Lifitegrast for the Treatment of Dry Eye Disease in Adults

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 in adults

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 on Pharmacotherapy, 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: 25 Aug 2017. Published online: 04 Sep 2017.

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Download by: [108.6.184.233] Date: 04 September 2017, At: 04:29 EXPERT OPINION ON PHARMACOTHERAPY, 2017 https://doi.org/10.1080/14656566.2017.1372748

DRUG EVALUATION Lifitegrast for the treatment of dry eye disease in adults Eric 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

ABSTRACT ARTICLE HISTORY Introduction: Dry eye disease (DED) is a common ocular disorder that can have a substantial burden on Received 14 June 2017 quality of life and daily activities. Lifitegrast ophthalmic solution 5.0% is the first medication approved in Accepted 24 August 2017 the US for the treatment of the signs and symptoms of DED. The aim of this article is to summarize the KEYWORDS preclinical and clinical data on lifitegrast and discuss how lifitegrast may fit into the current treatment Dry eye disease; efficacy; landscape for DED. lifitegrast; lymphocyte Areas covered: A literature search of published preclinical and clinical data was conducted to review function-associated antigen- the chemistry, pharmacodynamics, pharmacokinetics, and clinical efficacy/safety of lifitegrast. The 1 antagonist; safety impact that lifitegrast may have on DED treatment practices is also discussed. Expert opinion: The introduction of lifitegrast provides a potentially important additional option for eye care professionals treating DED. In clinical trials conducted in adults with DED, lifitegrast ophthalmic solution 5.0% improved both signs and symptoms of DED. Of note, in 2 phase 3 trials, symptom improvements were observed as early as 2 weeks, which may be explained by lifitegrast’s unique mechanism of action of blocking a specific signaling pathway in inflammation. Future research should include evaluation of whether lifitegrast can be used in combination with other DED treatments.

1. Introduction designated as the first in a new class of drugs called lymphocyte function-associated antigen-1 (LFA-1) antagonists. Dry eye disease (DED) is a complex, multifactorial disease of the Lifitegrast blocks the interaction of cell surface proteins LFA-1 ocular surface that involves a loss of homeostasis of the tear film and intercellular adhesion molecule-1 (ICAM-1), and is believed and can lead to ocular symptoms. Tear film instability and hyper- to inhibit T-cell-mediated inflammation in DED. osmolarity, ocular surface inflammation, and neurosensory In the interval between the approval of cyclosporine abnormalities play roles in the etiology of the disease [1]. ophthalmic emulsion (CsA; Restasis , Allergan, Dublin, Different types of DED exist, with the two major classes being ® Ireland) in 2003 and lifitegrast’s approval in 2016, numerous aqueous tear-deficient DED and evaporative DED [1]. As no single candidates were tested for the treatment of DED. Until the reliable test for DED is available, clinicians rely on a combination of lifitegrast clinical trials program, none (including CsA) demon- DED symptoms and clinical signs to diagnose the condition. strated statistical significance in primary end points for both However, there is poor correlation between the signs and symp- signs and symptoms of DED. In a 2008 survey of ophthalmol- Downloaded by [108.6.184.233] at 04:29 04 September 2017 toms of DED [2,3], which, along with the multifactorial nature of ogists treating DED, almost all (94%) responded that more the condition, complicates its diagnosis and management. treatment options are needed for moderate or severe DED DED represents a public health concern due to its high [9]. Important attributes of a new therapeutic for DED, which prevalenceandburdenonthepatientintermsofqualityof lifitegrast may offer, are the treatment of both signs and vision, quality of life, physical/social functioning, and eco- symptoms of DED, protection of the ocular surface, relatively nomiccost(duemainlytolossofworkproductivity)[4,5]. It rapid onset of action, good tolerability, and long-term safety. is recognized that the prevalence of DED is higher in women In this review, we provide an overview of the pharmacological and older individuals. In the Women’sHealthStudyand properties of lifitegrast and key data from clinical trials, and Physicians’ Health Study, the prevalence of DED (clinician discuss how lifitegrast is likely to fit into the current treatment diagnosed and/or severe symptoms of dryness and irritation paradigm for DED. constantly or often) was estimated at 7.8% in women and 4.3% in men aged 50 years or older [6,7]. Other studies have estimated the prevalence of DED (defined as subject- 2. Overview of the market reported symptoms), in the range of 5–34% of the popula- DED presents variable signs and/or symptoms, and available tion aged over 50 years [8]. treatment options address different aspects of the disease. Lifitegrast ophthalmic solution 5.0% received approval from In the United States, CsA 0.05% (Restasis and Restasis the US Food and Drug Administration (FDA) in 2016 for treat- ® multidose™, Allergan, Dublin, Ireland) is approved to ment of the signs and symptoms of DED in adults. It was

