Drugs

DOI 10.1007/s40265-016-0681-1

ADIS DRUG EVALUATION

Lifitegrast Ophthalmic Solution 5%: A Review in Dry Eye Disease

Gillian M. Keating1

Ó Springer International Publishing Switzerland 2017

Abstract Lifitegrast is a novel small molecule integrin

antagonist that blocks the binding of intercellular adhesion
molecule 1 (ICAM-1) to lymphocyte function-associated
antigen 1 (LFA-1). Lifitegrast ophthalmic solution 5%
(XiidraTM) was recently approved in the USA for the
treatment of dry eye disease. The efficacy of lifitegrast
ophthalmic solution 5% was compared with vehicle in a
12-week phase 2 study and three 12-week phase 3 studies
(OPUS-1, OPUS-2 and OPUS-3) in patients with dry eye
disease. Taken as a whole, results of these trials support the
treatment effect of lifitegrast ophthalmic solution 5% in
improving a symptom of dry eye disease (i.e. the change
from baseline to day 84 in the eye dryness visual analogue
scale score) and a sign of dry eye disease (i.e. the change
from baseline to day 84 in the inferior corneal fluorescein
staining score). Lifitegrast ophthalmic solution 5% was
generally well tolerated. In conclusion, lifitegrast oph-
thalmic solution 5% provides a new option for the treat-
ment of dry eye disease.
The manuscript was reviewed by: M. A. Lemp, Department of
Ophthalmology, Georgetown University, Washington, DC, USA;
S. C. Pflugfelder, Ocular Surface Center, Department of
Ophthalmology, Baylor College of Medicine, Houston, TX, USA.
& Gillian M. Keating
demail@springer.com
1
Springer, Private Bag 65901, Mairangi Bay, 0754 Auckland,
New Zealand
Lifitegrast ophthalmic solution 5%: clinical
considerations in dry eye disease
Novel small molecule integrin antagonist that blocks
the binding of ICAM-1 to LFA-1.
Improves the symptom of eye dryness.
Improves the sign of inferior corneal fluorescein
staining.
Generally well tolerated.
1 Introduction
Dry eye disease (keratoconjunctivitis sicca) is a disease of
the tears and ocular surface [1]. It is characterized by
symptoms of ocular discomfort (e.g. dryness, itching, irri-
tation, foreign body sensation) and visual disturbance,
which have a substantial impact on the patient’s visual-
related quality of life [1]. The pathophysiology of dry eye
disease is complex, with core causative mechanisms
including tear film instability and tear hyperosmolarity,
which is associated with ocular surface inflammation and
damage [1].
Intercellular adhesion molecule 1 (ICAM-1) is highly
expressed on epithelial cells, endothelial cells and immune
function cells in the setting of inflammation [2]. Indeed,
increased expression of ICAM-1 and T cell infiltration
were seen in the conjunctiva and lacrimal glands of patients
with dry eye disease [3, 4]. ICAM-1 is the cognate ligand
of lymphocyte function-associated antigen 1 (LFA-1), an
integrin receptor expressed on T cells [2, 5]. The

interaction of ICAM-1 with LFA-1 is critical to the T cell
inflammatory response, with the binding of ICAM-1 to
LFA-1 implicated in the formation of an immunological
synapse between T cells and antigen-presenting cells and in
the processes of T cell activation, adhesion, migration and
cytokine release [2, 5].
Although various over-the-counter products such as
artificial tears are available for the treatment of dry eye
disease, ciclosporin ophthalmic emulsion 0.05% was pre-
viously the only agent approved by the US FDA for use in
this indication (specifically to increase tear production) [6].
Thus, there has been a need for new agents to treat dry eye
disease.
Lifitegrast is a novel small molecule integrin antagonist
that blocks the binding of ICAM-1 to LFA-1. Lifitegrast
ophthalmic solution 5% (XiidraTM) was recently approved in
the USA for the treatment of the signs and symptoms of dry
eye disease [7]. This narrative review provides an overview
of the efficacy and tolerability of lifitegrast ophthalmic
solution 5% in patients with dry eye disease, as well as
summarizing the pharmacological properties of lifitegrast.
