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Expert Opinion on Pharmacotherapy

ISSN: 1465-6566 (Print) 1744-7666 (Online) Journal homepage: http://www.tandfonline.com/loi/ieop20

Lifitegrast for the treatment of dry eye disease inadults

Eric D. Donnenfeld, Henry D. Perry, Alanna S. Nattis & Eric D. Rosenberg

To cite this article: Eric D. Donnenfeld, Henry D. Perry, Alanna S. Nattis & Eric D.Rosenberg (2017): Lifitegrast for the treatment of dry eye disease in adults, Expert Opinion onPharmacotherapy, DOI: 10.1080/14656566.2017.1372748

To link to this article: http://dx.doi.org/10.1080/14656566.2017.1372748

Accepted author version posted online: 25Aug 2017.Published online: 04 Sep 2017.

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DRUG EVALUATION

Lifitegrast for the treatment of dry eye disease in adultsEric D. Donnenfelda, Henry D. Perryb, Alanna S. Nattisb and Eric D. Rosenbergc

aOphthalmic Consultants of Long Island, New York University Medical Center, Garden City, NY, USA; bOphthalmic Consultants of Long Island,Nassau University Medical Center, Rockville Centre, NY, USA; cWestchester Medical Center, Valhalla, NY, USA

ABSTRACTIntroduction: Dry eye disease (DED) is a common ocular disorder that can have a substantial burden onquality of life and daily activities. Lifitegrast ophthalmic solution 5.0% is the first medication approved inthe US for the treatment of the signs and symptoms of DED. The aim of this article is to summarize thepreclinical and clinical data on lifitegrast and discuss how lifitegrast may fit into the current treatmentlandscape for DED.Areas covered: A literature search of published preclinical and clinical data was conducted to reviewthe chemistry, pharmacodynamics, pharmacokinetics, and clinical efficacy/safety of lifitegrast. Theimpact that lifitegrast may have on DED treatment practices is also discussed.Expert opinion: The introduction of lifitegrast provides a potentially important additional option foreye care professionals treating DED. In clinical trials conducted in adults with DED, lifitegrast ophthalmicsolution 5.0% improved both signs and symptoms of DED. Of note, in 2 phase 3 trials, symptomimprovements were observed as early as 2 weeks, which may be explained by lifitegrast’s uniquemechanism of action of blocking a specific signaling pathway in inflammation. Future research shouldinclude evaluation of whether lifitegrast can be used in combination with other DED treatments.

ARTICLE HISTORYReceived 14 June 2017Accepted 24 August 2017

KEYWORDSDry eye disease; efficacy;lifitegrast; lymphocytefunction-associated antigen-1 antagonist; safety

1. Introduction

Dry eye disease (DED) is a complex, multifactorial disease of theocular surface that involves a loss of homeostasis of the tear filmand can lead to ocular symptoms. Tear film instability and hyper-osmolarity, ocular surface inflammation, and neurosensoryabnormalities play roles in the etiology of the disease [1].Different types of DED exist, with the two major classes beingaqueous tear-deficient DED and evaporative DED [1]. As no singlereliable test for DED is available, clinicians rely on a combination ofDED symptoms and clinical signs to diagnose the condition.However, there is poor correlation between the signs and symp-toms of DED [2,3], which, along with the multifactorial nature ofthe condition, complicates its diagnosis and management.

DED represents a public health concern due to its highprevalence and burden on the patient in terms of quality ofvision, quality of life, physical/social functioning, and eco-nomic cost (due mainly to loss of work productivity) [4,5]. Itis recognized that the prevalence of DED is higher in womenand older individuals. In the Women’s Health Study andPhysicians’ Health Study, the prevalence of DED (cliniciandiagnosed and/or severe symptoms of dryness and irritationconstantly or often) was estimated at 7.8% in women and4.3% in men aged 50 years or older [6,7]. Other studies haveestimated the prevalence of DED (defined as subject-reported symptoms), in the range of 5–34% of the popula-tion aged over 50 years [8].

Lifitegrast ophthalmic solution 5.0% received approval fromthe US Food and Drug Administration (FDA) in 2016 for treat-ment of the signs and symptoms of DED in adults. It was

designated as the first in a new class of drugs called lympho-cyte function-associated antigen-1 (LFA-1) antagonists.Lifitegrast blocks the interaction of cell surface proteins LFA-1and intercellular adhesion molecule-1 (ICAM-1), and is believedto inhibit T-cell-mediated inflammation in DED.