Box 1. Drug summary

Drug name Lifitegrast ophthalmic solution 5.0% Phase Approved in the United States Indication Signs and symptoms of DED Pharmacology description/mechanism of LFA-1 antagonist that blocks the interaction of ICAM-1 and LFA-1 thereby inhibiting T-cell-mediated action inflammation Route of administration Ophthalmic Chemical structure

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

increase tear production in patients whose tear production 3. Introduction to the compound is presumed to be suppressed due to ocular inflammation. 3.1. Chemistry Other topical medications that are used to address DED in the United States [10] include over-the-counter artificial tear Lifitegrast was designed to bind to LFA-1, a cell surface protein substitutes that augment the tear film. Antibiotics are used expressed on T lymphocytes (T cells), thus blocking the inter- off-label to treat meibomianglanddysfunction,amajor action of LFA-1 with its ligand, ICAM-1 [14]. Lifitegrast was cause of evaporative DED. Oral tetracyclines (e.g. doxycy- discovered through a rational design approach that focused cline) inhibit the production of bacterial lipases [11], thus on the binding epitope of ICAM-1, a region of six binding improving the lipid profile of meibomian oils. Both tetracy- residues [15,16]. A tetrahydroisoquinoline analogue desig- clines and topical azithromycin are antibacterial and have nated SAR 1118 (lifitegrast) was selected based on potency anti-inflammatory properties [12]. Short-term therapy with of binding in a HuT 78 T-cell adhesion assay, and the short ophthalmic corticosteroids (e.g. loteprednol 0.5%; half-life, fast clearance, and low exposure observed in rat Lotemax®,Bausch&Lomb,Rochester,NY,USA)isalso pharmacokinetic studies [17]. Lifitegrast is highly aqueous used off-label to reduce ocular surface inflammation. soluble (>100 mg/mL), which allows it to be formulated at A number of devices are available for the treatment of DED. 50 mg/mL (5.0%), thus maintaining physiological pH [17]. These include the TrueTear™ Intranasal Tear Neurostimulator Lifitegrast ophthalmic solution 5.0% is a preservative-free, (Allergan, Dublin, Ireland) device, which temporarily increases sterile eye drop that has a target pH of 7.0–8.0, an osmolality tear production during neurostimulation in adult patients with range of 200–330 mOsmol/kg, and stability in aqueous solu- aqueous tear deficiency, and the Lipiflow system (TearScience, tion at room temperature [18]. Morrisville, NC, USA) which helps to clear blockages in the meibomian glands of patients with obstructive meibomian Downloaded by [108.6.184.233] at 04:29 04 September 2017 gland dysfunction. In Japan, the mucin secretagogues diqua- 3.2. Pharmacodynamics fosol ophthalmic solution (3% Diquas®; Santen Pharmaceutical, Osaka, Japan) and rebamipide (Mucosta® Based on the available evidence, it is postulated that LFA-1/ ophthalmic suspension unit dose 2%; Otsuka Pharmaceutical, ICAM-1 interaction has roles in T-cell activation, through the Tokyo, Japan) are approved for the treatment of DED. These formation of immunological synapses between T cells and drugs promote the secretion of fluid and mucin from the antigen-presenting cells (e.g. dendritic cells), and in the migra- ocular surface, thus improving tear film stability. Rebamipide tion of T cells to the ocular surface [19]. In DED, research also has anti-inflammatory properties [13]. Drugs currently in suggests that stress (environmental and/or microbial) to the development in the United States include preparations that ocular surface results in increased ICAM-1 expression in the use nanotechnology to improve the delivery of available ocular surface tissues [20–22]. Although the precise mechan- drugs. These include KPI-121 (Kala Pharmaceuticals, Waltham, ism of action of lifitegrast in DED has not been established, it MA, USA), a nanoparticle formulation of the corticosteroid, is thought that by blocking LFA-1/ICAM-1 interaction, lifite- loteprednol etabonate, and OTX-101 (Seciera™, Sun Pharma, grast inhibits T-cell migration, T-cell activation, and the release Mumbai, India), a nanomicellar formulation of cyclosporine. In of pro-inflammatory cytokines (Figure 1). This is supported by addition, RGN-259 (ReGenTree, Princeton, NJ, USA), a synthetic data from in vitro studies that demonstrated that lifitegrast copy of the naturally occurring protein thymosin β4, which is inhibits Jurkat T-cell and HuT 78 T-cell adhesion to ICAM-1