2 Pharmacological Properties of Lifitegrast
2.1 Mechanism of Action
Lifitegrast is a novel small molecule integrin antagonist
that mimics the binding epitope of ICAM-1 [2, 5]. Lifite-
grast acts as a direct competitive antagonist of the binding
of ICAM-1 to LFA-1, thereby blocking the T cell-mediated
inflammatory cycle [2, 5, 8].
2.2 Pharmacodynamic Profile
In vitro, lifitegrast potently inhibited the attachment of
Jurkat T cells to ICAM-1 in a concentration-dependent
manner, with a half-maximal inhibitory concentration
(IC50) of 2.98 nmol/L [9]. Lifitegrast also inhibited T cell
activation and the release of inflammatory cytokines from
peripheral blood mononuclear cells in a concentration-de-
pendent manner in vitro [9]. For example, lifitegrast
inhibited the release of interferon-c, interleukin (IL)-1a,
IL-1b, IL-10 and macrophage inflammatory protein-1a
(cytokines shown to correlate with the severity of ocular
surface epithelial disease [10]) with half-maximal effective
concentration (EC50) values of 0.0016, 0.24, 0.36, 0.15 and
0.02 lmol/L, respectively [9].
Lifitegrast ophthalmic solution demonstrated activity in
animal studies, reducing corneal inflammation in mice [11]
and significantly (p \ 0.025 vs. baseline) increasing tear
production in dogs with spontaneous keratoconjunctivitis
sicca [9].
G. M. Keating
2.3 Pharmacokinetic Profile
Lifitegrast has high aqueous solubility ([100 mg/mL) [2].
Plasma exposure to lifitegrast was undetectable or minimal
following administration of twice-daily lifitegrast oph-
thalmic solution 5% to healthy volunteers [12] or patients
with dry eye disease [13]. For example, in a substudy (n =
47) of the phase 3 SONATA trial [13] (see Sect. 4) in
patients with dry eye disease who received twice-daily
lifitegrast ophthalmic solution 5%, trough plasma concen-
trations (Ctrough) of lifitegrast (assessed on days 0, 180 and
360) were quantifiable (i.e. [0.5 ng/mL) in nine patients,
with Ctrough values ranging from 0.55 to 3.74 ng/mL [7].
Peak plasma concentrations of lifitegrast were detected
within 5 min of instillation of lifitegrast ophthalmic solu-
tion 5% in healthy volunteers [12]. There was no evidence
of accumulation with repeated administration, and lifite-
grast was cleared from plasma within 1–4 h [12].
Tear concentrations of lifitegrast generally exceeded the
target ocular therapeutic concentration of 1 lmol/L
(&600 ng/mL) (i.e. tear concentrations exceeded the IC50
for LFA-1/ICAM-1 binding and the EC50 values for cyto-
kine inhibition; Sect. 2.2) [12]. Following administration of
lifitegrast ophthalmic solution 5% twice daily for 10 days
to healthy volunteers, the mean maximum tear concentra-
tion of lifitegrast (91,413 ng/mL) was reached in a median
time of 0.3 h [12]. No unexpected accumulation of lifite-
grast in tears was observed [12]. In the normal dog eye, tear
concentrations of lifitegrast remained [1 lmol/L for 24 h
after ocular instillation of lifitegrast ophthalmic solution 1
or 3% three times daily [9].
Following ocular instillation of radiolabelled lifitegrast
to rats [14] and dogs [9], lifitegrast was detectable in most
ocular tissues, with particularly high concentrations seen in
the bulbar and palpebral conjunctiva and cornea.
Radioactivity was still detectable in most ocular tissues
24 h after administration of lifitegrast, particularly in the
bulbar and palpebral conjunctiva [9].
Lifitegrast showed low potency in CYP3A4 and
CYP2C9 inhibition assays in vitro [8]; CYP enzymes are
known to be present in corneal tissue [5].