In the interval between the approval of cyclosporineophthalmic emulsion (CsA; Restasis®, Allergan, Dublin,Ireland) in 2003 and lifitegrast’s approval in 2016, numerouscandidates were tested for the treatment of DED. Until thelifitegrast clinical trials program, none (including CsA) demon-strated statistical significance in primary end points for bothsigns and symptoms of DED. In a 2008 survey of ophthalmol-ogists treating DED, almost all (94%) responded that moretreatment options are needed for moderate or severe DED[9]. Important attributes of a new therapeutic for DED, whichlifitegrast may offer, are the treatment of both signs andsymptoms of DED, protection of the ocular surface, relativelyrapid onset of action, good tolerability, and long-term safety.In this review, we provide an overview of the pharmacologicalproperties of lifitegrast and key data from clinical trials, anddiscuss how lifitegrast is likely to fit into the current treatmentparadigm for DED.

2. Overview of the market

DED presents variable signs and/or symptoms, and availabletreatment options address different aspects of the disease.In the United States, CsA 0.05% (Restasis® and Restasismultidose™, Allergan, Dublin, Ireland) is approved to

CONTACT Eric D. Donnenfeld edonnenfeld@ocli.net 711 Stewart Avenue, Suite 160, Garden City, NY 11530, USA.

EXPERT OPINION ON PHARMACOTHERAPY, 2017https://doi.org/10.1080/14656566.2017.1372748

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increase tear production in patients whose tear productionis presumed to be suppressed due to ocular inflammation.Other topical medications that are used to address DED inthe United States [10] include over-the-counter artificial tearsubstitutes that augment the tear film. Antibiotics are usedoff-label to treat meibomian gland dysfunction, a majorcause of evaporative DED. Oral tetracyclines (e.g. doxycy-cline) inhibit the production of bacterial lipases [11], thusimproving the lipid profile of meibomian oils. Both tetracy-clines and topical azithromycin are antibacterial and haveanti-inflammatory properties [12]. Short-term therapy withophthalmic corticosteroids (e.g. loteprednol 0.5%;Lotemax®, Bausch & Lomb, Rochester, NY, USA) is alsoused off-label to reduce ocular surface inflammation.

A number of devices are available for the treatment of DED.These include the TrueTear™ Intranasal Tear Neurostimulator(Allergan, Dublin, Ireland) device, which temporarily increasestear production during neurostimulation in adult patients withaqueous tear deficiency, and the Lipiflow system (TearScience,Morrisville, NC, USA) which helps to clear blockages in themeibomian glands of patients with obstructive meibomiangland dysfunction. In Japan, the mucin secretagogues diqua-fosol ophthalmic solution (3% Diquas®; SantenPharmaceutical, Osaka, Japan) and rebamipide (Mucosta®ophthalmic suspension unit dose 2%; Otsuka Pharmaceutical,Tokyo, Japan) are approved for the treatment of DED. Thesedrugs promote the secretion of fluid and mucin from theocular surface, thus improving tear film stability. Rebamipidealso has anti-inflammatory properties [13]. Drugs currently indevelopment in the United States include preparations thatuse nanotechnology to improve the delivery of availabledrugs. These include KPI-121 (Kala Pharmaceuticals, Waltham,MA, USA), a nanoparticle formulation of the corticosteroid,loteprednol etabonate, and OTX-101 (Seciera™, Sun Pharma,Mumbai, India), a nanomicellar formulation of cyclosporine. Inaddition, RGN-259 (ReGenTree, Princeton, NJ, USA), a syntheticcopy of the naturally occurring protein thymosin β4, which ispredicted to promote corneal epithelial cell migration anddecrease inflammation, is currently in phase 3 trials.

3. Introduction to the compound

3.1. Chemistry

Lifitegrast was designed to bind to LFA-1, a cell surface proteinexpressed on T lymphocytes (T cells), thus blocking the inter-action of LFA-1 with its ligand, ICAM-1 [14]. Lifitegrast wasdiscovered through a rational design approach that focusedon the binding epitope of ICAM-1, a region of six bindingresidues [15,16]. A tetrahydroisoquinoline analogue desig-nated SAR 1118 (lifitegrast) was selected based on potencyof binding in a HuT 78 T-cell adhesion assay, and the shorthalf-life, fast clearance, and low exposure observed in ratpharmacokinetic studies [17]. Lifitegrast is highly aqueoussoluble (>100 mg/mL), which allows it to be formulated at50 mg/mL (5.0%), thus maintaining physiological pH [17].Lifitegrast ophthalmic solution 5.0% is a preservative-free,sterile eye drop that has a target pH of 7.0–8.0, an osmolalityrange of 200–330 mOsmol/kg, and stability in aqueous solu-tion at room temperature [18].