predicted to promote corneal epithelial cell migration and (half-maximal inhibitory concentration [IC50] of 2.98 and decrease inflammation, is currently in phase 3 trials. 9 nmol/L, respectively) and inhibits the secretion of pro- EXPERT OPINION ON PHARMACOTHERAPY 3

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. This leads 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-inflammatory cytokine release by blocking LFA-1/ICAM-1 interaction. DED: dry eye disease; ICAM-1: intercellular adhesion molecule-1; LFA-1: lymphocyte function-associated antigen-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.

inflammatory cytokines including interferon-γ, interleukin (IL)- and vitreous humor [0–36]), suggesting a low potential for off- 1β, and tumor necrosis factor-α in a concentration-dependent target systemic or ocular effects [26]. manner in activated peripheral blood mononuclear cells (half In a phase 1 trial [27], twice-daily administration of lifitegrast

maximal effective concentration [EC50] of 0.0016, 0.36, and ophthalmic solution 5.0% to healthy volunteers resulted in a tear 0.076 μM, respectively) [17,23]. Further, in a mouse model in fluid lifitegrast concentration that exceeded the target therapeu- which corneal inflammation was induced by epithelial abra- tic level in the eye of >1 μM (~600 ng/mL), i.e. substantially

sion and exposure to tobramycin-killed Pseudomonas aerugi- higher than the IC50 and EC50 values demonstrated in vitro for nosa or Staphylococcus aureus, lifitegrast ophthalmic solution LFA-1/ICAM-1 binding and cytokine inhibition, respectively reduced corneal inflammation [24]. Lifitegrast also significantly (Section 3.2). In participants administered lifitegrast twice daily increased tear production from baseline in dogs diagnosed for 10 days, a maximum tear fluid lifitegrast concentration with idiopathic keratoconjunctivitis sicca [23]. (91,413 ng/mL) was achieved in a median time of 0.3 h, and there was no evidence of lifitegrast accumulation in tears during repeated ocular dosing. In the same study, low levels of lifitegrast Downloaded by [108.6.184.233] at 04:29 04 September 2017 in the plasma were detected within 5 min of instillation and were 3.3. Pharmacokinetics and metabolism cleared from the plasma within 1–4h.TheCmax of lifitegrast Following ophthalmic administration of radiolabeled lifitegrast following ocular administration was <5 nM (<3 ng/mL) and to rats [25] and dogs [23], the highest concentration of lifite- there was no indication of systemic accumulation with repeated grast (ng equivalents [14C]-lifitegrast/g) at 0.5 h post dose was ocular dosing [17,27]. In the SONATA (Safety Of a 5.0% detected in the bulbar conjunctiva (31,500, 4510, rats [25] and coNcentrATion of lifitegrAst ophthalmic solution) 1-year safety dogs [23], respectively), palpebral conjunctiva (26,300, 3790), trial [28], plasma concentrations of lifitegrast were low, and there and cornea (17,150, 2130). In a study by Rao et al., the plasma was no accumulation in plasma over time (mean concentration concentration of lifitegrast post dose reached a maximum at of lifitegrast in plasma was below the lower limit of quantification 0.25 h (194 ng equivalents [14C]-lifitegrast/g) and decreased [0.5 ng/mL] at days 0, 180, and 360). to below the level of quantification from 12 h [25]. Similarly, in In tests of in vitro toxicology, lifitegrast was negative in the rabbits that received twice-daily ophthalmic lifitegrast for Ames mutagenicity test (a bacterial assay for identifying 5 days, the highest concentrations of lifitegrast (ng/g) were potential carcinogens) and demonstrated low potency in localized in the ocular anterior segment tissues (bulbar con- human liver microsomal studies that assessed metabolism by junctiva [9370–14,200], palpebral conjunctiva [9620–11,900], cytochrome P450 enzymes, CYP3A4 (IC50 >20μM) and cornea [5190–5930], and anterior sclera [5870–11,200]), CYP2C9 (IC50 = 3.0 μM) [17]. In the human ether-à-go-go- whereas there was low exposure in the plasma (maximum related gene (hERG) patch clamp assay, which tests for the

plasma concentration [Cmax]: 9.5–17.4 ng/mL) and posterior potential of cardiac arrhythmia, lifitegrast had an IC50 of >20 segment tissues (posterior sclera [369–826], optic nerve, retina, μM[17]. These IC50 values are several orders higher than those 4 E. D. DONNENFELD ET AL.