3 Therapeutic Efficacy of Lifitegrast Ophthalmic
Solution 5%
The efficacy of lifitegrast ophthalmic solution 5% in
patients with dry eye disease was examined in a phase 2
trial [15] and in the phase 3 OPUS-1 [16], OPUS-2 [17]
and OPUS-3 [18] trials, all of which were of random-
ized, double-masked, multicentre design. Inclusion cri-
teria were age C18 years [15–18], a history of dry eye
disease [15–18], a best-corrected visual acuity (BCVA)
Lifitegrast Ophthalmic Solution 5%: A Review
of C0.7 logarithm of the minimum angle of resolution
(logMAR) [15–18], a corneal fluorescein staining score
of C2 in at least one region [15–18], a conjunctival
redness score of C1 (0–4 point scale) in at least one eye
[17, 18] or conjunctival redness in any eye [15, 16] and
an unanaesthetized Schirmer test score (mm/5 min) of
C1 and B10 mm in any eye [15, 16]. Exclusion criteria
included laser-assisted in situ keratomileusis (LASIK)
or similar surgery within the past 12 months and a need
for contact lens use during the study [15–18]. Most of
the patients in the phase 2 trial [15] and OPUS-1 [16]
had mild to moderate dry eye disease and had used or
desired to use artificial tears within the past 6 months,
whereas OPUS-2 [17] and OPUS-3 [18] included
patients with moderate to severe dry eye disease who
had used artificial tears within the past 30 days and had
an eye dryness visual analogue scale (VAS) score of
C40 at baseline.
In the phase 2 trial [15] and in OPUS-1 [16], patients
meeting initial screening requirements then underwent
90 min exposure to acute environmental stress using a
controlled adverse environment (CAE) model. Patients
with a positive response to CAE (i.e. an exacerbation in the
ocular discomfort score and the inferior corneal fluorescein
staining score), a pre-CAE Schirmer test score of C1 and
B10 mm and who met all other eligibility criteria then
received twice-daily vehicle in a 14-day screening period
(from day -14 to day 0). The designated study eye (i.e. the
worst eye or the right eye if both eyes were equal) had to
meet the same qualification criteria on days -14 and 0 for
the patient to enter the treatment period of the study
[15, 16].
In OPUS-2 and OPUS-3, patients meeting eligibility
criteria received twice-daily vehicle during a 14-day
screening period (from day -14 to day 0) [17, 18]. To
progress to the treatment period, patients had to have a
positive response in at least one eye (defined as having an
inferior corneal fluorescein staining score of C0.5 and a
Schirmer test score of C1 and B10 mm in the same eye on
days -14 and 0). The eye with the worst inferior corneal
fluorescein staining score on days -14 and 0 [17] or on day
0 [18] was designated the study eye.
In terms of the endpoints assessed in these trials, sub-
jective endpoints (i.e. assessing symptoms) included eye
dryness, discomfort, burning/stinging, photophobia, for-
eign body sensation, blurred vision, itching and/or pain
scores [scored using a VAS ranging from 0 (no discomfort)
to 100 (maximal discomfort); OPUS-2 and OPUS-3 spec-
ified that VAS scores were reported as a single score for
both eyes]; the ocular discomfort score in the designated
study eye [scored from 0 (no discomfort) to 4 (severe
discomfort)]; and/or the visual-related function, symptom
and environmental trigger subscales of a symptom scale
[with each item scored from 0 (none of the time) to 4 (all of
the time)], with the total symptom scale score ranging from
0 to 100 [15–18]. Objective endpoints (i.e. assessing signs)
in the designated study eye included the corneal fluorescein
staining scores in the superior, central and inferior regions
[scored from 0 (no staining) to 4 (confluent)]; the total
corneal fluorescein staining score [scored from 0 (no
staining) to 12 (confluent)]; and the conjunctival lissamine
staining score [scored from 0 (no staining) to 4 (confluent)]
[15–18].