3.2. Pharmacodynamics

Based on the available evidence, it is postulated that LFA-1/ICAM-1 interaction has roles in T-cell activation, through theformation of immunological synapses between T cells andantigen-presenting cells (e.g. dendritic cells), and in the migra-tion of T cells to the ocular surface [19]. In DED, researchsuggests that stress (environmental and/or microbial) to theocular surface results in increased ICAM-1 expression in theocular surface tissues [20–22]. Although the precise mechan-ism of action of lifitegrast in DED has not been established, itis thought that by blocking LFA-1/ICAM-1 interaction, lifite-grast inhibits T-cell migration, T-cell activation, and the releaseof pro-inflammatory cytokines (Figure 1). This is supported bydata from in vitro studies that demonstrated that lifitegrastinhibits Jurkat T-cell and HuT 78 T-cell adhesion to ICAM-1(half-maximal inhibitory concentration [IC50] of 2.98 and9 nmol/L, respectively) and inhibits the secretion of pro-

Box 1. Drug summary

Drug name Lifitegrast ophthalmic solution 5.0%Phase Approved in the United StatesIndication Signs and symptoms of DEDPharmacology description/mechanism ofaction

LFA-1 antagonist that blocks the interaction of ICAM-1 and LFA-1 thereby inhibiting T-cell-mediatedinflammation

Route of administration OphthalmicChemical structure

Pivotal trials OPUS-1 [30], OPUS-2 [31], and OPUS-3 [32]

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inflammatory cytokines including interferon-γ, interleukin (IL)-1β, and tumor necrosis factor-α in a concentration-dependentmanner in activated peripheral blood mononuclear cells (halfmaximal effective concentration [EC50] of 0.0016, 0.36, and0.076 μM, respectively) [17,23]. Further, in a mouse model inwhich corneal inflammation was induced by epithelial abra-sion and exposure to tobramycin-killed Pseudomonas aerugi-nosa or Staphylococcus aureus, lifitegrast ophthalmic solutionreduced corneal inflammation [24]. Lifitegrast also significantlyincreased tear production from baseline in dogs diagnosedwith idiopathic keratoconjunctivitis sicca [23].

3.3. Pharmacokinetics and metabolism

Following ophthalmic administration of radiolabeled lifitegrastto rats [25] and dogs [23], the highest concentration of lifite-grast (ng equivalents [14C]-lifitegrast/g) at 0.5 h post dose wasdetected in the bulbar conjunctiva (31,500, 4510, rats [25] anddogs [23], respectively), palpebral conjunctiva (26,300, 3790),and cornea (17,150, 2130). In a study by Rao et al., the plasmaconcentration of lifitegrast post dose reached a maximum at0.25 h (194 ng equivalents [14C]-lifitegrast/g) and decreasedto below the level of quantification from 12 h [25]. Similarly, inrabbits that received twice-daily ophthalmic lifitegrast for5 days, the highest concentrations of lifitegrast (ng/g) werelocalized in the ocular anterior segment tissues (bulbar con-junctiva [9370–14,200], palpebral conjunctiva [9620–11,900],cornea [5190–5930], and anterior sclera [5870–11,200]),whereas there was low exposure in the plasma (maximumplasma concentration [Cmax]: 9.5–17.4 ng/mL) and posteriorsegment tissues (posterior sclera [369–826], optic nerve, retina,

and vitreous humor [0–36]), suggesting a low potential for off-target systemic or ocular effects [26].

In a phase 1 trial [27], twice-daily administration of lifitegrastophthalmic solution 5.0% to healthy volunteers resulted in a tearfluid lifitegrast concentration that exceeded the target therapeu-tic level in the eye of >1 μM (~600 ng/mL), i.e. substantiallyhigher than the IC50 and EC50 values demonstrated in vitro forLFA-1/ICAM-1 binding and cytokine inhibition, respectively(Section 3.2). In participants administered lifitegrast twice dailyfor 10 days, a maximum tear fluid lifitegrast concentration(91,413 ng/mL) was achieved in a median time of 0.3 h, andthere was no evidence of lifitegrast accumulation in tears duringrepeated ocular dosing. In the same study, low levels of lifitegrastin the plasmawere detected within 5min of instillation and werecleared from the plasma within 1–4 h. The Cmax of lifitegrastfollowing ocular administration was 20μM [17]. These IC50 values are several orders higher than those

Figure 1. Current understanding of the mechanism of action of lifitegrast in DED. (a) In DED, stress to the ocular surface can result in overexpression of ICAM-1. Thisleads to increased migration of T cells to the ocular surface, activation of T cells through the formation of immunological synapses, and the release of pro-inflammatory cytokines, which can cause damage to the ocular tissues. (b) Lifitegrast is thought to reduce T-cell migration, T-cell activation, and pro-inflammatorycytokine release by blocking LFA-1/ICAM-1 interaction. DED: dry eye disease; ICAM-1: intercellular adhesion molecule-1; LFA-1: lymphocyte function-associatedantigen-1; mAPC: mature antigen-presenting cell. Adapted with permission from Perez et al., Lifitegrast, a novel integrin antagonist for treatment of dry eye disease.Ocul Surf; 2016; 14; 207–215 [14]. DOI: http://dx.doi.org/10.1016/j.jtos.2016.01.001.