demonstrated in vitro for LFA-1/ICAM-1 binding and cytokine With respect to DED symptoms, lifitegrast significantly inhibition (Section 3.2). Thus, given the very low lifitegrast improved EDS (VAS) versus placebo in OPUS-2 (co-primary end plasma levels in human trials following ocular administration point; TE 12.61; 95% CI 8.51–16.70; p < 0.0001) and OPUS-3 (<5 nM), the potential for systemically absorbed lifitegrast to (primary end point; TE 7.16; 95% CI 3.04–11.28; p = 0.0007). In cause drug–drug interactions mediated by CYP450 or hERG the OPUS-1 trial, the co-primary symptom end point of visual- ion channel inhibition is very low. related function subscale did not achieve statistical significance. It is noteworthy that in OPUS-2 and OPUS-3 lifitegrast significantly improved EDS (VAS) as early as 2 weeks after the start of treatment (Figure 2(b)). A pooled analysis of data from these similarly 4. Clinical efficacy and safety designed trials demonstrated significant improvement in EDS 4.1. Effect on signs and symptoms of DED (VAS) from baseline to day 84 (TE 9.92; 95% CI 7.01–12.83; p < 0.0001), day 42 (TE 9.75; 95% CI 6.99–12.50; p < 0.0001), and Four 12-week, multicenter, randomized-controlled trials con- day 14 (TE 7.23; 95% CI 4.71–9.76; p < 0.0001) versus participants ducted in the United States have evaluated the efficacy and receiving placebo [33]. safety of lifitegrast versus placebo in adults with DED. These were a phase 2 trial [29] and three phase 3 trials: OPUS-1 [30], OPUS-2 [31], and OPUS-3 [32]. Key inclusion criteria included 4.2. Safety and tolerability subject-reported history of DED, Schirmer Tear Test without Across the four 12-week trials, lifitegrast ophthalmic solution 5.0% anesthesia of ≥1 and ≤10 mm in ≥1 eye, and corneal fluor- was generally well-tolerated with no serious ocular treatment- escein staining score ≥2.0 in ≥1 eye (0–4 point scale). In emergent adverse events (TEAEs) reported. The TEAEs rarely led addition, in OPUS-2 and OPUS-3, participants had more severe to discontinuation and most were mild to moderate in severity. symptomatology (baseline eye dryness score [EDS, visual ana- Overall, the most common (>5% in either treatment group) ocular logue scale (VAS), 0–100 point scale] ≥40 and artificial tear use TEAEs reported in these trials were visual acuity reduced, instilla- within 30 days of study entry) than participants in the phase 2 tion-site pain, instillation-site irritation, and instillation-site reac- and OPUS-1 trials. The use of ophthalmic medications, includ- tion. Each of these TEAEs occurred at a higher rate in the lifitegrast ing corticosteroids and artificial tears, was not allowed during versus the placebo group, except for visual acuity reduced, which these studies. In all lifitegrast trials, the placebo comprised the in three trials was slightly higher in the placebo group (placebo vs. same components of the investigational product solution lifitegrast: phase 2, 5.2% vs. 1.7%; OPUS-1, 5.1% vs. 4.8%; OPUS-2, minus lifitegrast. 