A Novel Compound for Alcoholism Treatment: A Translational Strategy

Objective:

Ghrelin is a 28-amino acid peptide that stimulates appetite and food intake. It is an
endogenous ligand for the growth hormone secretagogue receptor (GHSR1a). Preclinical studies
suggest that ghrelin modulates alcohol reward processing. Previous work from our research
team, indicated that intravenous (IV) ghrelin administration, compared to placebo, results in
an acute increase in alcohol craving during a cue-reactivity experiment in alcoholic
individuals. Therefore, an oral bioavailable, ghrelin receptor antagonist that is able to
pass through the blood brain barrier holds particular promise as a treatment for alcohol use
disorder (AUD). This protocol is part of a grant project funded by National Center for
Advancing Translational Sciences (NCATS) aimed to generate preliminary evidence in AUD on the
safety and efficacy of a ghrelin receptor (GHSR1a) antagonist, PF-05190457, an existing
molecule available under the NIH-Industry Pilot Program at NCATS. Completed preclinical and
clinical (Protocol #14-AA-0042) work has demonstrated the safety of PF-05190457/alcohol
interaction. The goal of this protocol is to conduct a proof-of-concept human laboratory
study to assess an early-signal of efficacy of PF-05190457 in AUD.

Study population:

The study population will be AUD individuals (n = 55).

Study Design:

A within-subject, counterbalanced, double-blind, placebo-controlled study.

Outcome measures:

The primary aim will be to determine whether PF-05190457, compared to placebo, reduces
alcohol cue-elicited craving. The main secondary aim will be to determine whether
PF-05190457, compared to placebo, reduces brain blood oxygen level dependent (BOLD) response
during exposure to alcohol cues, during a task-based fMRI scan. We will also investigate the
effects of PF-05190457 on food craving as well as on food choices using a virtual buffet
experimental procedure. All these outcomes will be assessed in the inpatient Unit at the NIH
CC. After the inpatient portion of the protocol, patients will be followed-up as outpatients.
During the outpatient phase, patients will be offered motivational interviewing and video
feedback to explore the effects of this intervention, compared to supportive counseling, on
maintaining motivation for alcohol abstinence and inform future studies where medications
like PF-05190457 and behavioral treatments may be combined. The outpatient phase is optional
for treatment seeking and nontreatment seeking participants.

- INCLUSION CRITERIA:

- Male or female individuals 18-70 years old (inclusive)

- Current Alcohol Use Disorder (AUD) by DSM-5 criteria based on the SCID

- Most recent urine drug test for illegal drugs of abuse is negative

- Most recent Clinical Institute Withdrawal Assessment for Alcohol - revised (CIWA-Ar)
score is less than or equal to 8

- Heart rate less than or equal to 100 on two separate measurements, both assessed after
CIWA-Ar score is less than or equal to 8

- Female subjects must be of non childbearing potential as defined by at least one of
the following criteria:

a) Females 45-70 years old, who are menopausal, defined as follow:

i) Females who are between 45-55 years old: they will be considered menopausal if they
satisfy all the following three requirements during screening: 1) they are in
amenorrhea, defined as absence of menstruation for the previous 12 months; 2) they
have a negative urine pregnancy test; and 3) they have a serum FSH level within the
laboratory s reference range for postmenopausal females.

ii) Females who are between 56-70 years old: they will be considered menopausal if they are
in amenorrhea, defined as absence of menstruation for the previous 12 months before
screening.

OR

b) Females 21-70 years old, who have a documented hysterectomy and/or bilateral
oophorectomy.

All other female subjects (including females with tubal ligations and females that do NOT
have a documented hysterectomy) will be considered to be of childbearing potential.

- Male subjects must use one of the following methods of contraception from the first
dose of study medication and until 28 days after dosing (given that it is unknown
whether the effects of this drug can cause birth defects):

1. Abstinence.

2. A condom AND one of the following:

- Vasectomy for more than 6 months.

- Female partner who meets one of the following conditions:

1. Has had a tubal ligation, hysterectomy, or bilateral oophorectomy;

2. Is post menopausal;

3. Uses one of the following forms of contraception:

Copper or hormonal containing IUD;

Spermicidal foam/gel/film/cream/suppository;

Diaphragm with spermicide;

Oral contraceptive;

Injectable progesterone;

Subdermal implant.

EXCLUSION CRITERIA:

- Lifetime clinical diagnosis of schizophrenia or bipolar disorder

- EKG with QTc > 450 msec as determined by either the Bazett or Fridericia formulas
using the QTc value that is the longest in duration.

- BMI less than or equal to 18.5 kg/M(2) or anorexia

- BMI greater than or equal to 40 kg/m(2)

- History of epilepsy and/or seizures

NOTE: individuals who have a history of alcohol withdrawal seizures may be in the study as
long as they have been abstinent from alcohol for at least 2 weeks prior to consent and
during that period of abstinence, there were no seizure episodes (otherwise, participant
remains not eligible).

- Most recent blood tests show creatinine greater than or equal to 2 mg/dL, AST or ALT >
3 times the upper normal limit, hemoglobin <10.5 g/dl

- Subjects who have diabetes and/or are treated with any drug with glucose lowering
properties such as sulfonylurea, insulin, metformin, thiazolidinediones (TZD),
Dipeptidyl peptidase-4 (DPP4) inhibitors, or Glucagon-like peptide-1(GLP-1)agonists
(due to the glucose-lowering properties of PF-05190457 observed in healthy volunteers)

- Exclusionary Medications:

--A. Naltrexone, acamprosate, alcohol dehydrogenase inhibitors, topiramate,
gabapentin, ondansetron, benzodiazepines, baclofen, drugs that are known to prolong
the QTc interval and barbiturates as well as hormone replacement therapy; medications
and dietary/herbal supplements (like St. John's wort) that interact with Cytochrome
P450 3A4. Patients who take these medications may be enrolled in the study only if the
potentially interacting medication has been stopped for a period of at least 5
half-lives of the interacting medication before PF-05190457 administration.

- Unable to pass a finger rub hearing test

- Vision is unable to be corrected to (Snellen) 20/100

- Clinically-significant history of motion or car sickness, or history of vestibular
disorders

- Any other reason or clinical condition for which the PI or the MAI will consider
unsafe for a possible participant to participate in this study

EXCLUSION CRITERIA FOR fMRI ONLY:

- Have contraindications for brain fMRI, as determined by the NIAAA MRI Safety screening
form (conducted under the 14-AA-0181 Screening Protocol)

- Colorblindness (this would prevent subject from completing the Stroop task) using the
Ishihara Test for Color Deficiency, Concise Edition, 2014.