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demonstrated in vitro for LFA-1/ICAM-1 binding and cytokineinhibition (Section 3.2). Thus, given the very low lifitegrastplasma levels in human trials following ocular administration(5% in either treatment group) ocularTEAEs reported in these trials were visual acuity reduced, instilla-tion-site pain, instillation-site irritation, and instillation-site reac-tion. Each of these TEAEs occurred at a higher rate in the lifitegrastversus the placebo group, except for visual acuity reduced, whichin three trials was slightly higher in the placebo group (placebo vs.lifitegrast: phase 2, 5.2% vs. 1.7%; OPUS-1, 5.1% vs. 4.8%; OPUS-2,6.4% vs. 5.0%). Themost common (>5% in either treatment group)non-ocular TEAE in all of the trials was dysgeusia, which alsooccurred at a higher rate in the lifitegrast group.

To assess the longer-term tolerability and safety of twice-dailylifitegrast, the SONATA 1-year safety studywas conducted in DEDpatients (lifitegrast, n = 220; placebo, n = 111) [28]. Key inclusioncriteria were adults (aged ≥18 years) with self-reported DED,Schirmer Tear Test without anesthesia ≥1 and ≤10 mm in ≥1eye, corneal fluorescein staining score ≥2.0 in≥1 eye, and the useof and/or desire to use artificial tears in the last 6 months.Participants were randomized 2:1 to lifitegrast ophthalmic solu-tion 5.0% or placebo. To reflect real-world use, after day 14,participants were allowed to use as required artificial tears (≤4times daily, as needed), topical ophthalmic/nasal steroids (onlyloteprednol etabonate ≤4 weeks at a time), antihistamines, mastcell stabilizers, and contact lenses. The primary end point was thepercentage and severity of ocular and non-ocular TEAEs. InSONATA, lifitegrast appeared safe and well-tolerated, with noserious ocular TEAEs, and a similar safety profile as the previous12-week trials. The most frequent (>5% in either group) TEAEswere instillation-site irritation (lifitegrast, 15.0%; placebo, 4.5%),instillation-site reaction (lifitegrast, 13.2%; placebo, 1.8%), visualacuity reduced (lifitegrast, 11.4%; placebo, 6.3%), and dysgeusia(lifitegrast, 16.4%; placebo, 1.8%).

A pooled analysis of the safety data from all five clinicaltrials has also been completed, including 1287 participantswho received at least one dose of lifitegrast (n = 1177, pla-cebo), with total exposure to lifitegrast treatment of 415.65person-years (332.15 person-years for placebo) [34]. Theresults of the pooled analysis further support the tolerabilityof lifitegrast ophthalmic solution 5.0% across all trials. The

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most common adverse events in the pooled analysis wereinstillation-site irritation (lifitegrast, 15.2%; placebo, 2.8%),instillation-site reaction (lifitegrast, 12.3%; placebo, 2.3%),instillation-site pain (lifitegrast, 9.8%; placebo, 2.1%), and dys-geusia (lifitegrast, 14.5%; placebo, 0.3%) [34]. To date, therehave been no postmarketing adverse events reported.

Given the mechanism of action of lifitegrast on T-cell func-tion, the effect of twice-daily lifitegrast ophthalmic solution5.0% on whole blood CD3, CD4, and CD8 lymphocyte countswas assessed in SONATA in a subset of participants (n = 75) ondays 0 (baseline), 180, and 360 [28]. There were minimal andsimilar changes in lymphocyte counts in both treatmentgroups, suggesting that lifitegrast did not cause chronic sup-pression of lymphocytes. In addition, there was no pattern ofadverse events to suggest systemic toxicities or localizedinfectious complications resulting from chronic T-cell suppres-sion [28] (similar to findings from trials of CsA 0.05% [35]).

5. Regulatory affairs

Lifitegrast was discovered at Sunesis (South San Francisco, CA,USA) and developed clinically by Shire (Lexington, MA, USA). ANew Drug Application was submitted to the FDA in March2015 for the approval of lifitegrast ophthalmic solution 5.0%to treat DED in adults. Efficacy data from the phase 2, OPUS-1,and OPUS-2 trials were included in the NDA application. Theapplication was granted priority review in April 2015. InOctober 2015, Shire received a complete response letterfrom the FDA for lifitegrast, indicating that the marketingapplication would not be approved without additional clinicaldata. Shire responded 3 months later with a resubmission thatincluded data from the OPUS-3 trial, which had been initiatedfollowing pre-submission feedback from the agency; the aimof OPUS-3 was to demonstrate efficacy in a symptom endpoint, EDS. The FDA subsequently approved Xiidra® (lifitegrastophthalmic solution 5.0%) for the treatment of signs and