6.4% vs. 5.0%). The most common (>5% in either treatment group) In the phase 2 trial, participants were randomized 1:1:1:1 to non-ocular TEAE in all of the trials was dysgeusia, which also lifitegrast ophthalmic solution 0.1%, 1.0%, or 5.0%, or placebo occurred at a higher rate in the lifitegrast group. twice daily for 84 days. Based on the results of this trial, To assess the longer-term tolerability and safety of twice-daily lifitegrast 5.0% was selected for investigation in the phase 3 lifitegrast, the SONATA 1-year safety study was conducted in DED trials. In OPUS-1, -2, and -3, following a 14-day open-label, patients (lifitegrast, n =220;placebo,n =111)[28]. Key inclusion placebo run-in period, participants were randomized 1:1 to criteria were adults (aged ≥18 years) with self-reported DED, twice-daily doses of lifitegrast ophthalmic solution 5.0% or Schirmer Tear Test without anesthesia ≥1and≤10 mm in ≥1 placebo. The effect on DED signs and symptoms was assessed eye, corneal fluorescein staining score ≥2.0 in ≥1eye,andtheuse on days 14, 42, and 84. In the phase 2 trial, the primary of and/or desire to use artificial tears in the last 6 months. outcome end point was inferior corneal staining score (ICSS; Participants were randomized 2:1 to lifitegrast ophthalmic solu- Downloaded by [108.6.184.233] at 04:29 04 September 2017 0–4 point scale) at day 84. In the OPUS-1 trial the co-primary tion 5.0% or placebo. To reflect real-world use, after day 14, sign and symptom end points, respectively, were change from participants were allowed to use as required artificial tears (≤4 baseline to day 84 in ICSS and visual-related function subscale times daily, as needed), topical ophthalmic/nasal steroids (only of a symptom scale (0–4 point scale). In OPUS-2 the co-primary loteprednol etabonate ≤4 weeks at a time), antihistamines, mast sign end point was change from baseline to day 84 in ICSS; the cell stabilizers, and contact lenses. The primary end point was the co-primary symptom end point was change from baseline to percentage and severity of ocular and non-ocular TEAEs. In day 84 in EDS (VAS), a patient-reported measure reported as a SONATA, lifitegrast appeared safe and well-tolerated, with no single score for both eyes. In OPUS-3, the primary efficacy end serious ocular TEAEs, and a similar safety profile as the previous point was change from baseline to day 84 in EDS (VAS). In this 12-week trials. The most frequent (>5% in either group) TEAEs trial, ICSS was analyzed ad hoc. were instillation-site irritation (lifitegrast, 15.0%; placebo, 4.5%), In relation to DED signs (Figure 2(a)), lifitegrast significantly instillation-site reaction (lifitegrast, 13.2%; placebo, 1.8%), visual improved ICSS versus placebo in the phase 2 trial (secondary acuity reduced (lifitegrast, 11.4%; placebo, 6.3%), and dysgeusia end point; treatment effect [TE] 0.35; 95% confidence interval (lifitegrast, 16.4%; placebo, 1.8%). [CI] 0.05–0.65; nominal p = 0.0209) and in OPUS-1 (co-primary A pooled analysis of the safety data from all five clinical end point; TE 0.24; 95% CI 0.10–0.38; p = 0.0007). In OPUS-3, trials has also been completed, including 1287 participants ad hoc analysis of ICSS demonstrated a nominally significant who received at least one dose of lifitegrast (n = 1177, pla- mean reduction from baseline to day 84 that favored lifitegrast cebo), with total exposure to lifitegrast treatment of 415.65 compared with placebo (study eye; TE 0.17; 95% CI 0.03–0.30; person-years (332.15 person-years for placebo) [34]. The nominal p = 0.0144). In OPUS-2, the co-primary sign end point results of the pooled analysis further support the tolerability of ICSS did not achieve statistical significance. of lifitegrast ophthalmic solution 5.0% across all trials. The EXPERT OPINION ON PHARMACOTHERAPY 5

