are underway to help advance cocaine addiction, but a therapeutic vaccine in develop- research into potential new treatments for mental disor- ders. One project is focused on creating a new framework to classify mental disorders based on observable behavior and neurobiological measures, such as biomarkers. Current MENTAL HEALTH classifi cations are based on clinical observation and patient- MEDICINES IN DEVELOPMENT reported symptoms. As scientists gain more knowledge of the underlying biologic causes of mental disorders, having a TOTAL Medicines disorder classifi cation framework ready will aid in a faster and 119 more accurate diagnosis, leading to real progress in research- ing new treatments. 36 for 15for SCHIZOPHRENIA ATTENTION-DEFICIT/ For example, several research collaborations are looking at HYPERACTIVITY DISORDER the human genome to identify potential genetic indicators for 29for 15 for schizophrenia and understand the association between dif- DEPRESSION ANXIETY DISORDERS ferent genetic factors and different subpopulations of people diagnosed with the disorder. Such research could lead to the 20for 6for identifi cation of new targets more closely linked to disease SUBSTANCE USE/ AUTISM SPECTRUM pathology versus overall symptoms. In addition, the research ADDICTIVE DISORDERS DISORDERS has highlighted how diffi cult it is to fi nd specifi c markers or and more… targets because some gene variants are associated with mul- Source: PhRMA 2014 Medicines in Development for Mental Health.

Medicines in Development for Mental Health 2014 3 Key Issues

Social Phobia MENTAL HEALTH One medicine in development is part of a new class of psychotropic pherines. The drug, which has a unique mecha- nism of action, is being developed to be administered in an intranasal spray and to act with rapid-onset on peripheral receptors from nasal chemosensory neurons that act on the hypothalamic-limbic system in the brain, which is thought to be the primary center of emotion. In clinical trials, it was shown to improve social performance and social interaction anxiety within 10 minutes of administration.

Schizophrenia

ADHD Several medicines in development for schizophrenia are AFF ECTS 1 in 20 inhibitors of a subtype of phosphodiesterase (PDE), a key regulator of signaling in the brain. The PDE10 subtype is U.S. CHILDREN important in regulating the activity of neurons in the brain

Source: Mental Health America. and is a target of current antipsychotic treatments. PDE10 inhibitors are highly selective and mimic the effects of current treatments, but also activate certain receptors which may ment may prove to be an effective treatment. The vaccine is decrease the negative side effects of current treatments and designed to induce antibodies that bind specifi cally to cocaine increase the positive effect on cognition. in the blood and prevent it from reaching the brain. The physiological response to cocaine is thus altered, reducing the reinforcing properties of cocaine. Depression MENTAL HEALTH One medicine in development targets pathways involving glutamate, a common neurotransmitter found in the brain and involved in memory, learning and cognition. Dysfunction of the glutamate system can lead to seizures and cell death and may contribute to some mental disorders. The medicine targets a specifi c type of glutamate receptor in the brain—the NMDA DEPRESSION receptor—resulting in rapid-onset of therapeutic effects—from weeks to hours. An intranasal formulation of the medicine is being developed for treatment-resistant depression.

AFFECTS A medicine in development for major depressive disorder in patients who have not responded to current treatments com- bines an opioid modulator with an opioid stimulator. Opioid 21 MILLION stimulators have been shown to help in the treatment of AMERICAN ADULTS depression, but they can also be highly addictive. By coupling the stimulant with an opioid receptor blocker, the addictive Source: NIMH. qualities are “decoupled” from the antidepressant properties.

4 Medicines in Development for Mental Health 2014 Key Issues

MENTAL HEALTH “We are still at the beginning of what could be an era of brain exploration, with great promise for understanding obsessive-compulsiv social phobia more about how each of us thinks and dreams and loves, but perhaps even disorder

post-traumatic stress disorder greater promise for helping people with anxiety panic disorder mental disorders.” e

— Tom Insel, M.D. ANXIETY Director, National Institute of Mental Health DI SORDERS academic-industry research collaboration dedicated to AFFECT fi nding new methods for developing drugs for schizophre- 40 MILLION nia and depression. NEWMEDS is based in Europe but AMERICAN ADULTS involves many U.S. industry partners. Ultimately, the goal of NEWMEDS is to develop new approaches for shorter Source: NIMH. and more effi cient trials of new medications, with clinical trials that may require fewer patients and give faster results. Collaborative Research Partnerships Are Critical to Advancing Science BRAINSPAN ATLAS OF THE DEVELOPING HUMAN BRAIN Collaboration among partners in the entire biomedical ecosystem is critical to helping advance scientifi c understand- The “BrainSpan Atlas” is a comprehensive three- ing of brain disorders, one of the most complex areas for dimensional atlas of the developing human brain that incorporates gene activity along with anatomical researchers. Federal research institutions, academia, bio- reference atlases and neuroimaging data. The Atlas pharmaceutical research companies and patient communities highlights the transcriptome—a map showing when all play an important role in furthering research into those and where genes are turned on in the brain—and disorders. Some examples of key partnerships include: anatomy of the human brain during mid-term pregnancy. Some researchers have already had success • One Mind, a non-profi t organization that brings together using the BrainSpan map to associate genes in the a broad international coalition of scientists, advocates, developing brain with the adult brain, whereas before philanthropists, government, and the pharmaceutical and they were seemingly unrelated. health care industries, is dedicated to aiding the accelera- The BrainSpan Atlas was developed by a consortium of tion of development of new treatments for brain disorders public and private institutions led by the Allen Institute and injury. The organization’s 10-year plan addresses current for Brain Science in Seattle and funded through awards gaps in basic science, ways to expand translational efforts, from the NIMH. It is available free to the public and is and regulatory reforms that are necessary to achieve their intended to help researchers better understand mental mission of cures in the next decade through data sharing, disorders that may result from changes or problems occurring early during brain development, such as cooperative efforts and public-private partnerships. autism and schizophrenia. This understanding may in • NEWMEDS (Novel Methods leading to New Medica- turn provide new insight into therapeutic targets and improved screening and diagnosis. tions in Depression and Schizophrenia) is an international,

Medicines in Development for Mental Health 2014 5 Key Issues

MENTAL HEALTH Early Scientifi c Discoveries Early-stage research fi ndings are critical for understanding ILLNESS disease pathology and developing new, effective treatments. GENETIC O DISORGANIZED PSYCHOSIS Many of the challenges in mental health research refl ect the

THOUGHT PROCESS HALLUCINATREA TIONS reality that we are still learning how the human brain works. DIAGNOSISCOGNITIVE YMPTOMS PSYCHOLOGICALCHOLOGICAL Also, research efforts are complicated by the fact that many SCHIZOPHRETMENT NIA disorders fall under the broad umbrella of mental health, ENETIC BRAIN CHEMISTRY DELUSIONSDIAGNOSIS ranging from anxiety to depression to developmental disor- DI TREATMENT GEN DISORDERDISORDE ders to substance use disorders. Early scientifi c discoveries EMOTIONA can provide biopharmaceutical companies with potential new PSYCHOSIS treatment pathways for research or for refi nement of existing AFFECTS known pathways. Some recent discoveries include: 2.4 MILLION • The human genome is under examination by research- AMERICAN ADULTS based institutions around the globe looking for genetic associations in schizophrenia and other mental disorders.