-0.50 -0.25 0.25 0.50 0.75 1.00 1.25

Treatment effect, 95% CI

0

Phase 2 51.8, 51.6

OPUS-1 41.6, 40.2

OPUS-2 69.2, 69.7

OPUS-3 69.0, 68.3

Day 84: 0.03 (−0.10, 0.17), p = NS

Day 84: 0.17 (0.03, 0.30), nominal p = 0.0144

Day 14: 0.04 (−0.08, 0.17), p = NS

Day 84: 0.24 (0.10, 0.38), p = 0.0007

Day 42: 0.12 (−0.02, 0.26), p = NS

Day 14: 0.19 (−0.05, 0.43), p = NS

Day 84: 0.35 (0.05, 0.65), nominal p = 0.0209

Day 42: 0.12 (−0.14, 0.37), p = NS

TE (95% CI)Mean baseline EDS(PBO, LIF)

Study

(a) ICSS (study eye)

Favors lifitegrastFavors placebo

-10 -5 5 10 15 20 25

Treatment effect, 95% CI

0

Phase 2 51.8, 51.6

OPUS-1 41.6, 40.2

OPUS-2 69.2, 69.7

OPUS-3 69.0, 68.3

Day 84: 12.61 (8.51, 16.70), p < 0.0001

Day 84: 7.16 (3.04, 11.28), p = 0.0007

Day 42: 9.32 (5.44, 13.20), p < 0.0001

Day 14: 7.85 (4.33, 11.37), p < 0.0001

Day 14: 6.67 (3.05, 10.30), nominal p = 0.0003

Day 42: 10.63 (6.71, 14.55),nominal p < 0.0001

Day 14:−0.75 (−5.32, 3.81), p = NS

Day 84: 3.94 (−0.95, 8.83), p = NSDay 42: 3.48 (−1.44, 8.40), p = NS

Day 14: 5.38 (−4.01, 14.77), p = NS

Day 84: 7.95 (−1.96, 17.85), p = NS

Day 42: 10.20 (1.49, 18.92),nominal p = 0.0222

(b) EDS (VAS)

Favors lifitegrastFavors placebo

TE 95% CIMean baseline EDS(PBO, LIF)

Study

Figure 2. Treatment effects in ICSS and EDS across the 12-week randomized controlled trials (ITT population with LOCF). Day 14 and day 42 TEs in ICSS are notavailable for the OPUS-2 and OPUS-3 trials. CI: confidence interval; EDS: eye dryness score; ICSS: inferior corneal staining score; ITT: intent-to-treat; LIF: lifitegrast;LOCF: last observation carried forward; NS: not significant; PBO: placebo; VAS: visual analogue scale.

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symptoms of DED in July 2016. The agency based its approvalon the efficacy of lifitegrast for the treatment of DED asdemonstrated by replication of the sign and symptom endpoint results in the four submitted efficacy/safety trials com-pared with vehicle. Lifitegrast was granted designation as thefirst in a new class of drugs, LFA-1 antagonists.

6. Conclusion

Lifitegrast is the first medication approved by the FDA for thetreatment of both the signs and symptoms of DED. Key fea-tures of lifitegrast include high aqueous solubility, rapidabsorption into the ocular tissues, rapid systemic elimination,and a unique mechanism of action. In clinical trials, lifitegrastophthalmic solution 5.0% improved signs and symptoms ofDED in adults with DED across four 12-week efficacy/safetytrials. Most notably, symptom improvements were observed asearly as 2 weeks. Lifitegrast was well tolerated in the 12-weektrials and a 1-year safety study, with no serious ocular TEAEsreported.

7. Expert opinion

Lifitegrast ophthalmic solution 5.0% is the first pharmacologicalmedication to be approved by the FDA for the treatment of DEDsince 2003, when CsA 0.05% was approved for the indication ofincreasing tear production in DED patients. The approval of CsA0.05% was based on significant improvements in Schirmer wet-ting in clinical trials; CsA 0.05% is not indicated for the treatmentof the symptoms of DED. Results from clinical trials [35,36], andclinical experience post approval, have shown that markedimprovement with CsA 0.05% generally takes at least 3 months.In contrast, significant symptom improvements occurred withlifitegrast in three of four 12-week trials (phase 2, OPUS-2, andOPUS-3) by 6 weeks and as early as 2 weeks in two trials (OPUS-2and OPUS-3). The faster time to efficacy for lifitegrast could be akey factor for eye care professionals and may potentially beexplained by differences in themechanism of action. CsA inhibitsthe protein phosphatase, calcineurin, which results in inhibitionof IL-2 production and inhibition of T-cell activation [37].However, CsA does not inhibit activated T cells [38,39], so thereis a delay for activated T cells to undergo apoptosis and for newunstimulated T cells to form. Estimates for themedian life span ofhuman T cells are reported as up to 164 days for CD4+ and157 days for CD8+ memory T cells [40]. In contrast to CsA,lifitegrast is expected to act on all circulating T cells because itblocks a specific pathway (LFA-1/ICAM-1) in the DED inflamma-tory process, which has a role in T-cell activation and the migra-tion/recruitment of activated T cells to ocular surface tissues [19].