3.1 Phase 2 Trial
During the treatment period of the phase 2 trial, eligible
patients were randomized to receive lifitegrast ophthalmic
solution 0.1% (n = 57), lifitegrast ophthalmic solution 1%
(n = 57), lifitegrast ophthalmic solution 5% (n = 58) or
vehicle (n = 58) twice daily for 84 days [15]. Based on the
results of this phase 2 trial, lifitegrast ophthalmic solution
5% was selected for use in phase 3 trials [19], and was
subsequently approved (Sect. 5). Thus, this section focuses
on results pertaining to lifitegrast ophthalmic solution 5%.
Patients were not permitted to use artificial tears, topical
ciclosporin or any other ophthalmic medication during the
trial. The primary endpoint was the inferior corneal fluo-
rescein staining score at day 84. Efficacy was assessed in
the intent-to-treat (ITT) population [15]. Re-analysis of
data from the phase 2 trial means that some p values are
reported as nominal p values [19].
The mean inferior corneal fluorescein staining score did
not significantly differ between patients receiving lifite-
grast ophthalmic solution 5% and those receiving vehicle at
day 84, although results across the three lifitegrast oph-
thalmic solution 0.1, 1 and 5% treatment arms were sug-
gestive of a dose response (p = 0.0566) [15]. The mean
change from baseline to day 84 in the inferior corneal
fluorescein staining score (a prespecified secondary end-
point) significantly favoured lifitegrast ophthalmic solution
5% versus vehicle recipients (Table 1). No significant
difference in the conjunctival lissamine staining score was
seen between lifitegrast ophthalmic solution 5% and vehi-
cle [15].
In terms of subjective endpoints, the mean changes from
baseline to day 84 in the eye dryness VAS score (Table 1)
and the ocular discomfort score did not significantly differ
between patients receiving lifitegrast ophthalmic solution
5% and those receiving vehicle [15]. The mean reduction
from baseline to day 84 in the visual-related function
subscale score was significantly (nominal p = 0.0394)
greater with lifitegrast ophthalmic solution 5% then with
vehicle [15, 19].
 G. M. Keating

Table 1 Efficacy of lifitegrast ophthalmic solution 5% in dry eye disease: results of randomized, double-masked, multicentre trials

Study Treatment No. of pts Mean eye dryness VAS score Mean inferior corneal fluorescein staining score
BL score Change from BL to day 84 BL score Change from BL to day 84

Phase 2 trial
Semba et al. [15]a LIF bid 58 51.6b -14.4b 1.77b ?0.04*b,c
b b b
VEH bid 58 51.8 -7.2 1.65 ?0.38b
Phase 3 trials
OPUS-1 [16]d LIF bid 293 40.2 -15.2b,e 1.84 -0.07b,f,g
b b
VEH bid 295 41.6 -11.2 1.81 ?0.17b,g
OPUS-2 [17]d LIF bid 358 69.7 -35.3***g,h 2.39 -0.73g
g
VEH bid 360 69.2 -22.8 2.40 -0.71g
d g,i
OPUS-3 [18] LIF bid 355 68.3 -37.9** 2.46 -0.80*b,c,j
g
VEH bid 356 69.0 -30.7 2.46 -0.63b
bid twice daily, BL baseline, LIF lifitegrast ophthalmic solution 5%, pts patients, VAS visual analogue scale, VEH vehicle
* p \ 0.05, ** p \ 0.001, *** p \ 0.0001 vs. VEH
a
This trial contained two additional treatment arms in which pts received LIF 0.1 or 1% bid; results for these treatment arms are not shown
b
Data obtained from the US prescribing information [7]
c
Nominal p value
d
Statistical analysis conducted using a stratified 2-sample t test
e
Treatment difference -4.7 (95% CI -8.9 to -0.4) (p value not reported) [7]
f
Treatment difference -0.23 (95% CI -0.36 to -0.10) (p value not reported) [7]
g
Primary endpoint
h
Treatment effect 12.61 (95% CI 8.51–16.70)
i
Treatment effect 7.16 (95% CI 3.04–11.28)
j
Treatment effect 0.17 (95% CI 0.03–0.30)

3.2 Phase 3 Trials: OPUS-1, -2 and -3 3.2.1 Effects on Symptoms

In the phase 3 OPUS-1 [16], OPUS-2 [17] and OPUS-3
[18] trials, eligible patients were randomized to receive
lifitegrast ophthalmic solution 5% or vehicle twice daily for
84 days. Patients were not permitted to use artificial tears,
topical ciclosporin or any other ophthalmic medication
during these trials [16–18].
