A first-in-human single-dose escalation study of the safety, pharmacokinetics and pharmacodynamics of the test drug including brain Serotonin Receptor Transporter (SERT) occupancy by Positron Emission Tomography (PET).

The drug to be given is a new, investigational compound that may eventually be
used for the treatment of pain affecting *soft* organs and body tissue
(visceral pain). Visceral pain is the pain we feel when our internal organs are
damaged or injured and it is, by far, the most common form of pain.
Few drugs have been approved for specific visceral pain conditions , and
current therapies offer limited efficacy.
The drug is a serotonine/norepinephrine (5-HT/NE) dual receptor reuptake
inhibitor (SNRI). SNRIs are utilized in the treatment of depression and chronic
pain. SNRIs increase the levels of both serotonin and norepinephrine by
inhibiting their reabsorption (reuptake) into the cells in the brain. Serotonin
and norepinephrine are both known to play an important part in mood. Elevation
of norepinephrine is thought to be necessary to be effective against pain as
well.

Part A: to investigate the safety and tolerability of the drug after a single
oral dose in healthy male volunteers
Part B: to explore the relationship between dose/exposure of the drug and brain
serotonin receptor transporter (SERT) occupancy after a single oral dose by
direct measurement using 11C-DASB ligand and Positron Emission Tomography
(PET)

Part A

Design:
A randomized, double-blind, placebo controlled, single dose escalating, three
period, incomplete cross-over design with two cohorts of eight healthy male
subjects each receiving a single oral dose of the drug or placebo (six verum
and three placebo); in the first period of the first cohort, two subjects (one
on active and one on placebo) will be dosed 24 h before the remaining six
subjects of the cohort; treatments for each cohort will be separated by a
washout of seven to ten days.

Procedures and assessments
Screening and follow-up:
Clinical laboratory, physical examination, ECG (in triplicate at screening),
vital signs; at eligibility screening: medical history, height and weight,
urine alcohol and drug screen, HBsAg, anti HCV, anti-HIV 1/2 and genotyping
(CYP2D6); to be repeated upon each admission: urine alcohol and drug screen,
ECG (in triplicate), vital signs, clinical laboratory and abbreviated physical
examination.

Observation period:
3 periods, each period in clinic from -17 h up to 24 h after drug
administration on Day 1 followed by ambulatory visits on Days 3 and 5.

Blood sampling:
- for pharmacokinetics of the drug in plasma: pre-dose and 0.5, 1, 2, 3, 4, 6,
8, 12, 24, 48 and 96 h post dose, and at follow-up visit
- for pharmacodynamics of DHPG and NE in plasma/posture test: pre-dose and 2, 6
and 24 h post dose
- for pharmacodynamics of DHPG and NE in serum: pre-dose and 2, 6 and 24 h post
dose
- for pharmacodynamics of ex vivo NE/5-HT uptake inhibition: pre-dose (evening
before dosing) and 2, 6 and 24 h post dose

Safety assessments:
Adverse events: throughout the study; ECG (in triplicate until 24 h post dose):
pre-dose and 0.5, 1, 2, 3, 4, 6, 8, 12, 24, 48 and 96 h post dose; brief
physical examination: once on Day 2; vital signs: once daily on Days -1 to 2
and on Day 3 and 5; clinical laboratory: 24 h post dose.

Bioanalysis:
- analysis of plasma LY2878735 samples using a validated method by PRA
International
- analysis of plasma and serum DHPG and NE samples using a validated method by
Sponsor
- analysis of ex vivo NE/5-HT samples using a validated method by Sponsor


PART B

Design:
An open label, single dose escalating design with three cohorts of four healthy
male subjects each receiving a single oral dose of LY2878735.

Procedures and assessments
Screening and follow-up:
Clinical laboratory, physical examination (brief physical examination at
follow-up), vital signs, ECG; at eligibility screening: medical history, urine
alcohol and drug screen, height and weight, HBsAg, anti HCV, anti-HIV 1/2,
genotyping (CYP2D6), MRI scan; to be repeated upon admission: urine alcohol and
drug screen, clinical laboratory and abbreviated physical examination.

Observation period:
One period in clinic from -17 h up to 24 h after drug administration on Day 1
and a baseline visit at approximately 2 weeks prior to dosing for PET scan.

Blood sampling:
- for pharmacokinetics of LY2878735 in plasma: pre-dose and just before Tmax,
just after Tmax, 6, 12 and 24 h post dose
- for pharmacodynamics of ex vivo NE/5-HT uptake inhibition: pre-dose and just
before Tmax, just after Tmax, 6, 12 and 24 h post dose
PET scan baseline scan, at Tmax and 26 h post dose

Safety assessments:
Adverse events: throughout the study; ECG: pre-dose, at Tmax and 24 h post
dose; vital signs and clinical laboratory: pre-dose and 24 h post dose;
abbreviated physical examination: pre-dose and 24 h post dose.

Bioanalysis:
Analysis of plasma LY2878735 samples using a validated method by PRA
International.

Active substance: LY2878735
Activity: Combined serotonin and noradrenaline transporter inhibitor
Indication: Visceral pain syndromes
Strength: 5 mg, 20 mg and 70 mg
Dosage form: capsules

Treatments
Part A:
Cohort 1:
Period 1: a single oral dose of 5 mg of drug or placebo on Day 1 in the fasted
state
Period 2: a single oral dose of 25 mg of drug or placebo on Day 1 in the fasted
state
Period 3: a single oral dose of 2.5 mg of drug or placebo on Day 1 in the
fasted state
Cohort 2:
Period 1: a single oral dose of 25 mg of drug or placebo on Day 1 in the fasted
state
Period 2: a single oral dose of 10 mg of drug or placebo on Day 1 in the fasted
state
Period 3: a single oral dose of tbd mg of drug or placebo on Day 1 in the
fasted state

Part B:
Cohort 3: a single oral dose of X mg of drug on Day 1 in the fasted state
Cohort 4: a single oral dose of Y mg of drug on Day 1 in the fasted state
Cohort 5: a single oral dose of Z mg of drug on Day 1 in the fasted state

Procedures: pain, light bleeding, heamatoma, possibly an infection.

Medication: as LY2878735 will be administered to man for the first time in this
study, to date adverse effects in man have not been reported. In previous
studies with rats and dogs, in which LY2878735 was administered daily in very
high doses convulsions were observed.
The currently available SNRIs have the following most common side effects: loss
of apetite, weight, and sleep. There may also be drowsiness, dizziness,
fatigue, headache, sexual dysfunction, and urinary retention. Elevated
norepinephrine levels van sometimes cause anxiety, mildly elevated pulse, and
elevated blood pressure.