Double blind, randomized, 2-way cross-over, placebo controlled study to evaluate the therapeutic and preventive effect of GLPG1205 on nociceptive and inflammation/sensitization induced pain in the UVB sunburn model in healthy male subjects

In vivo pharmacology effects observed with GLPG1205 confirm a role for GPR84 in
neuro-inflammatory biology and, more precisely, support its role in the
pathogenesis of pain.

An early indication for GLPG1205 efficacy in man is desired and can facilitate
further development of this potential new treatment for e.g. pain. Based on the
pre-clinical pharmacology of GLPG1205, the UVB sunburn model is a good model
for obtaining an early read out of GLPG1205 potential efficacy. This UVB
sunburn model is a method, well described in literature and widely applied in
healthy subjects. The UVB model is a human and animal experimental pain model
of a local cutaneous hyperalgesia and inflammation. The model is widely used
for assessing efficacy and mode-of-action of analgesic and anti-inflammatory
drugs in clinical trials. The UVB model induces thermal and mechanical
hyperalgesia (primary hyperalgesia) at the site of irradiation and occasionally
in the surrounding areas (secondary hyperalgesia). The induced inflammatory
process, tissue damage, and released cytokines cause a characteristic demarked
area of erythema (neurogenic inflammation). The UVB model is in particular
useful for pharmacological screening as it can help translating data from
animals to humans. The UVB induced primary hyperalgesia develops after approx.
24 h and remains for more than 48 h making the model useful in pharmacological
screening studies with repeated dosing or for compounds with long lasting
action.

Quantitative sensory testing (QST) assesses characteristic sensory patterns in
pain models. The QST battery assembles a comprehensive list of robust and
validated short form tests representing measures of all relevant sub-modalities
of the somatosensory system. In the applied model for this study, the test
battery of QST consists of mechanical detection threshold (MDT), mechanical
pain threshold (MPT), cold pain threshold (CPT) and heat pain threshold (HPT).

In the current study the effect of GLPG1205 on nociceptive and
inflammation/sensitization induced pain (thermal and mechanical hyperalgesia)
will be investigated by applying the UVB sunburn model in healthy male
subjects. GLPG1205 will be evaluated in a therapeutic (after UV burn) and
preventive setting (before UV burn) and compared with placebo.

Primary
To assess the preventative effect of GLPG1205 on nociceptive and
inflammation/sensitization induced pain in the UVB sunburn model using HPTol
upon multiple dosing of GLPG1205 versus placebo.

Secondary
To further assess the preventative effect of GLPG1205 on nociceptive and
inflammation/sensitization induced pain in the UVB sunburn model using other
QST testing upon multiple dosing of GLPG1205 versus placebo.
To assess the therapeutic effect of GLPG1205 on nociceptive and
inflammation/sensitization induced pain in the UVB sunburn model upon dosing of
GLPG1205 versus placebo.
To evaluate the safety and tolerability of GLPG1205 after multiple oral dosing.
To assess the pharmacokinetics of GLPG1205 after multiple oral dosing.

3.3. EXPLORATORY OBJECTIVE
To explore the effect of GLPG1205 on inflammatory gene expression in skin
biopsies following exposure to UVB radiation.

This study will be conducted as a randomized, placebo controlled, double blind,
2-way cross-over, and multiple oral dose study.

The study will consist of a screening period, 2 treatment periods of 8 days
each separated by a washout period of at least 3 weeks. A follow-up examination
will be performed 21 days (±2 days) after the last dose of the second treatment
period.

After assessing eligibility during a 3-week screening period, 20 subjects will
participate in the study. In each period, subjects will come to the study
center on the day before first administration (Day -1) of the study drug.
Baseline assessments and (re*)confirmation of eligibility will be assessed on
Day -1 of Period 1. Subjects will remain in the study center until finalization
of Day 3 study procedures. On Day 4, an ambulatory visit will take place. On
Day 5, subjects will come back to the study center and remain in the study
center until finalization of Day 8 study procedures. On Day 10 a phone call
will take place for a post skin biopsy review.

Subjects will be randomized to one of the treatment sequences (GLPG1205 or
placebo in a 1:1 ratio) prior to dosing on Day 1 of Period 1. On Day 1 of each
period, subjects will receive an oral dose of either GLPG1205 500 mg or
placebo. On Days 2 to 7, subjects will receive an oral dose of either GLPG1205
100 mg or placebo.

Safety and tolerability will be assessed throughout the study by adverse event
reporting, vital signs recording, ECG recordings, physical examination, and
clinical safety laboratory assessments. Subjects will also be assessed by a
follow-up examination 21 days (±2 days) after the last dose.

During the screening process, subjects will be assessed for the minimal
erythema dose (MED) of UVB light on the upper part of the left leg. Subjects
subsequently will be exposed to three times the minimal erythema dose (MED) of
UVB light on an approximately 4 x 4 cm area on the upper part of the leg in the
morning of Day -1 and Day 5 (on Day -1 right leg, on Day 5 left leg). The MDT,
MPT, CPT and HPT for assessing the pharmacodynamic effects will be assessed as
detailed in the study flow chart (see protocol).

UVB radiation on a second area of the upper part of the leg (different area
than the area used for QST testing) will be performed on Day 5 of Period 2 for
collection of a skin biopsy 25 hours after first QST testing on Day 6 of Period
2.
Pharmacokinetic samples will be collected throughout the study to confirm
steady state and exposure to GLPG1205, as per study flow chart (see protocol).

The dose levels of the study drugs are based on the previous clinical trials
that were conducted by the sponsor. The risk to health at the chosen dosage is
limited but subjects may experience one of the in the ICF mentioned
side-effects or symptoms not previously reported. The subjects health will be
closely monitored during the study to minimize these risks. If the subjects
experience any side effects, the research physician will treat these where
necessary. If new information becomes available about the safety of the study
drug, the subjects will be informed as soon as possible.

In total, subjects will be exposed on 5 moments to UVB-radiation on an area of
the skin on the upper leg to determine the Minimal Erythema Dose (MED) and for
further tests. The symptoms related to this can be compared to a (very) light
sunburn. In Period 2 on Day 5 subjects will be exposed to UVB-radiation on two
areas instead of one. The second area will be used to collect skin tissue. In
addition, the sensitivity to mechanical pressure, pain, heat and cold will be
tested. These tests can lead to some discomfort.

To investigate the effect the study drug on the inflammatory gene expression of
the skin after UVB radiation, 2 skin tissue samples (both 4 mm in diameter)
will be collected from the upper leg: one from skin exposed to UVB and one from
skin not exposed to UVB. The possible side effects related to this procedure
are: formation of scar tissue, bleeding, bruising, infection, inflammation,
soreness, and mild localized pain. Local anesthesia is used during the
procedure.

The blood collection procedure is not dangerous, but may cause discomfort or
bruising. Occasionally, fainting, bleeding or an infection at the blood
sampling site can occur.