Primary endpoints were the mean changes from baseline
to day 84 in the eye dryness VAS score (OPUS-2 [17] and
OPUS-3 [18]), the visual-related function subscale score
(OPUS-1 [16]) and the inferior corneal fluorescein staining
score (OPUS-1 [16] and OPUS-2 [17]). Efficacy was
assessed in the ITT population [16–18]. Unless specified
otherwise, statistical analyses for the mean changes from
baseline in the eye dryness VAS score and the inferior
corneal fluorescein staining score for OPUS-1, OPUS-2
and OPUS-3 were conducted using a stratified 2-sample t
test [7, 16–18]. Re-analysis of data from OPUS-1 means
that some p values are reported as nominal p values [19],
and because statistical significance was achieved for only
one of the two co-primary endpoints in OPUS-2, p values
for other endpoints are considered nominal [17].
Lifitegrast ophthalmic solution 5% significantly improved
the symptom of eye dryness [7, 16–18]. At day 84, the
mean reduction from baseline in the eye dryness VAS
score (primary endpoint in OPUS-2 [17] and OPUS-3 [18])
was significantly greater with lifitegrast ophthalmic solu-
tion 5% than with vehicle in all three OPUS trials (stratified
2-sample t test; Table 1) [7, 16–18].
Use of a ‘simple’ 2-sample t test revealed a nominal
p value of 0.1137 for the between-group difference in the
mean reduction from baseline to day 84 in the eye dryness
VAS score in OPUS-1 [19]. The treatment effect appeared
greater in the subgroup of patients with prior use of arti-
ficial tears and a baseline eye dryness VAS score of C40
(nominal p = 0.0178), according to post hoc analysis [19].
This led to inclusion of artificial tear use within 30 days of
screening and a baseline eye dryness VAS score of C40 in
the eligibility criteria for OPUS-2 and OPUS-3, and to the
eye dryness VAS score being selected as a primary end-
point in these trials [19].
The mean change from baseline to day 42 in the eye
dryness VAS score was -12.6 with lifitegrast ophthalmic
Lifitegrast Ophthalmic Solution 5%: A Review
solution 5% and -9.1 with vehicle in OPUS-1 (treatment
difference -4.2; 95% CI -8.5 to 0.0) [7, 16]. Post hoc
analysis in OPUS-2 found that the treatment effect for the
eye dryness VAS score with lifitegrast ophthalmic solution
5% versus vehicle was 6.67 (95% CI 3.05–10.30; nominal
p = 0.0003) at day 14 and 10.63 (95% CI 6.71–14.55;
nominal p \ 0.0001) at day 42 [17]. In OPUS-3, the eye
dryness VAS score was reduced from baseline to a sig-
nificantly greater extent with lifitegrast ophthalmic solution
5% than with vehicle at day 14 (treatment effect 7.85; 95%
CI 4.33–11.37; p \ 0.0001) and day 42 (treatment effect
9.32; 95% CI 5.44–13.20; p \ 0.0001) [18].
No significant difference was seen between patients
receiving lifitegrast ophthalmic solution 5% and those
receiving vehicle in terms of mean VAS scores for burning/
stinging, foreign body sensation, blurred vision, itching or
pain in OPUS-1 [16]. In OPUS-2, the mean change from
baseline to day 84 in the eye discomfort VAS score was
-26.46 with lifitegrast ophthalmic solution 5% versus
-16.73 with vehicle (treatment effect 9.77; 95% CI
5.27–14.28; nominal p \ 0.0001) [17]. In OPUS-3, no
significant difference was seen between lifitegrast oph-
thalmic solution 5% and vehicle in terms of mean
improvements from baseline to days 14 or 84 in VAS
scores for burning/stinging, foreign body sensation, dis-
comfort, itching, photophobia or pain [18]. However, sig-
nificantly (nominal p \ 0.05) greater improvements from
baseline to day 42 were seen in itching, foreign body
sensation and eye discomfort VAS scores with lifitegrast
ophthalmic solution 5% versus vehicle [18].