Source: NIMH. Scientists have identifi ed gene variants and mutations in people with schizophrenia and compared them to healthy people, identifying the location and patterns of • Fast-Fails Trials (FAST) is an NIMH program in collabo- the mutations. Scientists are optimistic that those dis- ration with select academic research teams working to coveries will reveal clues about the underlying biology of accelerate the pace of psychiatric drug discovery through schizophrenia. rapid testing of new or repurposed compounds for their potential as psychiatric medications. • The Army Study to Assess Risk and Resilience in Ser- MENTAL HEALTH vicemembers (Army STARRS) is an unparalleled research study on suicide prevention—a critical area of research for the Army, other military personnel and the general population. The 5-year study, one of the largest and most complex studies ever administered by NIMH, is being conducted in collaboration with select academic research teams.

• The White House Brain Initiative (Brain Research through Advancing Innovative Neurotechnologies) is a SUBSTANCE USE/ public-private partnership for brain research focused on ADDICTIVE DISORDERS increasing our understanding of the human brain by ac- COST THE MILLION celerating the development and application of innovative U.S. MORE THAN $600YEARLY technologies. Through those technologies, researchers will be able to produce a new dynamic picture of the brain

that, for the fi rst time, will show how individual cells and Source: National Institute on Drug Abuse. complex neural circuits interact in both time and space.

6 Medicines in Development for Mental Health 2014 Key Issues

• New data from a team of researchers from Emory University, the University of Miami, and Scripps Re- ADHERENCE TO TREATMENT search Institute have identifi ed a potential new treat- CAN IMPROVE HEALTH ment for post-traumatic stress disorder (PTSD). In mice, OUTCOMES AND COSTS the compound reduced PTSD-like symptoms after the animals were exposed to stress. Researchers believe the Adherence to medication dosing and scheduling compound affects the fear learning process. Such fi ndings is important to treat mental health conditions effectively and help control costs by limiting relapses, could potentially lead to a treatment that could prevent hospitalizations and limiting indirect costs like lost PTSD after an individual is exposed to a psychologically productivity. Data highlighted by the American traumatic event. Pharmacists Association estimated that nonadherence rates are between 30 percent and 65 percent in • New research from Oregon Health & Science University’s individuals diagnosed with a severe mental illness. Vollum Institute is giving scientists a “never-before-seen” Many barriers to adherence have been identifi ed, view of how nerve cells communicate with each other including patient and family attitudes, treatment- and possibly a better understanding of how antidepres- related issues (side effects), health system factors, sants work in the human brain. Using special methods, cultural infl uences, and the perceived stigma scientists focused on the structure of the dopamine associated with mental disorders. transporter, which helps regulate dopamine levels in the brain—abnormal levels of dopamine are present in many disorders, including depression. The more detailed view and understanding of the dopamine transporter could help biopharmaceutical researchers develop more effective antidepressants.

Medicines in Development By Disease and Phase Some medicines are listed in more than one category.

All Medicines 119

Anxiety Disorders 15 Attention-Deficit Hyperactivity/Disorder 15 Autism Spectrum Disorders 6 Bipolar Disorders 5 Application Depression 29 Submitted Phase III Eating Disorders 2 Phase II Schizophrenia 36 Phase I

Substance Use 20 Disorders Tic Disorders 3

Other Disorders 2

Medicines in Development for Mental Health 2014 7 Facts

Selected Facts about Mental Health in the United States

Overview1 social and personal impairment as well as other psychiat- ric conditions.2 • An estimated 61.5 million Americans—about one in four adults—suffer from a diagnosable mental disorder in a • It is estimated that depression occurs in 50 percent of pa- given year. About 13.6 million Americans, or 1 in 17, suf- tients diagnosed with schizophrenia, and about 47 percent fer from a serious mental illness. have a lifetime diagnosis of comorbid substance abuse.3

• About 20 percent of young Americans ages 13 to 18 Anxiety Disorders1 and 13 percent of those ages 8 to 15 experience severe mental disorders in a given year. • Anxiety disorders, which include panic disorder, obses- sive-compulsive disorder, PTSD, generalized anxiety • Mental disorders are the leading cause of disability in disorder, phobias and social anxiety disorder, affect the United States. Many people suffer from more than some 40 million adults ages 18 and older, or about 18 one mental disorder at a given time. Nearly half (45 percent of people in that age group in a given year. percent) of those with any mental disorder meet criteria for two or more disorders. • Generalized anxiety disorder affects about 6.8 million American adults, including twice as many women as men. • In 2011, suicide was the tenth leading cause of death in the United States, accounting for 38,285 deaths. Risk • Obsessive-compulsive disorder affects about 2.2 million factors for suicide include depression and other mental American adults, striking men and women in roughly disorders or a substance use disorder (often in combi- equal numbers. nation with other mental disorders). • Panic disorder affects about 6 million American adults • Serious mental illnesses cost the United States more and is twice as common in women as men. than $317 billion annually in lost wages, health care ex- • PTSD affects about 7.7 million American adults, but it penditures, and disability benefi ts. Lost earnings alone can occur at any age, including childhood. Women are account for $193 billion per year. more likely to develop PTSD than men, and there is some evidence that susceptibility to the disorder may Co-occurrence/Comorbidity in Mental Health run in families. • Treatment challenges are exacerbated by co-occurrence or comorbidity of mental disorders. One study found • Social phobia affects about 15 million American adults. that nearly half of individuals seeking treatment for sub- Women and men are equally likely to develop the disorder. stance use disorder meet diagnostic criteria for PTSD, and individuals with co-occurring PTSD and substance Attention-Defi cit/Hyperactivity Disorder (ADHD) use disorder tended to have poorer treatment outcomes • ADHD is the most common mental disorder in children compared to those without the comorbidity.2 and adolescents.1 It affects as many as one in every 20 children, and boys are three to four times more likely • About one-third of people diagnosed with major depres- than girls to experience the disorder.4 About 4 percent sive disorder also have substance use disorder, and the of adults ages 18 to 44 are affected by ADHD.1 comorbidity results in a higher risk of suicide and greater

8 Medicines in Development for Mental Health 2014 Facts

• Although most children with ADHD have normal or • Major depressive disorder is the leading cause of dis- above-normal intelligence, 40 percent to 60 percent ability among Americans ages 15-44. It affects nearly have serious learning diffi culties.4 15 million U.S. adults.