The introduction of lifitegrast will provide an additionaloption for treating DED, potentially helping to fulfill an importantunmet need for eye care professionals treating this condition [9].A summary of the status of lifitegrast is listed in Box 1. Currentlimitations of the clinical data are a lack of head-to-head compar-isons between lifitegrast and CsA, limited published data on thereal-world use of lifitegrast and on the predictors of the responseto treatment with lifitegrast. In addition, given the heteroge-neous nature of DED, it is not clear whether everyone with thesymptoms of the condition would benefit from an agent that

inhibits ocular surface inflammation. Further studies are alsoneeded to investigate whether lifitegrast could be used in acombination pharmacotherapy approach utilizing medicationswith different mechanisms of action that reduce inflammation(e.g. lifitegrast, corticosteroids, CsA) and improve tear function/protection of the ocular surface (e.g. artificial tear substitutes,mucin and tear secretagogues). In particular, whether the com-bination of lifitegrast with topical CsA has synergistic/additiveeffects, as has been observed for CsA 0.05% plus loteprednol[41], would be of interest. It would also be interesting to deter-mine whether the incidence of dysgeusia (unpleasant taste/change in taste sensation), which has been observed in lifitegrasttrials, could be reducedwith punctal plugs. Other future researchcould also provide information on whether lifitegrast can pene-trate other parts of the eye (e.g. the meibomian glands andlacrimal glands), which would be useful in understandingwhether lifitegrast has a particular role in treating evaporativeDED caused by meibomian gland dysfunction.

Funding

This paper was funded SARcode Bioscience, a fully owned company ofShire PLC.

Declaration of interest

E.D. Donnenfeld has been a consultant for AcuFocus, Alcon, Allergan,Abbott Medical Optics, Aquesys, Bausch & Lomb, CRST, Elenza, Glaukos,Icon Bioscience, Kala, Katena, LacriPen, Mati Therapeutics, Merck,Mimetogen, NovaBay, Novaliq, OcuHub, Odyssey, Omeros, PhysicianRecommended Nutriceuticals, RPS, Shire, Strathspey Crown, TearLab, TLCLaser Eye Centers, TrueVision, Versant Ventures, WaveTec, and Zeiss; and isan investor in AcuFocus, Aquesys, Elenza, Glaukos, LacriPen, MatiTherapeutics, Mimetogen, NovaBay, OcuHub, RPS, Shire/SARcode,Strathspey Crown, TearLab, TrueVision, Versant Ventures, and WaveTec.H.D. Perry has been a consultant for Alcon, Allergan, Blephex, Novabay,Omeros, and Physician Recommended Nutriceuticals. Medical writingassistance, provided by Nasser Malik, PhD, of Excel Scientific Solutions,was utilized in the production of this paper and funded by SARcodeBioscience, a fully owned company of Shire PLC. The authors have noother relevant affiliations or financial involvement with any organizationor entity with a financial interest in or financial conflict with the subjectmatter or materials discussed in the manuscript apart from thosedisclosed.

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6. Schaumberg DA, Dana R, Buring JE, et al. Prevalence of dry eyedisease among US men: estimates from the Physicians’ HealthStudies. Arch Ophthalmol. 2009;127:763–768.

7. Schaumberg DA, Sullivan DA, Buring JE, et al. Prevalence of dry eyesyndrome among US women. Am J Ophthalmol. 2003;136:318–326.

8. DEWS. The epidemiology of dry eye disease: report of theEpidemiology Subcommittee of the International Dry EyeWorkShop (2007). Ocul Surf. 2007;5:93–107.

9. Asbell PA, Spiegel S. Ophthalmologist perceptions regarding treat-ment of moderate-to-severe dry eye: results of a physician survey.Eye Contact Lens. 2010;36:33–38.

10. AAO. Cornea/External Disease PPP Panel, Hoskins Center for QualityEye Care. Dry eye syndrome PPP – 2013. 2013 [cited 2017 May 12].Available from: http://www.aao.org/preferred-practice-pattern/dry-eye-syndrome-ppp–2013#CAREPROCESS

11. Dougherty JM, McCulley JP, Silvany RE, et al. The role of tetracy-cline in chronic blepharitis. Inhibition of lipase production in sta-phylococci. Invest Ophthalmol Vis Sci. 1991;32:2970–2975.

12. Foulks GN, Borchman D, Yappert M, et al. Topical azithromycin andoral doxycycline therapy of meibomian gland dysfunction: a com-parative clinical and spectroscopic pilot study. Cornea. 2013;32:44–53.