The mean change from baseline to day 84 in the visual-
related function subscale score (co-primary endpoint) did
not significantly differ between lifitegrast ophthalmic
solution 5% and vehicle recipients in OPUS-1 [16]. In
addition, no significant between-group differences were
seen in terms of the symptom and environmental trigger
subscale scores or the total symptom score [16].
In OPUS-2, the mean change from baseline to day 84
in the ocular discomfort score was -0.91 with lifitegrast
ophthalmic solution 5% versus -0.57 with vehicle
(treatment effect 0.34; 95% CI 0.15–0.53; nominal p =
0.0005) [17]. In OPUS-3, mean changes from baseline
to days 14, 42 or 84 in the ocular discomfort score did
not significantly differ between patients receiving
lifitegrast ophthalmic solution 5% and those receiving
vehicle [18].
3.2.2 Effects on Signs
At day 84, the mean change from baseline in the inferior
corneal fluorescein staining score (co-primary endpoint in
OPUS-1 [16] and OPUS-2 [17]) significantly favoured
lifitegrast ophthalmic solution 5% versus vehicle in OPUS-
1 [7, 16] and OPUS-3 [7, 18], with no significant between-
group difference seen in OPUS-2 [17] (stratified 2-sample t
test; Table 1).
In OPUS-2, the mean change from baseline to day 84
with lifitegrast ophthalmic solution 5% versus vehicle was
-1.62 vs. -1.49 for the total corneal fluorescein staining
score (treatment effect 0.14; 95% CI -0.16 to 0.44) and
-0.25 vs. -0.27 for the nasal lissamine staining score
(treatment effect -0.02; 95% CI -0.14 to 0.10) [17].
4 Tolerability and Safety of Lifitegrast
Ophthalmic Solution 5%
The tolerability and safety of lifitegrast ophthalmic solution
5% was examined in the randomized, double-masked,
multicentre phase 3 SONATA trial [13]. SONATA inclu-
ded patients aged C18 years with a history of dry eye
disease, a BCVA of C0.7 logMAR, a corneal fluorescein
staining score of C2 in at least one region, an eye dryness
or discomfort VAS score of C40, use of and/or the desire to
use artificial tears in the past 6 months and an unanaes-
thetized Schirmer test score of C1 and B10 mm. Patients
received lifitegrast ophthalmic solution 5% (n = 220) or
vehicle (n = 111) twice daily for 360 days. After 14 days
post-randomization, patients were permitted to receive
artificial tears, topical ophthalmic/nasal antihistamines,
mast cell stabilizers and corticosteroids, and to wear daily
disposable contact lenses. The primary safety endpoint in
SONATA was the incidence and severity of ocular and
non-ocular treatment-emergent adverse events (TEAEs).
The adherence rate was 84.1% in patients receiving lifite-
grast ophthalmic solution 5% and 81.1% in patients
receiving vehicle [13].
Lifitegrast ophthalmic solution 5% was generally well
tolerated in patients with dry eye disease [13]. Ocular
TEAEs occurred in 53.6% of patients receiving lifitegrast
ophthalmic solution 5% and in 34.2% of patients receiving
vehicle [13]. Ocular TEAEs were mild in 38.6% of lifite-
grast ophthalmic solution 5% recipients versus 24.3% of
vehicle recipients, moderate in 13.2 vs. 7.2% and severe in
1.8 vs. 2.7%. The most commonly reported ocular TEAEs
(occurring in [5% of patients) were instillation-site irrita-
tion (15.0% of lifitegrast ophthalmic solution 5% recipients
vs. 4.5% of vehicle recipients), instillation-site reaction
(13.2 vs. 1.8%), reduced visual acuity (11.4 vs. 6.3%) and
dry eye (1.8 vs. 5.4%). Ocular TEAEs considered to be
possibly or probably related to the study drug occurred in
40.0% of patients receiving lifitegrast ophthalmic solution
5% and in 20.7% of patients receiving vehicle. No serious
ocular TEAEs were reported during SONATA. Ocular
TEAEs resulted in discontinuation in 8.2% of patients
receiving lifitegrast ophthalmic solution 5% vs. 5.4% of

patients receiving vehicle, most commonly because of
instillation-site reaction, irritation or pain, increased
lacrimation, reduced visual acuity or blurred vision [13].