• Children and adolescents with ADHD are more likely Eating Disorders1 than children without the disorder to suffer from other • In their lifetime, an estimated 0.6 percent of the U.S. adult mental disorders.4 population will suffer from anorexia, 1.0 percent from Autism Spectrum Disorders5 bulimia, and 2.8 percent from a binge-eating disorder. • In 2010, about 1 in 68 8-year-olds were identifi ed with • Women are much more likely than men to develop an autism spectrum disorder (ASD).* The 2010 estimate is eating disorder. They are three times as likely to experi- roughly 30 percent higher than the estimate for 2008 ence anorexia (0.9 percent of women vs. 0.3 percent of (1 in 88), 60 percent higher than the estimate for 2006 men) and bulimia (1.5 percent of women vs. 0.5 percent (1 in 110), and 120 percent higher than the estimates of men) during their lives. They are also 75 percent more for 2002 and 2000 (1 in 150). (The exact cause of the likely to have a binge-eating disorder (3.5 percent of increase is unknown, but researchers believe some of it women vs. 2.0 percent of men). may be due to the way children are identifi ed, diagnosed, and served in their local communities.) Schizophrenia • Approximately 2.4 million American adults age 18 and • Boys were almost fi ve times more likely to be identifi ed older have schizophrenia in a given year. It affects men with ASD than girls in 2010. About 1 in 42 boys and 1 in and women with equal frequency. Schizophrenia often 189 girls were identifi ed with ASD. fi rst appears in men in their late teens or early twenties. Depression1 In contrast, women are generally affected in their twen- ties or early thirties.1 • Mood disorders, which include major depressive dis- order, dysthymic disorder, and bipolar disorder, affect • The appearance of schizophrenic symptoms before age nearly 21 million adults, or about 9.5 percent of the U.S. 12 is rare—less than one-sixtieth as common as the population age 18 and older in a given year. adult-onset type. Neurodevelopmental damage seems to be greater in childhood schizophrenia than in the adult- • Bipolar disorder affects approximately 5.7 million Ameri- onset type.5 can adults, or about 2.6 percent of the U.S. population age 18 and older in a given year. The median age of Substance Use/Addictive Disorders onset for bipolar disorder is 25 years. • An estimated 17 million Americans have an alcohol use • Depression can strike anyone regardless of age, ethnic disorder—a medical term that includes both alcoholism background, socioeconomic status, or gender; however, and harmful drinking that does not reach the level of studies have found that depression is about twice as dependence.6 common in women as in men. In any given one year • Each year in the United States, nearly 80,000 people die period, depressive illnesses affect more than 12 million from alcohol-related causes, making it the third leading women and more than 6 million men. preventable cause of death in our country.6

* Estimates are based on information collected from the health and special education records of 8-year-old children living in areas of 11 different states. They do not represent the entire population of children in the United States.

Medicines in Development for Mental Health 2014 9 Facts

• Illicit drug use in America has been increasing. In 2012, Sources: an estimated 23.9 million Americans ages 12 or older— 1. National Institute of Mental Health, www.nimh.nih.gov or 9.2 percent of the population—had used an illicit drug or abused a psychotherapeutic medication (such as a 2. National Center for Biotechnology Information, pain reliever, stimulant, or tranquilizer) in the past month. www.ncbi.nlm.nih.gov That was up from 8.3 percent in 2002.7 3. Schizophrenia Bulletin, www.schizophreniabulletin.oxfordjournals.org • In 2008 there were 1.9 million cocaine users. Adults ages 18 to 25 have a higher rate of current cocaine use 4. Mental Health America, www.mentalhealthamerica.net than any other age group. Overall, men report higher 5. U.S. Centers for Disease Control and Prevention, rates of cocaine use than women.8 www.cdc.gov

• Estimates of the total overall costs of substance abuse 6. National Institute on Alcohol Abuse and Alcoholism, in the United States, including productivity and health- www.niaaa.nih.gov and crime-related costs, exceed $600 billion annually. 7. National Institute on Drug Abuse, www.drugabuse.gov That includes approximately $193 billion for illicit drugs, 8. Substance Abuse and Mental Health Services Adminis- 7 $193 billion for tobacco, and $235 billion for alcohol. tration, www.samhsa.gov

Tourette’s Syndrome9 9. National Alliance on Mental Illness, www.nami.org • Approximately 1 in 200 children have Tourette’s syn- drome.

10 Medicines in Development for Mental Health 2014 Medicines in Development for Mental Health

Anxiety Disorders

Product Name Sponsor Indication Development Phase*

aloradine Pherin Pharmaceuticals social anxiety disorder Phase II completed (sensory receptor cell modulator) Los Altos, CA (social phobia) www.pherin.com

alprazolam patch Nuvo Research panic disorder Phase I Mississauga, Canada www.nuvoresearch.com

AVN-101 AllaChem anxiety Phase II (5-HT6 receptor antagonist) Hallandale Beach, FL www.allachem.com Avineuro www.avineuro.com San Diego, CA

AVP-923 Avanir aggitation in Alzheimer’s disease Phase II (dextromethorphan/quinidine Aliso Viejo, CA www.avanir.com xed-dose combination)

bitopertin Roche obsessive-compulsive disorder Phase II (GlyT1 inhibitor) Nutley, NJ (see also schizophrenia) www.roche.com

brexpiprazole Lundbeck agitation associated with Phase III (dopamine partial agonist) Deer eld, IL Alzheimer’s disease www.lundbeck.com Otsuka Pharmaceutical (see also ADHD, depression, www.otsuka.com Rockville, MD schizophrenia) ------post-traumatic stress disorder Phase III (PTSD) www.lundbeck.com www.otsuka.com

Brintellix® Lundbeck generalized anxiety disorder Phase III vortioxetine Deer eld, IL (see also depression) www.lundbeck.com Takeda Pharmaceuticals www.takeda.com Deer eld, IL ------anxiety disorders Phase II (children and adolescents) www.lundbeck.com www.takeda.com

ELND005 Transition Therapeutics agitation and aggression associated Phase II Toronto, Canada with Alzheimer’s disease www.transitiontherapeutics.com (Fast Track)

ganaxolone Marinus Pharmaceuticals PTSD Phase II New Haven, CT www.marinuspharma.com

guanfacine extended release Shire generalized anxiety disorder Phase II completed (SPD503) Wayne, PA separation anxiety disorder, www.shire.com social phobia

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

Medicines in Development for Mental Health 2014 11 Medicines in Development for Mental Health

Anxiety Disorders

Product Name Sponsor Indication Development Phase

IW-2143 Bionomics anxiety Phase I Thebarton, Australia www.bionomics.com.au Ironwood Pharmaceuticals www.ironwoodpharma.com Cambridge, MA

JNJ-42165279 Janssen Research & Development anxiety disorders Phase I Raritan, NJ www.janssenrnd.com

nepicastat Biotie Therapies PTSD Phase II (SYN117) Turku, Finland (see also substance use) www.biotie.com U.S. Department of Defense Washington, DC

SRX246 Azevan Pharmaceuticals stress-related a ective disorders Phase I (vasopressin 1a receptor Bethlehem, PA www.azevan.com antagonist)

Viibryd® Forest Laboratories generalized anxiety disorder Phase III vilazodone New York, NY (see also depression) www.frx.com

Attention-Defi cit/Hyperactivity Disorder

Product Name Sponsor Indication Development Phase

ADHD therapeutic Neos Therapeutics attention-de cit/hyperactivity in clinical trials Grand Prairie, TX disorder (ADHD) www.neostx.com