(a) ICSS (study eye)

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

Day 14: 0.19 (−0.05, 0.43), p = NS − p Phase 2 51.8, 51.6 Day 42: 0.12 ( 0.14, 0.37), = NS Day 84: 0.35 (0.05, 0.65), nominal p = 0.0209

Day 14: 0.04 (−0.08, 0.17), p = NS − p OPUS-1 41.6, 40.2 Day 42: 0.12 ( 0.02, 0.26), = NS Day 84: 0.24 (0.10, 0.38), p = 0.0007

OPUS-2 69.2, 69.7 Day 84: 0.03 (−0.10, 0.17), p = NS

p OPUS-3 69.0, 68.3 Day 84: 0.17 (0.03, 0.30), nominal = 0.0144

Favors placebo Favors lifitegrast

-0.50 -0.25 0 0.25 0.50 0.75 1.00 1.25 Treatment effect, 95% CI (b) EDS (VAS)

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

Day 14: 5.38 (−4.01, 14.77), p = NS Day 42: 10.20 (1.49, 18.92),nominal p = 0.0222 Phase 2 51.8, 51.6 Day 84: 7.95 (−1.96, 17.85), p = NS

Day 14:−0.75 (−5.32, 3.81), p = NS Day 42: 3.48 (−1.44, 8.40), p = NS OPUS-1 41.6, 40.2 Day 84: 3.94 (−0.95, 8.83), p = NS

Day 14: 6.67 (3.05, 10.30), nominal p = 0.0003 Day 42: 10.63 (6.71, 14.55),nominal p < 0.0001 OPUS-2 69.2, 69.7 Day 84: 12.61 (8.51, 16.70), p < 0.0001

Day 14: 7.85 (4.33, 11.37), p < 0.0001 OPUS-3 69.0, 68.3 Day 42: 9.32 (5.44, 13.20), p < 0.0001 Day 84: 7.16 (3.04, 11.28), p = 0.0007

Favors placebo Favors lifitegrast

-10-5 0 5 10 15 20 25 Treatment effect, 95% CI

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 not available 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. Downloaded by [108.6.184.233] at 04:29 04 September 2017