Non-ocular TEAEs occurred in 47.3% of patients
receiving lifitegrast ophthalmic solution 5% and in 36.0%
of patients receiving vehicle [13]. Non-ocular TEAEs
were mild in 25.0% of lifitegrast ophthalmic solution 5%
recipients versus 18.0% of vehicle recipients, moderate in
17.7 vs. 12.6% and severe in 4.5 vs. 5.4%. The most
commonly reported non-ocular TEAE (occurring in [5%
of patients) was dysgeusia (16.4% of lifitegrast oph-
thalmic solution 5% recipients versus 1.8% of vehicle
recipients). Non-ocular TEAEs considered to be possibly
or probably related to the study drug occurred in 18.6% of
patients receiving lifitegrast ophthalmic solution 5% and
in 5.4% of patients receiving vehicle. Serious non-ocular
TEAEs were reported in 4.1% of patients receiving
lifitegrast ophthalmic solution 5% and in 5.4% of patients
receiving vehicle, although none of them were considered
to be related to the study drug. Non-ocular TEAEs
resulted in discontinuation in 4.1% of patients receiving
lifitegrast ophthalmic solution 5% versus 3.6% of patients
receiving vehicle, most commonly because of dysgeusia
[13].
Mean drop comfort scores were \2 within 3 min of
instillation of lifitegrast ophthalmic solution 5% [scored
from 0 (very comfortable) to 10 (very uncomfortable)]
[13]. During SONATA, changes in visual acuity were
minimal, and artificial tears were used by 32.8% of lifite-
grast ophthalmic solution 5% recipients and 43.9% of
vehicle recipients [13].
Patients receiving lifitegrast ophthalmic solution 5% or
vehicle experienced minimal changes in CD3, CD4 and
CD8 cell counts at days 180 or 360, and there no reports of
opportunistic infection or TEAEs suggestive of long-term
T cell suppression [13].
The adverse event profile seen in patients receiving
lifitegrast ophthalmic solution 5% in the OPUS-1 [16],
OPUS-2 [17] and OPUS-3 [18] trials was consistent with
that reported in SONATA [13]. Over 12 weeks in OPUS-1,
-2 and -3, the most commonly reported ocular TEAEs were
instillation-site irritation (8–24% of lifitegrast ophthalmic
solution 5% recipients vs. 1–4% of vehicle recipients)
[16–18], instillation-site pain (22 vs. 4%) [16], instillation-
site reaction (7–17 vs. 1–5%) [16–18] and instillation-site
pruritus (7 vs. 2%) [16]. In OPUS-1, most ocular TEAEs
occurred on day 0 following exit from the CAE [16], and in
all trials the vast majority of ocular TEAEs were of mild to
moderate severity [16–18]. Dysgeusia was the most com-
monly reported non-ocular TEAE and was reported in
13–16% of lifitegrast ophthalmic solution 5% recipients
and 0–0.3% of vehicle recipients [16–18].
G. M. Keating
5 Dosage and Administration of Lifitegrast
Ophthalmic Solution 5%
Lifitegrast ophthalmic solution 5% is approved in the USA
for the treatment of the signs and symptoms of dry eye
disease [7]. One drop of lifitegrast ophthalmic solution 5%
should be instilled twice daily (&12 h apart) into each eye
using a single-use container. Contact lenses should be
removed prior to the instillation of lifitegrast ophthalmic
solution 5%, and may be reinserted 15 min following
administration [7]. Local prescribing information should be
consulted for further information.
6 Current Status of Lifitegrast Ophthalmic
Solution 5% in Dry Eye Disease
The goal of treatment in dry eye disease is to return the tear
film and ocular surface to their normal homeostatic state,
thereby improving the patient’s ocular comfort and visual-
related quality of life [20].