AR08 Arbor Pharmaceuticals ADHD Phase II (adrenergic receptor agonist) Atlanta, GA www.arborpharma.com

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

brexpiprazole Lundbeck ADHD (adults) Phase II (dopamine partial agonist) Deer eld, IL (see also anxiety, depression, www.lundbeck.com Otsuka Pharmaceutical schizophrenia) www.otsuka.com Rockville, MD

EB-1020 Euthymics Biosciences ADHD (adults) Phase II (triple reuptake inhibitor) Cambridge, MA www.euthymics.com

edivoxetine Eli Lilly ADHD Phase II/III Indianapolis, IN www.lilly.com

12 Medicines in Development for Mental Health 2014 Medicines in Development for Mental Health

Attention-Defi cit/Hyperactivity Disorder

Product Name Sponsor Indication Development Phase

eltoprazine Amarantus Bioscience ADHD (adults) Phase II San Francisco, CA www.amarantus.com

HLD200 Highland Therapeutics ADHD (pediatric) Phase III (methylphenidate modi ed Toronto, Canada www.highlandtherapeutics.com release) Ironshore Pharmaceuticals and Development Toronto, Canada

metadoxine extended release Alcobra ADHD (adults) Phase II/III Tel-Aviv, Israel www.alcobra-pharma.com

NT0102 Neos Therapeutics ADHD (pediatric) Phase III Grand Prairie, TX www.neostx.com

NT0202 Neos Therapeutics ADHD application submitted (amphetamine polistirex Grand Prairie, TX www.neostx.com disintegrating tablet, extended release)

ORADUR®-ADHD DURECT ADHD Phase I methylphenidate sustained release Cupertino, CA www.durect.com

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

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

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

Autism Spectrum Disorders Autism spectrum disorders, although most commonly referred to as developmental disorders, are included here because individuals with autism can have mental health-related symptoms.

Product Name Sponsor Indication Development Phase

AT001 Autism Therapeutics autism Phase III ( uoxetine rapid dissolve) New York, NY (repetitive behaviors) www.autismtherapeutics.com ORPHAN DRUG (Fast Track)

CM-AT Curemark autism application submitted Rye, NY (Fast Track) www.curemark.com

Medicines in Development for Mental Health 2014 13 Medicines in Development for Mental Health

Autism Spectrum Disorders

Product Name Sponsor Indication Development Phase

CNDO-201 Coronado Biosciences autism Phase II (Trichuris suis ova) Burlington, MA www.coronadobiosciences.com

memantine Forest Laboratories pervasive developmental disorder Phase II completed New York, NY not otherwise speci ed, Asperger’s www.frx.com syndrome, autism (pediatric)

RG7314 Roche autism Phase II (vasopressin-1 receptor Nutley, NJ www.roche.com antagonist)

syntocinon nasal spray Retrophin autism Phase II New York, NY (see also schizophrenia) www.retrophin.com

Bipolar Disorders

Product Name Sponsor Indication Development Phase

Abilify® Maintena® Otsuka Pharmaceutical bipolar disorder Phase III aripiprazole for extended release Rockville, MD www.otsuka.com injectable suspension (depot injection)

cariprazine Forest Laboratories manic or mixed episodes associated application submitted New York, NY with bipolar I disorder www.frx.com (see also depression, schizophrenia)

Latuda® Sunovion bipolar maintenance Phase III lurasidone Marlborough, MA (see also depression) www.sunovion.com

Rozerem® Takeda Pharmaceutical bipolar 1 disorder Phase III ramelteon Deer eld, IL www.takeda.com (sublingual formulation)

Saphris® Forest Laboratories bipolar disorder Phase III asenapine New York, NY (children and adolescents) www.frx.com Merck www.merck.com Whitehouse Station, NJ

14 Medicines in Development for Mental Health 2014 Medicines in Development for Mental Health

Depression

Product Name Sponsor Indication Development Phase

ademetionine MSI Methylation Sciences major depressive disorder Phase II (MSI-195) Burnaby, Canada www.methylationsciences.com

ALKS 5461 Alkermes major depressive disorder Phase III (buprenorphine/samidorphan) Waltham, MA (Fast Track) www.alkermes.com

amitifadine Euthymics Bioscience major depressive disorder Phase II/III (triple reuptake inhibitor) Cambridge, MA www.euthymics.com

armoda nil Teva Pharmaceutical major depressive disorder associated Phase III completed North Wales, PA with bipolar 1 disorder www.tevapharm.com (see also eating disorders)

AVP-786 Avanir Pharmaceuticals treatment-resistant depression Phase I completed (deuterium modi ed Aliso Viejo, CA www.avanir.com dextromethorphan and ultra-low Concert Pharmaceuticals www.concertpharma.com dose quinidine) Lexington, MA

AZD6423 AstraZeneca suicidal ideation Phase I (NMDA modulator) Wilmington, DE www.astrazeneca.com

Botox® Allergan major depressive disorder Phase II onabotulinumtoxinA Irvine, CA www.allergan.com

brexpiprazole Lundbeck major depressive disorder Phase III (dopamine partial agonist) Deer eld, IL (adjunctive treatment) www.lundbeck.com Otsuka Pharmaceutical (see also ADHD, anxiety, www.otsuka.com Rockville, MD schizophrenia)

Brintellix® Lundbeck depressive disorders Phase II vortioxetine Deer eld, IL (children and adolescents) www.lundbeck.com Takeda Pharmaceutical (see also anxiety) www.takeda.com Deer eld, IL

cariprazine Forest Laboratories bipolar depression, major depressive Phase II New York, NY disorder (adjunctive treatment) www.frx.com (see also bipolar, schizophrenia)

CERC-301 Cerecor major depressive disorder Phase II (NR2B antagonist) Baltimore, MD (Fast Track) www.cerecor.com ------active suicidal ideation Phase II www.cerecor.com

DSP-1053 Sunovion major depressive disorder Phase I (serotonin uptake inhibitor) Marlborough, MA www.sunovion.com

Medicines in Development for Mental Health 2014 15 Medicines in Development for Mental Health

Depression

Product Name Sponsor Indication Development Phase

esketamine Janssen Research & Development treatment-resistant major depressive Phase II (intranasal) Raritan, NJ disorder www.janssenrnd.com (Fast Track)

GLYX-13 Naurex major depressive disorder Phase II Evanston, IL (Fast Track) www.naurex.com

HT-2157 Dart NeuroScience major depressive disorder Phase II (GALR3 antagonist) San Diego, CA www.dartneuroscience.com

JNJ-42847922 Janssen Research & Development major depressive disorder Phase I Raritan, NJ www.janssenrnd.com

Latuda® Sunovion major depressive disorder with mixed Phase III lurasidone Marlborough, MA features www.sunovion.com (see also bipolar)

LY03005 Luye America Pharmaceuticals major depressive disorder Phase I Princeton, NJ www.luye.cn

LY2940094 Eli Lilly major depressive disorder Phase II (NOC-1 antagonist) Indianapolis, IN (see also substance use) www.lilly.com

mifepristone Corcept Therapeutics major depression disorder with Phase III Menlo Park, CA psychotic features www.corcept.com

