ABT-436 for Alcohol Dependence

Adrenocorticotropic hormone (ACTH) release from the pituitary gland via V1B stimulation is
central to the hypothalamus-pituitary-adrenal (HPA) axis stress response (Carrasco & Van de
Kar-2003, Herman & Cullinan-1997, Sapolsky et al-2000; Tsigos & Chrousos-2002). Chronic
dysregulation of the HPA axis is common in major depressive disorder, anxiety disorders, and
substance abuse disorders characterized by elevated AVP, increased responsiveness to AVP, as
well as either increased or decreased overall HPA axis activity or responsiveness (Dinan &
Scott-2005). HPA axis normalization via pituitary V1B antagonism is a mechanism for
potential ABT-436 efficacy in these disorders (Schüle et al-2009). Limbic V1B antagonism in
the brain may also contribute to efficacy (Roper et al-2011).

Alcohol dependence, or alcoholism, is characterized by a chronic relapsing course, in which
alcohol-associated cues and stress are known relapse triggers (Brownell et al-1986, Heilig &
Egli-2006, Sinha & Li-2007). Recent research suggests that neural systems mediating
behavioral stress responses may offer useful targets for pharmacotherapy of alcoholism. In
animal models, excessive alcohol consumption that results from a history of alcohol
dependence is accompanied by increased behavioral sensitivity to stress (Heilig &
Koob-2007). Preclinical studies have shown that V1B antagonists can attenuate reinstatement
of heroin and alcohol self-administration, and block dependence-induced exaggeration of
alcohol intake, in rats. V1B antagonists have also been shown to block stress-induced
reinstatement of drug and alcohol seeking in ethanol dependent rats (Zhou-2011). For these
reasons the NIAAA Clinical Investigations Group (NCIG) proposes to test ABT-436 in a Phase
2, proof of concept trial for the treatment of alcohol dependence.

Inclusion Criteria:

- Be at least 21 years of age and no more than 65 years of age.

- Have a current (past 12 months) DSM-IV-TR diagnosis of alcohol dependence.

- Be seeking treatment for alcohol dependence and desire a reduction or cessation of
drinking.

Exclusion Criteria:

- current (past 12 months) abuse or dependence on any psychoactive substance other than
alcohol, caffeine and nicotine, including sedatives and hypnotics, as defined by
DSM-IV-TR criteria.

- positive urine toxicology screen performed during screening or baseline.

- been hospitalized for alcohol intoxication delirium, alcohol withdrawal delirium,
alcohol-induced persisting dementia or amnestic disorder, or have had an alcohol
withdrawal seizure, alcohol-induced psychotic disorder with a primary diagnosis of
alcohol dependence or a history of any seizure disorder.

- Have any of the following, based on DSM-IV-TR criteria as assessed using the MINI:

1. Current, past, or lifetime diagnosis of psychotic disorders (note schizophrenia
is diagnosed under the psychotic disorder module of the MINI)

2. Current or past diagnosis of bipolar disorder,

3. Current or past year major depressive episode,

4. Current (past 3 months) eating disorder (anorexia or bulimia), or

5. Current (within past year) diagnosis of panic disorder with or without
agoraphobia,

6. Anti-social personality disorder.

- Have any underlying medical condition that could exacerbate during trial
participation causing hospitalization, surgery, and/or the need to use exclusionary
medications to treat condition.

- Be pregnant or breast-feeding or have plans to become pregnant at any time during the
study.

- Have a clinically significant abnormal laboratory value;

- Hemoglobin A1c value > 7%.

- Have a clinically significant ECG as determined by the investigator or abnormal ECG
heart rate (<45 or > 100 bpm or QTc interval corrected for heart rate using the
Fridericia formula (QTcF) > 450 msec.

- Have HIV or Hepatitis A, B or C.