Lifitegrast ophthalmic solution 5% is the first product
approved in the USA to improve the signs and symptoms
of dry eye disease [7]. The only other approved product,
ciclosporin ophthalmic emulsion 0.05%, is indicated to
increase tear production in patients whose tear production
is suppressed, presumably because of ocular inflammation
associated with dry eye disease [6].
The FDA expects that a product with efficacy for the
treatment of the signs and symptoms of dry eye disease will
improve both a sign and a symptom, although not necessarily
both in the same trial [21]. The eye dryness VAS score was
significantly reduced from baseline to day 84 with lifitegrast
ophthalmic solution 5% versus vehicle in the OPUS-1,
OPUS-2 and OPUS-3 trials, and the inferior corneal fluo-
rescein staining score was significantly reduced from base-
line to day 84 with lifitegrast ophthalmic solution 5% versus
vehicle in OPUS-1 and OPUS-3, but not in OPUS-2 (Sect.
3.2). Thus, the FDA concluded that, taken as a whole, trial
data support the treatment effect of lifitegrast ophthalmic
solution 5% in improving both a clinical sign and a clinical
symptom of dry eye disease [21]. It should be noted that there
is not a strong correlation between signs and symptoms in dry
eye disease [22, 23]. It should also be noted that patients who
had undergone LASIK or similar surgery in the past 12
months and contact lens wearers were excluded from the
phase 2 trial and OPUS-1, OPUS-2 and OPUS-3, although
use of daily disposable contact lenses was permitted in the
1-year SONATA trial.
Symptoms of dry eye disease may improve within 14 days
of starting treatment with lifitegrast ophthalmic solution 5%,
with a significant improvement in the eye dryness VAS score
Lifitegrast Ophthalmic Solution 5%: A Review
seen by day 14 in OPUS-2 and OPUS-3 and by day 42 in
OPUS-1 (Sect. 3.2.1). Additional data concerning the
longer-term efficacy of lifitegrast ophthalmic solution 5% in
dry eye disease and its efficacy in combination with other dry
eye disease therapies would be of interest. In addition, data
are needed regarding the efficacy of lifitegrast ophthalmic
solution 5% in dry eye disease associated with decreased
aqueous tear production (e.g. in Sjögren’s syndrome) versus
excessive tear evaporation (e.g. in meibomian gland dys-
function). The effect of lifitegrast ophthalmic solution 5% on
other symptoms of dry eye disease, in different degrees of
severity of dry eye disease and on other biomarkers of dry
eye disease (e.g. tear osmolarity and tear film instability) also
requires further study.
Lifitegrast ophthalmic solution 5% was generally well
tolerated in patients with dry eye disease, with most
TEAEs being of mild to moderate severity (Sect. 4).
In conclusion, lifitegrast ophthalmic solution 5% pro-
vides a new option for the treatment of dry eye disease.
Data Selection Lifitegrast Ophthalmic Solution 5%:
50 records identified
Duplicates removed
Excluded at initial screening (e.g. press releases; news
reports; not relevant drug/indication)
Excluded during initial selection (e.g. preclinical study;
review; case report; not randomized trial)
Excluded by author (e.g. not randomized trials; review;
duplicate data; small patient number; phase 1/2 trials)
Cited efficacy/tolerability articles
Cited articles not efficacy/tolerability
Search Strategy: EMBASE, MEDLINE and PubMed from 1946
to present. Clinical trial registries/databases and websites were also
searched for relevant data. Key words were lifitegrast, SAR-1118,
Xiidra. Records were limited to those in English language.
Searches last updated 12 December 2016.
Acknowledgements During the peer review process, the manufac-
turer of lifitegrast ophthalmic solution 5% was also offered an
opportunity to review this article. Changes resulting from comments
received were made on the basis of scientific and editorial merit.
Compliance with Ethical Standards
Funding The preparation of this review was not supported by any
external funding.
Conflict of interest Gillian Keating is a salaried employee of Adis/
Springer, is responsible for the article content and declares no rele-
vant conflicts of interest.
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