MIN-117 Minerva Neurosciences major depressive disorder Phase II (5-HT1A/5-HTT receptor Cambridge, MA www.minervaneurosciences.com antagonist)

NRX-1074 Naurex major depressive disorder Phase I (NMDA receptor agonist) Evanston, IL www.naurex.com

NSI-189 Neuralstem major depressive disorder Phase I (stimulating neurogenesis) Germantown, MD www.neuralstem.com

Pristiq® P zer major depressive disorder Phase III desvenlafaxine New York, NY (children and adolescents) www.pfizer.com

RG1578 Roche major depressive disorder Phase II (mGluR2) Nutley, NJ www.roche.com

RG7090 Roche treatment-resistant depression Phase II (mGluR5 antagonist) Nutley, NJ www.roche.com

16 Medicines in Development for Mental Health 2014 Medicines in Development for Mental Health

Depression

Product Name Sponsor Indication Development Phase

RO4995819 Roche major depressive disorder Phase II Nutley, NJ www.roche.com

tedatioxetine Lundbeck major depressive disorder Phase II Deer eld, IL www.lundbeck.com Takeda Pharmaceutical www.takeda.com Deer eld, IL

Viibryd® Forest Laboratories major depressive disorder Phase III vilazodone New York, NY (adolescents) www.frx.com (see also anxiety)

Eating Disorders

Product Name Sponsor Indication Development Phase

armoda nil Teva Pharmaceutical binge-eating disorder Phase III North Wales, PA (see also depression) www.tevapharm.com Lindner Center of HOPE Cincinnati, OH

LDX Shire binge-eating disorder (adults) Phase III (lisdexamfetamine) Wayne, PA www.shire.com

Schizophrenia

Product Name Sponsor Indication Development Phase

ABT-126 AbbVie cognition impairment associated with Phase II (alpha7 NNR antagonist) North Chicago, IL schizophrenia (CIAS) www.abbvie.com

ADX71149/JNJ-40411813 Addex Therapeutics schizophrenia Phase II (mGlu2 PAM modulator) Geneva, Switzerland www.addextherapeutics.com Janssen Research & Development www.janssenrnd.com Raritan, NJ

ALKS 3831 Alkermes schizophrenia Phase II (olanzapine/samidorphan Waltham, MA www.alkermes.com xed-dose combination)

AMG 581 Amgen schizophrenia Phase I Thousand Oaks, CA www.amgen.com

Medicines in Development for Mental Health 2014 17 Medicines in Development for Mental Health

Schizophrenia

Product Name Sponsor Indication Development Phase

AQW051 Novartis Pharmaceuticals CIAS Phase II completed (alpha7 nicotinic acetylcholine East Hanover, NJ www.novartis.com receptor agonist)

aripiprazole lauroxil Alkermes schizophrenia Phase III (ALKS 9072) Waltham, MA www.alkermes.com

AVL-3288 Anvyl Pharmaceuticals CIAS Phase I (alpha7 nicotinic acetylcholine Irvine, CA www.anvylllc.com receptor modulator)

AVN-211 AllaChem schizophrenia Phase II (5-HT6 receptor antagonist) Hallandale Beach, FL www.allachem.com Avineuro Pharmaceuticals www.avineuro.com San Diego, CA

BI-409306 Boehringer Ingelheim Pharmaceuticals schizophrenia Phase I completed Ridge eld, CT www.boehringer-ingelheim.com

bitopertin Roche schizophrenia-suboptimally Phase III (GlyT1 inhibitor) Nutley, NJ controlled symptoms www.roche.com (see also anxiety)

brexpiprazole Lundbeck schizophrenia Phase III (dopamine partial agonist) Deer eld, IL (see also ADHD, anxiety, depression) www.lundbeck.com Otsuka Pharmaceutical www.otsuka.com Rockville, MD

cariprazine Forest Laboratories schizophrenia application submitted New York, NY (see also bipolar, depression) www.frx.com

CEP-26401 Teva Pharmaceutical CIAS Phase I completed (irdabisant) North Wales, PA www.tevapharm.com

encenicline Forum Pharmaceuticals CIAS Phase III (alpha-7 agonist) Watertown, MA www.forumpharma.com

FRM-6308 Forum Pharmaceuticals schizophrenia Phase I (PDE10 inhibitor) Watertown, MA www.forumpharma.vom

Invega® Sustenna® Alkermes schizoa ective disorder Phase III paliperidone palmitate Waltham, MA www.alkermes.com Janssen Research & Development www.janssenrnd.com Raritan, NJ ------schizophrenia (3 month injectable) Phase III www.alkermes.com www.janssenrnd.com

18 Medicines in Development for Mental Health 2014 Medicines in Development for Mental Health

Schizophrenia

Product Name Sponsor Indication Development Phase

ITI-007 Intra-Cellular Therapies schizophrenia Phase II (5-HT2A serotonin receptor New York, NY www.intracellulartherapies.com antagonist)

ITI-214 Intra-Cellular Therapies CIAS Phase I (PDE1 inhibitor) New York, NY www.intracellulartherapies.com Takeda Pharmaceuticals www.takeda.com Deer eld, IL

LY03004 Luye America Pharmaceuticals schizophrenia, schizoa ective disorder Phase I (risperidone controlled release) Princeton, NJ www.luye.cn

MIN-101 Minerva Neurosciences schizophrenia Phase II (5-HT2A/sigma-2 receptor Cambridge, MA www.minervaneurosciences.com antagonist)

NW-3509 Newron Pharmaceuticals schizophrenia Phase I (potent sodium channel blocker) Bresso, Italy www.newron.com

OMS824 Omeros schizophrenia Phase II (PDE10 inhibitor) Seattle, WA www.omeros.com

PF-02545920 P zer schizophrenia Phase II (PDE10 inhibitor) New York, NY (adjunctive treatment) www.pfizer.com

PF-04958242 P zer schizophrenia Phase I (AMPA receptor modulator) New York, NY www.pfizer.com

PF-06412562 P zer CAIS Phase I New York, NY www.pfizer.com

pimavanserin ACADIA Pharmaceuticals Parkinson’s disease psychosis Phase III San Diego, CA www.acadia-pharm.com ------Alzheimer’s disease psychosis, Phase II schizophrenia www.acadia-pharm.com

RBP-7000 Reckitt Benckiser Pharmaceutical schizophrenia Phase III (dopamine-D2/serotonin-2 Richmond, VA www.rb.com antagonist)

Relday™ DURECT schizophrenia Phase I risperidone controlled release Cupertino, CA www.durect.com Zogenix www.zogenix.com San Diego, CA

Medicines in Development for Mental Health 2014 19 Medicines in Development for Mental Health

Schizophrenia

Product Name Sponsor Indication Development Phase

RG7203 Roche schizophrenia Phase I (PDE10A inhibitor) Nutley, NJ www.roche.com

RO5545965 Roche schizophrenia Phase I Nutley, NJ www.roche.com

RP5063 Reviva Pharmaceuticals schizophrenia, schizoa ective disorder Phase II (partial agonist of dopamine and San Jose, CA www.revivapharma.com serotonin)