13. Arakaki R, Eguchi H, Yamada A, et al. Anti-inflammatory effects ofrebamipide eyedrop administration on ocular lesions in a murinemodel of primary Sjogren’s syndrome. PloS One. 2014;9:e98390.

14. Perez VL, Pflugfelder SC, Zhang S, et al. Lifitegrast, a novel integrinantagonist for treatment of dry eye disease. Ocul Surf.2016;14:207–215.

15. Gadek TR, Burdick DJ, McDowell RS, et al. Generation of an LFA-1antagonist by the transfer of the ICAM-1 immunoregulatory epi-tope to a small molecule. Science. 2002;295:1086–1089.

16. Keating SM, Clark KR, Stefanich LD, et al. Competition betweenintercellular adhesion molecule-1 and a small-molecule antagonistfor a common binding site on the alphal subunit of lymphocytefunction-associated antigen-1. Protein Sci. 2006;15:290–303.

17. Zhong M, Gadek TR, Bui M, et al. Discovery and development ofpotent LFA-1/ICAM-1 antagonist SAR 1118 as an ophthalmic solu-tion for treating dry eye. ACS Med Chem Lett. 2012;3:203–206.

18. Shire US Inc. Prescribing information (07/2016) Xiidra™ (lifitegrastophthalmic solution) 5% [cited 2017 Aug 30]. Available from:http://www.shirecontent.com/PI/PDFs/Xiidra_USA_ENG.pdf.

19. Pflugfelder SC, Stern M, Zhang S, et al. LFA-1/ICAM-1 interaction asa therapeutic target in dry eye disease. J Ocul Pharmacol Ther.2017;33:5–12.

20. Gao J, Morgan G, Tieu D, et al. ICAM-1 expression predisposes oculartissues to immune-based inflammation in dry eye patients andSjögrens syndrome-like MRL/lpr mice. Exp Eye Res. 2004;78:823–835.

•• This study demonstrated increased expression of intercellularadhesion molecule-1 (ICAM-1) in the lacrimal and conjunctivaltissues from patients with dry eye disease (DED), and using amouse model of DED, provided proof of concept that blockadeof lymphocyte function-associated antigen-1/ICAM-1 canreduce ocular surface inflammation in DED.

21. Stern ME, Gao J, Schwalb TA, et al. Conjunctival T-cell subpopula-tions in Sjögren’s and non-Sjögren’s patients with dry eye. InvestOphthalmol Vis Sci. 2002;43:2609–2614.

22. Stern ME, Schaumburg CS, Pflugfelder SC. Dry eye as a mucosalautoimmune disease. Int Rev Immunol. 2013;32:19–41.

23. Murphy CJ, Bentley E, Miller PE, et al. The pharmacologic assess-ment of a novel lymphocyte function-associated antigen-1 antago-nist (SAR 1118) for the treatment of keratoconjunctivitis sicca indogs. Invest Ophthalmol Vis Sci. 2011;52:3174–3180.

• This study demonstrated that lifitegrast inhibited in vitro T-cellattachment to ICAM-1, and cytokine release from stimulatedhuman peripheral bloodmononuclear cells; in addition, lifitegrastsignificantly increased tear production in an in vivomodel of DED.

24. Sun Y, Zhang R, Gadek TR, et al. Corneal inflammation is inhibitedby the LFA-1 antagonist, lifitegrast (SAR 1118). J Ocul PharmacolTher. 2013;29:395–402.

25. Rao VR, Prescott E, Shelke NB, et al. Delivery of SAR 1118 to theretina via ophthalmic drops and its effectiveness in a rat

streptozotocin (STZ) model of diabetic retinopathy (DR). InvestOphthalmol Vis Sci. 2010;51:5198–5204.

26. Chung J-K, Spencer E, Hunt M, et al. Ocular distribution and phar-macokinetics of lifitegrast following repeat topical ocular doseadministration to pigmented rabbits. Presented at the 2017Annual Meeting of the Association for Research in Vision andOphthalmology; May 7–11, 2017; Baltimore, MD.

27. Semba CP, Swearingen D, Smith VL, et al. Safety and pharmacoki-netics of a novel lymphocyte function-associated antigen-1 antago-nist ophthalmic solution (SAR 1118) in healthy adults. J OculPharmacol Ther. 2011;27:99–104.

28. Donnenfeld ED, Karpecki PM, Majmudar PA, et al. Safety of lifite-grast ophthalmic solution 5.0% in patients with dry eye disease: a1-year, multicenter, randomized, placebo-controlled study. Cornea.2016;35:741–748.

•• In this long-term phase 3 safety study (SONATA), lifitegrastophthalmic solution 5.0% administered twice daily for 360days in participants with DED appeared safe and well-toler-ated with no unexpected adverse events.

