Fast-Fail Trials in Mood and Anxiety Spectrum Disorders; Kappa Opioid Receptor Phase 2a

FAST-MAS addresses an important problem and critical barrier to progress in Mood and Anxiety
Spectrum Disorders and if the aims of the project are achieved, FAST-MAS could shift
scientific knowledge, technical capacity, and clinical practice in a positive direction.

The Mood and Anxiety Spectrum disorders are both extremely common and associated with
significant morbidity and mortality and, as such, represent an important public health
problem in the United States.

The mood disorders include the following diagnostic entities: major depressive disorder
(MDD), bipolar disorder (including subtypes of mania, mixed state, and depressed, as well as
types I and II), and dysthymic disorder. Available epidemiologic data suggest that the
prevalence of these mood disorders is extremely high among adults in the United States,
approaching 10%. Among the mood disorders, MDD has high lifetime prevalence, with recent
estimates up to 16%. According to the World Health Organization (WHO), MDD is currently the
leading cause of disability with the greatest burden of illness in developed countries and
the third most common cause of disability worldwide. MDD is life shortening due to both
suicide and its association with increased mortality from other medical conditions. It is
also a highly recurrent condition with between 50% and 75% of persons diagnosed with MDD
experiencing more than one episode. Bipolar Disorder is also a highly recurrent condition.
The lifetime prevalence of bipolar disorder has been estimated to be approximately 3.4% in
the World Health Survey Initiative. Approximately 60% of affected individuals experience
severe or very severe role impairment based on the Sheehan Disability Scale and, like MDD,
bipolar disorder is associated with significant suicide risk.

The anxiety disorders are also very common and associated with significant adverse impact on
affected individuals and society. These disorders include the following diagnostic entities:
generalized anxiety disorder (GAD), panic disorder, obsessive-compulsive disorder, social
phobia, specific phobias, and post-traumatic stress disorder (PTSD). As a group, these
conditions affect approximately 18% of adults in a given year and they are associated with
significant co-morbidities and adverse consequences. Of the anxiety disorders, GAD appears to
be associated with the greatest per patient cost and disability with a degree of disability
comparable to that of MDD and comparable to chronic medical conditions such as arthritis,
diabetes, and peptic ulcer disease. It affects approximately 6.8 million adults in the U.S.
and is a highly chronic condition. Panic disorder affects about 6 million American adults and
is twice as common in women as men. Panic disorder is also highly disabling and often chronic
and even mild forms of this disorder are linked to significantly increased impairment in
function and quality of life as well as a number of comorbidities. Approximately 2.2 million
adults in the U.S. are affected by obsessive-compulsive disorder and this disorder is often
accompanied by psychiatric comorbidities. Roughly half of individuals with this condition
have a chronic unremitting course which is associated with significant disability and
morbidity. Social phobia, also known as social anxiety disorder, is seen in roughly 15
million adults in the U.S. and is often associated with MDD or other anxiety disorders. It is
generally a chronic condition that leads to a great degree of disability due to substantial
impairment in social, educational, and occupational function. Approximately 8 million adults
in the U.S. experience PTSD and approximately 12% of the population have PTSD at some point
in their lives and affected individuals frequently experience associated MDD, other anxiety
disorders and substance use problems. The level of disability associated with this condition
tends to be quite high and includes impairment in social and occupational function and
quality of life. There are also substantial financial and social costs associated with PTSD
due to increased hospitalization rates, suicidality, and substance use problem.

Mood disorders and anxiety disorders are highly prevalent conditions, many of which are
chronic, nearly all of which are associated with substantial comorbidities, disability and
impairment and some are associated with an increased risk for mortality. Despite the
availability of many pharmacologic, psychotherapeutic, brain stimulation, and combination
treatment options available to clinicians, many patients with Mood and Anxiety Spectrum
Disorders respond poorly to treatment. In light of the impairments, costs, and risks of these
disorders, the limitations of the available treatments represents an enormous burden to
public health and speak strongly to the need for new treatments for these conditions as well
as novel methodologies of treatment development that are not only faster than existing
methodologies but which also promote new ways of thinking about these disorders and their
treatment and capitalize on recent and ongoing developments in basic science.