Saphris® Forest Laboratories schizophrenia (adolescents) Phase III completed asenapine New York, NY (see also bipolar) www.frx.com Merck www.merck.com Whitehouse Station, NJ

SEP-363856 Sunovion schizophrenia Phase I Marlborough, MA www.sunovion.com

syntocinon nasal spray Retrophin schizophrenia Phase II New York, NY (see also autism) www.retrophin.com

TAK-063 Takeda Pharmaceuticals schizophrenia Phase I (PDE10A inhibitor) Deer eld, IL www.takeda.com

zicronapine Lundbeck schizophrenia Phase III Deer eld, IL www.lundbeck.com

Substance Use/Addictive Disorders

Product Name Sponsor Indication Development Phase

ABT-436 AbbVie alcohol use disorder Phase II (selective vasopressin receptor North Chicago, IL www.abbvie.com antagonist) National Institute on Alcohol www.niaaa.nih.gov Abuse and Alcoholism Bethesda, MD

AD01 ADial Pharmaceuticals alcohol use disorder Phase II (ondansetron/topiramate) Charlottesville, VA www.adialpharma.com

AD04 ADial Pharmaceuticals alcohol use disorder Phase II (low-dose ondansetron) Charlottesville, VA www.adialpharma.com

Bunavail™ BioDelivery Sciences International opioid use disorder, opioid abuse application submitted buprenorphine/naloxone Raleigh, NC www.bdsi.com transmucosal

20 Medicines in Development for Mental Health 2014 Medicines in Development for Mental Health

Substance Use/Addictive Disorders

Product Name Sponsor Indication Development Phase

bupropion/mecamylamine Cary Pharmaceuticals smoking withdrawal Phase I completed once-daily tablet Great Falls, VA www.carypharma.com (QuitPak®)

Ch-mAb7F9 InterveXion Therapeutics methamphetamine use disorder Phase I completed (METH-mAb) Little Rock, AR www.intervexion.com

EMB-001 Embera NeuroTherapeutics cocaine use disorder Phase I completed (metyrapone/oxazepam) Sudbury, MA www.emberaneuro.com

lofexidine US WorldMeds opioid use disorder Phase III Louisville, KY www.usworldmeds.com National Institute on Drug Abuse www.drugabuse.gov Bethesda, MD

LY2940094 Eli Lilly alcohol use disorder Phase II (NOC-1 antagonist) Indianapolis, IN (see also depression) www.lilly.com

MN-166 MediciNova methamphetamine use disorder Phase II (ibudilast) La Jolla, CA (Fast Track) www.medicinova.com National Institute on Drug Abuse www.drugabuse.gov Bethesda, MD

naloxone nasal spray Lightlake Therapeutics opioid use disorder Phase II London, United Kingdom www.lightlaketherapeutics.com National Institute on Drug Abuse www.drugabuse.gov Bethesda, MD

nepicastat Biotie Therapies cocaine use disorder Phase II (SYN117) Turku, Finland (see also anxiety) www.biotie.com National Institute on Drug Abuse www.drugabuse.gov Bethesda, MD

OMS405 Omeros opioid use disorder, smoking Phase II (PPAR-gamma agonist) Seattle, WA withdrawal www.omeros.com

PF-05402536 P zer smoking withdrawal Phase I (smoking cessation vaccine) New York, NY www.pfizer.com

Probuphine® Braeburn Pharmaceuticals opioid use disorder application submitted buprenorphine implant Princeton, NJ www.braeburnpharmaceuticals.com Titan Pharmaceuticals www.titanpharm.com South San Francisco, CA

RBP-6000 Reckitt Benckiser Pharmaceutical opioid use disorder Phase II (buprenorphine depot) Richmond, VA www.rb.com

Medicines in Development for Mental Health 2014 21 Medicines in Development for Mental Health

Substance Use/Addictive Disorders

Product Name Sponsor Indication Development Phase

RBP-8000 Reckitt Benckiser Pharmaceutical cocaine use disorder Phase II (cocaine esterase) Richmond, VA www.rb.com

SEL-068 Selecta Biosciences smoking withdrawal Phase I (nicotine antibodies) Watertown, MA www.selectabio.com

TA-CD Baylor College of Medicine cocaine use disorder Phase II (cocaine abuse vaccine) Houston, Texas www.drugabuse.gov Celtic Pharma Holdings Hamilton, Bermuda National Institute on Drug Abuse Bethesda, MD

TV-1380 Teva Pharmaceutical cocaine use disorders Phase II (form of human plasma North Wales, PA www.tevapharm.com butyrylcholinesterase) TIC Disorders

Product Name Sponsor Indication Development Phase

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

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

ecopipam Psyadon Pharmaceuticals Tourette’s syndrome Phase II Germantown, MD www.psyadonrx.com

22 Medicines in Development for Mental Health 2014 Medicines in Development for Mental Health

Other Disorders

Product Name Sponsor Indication Development Phase

PH80-PMD Pherin Pharmaceuticals premenstrual dysphoric disorder, Phase II completed Los Altos, CA premenstrual syndrome www.pherin.com

RG1662 Roche cognitive impairment associated with Phase I (GABA-A alpha5 receptor Nutley, NJ Downs syndrome www.roche.com modulator)

The content of this report has been obtained through public, government and industry sources, and the Adis “R&D Insight” database based on the latest information. Report current as of April 28, 2014. The medicines in this report include medi- cines being developed by U.S.-based companies conducting trials in the United States and abroad, PhRMA-member compa- nies 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 specifi c 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 © 2014 by the Pharmaceutical Research and Manufacturers of America. Permission to reprint is awarded if proper credit is given.

Pharmaceutical Research and Manufacturers of America • 950 F Street, NW, Washington, DC 20004