most common adverse events in the pooled analysis were 5. Regulatory affairs instillation-site irritation (lifitegrast, 15.2%; placebo, 2.8%), Lifitegrast was discovered at Sunesis (South San Francisco, CA, instillation-site reaction (lifitegrast, 12.3%; placebo, 2.3%), USA) and developed clinically by Shire (Lexington, MA, USA). A instillation-site pain (lifitegrast, 9.8%; placebo, 2.1%), and dys- New Drug Application was submitted to the FDA in March geusia (lifitegrast, 14.5%; placebo, 0.3%) [34]. To date, there 2015 for the approval of lifitegrast ophthalmic solution 5.0% have been no postmarketing adverse events reported. to treat DED in adults. Efficacy data from the phase 2, OPUS-1, Given the mechanism of action of lifitegrast on T-cell func- and OPUS-2 trials were included in the NDA application. The tion, the effect of twice-daily lifitegrast ophthalmic solution application was granted priority review in April 2015. In 5.0% on whole blood CD3, CD4, and CD8 lymphocyte counts October 2015, Shire received a complete response letter was assessed in SONATA in a subset of participants (n = 75) on from the FDA for lifitegrast, indicating that the marketing days 0 (baseline), 180, and 360 [28]. There were minimal and application would not be approved without additional clinical similar changes in lymphocyte counts in both treatment data. Shire responded 3 months later with a resubmission that groups, suggesting that lifitegrast did not cause chronic sup- included data from the OPUS-3 trial, which had been initiated pression of lymphocytes. In addition, there was no pattern of following pre-submission feedback from the agency; the aim adverse events to suggest systemic toxicities or localized of OPUS-3 was to demonstrate efficacy in a symptom end infectious complications resulting from chronic T-cell suppres- point, EDS. The FDA subsequently approved Xiidra (lifitegrast sion [28] (similar to findings from trials of CsA 0.05% [35]). ® ophthalmic solution 5.0%) for the treatment of signs and 6 E. D. DONNENFELD ET AL.

symptoms of DED in July 2016. The agency based its approval inhibits ocular surface inflammation. Further studies are also on the efficacy of lifitegrast for the treatment of DED as needed to investigate whether lifitegrast could be used in a demonstrated by replication of the sign and symptom end combination pharmacotherapy approach utilizing medications point results in the four submitted efficacy/safety trials com- with different mechanisms of action that reduce inflammation pared with vehicle. Lifitegrast was granted designation as the (e.g. lifitegrast, corticosteroids, CsA) and improve tear function/ first in a new class of drugs, LFA-1 antagonists. protection of the ocular surface (e.g. artificial tear substitutes, mucin and tear secretagogues). In particular, whether the combination of lifitegrast with topical CsA has synergistic/additive 6. Conclusion effects, as has been observed for CsA 0.05% plus loteprednol Lifitegrast is the first medication approved by the FDA for the [41], would be of interest. It would also be interesting to deter- treatment of both the signs and symptoms of DED. Key fea- mine whether the incidence of dysgeusia (unpleasant taste/ tures of lifitegrast include high aqueous solubility, rapid change in taste sensation), which has been observed in lifitegrast absorption into the ocular tissues, rapid systemic elimination, trials, could be reduced with punctal plugs. Other future research and a unique mechanism of action. In clinical trials, lifitegrast could also provide information on whether lifitegrast can pene- ophthalmic solution 5.0% improved signs and symptoms of trate other parts of the eye (e.g. the meibomian glands and DED in adults with DED across four 12-week efficacy/safety lacrimal glands), which would be useful in understanding trials. Most notably, symptom improvements were observed as whether lifitegrast has a particular role in treating evaporative early as 2 weeks. Lifitegrast was well tolerated in the 12-week DED caused by meibomian gland dysfunction. trials and a 1-year safety study, with no serious ocular TEAEs reported. Funding