This study will be a six-site randomized, double-blind, PBO (placebo) -controlled,
parallel-group mono-therapy study to assess the effects of CERC-501 (formerly known as
LY2456302) compared to PBO in adults age 21-65 years with mood and anxiety spectrum
disorders. We will recruit a total of 90 subjects, of which 45 will be randomized to CERC-501
and 45 to placebo for 8 weeks of treatment

Inclusion Criteria:

- Age between 21 and 65 years of age

- Must meet DSM-IV TR (Diagnostic and Statistical Manual of Mental Disorders, 4th
edition, text revision) diagnostic criteria for: Major Depressive Disorder, Bipolar I
or II Depressed, Generalized Anxiety Disorder, Social Phobia, Panic Disorder, or Post
Traumatic Stress Disorder

- Snaith-Hamilton Pleasure Scale (SHAPS) score ≥ 20

- Reliable and willing to be available for the duration of the study

- Willing and able to give written informed consent to participate

- Able to understand and comply with instructions

- If female of childbearing potential, must agree to use dual methods of contraception
and be willing and able to continue contraception for 6 weeks after the last dose of
study drug. Females using oral contraception must have started using it at least 2
months prior to the Baseline Visit

- If male of childbearing potential, must have undergone surgical sterilization (such as
a vasectomy) or agree to use a condom used with a spermicide during participation in
the study and for 1 month afterward

Exclusion Criteria:

- Expected to require hospitalization during the course of the study

- Current/history of a psychotic disorder, current manic or mixed episode, autism
spectrum disorders, mental retardation

- Met DSMIV-TR (Diagnostic and Statistical Manual of Mental Disorders, 4th edition, text
revision) criteria for substance abuse within the last 3 months or substance
dependence within the last 6 months, excluding caffeine and/or nicotine

- History of unstable or untreated serious medical condition based on physician
evaluation, medical history, and screening laboratory testing

- Active suicidal intent or plan, or history of attempt within the past 3 months based
on physician evaluation and Columbia Suicide Severity Rating Scale (C-SSRS)

- Use of any antidepressant, antipsychotic, anxiolytic, anticonvulsant, mood
stabilizing, muscle relaxant, centrally acting antihistaminergic, stimulant or
insomnia medications (See Appendix 2) within 5 half-lives of baseline or at any time
during after baseline

- Use of any medication that is primarily metabolized by Cytochrome P450 2C8 within 14
days of baseline or at any time during the study. This includes: Cerivastatin,
Paclitaxel, Repaglinide, Sorafenib, Rosiglitazone, Trimethoprim, Amodiaquine,
Morphine, Amiodarone, Cabazitaxel, Carbamazepine, Chloroquine, Ibuprofen, Trepostinil,
Torsemide.

- Any contraindications to the magnetic resonance imaging procedures

- Positive urine drug screen at any time during the study

- Use of any investigational medication within 3 months prior to the start of this study
or scheduled to receive an investigational drug other than the study drug during the
course of this study

- Known hypersensitivity to CERC-501 (formerly known as LY2456302)

- History of severe allergies or multiple adverse drug reactions

- History of gastric disease (including peptic ulcer disease, gastritis, upper GI
bleeding, or any GI precancerous condition), current clinically evident
gastrointestinal complaints, or positive urea breath test

- Current use of a proton pump inhibitor or histamine 2 blocker, or a history of chronic
NSAID (nonsteroidal anti-inflammatory drug) use.

- History of use of Salvia divinorum or use of Salvia divinorum at any time during the
study.

- Any other condition that in the opinion of the investigator would preclude
participation in the study

- Any smoking of cigarettes or use of other nicotine containing products within the last
month or at any time during the study

- Pregnant or lactating