Medicines in Development for Mental Health 2014 23 Glossary

anxiety disorders—Anxiety is a normal combination of different symptom types. high blood pressure. They also experi- reaction to stress and can be benefi - Those with mostly inattentive symptoms ence guilt, shame, and distress about cial in some situations, but for some are sometimes said to have attention their binge-eating, which can lead to people anxiety may become excessive. defi cit disorder (ADD). They tend to be more binge-eating. While people suffering may realize their less disruptive and are more likely not to —Also known as manic- anxiety is too much, they may also be diagnosed with ADHD. bipolar disorder depressive illness, a brain disorder that have diffi culty controlling it, and it may —ASD causes unusual shifts in mood, energy, negatively affect their day-to-day living. autism spectrum disorder (ASD) is a developmental disability that can activity levels, and the ability to carry The wide variety of anxiety disorders cause signifi cant social, communica- out day-to-day tasks. Symptoms of includes generalized anxiety disorder tion and behavioral challenges. People bipolar disorder are severe. They are dif- (GAD), obsessive-compulsive disorder with ASD may communicate, interact, ferent from the normal ups and downs (OCD), panic disorder, post-traumatic behave, and learn in ways that are that everyone goes through from time stress disorder (PTSD), and social different from most other people. The to time. People with bipolar disorder phobia. Collectively, they are among the learning, thinking, and problem-solving experience unusually intense emotional most common mental health disorders abilities of people with ASD can range states that occur in distinct periods experienced by Americans. from gifted to severely challenged. called “mood episodes.” Each mood epi- application submitted—An application Some people with ASD need a lot of sode represents a drastic change from for marketing has been submitted by help in their daily lives; others need less. a person’s usual mood and behavior. the company to the U.S. Food and Drug People with ASD often have problems An overly joyful or overexcited state is Administration (FDA). with social, emotional, and communica- called a manic episode, and an ex- tion skills. They might repeat certain tremely sad or hopeless state is called a attention defi cit/hyperactivity disor- behaviors and might not want change depressive episode. Sometimes, a mood der (ADHD)—ADHD is a problem of in their daily activities. Many people episode includes symptoms of both not being able to focus, being overac- with ASD also have different ways of mania and depression, called a mixed tive, not being able control behavior, learning, paying attention, or reacting to state. People with bipolar disorder also or a combination of these symptoms. things. Signs of ASD begin during early may be explosive and irritable during For those problems to be diagnosed as childhood and typically last throughout a mood episode. Extreme changes in ADHD, they must be out of the normal a person’s life. A diagnosis of ASD now energy, activity, sleep, and behavior range for a person’s age and develop- includes several conditions that used to go along with those changes in mood. ment. ADHD usually begins in childhood be diagnosed separately: autistic disor- Bipolar disorder symptoms can result but may continue into the adult years. der, pervasive developmental disorder in damaged relationships, poor job or It is the most commonly diagnosed not otherwise specifi ed, and Asperger’s school performance, and even suicide. behavioral disorder in children. ADHD syndrome. Those conditions are now all But bipolar disorder can be treated, and is diagnosed much more often in boys called autism spectrum disorder. people with the illness can lead full and than in girls. A combination of genes productive lives. and environmental factors likely plays a binge-eating disorder—With binge-eat- role in the development of the condi- ing disorder a person loses control over depression—Everyone occasionally feels tion. Symptoms of ADHD fall into three his or her eating. Unlike bulimia nervosa, blue or sad, but those feelings are usu- groups: not being able to focus (inatten- periods of binge-eating are not fol- ally short-lived and pass within a couple tiveness); being extremely active (hyper- lowed by purging, excessive exercise, or of days. Depression, however, interferes activity); and not being able to control fasting. As a result, people with binge- with daily life and causes pain for both behavior (impulsivity). Some people with eating disorder often are overweight or the sufferers and those who care about ADHD have mainly inattentive symp- obese. People with binge-eating disor- them. Depression is a common but seri- toms. Some have mainly hyperactive der who are obese are at higher risk for ous illness. Major depression and persis- and impulsive symptoms. Others have a developing cardiovascular disease and tent depressive disorder are among the

24 Medicines in Development for Mental Health 2014 Glossary

several forms of depressive disorders. where none exists or providing a therapy an overwhelming urge to repeat certain Major depression causes severe symp- that may be potentially superior to exist- rituals or behaviors called compulsions. toms that interfere with a person’s abil- ing therapy. Once a drug receives Fast People with OCD can’t control those ity to work, sleep, study, eat, and enjoy Track designation, early and frequent obsessions and compulsions—the rituals life. An episode can occur only once in communication between the FDA and a usually end up controlling them. For a person’s lifetime, but more often, a drug company is encouraged throughout example, if people are obsessed with person has several episodes. Persistent the entire drug development and review germs or dirt, they may develop a com- depressive disorder causes a depressed process. The frequency of communica- pulsion to wash their hands over and mood that lasts for at least 2 years. tion ensures that questions and issues over again. If they develop an obsession A person diagnosed with persistent are resolved quickly, often leading to with intruders, they may lock and relock depressive disorder may have episodes earlier drug approval and access by their doors many times before going of major depression along with periods patients. to bed. Performing such rituals is not of less severe symptoms, but symp- pleasurable. At best, it produces tempo- — toms must last for 2 years. People with generalized anxiety disorder (GAD) rary relief from the anxiety created by While everyone worries about things depressive illnesses do not all experi- obsessive thoughts. People with OCD like health, money, or family problems, ence the same symptoms. The severity, perform their rituals even though doing people with GAD are extremely worried frequency, and duration of symptoms so interferes with daily life, and they fi nd about those problems and many other vary depending on the individual and the repetition distressing. Although most things, even when there is little or no his or her particular illness. A few of the adults with OCD recognize that what reason to worry about them. They are many signs and symptoms of depression they are doing is senseless, some adults very anxious about just getting through are: persistent sad, anxious, or “empty” and most children may not realize that the day, thinking that things will always feelings; feelings of hopelessness or pes- their behavior is out of the ordinary. go badly. At times, worrying keeps simism; fatigue and decreased energy; people with GAD from doing everyday —A drug to treat a dis- diffi culty concentrating, remembering Orphan Drug tasks. They can’t relax, startle easily, and ease that has a patient population of details, and making decisions; overeating, have diffi culty concentrating. Often they 200,000 or less in the United States, or or appetite loss; and thoughts of suicide, have trouble falling asleep or staying a disease that has a patient population or suicide attempts. asleep. Physical symptoms that often of more than 200,000 and a develop- Fast Track—A process designed to accompany the anxiety include fatigue, ment cost that will not be recovered facilitate the development and expedite headaches, muscle tension, muscle from sales in the United States. the review of drugs to treat serious aches, diffi culty swallowing, trembling, —People with panic dis- diseases and fi ll an unmet medical need. twitching, irritability, sweating, nausea, panic disorder order have sudden and repeated attacks The status is assigned by the U.S. Food lightheadedness, having to go to the of fear that last for several minutes. and Drug Administration (FDA). The bathroom frequently, feeling out of Sometimes symptoms may last longer purpose of this process is to get impor- breath, and hot fl ashes. and are called panic attacks. Panic tant new drugs to the patient earlier. —New chemical entity. attacks are characterized by a fear of Fast Track addresses a broad range of NCE disaster or of losing control even when serious diseases. In general, determining obsessive-compulsive disorder (OCD)— there is no real danger. A person may factors for whether a drug receives Fast People with OCD feel the need to also have a strong physical reaction dur- Track include whether the drug will af- check things repeatedly or have certain ing a panic attack. It may feel like having fect factors such as survival, day-to-day thoughts or perform routines and rituals a heart attack. Panic attacks can occur functioning, or the likelihood that the over and over. The thoughts and rituals at any time, and many people with panic disease, if left untreated, will progress associated with OCD cause distress and disorder worry about and dread the from a less severe condition to a more get in the way of daily life. The frequent possibility of having another attack. A serious one. Filling an unmet medical upsetting thoughts are called obsessions. person with panic disorder may become need is defi ned as providing a therapy To try to control them, a person will feel discouraged and feel ashamed because

