A Novel Compound for Alcoholism Treatment

Objective: Ghrelin is a 28-aminoacid 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. Furthermore, findings from
a translational human lab study at Brown University (PI: Leggio) indicate that intravenous
(IV) ghrelin administration, compared to placebo, results in an acute increase in craving for
alcohol during a cue-reactivity experiment in alcoholic individuals. Therefore, an orally
bioavailable, ghrelin receptor antagonist, that can pass through the blood brain barrier
holds particular promise as an AD treatment. This project has been recently funded by NCATS.
The goals of this protocol are to generate preliminary evidence on the safety and efficacy of
a ghrelin receptor antagonist (GHSR1a antagonist), PF-05190457, an existing molecule
available under the NIH-Industry Pilot Program at NCATS.

Study population: Non-treatment seeking heavy drinkers (n =20). The study will be conducted
in the Inpatient Unit at the NIAAA Intramural Clinical Program.

Study Design: Single-blind dose-escalating placebo-controlled inpatient study using
PF-05190457, in non-treatment seeking heavy drinking subjects. This Phase 1b study will be a
within-subject design.

Outcome measures: Primary objectives will be to determine: 1) the number of adverse events
(AEs) experienced, compared between all three PF-05190457 dose categories (0mg or placebo,
50mg, and 100mg b.i.d.); and 2) the total concentration of the drug, compared between the two
non-placebo drug doses (50mg and 100mg b.i.d.), when co-administered with alcohol. We
hypothesize that both doses of PF-05190457, as compared to placebo, will not result in an
increased number of AEs. As a secondary objective, we will determine whether PF-05190457
dose-dependently affects the subjective effects of alcohol and craving. We will include
pharmacokinetics (PK) and pharmacodynamic (PD) investigations conducted at University of
Rhode Island (URI; Associate Investigator: Akhlaghi). The PK/PD component will include (i)
measuring total, unbound or tissue concentrations of the drug using liquid chromatography
tandem mass spectrometry (LC-MS/MS) and evaluation of biomarkers of effect and (ii)
estimation of PK and PD parameters by the use of conventional and semi-mechanistic modeling
approaches to assist in identifying an optimal dosing regimen of the drug in AD.

- INCLUSION CRITERIA:

- Males or females 21-65 years old (inclusive);

- Heavy drinking defined as on average at least 21 drinks per week for men or at least
14 drinks for women based on the timeline follow-back (TLFB) done at screening.

- Be in good health as confirmed by medical history, physical examination, ECG,
blood/urine lab tests;

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

- Females 45 65 years old, who are menopausal, defined as follows:

- 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.

- Females who are between 56 65 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

- Females 21-65 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:

- Abstinence.

- A condom AND one of the following:

- Vasectomy for more than 6 months.

- Female partner who meets one of the following conditions:

- Has had a tubal ligation, hysterectomy, or bilateral oophorectomy;

- Is post menopausal;

- 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:

- Interest in receiving treatment for heavy drinking.

- Current DSM-IV diagnosis (based on SCID) of substance dependence (other than alcohol
and/or nicotine); a negative urine drug screen will also be required.

- DSM-IV Axis I criteria for a lifetime diagnosis of schizophrenia, bipolar disorder, or
other psychoses;

- Active illness within the past 6 months of the screening visit that meet the DSM-IV
criteria for a diagnosis of major depressive disorder or anxiety disorder; subjects
with a history of attempted suicide will be excluded;

- Clinically significant medical abnormalities (e.g., unstable hypertension, clinically
significant EKG abnormalities, Creatinine greater than or equal to 2 mg/dL, liver
cirrhosis, AST or ALT > 3x the upper normal limit, hemoglobin <10.5 g/dl);

- Heart rate >100 at screening on two separate measurements given potential of study
medication to increase heart rate.

- BMI less than or equal to 18.5 or anorexia given potential of the study medication to
reduce appetite.

- BMI greater than or equal to 35 kg/m^2.

- Exclusionary Medications:

- Naltrexone, acamprosate, alcohol dehydrogenase inhibitors, topiramate,
gabapentin, ondansetron, benzodiazepines, beta-blockers, H2-blockers, and alpha-1
blockers, baclofen, and barbiturates as well as hormone replacement therapy;
medications and dietary/herbal supplements (like St. John's wort) that interact
with Cytochrome P450 3A4. All of the medications in the previous sentence will
not be allowed if they have been taken within 2 weeks of study medication
administration.

- PF-05190457 is a substrate for P-glycoproteins (P-gp or encoded by ABCB1 gene)
based on information from in vitro or animal models. Patients that are required
to take the following inhibitors and inducers of P-gp are excluded unless the
subject stops taking these agents for 2 weeks for P-gp inhibitors or 6 weeks for
P-gp inducers before study medication administration.

Inhibitors: Amiodarone, azithromycin, captopril, carvedilol, clarithromycin, conivaptan,
cyclosporine, diltiazem, dronedarone, erythromycin, felodipine, itraconazole, ketoconazole,
lopinavir and ritonavir, quercetin, quinidine, ranolazine, verapamil

Inducers: Avasimibe, carbamazepine, phenytoin, rifampin, St John s wort,
tipranavir/ritonavir [From Drug Development and Drug Interactions: Table of Substrates,
Inhibitors and Inducers, table 12, from
http://www.fda.gov/Drugs/DevelopmentApprovalProcess/DevelopmentResources/DrugInteractionsLa
beling/ucm093664.htm#substrates]

- History of epilepsy or alcohol-related seizures;

- patients 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);

- History of alcohol-induced flushing reactions.

- Clinically significant alcohol withdrawal symptoms, as assessed by a CIWA-Ar score > 8
at screening.

- 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.