This paper was funded SARcode Bioscience, a fully owned company of 7. Expert opinion Shire PLC. Lifitegrast ophthalmic solution 5.0% is the first pharmacological medication to be approved by the FDA for the treatment of DED since 2003, when CsA 0.05% was approved for the indication of Declaration of interest increasing tear production in DED patients. The approval of CsA E.D. Donnenfeld has been a consultant for AcuFocus, Alcon, Allergan, 0.05% was based on significant improvements in Schirmer wet- Abbott Medical Optics, Aquesys, Bausch & Lomb, CRST, Elenza, Glaukos, ting in clinical trials; CsA 0.05% is not indicated for the treatment Icon Bioscience, Kala, Katena, LacriPen, Mati Therapeutics, Merck, of the symptoms of DED. Results from clinical trials [35,36], and Mimetogen, NovaBay, Novaliq, OcuHub, Odyssey, Omeros, Physician clinical experience post approval, have shown that marked Recommended Nutriceuticals, RPS, Shire, Strathspey Crown, TearLab, TLC improvement with CsA 0.05% generally takes at least 3 months. Laser Eye Centers, TrueVision, Versant Ventures, WaveTec, and Zeiss; and is an investor in AcuFocus, Aquesys, Elenza, Glaukos, LacriPen, Mati In contrast, significant symptom improvements occurred with Therapeutics, Mimetogen, NovaBay, OcuHub, RPS, Shire/SARcode, lifitegrast in three of four 12-week trials (phase 2, OPUS-2, and Strathspey Crown, TearLab, TrueVision, Versant Ventures, and WaveTec. OPUS-3) by 6 weeks and as early as 2 weeks in two trials (OPUS-2 H.D. Perry has been a consultant for Alcon, Allergan, Blephex, Novabay, and OPUS-3). The faster time to efficacy for lifitegrast could be a Omeros, and Physician Recommended Nutriceuticals. Medical writing key factor for eye care professionals and may potentially be assistance, provided by Nasser Malik, PhD, of Excel Scientific Solutions, was utilized in the production of this paper and funded by SARcode explained by differences in the mechanism of action. CsA inhibits Bioscience, a fully owned company of Shire PLC. The authors have no the protein phosphatase, calcineurin, which results in inhibition other relevant affiliations or financial involvement with any organization Downloaded by [108.6.184.233] at 04:29 04 September 2017 of IL-2 production and inhibition of T-cell activation [37]. or entity with a financial interest in or financial conflict with the subject However, CsA does not inhibit activated T cells [38,39], so there matter or materials discussed in the manuscript apart from those is a delay for activated T cells to undergo apoptosis and for new disclosed. unstimulated T cells to form. Estimates for the median life span of human T cells are reported as up to 164 days for CD4+ and 157 days for CD8+ memory T cells [40]. In contrast to CsA, References lifitegrast is expected to act on all circulating T cells because it Papers of special note have been highlighted as either of interest (•)orof blocks a specific pathway (LFA-1/ICAM-1) in the DED inflamma- considerable interest (••) to readers. tory process, which has a role in T-cell activation and the migra- 1. Craig JP, Nichols KK, Akpek EK, et al. TFOS DEWS II definition and tion/recruitment of activated T cells to ocular surface tissues [19]. classification report. Ocul Surf. 2017;15:276–283. The introduction of lifitegrast will provide an additional 2. Bartlett JD, Keith MS, Sudharshan L, et al. Associations between option for treating DED, potentially helping to fulfill an important signs and symptoms of dry eye disease: a systematic review. Clin Ophthalmol. 2015;9:1719–1730. unmet need for eye care professionals treating this condition [9]. 3. Baudouin C, Irkec M, Messmer EM, et al. Clinical impact of inflam- A summary of the status of lifitegrast is listed in Box 1. Current mation in dry eye disease: proceedings of the ODISSEY group limitations of the clinical data are a lack of head-to-head compar- meeting. Acta Ophthalmologica. 2017 Apr 8. doi:10.1111/aos. isons between lifitegrast and CsA, limited published data on the 13436. [Epub ahead of print]. real-world use of lifitegrast and on the predictors of the response 4. Li M, Gong L, Chapin WJ, et al. Assessment of vision-related quality of life in dry eye patients. Invest Ophthalmol Vis Sci. 2012;53:5722–5727. to treatment with lifitegrast. In addition, given the heteroge- 5. McDonald M, Patel DA, Keith MS, et al. Economic and humanistic neous nature of DED, it is not clear whether everyone with the burden of dry eye disease in Europe, North America, and Asia: a symptoms of the condition would benefit from an agent that systematic literature review. Ocul Surf. 2016;14:144–167. EXPERT OPINION ON PHARMACOTHERAPY 7

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