Medicines in Development for Mental Health 2014 25 Glossary

he or she cannot carry out normal rou- physical harm. The person who develops increased impulsive behaviors (e.g., tines like going to the grocery store or PTSD may have been the one who was sexual activities, drug and alcohol abuse, driving. Having panic disorder can also harmed, the harm may have happened gambling, or spending large amounts interfere with school or work. to a loved one, or the person may have of money). Many of the strategies used witnessed a harmful event that hap- to treat both schizophrenia and affec- Phase 0—First-in-human trials con- pened to loved ones or strangers. PTSD tive conditions can be employed for this ducted in accordance with FDA’s 2006 was fi rst brought to public attention in condition, including antipsychotic and guidance on exploratory Investigational relation to war veterans, but it can result mood stabilizing medications, family New Drug (IND) studies designed to from a variety of traumatic incidents, involvement, psychosocial strategies, speed development of promising drugs such as a mugging, rape, being kid- self-care peer support, psychotherapy by establishing early whether the tested napped or held captive, child abuse, and integrated care for co-occurring compound behaves in humans as was major accidents, or natural disasters substance abuse (when appropriate). anticipated from preclinical studies. such as fl oods or earthquakes. schizophrenia—A chronic, severe, and —Researchers test the drug in a Phase I schizoaffective disorder—A serious disabling brain disorder that has affected small group of people, usually between mental illness that affects about one people throughout history. About 1 20 and 80 healthy adult volunteers, to in 100 people. Schizoaffective disor- percent of Americans have the illness. evaluate its initial safety and tolerability der as a diagnostic entity has features People with the disorder may hear profi le, determine a safe dosage range, that resemble both schizophrenia and voices other people don’t hear. They and identify potential side effects. also serious mood (affective) symp- may believe other people are reading Phase II—The drug is given to volunteer toms. A person who has schizoaffec- their minds, controlling their thoughts, patients, usually between 100 and 300, tive disorder will experience delusions, or plotting to harm them. That can to determine whether the drug is effec- hallucinations, other symptoms that terrify people with the illness and make tive, identify an optimal dose, and to are characteristic of schizophrenia, and them withdrawn or extremely agitated. evaluate further its short-term safety. signifi cant disturbances in their mood People with schizophrenia may not make (e.g., affective symptoms). People who sense when they talk. They may sit for Phase III—The drug is given to a larger, experience more than two weeks of hours without moving or talking. Some- more diverse patient population, often psychotic symptoms in the absence times people with schizophrenia seem involving between 1,000 and 3,000 of severe mood disturbances—and perfectly fi ne until they talk about what patients (but sometimes many more then have symptoms of either depres- they are really thinking. Families and thousands), to generate statistically sion or bipolar disorder—may have society are affected by schizophrenia, signifi cant evidence to confi rm its safety schizoaffective disorder. Schizoaffective too. Many people with schizophrenia and effectiveness. Phase III studies are disorder is thought to be between the have diffi culty holding a job or caring the longest studies and usually take bipolar and schizophrenia diagnoses for themselves, so they rely on others place in multiple sites around the world. as it has features of both. Depressive for help. Cognitive symptoms are subtle symptoms associated with schizoaffec- and may be diffi cult to recognize as part post-traumatic stress disorder (PTSD)— tive disorder can include—but are not of the disorder. Often, they are detected When in danger, it’s natural to feel limited to—hopelessness, helplessness, only when other tests are performed. afraid. That fear triggers the “fi ght-or- guilt, worthlessness, disrupted appetite, Cognitive symptoms include the follow- fl ight” response as a healthy reaction disturbed sleep, inability to concentrate, ing: poor “executive functioning” (the meant to protect a person from harm. and depressed mood (with or without ability to understand information and But in PTSD, that reaction is changed suicidal thoughts). Manic (bipolar) symp- use it to make decisions); trouble focus- or damaged. People who have PTSD toms associated with schizoaffective ing or paying attention; problems with may feel stressed or frightened even disorder can include increased energy, “working memory” (the ability to use in- when they’re no longer in danger. PTSD decreased sleep (or decreased need for formation immediately after learning it). develops after a terrifying ordeal that sleep), distractibility, fast speech, and Cognitive symptoms often make it hard involved physical harm or the threat of

26 Medicines in Development for Mental Health 2014 Glossary

to lead a normal life and earn a living. substance use disorders—A term used harmful consequences. It is considered a They can cause great emotional distress. to characterize illnesses associated with brain disease because drugs change the Treatment helps relieve many symptoms drug use. There are two broad catego- brain—its structure and how it works. of schizophrenia, but most people who ries: substance abuse and substance Those brain changes can be long lasting have the disorder cope with symptoms dependence. Both are associated with and can lead to many harmful, often throughout their lives. a maladaptive pattern of substance self-destructive, behaviors. use that leads to clinically signifi cant —A neurologi- social phobia (social anxiety disorder)— impairment. Drug abuse includes such Tourette’s syndrome (TS) cal disorder characterized by repetitive, Social phobia is a strong fear of being symptoms as: failure to fulfi ll major involuntary movements and vocaliza- judged by others and of being embar- role obligations; legal problems; use in tions called tics. The early symptoms of rassed. The fear can be so strong that situations that are physically hazardous; TS are typically noticed fi rst in child- it gets in the way of going to work or and continued use despite persistent hood, with the average onset between school or doing other everyday things. social or interpersonal problems. The the ages of 3 and 9. TS occurs in people Meeting new people or giving a public term dependence includes such symp- from all ethnic groups; males are af- speech can make anyone nervous, but toms as: drug taking in larger amounts fected about three to four times more people with social phobia worry about than intended; inability to cut down on often than females. It is estimated that such things for weeks before they hap- drug use; a great deal of time spent in 200,000 Americans have the most pen. People with social phobia are afraid activities necessary to obtain the drug; severe form of TS, and as many as 1 of doing common things in front of and continued use despite knowledge in 100 exhibit milder and less complex other people. For example, they might of health or social problems caused by symptoms such as chronic motor or be afraid to sign a check in front of a the drug. Dependence may or may not vocal tics. Although TS can be a chronic cashier at the grocery store, or they include “physical dependence,” defi ned condition with symptoms lasting a might be afraid to eat or drink in front by withdrawal symptoms when drug use lifetime, most people with the condition of other people. Most people who have is abruptly ceased, and “tolerance,” the experience their worst tic symptoms in social phobia know that they shouldn’t need for more of a drug to achieve a their early teens, with improvement oc- be as afraid as they are, but they can’t desired effect. The term “dependence” curring in the late teens and continuing control their fear. For some people, can also refer to “addiction.” Addiction into adulthood. social phobia is a problem only in certain is defi ned as a chronic, relapsing brain situations, while others have symptoms disease that is characterized by com- in almost any social situation. pulsive drug seeking and use, despite

Medicines in Development for Mental Health 2014 27 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 signifi cant evidence to confi rm 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 fi ve 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 fi ve is analyzes all of the data and fi les 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 scientifi c 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 profi le, deter- the new medicine becomes available for physi- Once a new compound has been identifi ed 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, diffi cult, 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 $51.1 billion in research and develop- pany fi les an IND with the U.S. Food and Drug (but sometime many more thousands), to gener- ment in 2013. Administration (FDA) to begin to test the drug