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Basilio
Colligris,
Jesús
Pintor

cells
isolated
from
R932348-­-treated
mice
also
showed
reduced
phosphorylation
of

Stat5
after
stimulation
with
IL-­-2
(89).
The
company
in
July
2013,
started
Phase
II

safety,
tolerability
and
pharmacokinetics
studies
(ClinicalTrials.gov
Identifier:

NCT01900249)
for
0.2%
and
0.5%
R932348
ophthalmic
solution
in
patients
with

dry
eye
disease.

EBI-­-005

Eleven
Biotherapeutics
is
developing
chimeric
IL-­-1
receptor
type
I
agonists

and
antagonists
as
dry
eye
treatment.
These
non-­-naturally
occurring
cytokine

domains
can
modulate
cellular
signaling
response
to
interleukin-­-1
receptor
I
(IL-­-1

RI),
and
to
detect
and
or
even
bind
on
cellular
receptors(90).
The
drug
started
in

December
2012
Phase
I
multi-­-center
clinical
trials
(ClinicalTrials.gov
Identifier:

NCT01745887)
with
the
name
EBI-­-005-­-2,
an
IL-­-1
receptor
blocker,
single-­-domain

protein,
optimized
for
topical
ocular
delivery.
The
EBI-­-005
has
been
validated
in

clinical
proof-­-of-­-concept
studies
in
which
IL-­-1
blockage
was
shown
to
be
safe
and

well
tolerated
without
adverse
side
effects.
According
to
the
results
presented
in

ARVO
2012
(91)
it
was
created
by
combining
the
IL-­-1
receptor
binding
the
sub-­-
domains
IL-­-1ß
and
IL-­-1Ra.
During
the
pre-­-clinical
trials
EBI-­-005
was
shown
more

active
than
topical
Cyclosporine
(the
active
ingredient
of
Restasis™
ophthalmic

emulsion
eye
drops)
in
mouse
models.
Topical
delivery
resulted
in
distribution
to

multiple
eye
compartments,
but
very
low
systemic
exposure
in
rabbits
(F
<
0.2%).

EBI-­-005
was
9°C
more
thermally
stable
than
anakinra
an
interleukin-­-1
receptor

antagonist
(92).
Eleven
Biotherapeutics
presented
promising
preliminary
clinical

data
from
the
trials.

CONCLUDING
REMARKS

Many
of
the
above
mentioned
potential
drugs
are
anti-­-inflammatory

compounds
and
some
are
mucin
secretagogue,
promoting
mucin
and
water

production,
and
also
there
are
a
few
eye
lubricants.
Most
of
the
anti-­-
inflammatories
are
corticosteroids
because
of
their
noteworthy
anti-­-inflammatory

properties
and
rapid
action.
Normally
they
are
used
for
a
limited
period
of
time

and
depending
on
the
severity
of
the
case,
after
treatment
the
patient
returns
to

the
initial
inflammatory
condition.
This
limitation
makes
them
unsuitable
for

chronic
dry
eye
therapy
as
steroidal
compounds
present
important
side
effects,

such
as
increase
in
intraocular
pressure
and
posterior
sub-­-capsular
cataract
(93).

166