29. Semba CP, Torkildsen GL, Lonsdale JD, et al. A phase 2 randomized,double-masked, placebo-controlled study of a novel integrinantagonist (SAR 1118) for the treatment of dry eye. Am JOphthalmol. 2012;153:1050.e1051–1060.e1051.

• In this phase 2 randomized-controlled trial, lifitegrast ophthal-mic solution 5.0% did not meet the primary sign end point ofmean inferior corneal staining score (ICSS) at day 84, but met aprespecified secondary sign end point of mean change in ICSSfrom baseline to day 84.

30. Sheppard JD, Torkildsen GL, Lonsdale JD, et al. Lifitegrast ophthal-mic solution 5.0% for treatment of dry eye disease: results of theOPUS-1 phase 3 study. Ophthalmology. 2014;121:475–483.

•• In this phase 3 randomized-controlled trial (OPUS-1), lifitegrastophthalmic solution 5.0% significantly improved the co-pri-mary sign end point of ICSS from baseline to day 84 versusthe placebo group but the co-primary symptom end point ofchange from baseline to day 84 on the visual-related functionsubscale was not met.

31. Tauber J, Karpecki P, Latkany R, et al. Lifitegrast ophthalmic solu-tion 5.0% versus placebo for treatment of dry eye disease: results ofthe randomized phase III OPUS-2 study. Ophthalmology.2015;122:2423–2431.

•• In this phase 3 randomized-controlled trial (OPUS-2), lifitegrastophthalmic solution 5.0% met the co-primary symptom endpoint of change from baseline to day 84 in eye dryness scorebut not the co-primary sign end point of change from baselineto day 84 in ICSS.

32. Holland EJ, Luchs J, Karpecki PM, et al. Lifitegrast for the treatmentof dry eye disease: results of a phase iii, randomized, double-masked, placebo-controlled trial (OPUS-3). Ophthalmology.2017;124:53–60.

•• In this phase 3 randomized-controlled trial (OPUS-3), lifitegrastophthalmic solution 5.0% significantly improved symptoms ofeye dryness from as early as 2 weeks in participants with DEDversus those treated with placebo.

33. Matossian C, Karpecki P, Sall K, et al. Lifitegrast 5.0% versus placebofor dry eye disease: pooled symptom outcomes from the OPUS-2and OPUS-3 phase 3 studies. Presented at the 2016 AnnualMeeting of the American Academy of Ophthalmology; October15–18, 2016; Chicago, IL.

34. Shojaei A, Tauber J, Nichols KK, et al. Overview of clinical efficacyand safety of lifitegrast ophthalmic solution 5.0% for treatment ofdry eye disease. Presented at the 8th International Conference onthe Tear Film & Ocular Surface; September 7–10, 2016; Montpellier,France.

35. Sall K, Stevenson OD, Mundorf TK, et al. Two multicenter, rando-mized studies of the efficacy and safety of cyclosporine ophthalmicemulsion in moderate to severe dry eye disease. CsA Phase 3 StudyGroup. Ophthalmology. 2000;107:631–639.

36. Stevenson D, Tauber J, Reis BL. Efficacy and safety of cyclosporin Aophthalmic emulsion in the treatment of moderate-to-severe dry

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eye disease: a dose-ranging, randomized trial. The Cyclosporin APhase 2 Study Group. Ophthalmology. 2000;107:967–974.

37. Yavuz B, Bozdağ Pehlivan S, Ünlü N. An overview on dry eyetreatment: approaches for cyclosporin A delivery. Scientific WorldJ. 2012;2012:194848.

38. Kay JE, Benzie CR. Effects of cyclosporin A on the metabolism ofunstimulated and mitogen-activated lymphocytes. Immunology.1983;49:153–160.

39. Strauss G, Osen W, Debatin KM. Induction of apoptosis and mod-ulation of activation and effector function in T cells by immuno-suppressive drugs. Clin Exp Immunol. 2002;128:255–266.

40. Westera L, Drylewicz J, den Braber I, et al. Closing the gap betweenT-cell life span estimates from stable isotope-labeling studies inmice and humans. Blood. 2013;122:2205–2212.

41. Sheppard JD, Donnenfeld ED, Holland EJ, et al. Effect of lotepred-nol etabonate 0.5% on initiation of dry eye treatment with topicalcyclosporine 0.05%. Eye Contact Lens. 2014;40:289–296.

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Abstract1. Introduction2. Overview of the market3. Introduction to the compound3.1. Chemistry3.2. Pharmacodynamics3.3. Pharmacokinetics and metabolism

4. Clinical efficacy and safety4.1. Effect on signs and symptoms of DED4.2. Safety and tolerability

5. Regulatory affairs6. Conclusion7. Expert opinionFundingDeclaration of interestReferences