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Review Article

Current and Future Pharmacological Therapies for the Management of Dry Eye

Gupta, Preeya K. M.D.; Asbell, Penny M.D.; Sheppard, John M.D.

Author Information
Eye & Contact Lens: Science & Clinical Practice: March 2020 - Volume 46 - Issue - p S64-S69
doi: 10.1097/ICL.0000000000000666
  • Open

Abstract

As defined by the Dry Eye Workshop II International Task Force, dry eye disease (DED) is a multifactorial disease of the ocular surface, characterized by loss of homeostasis of the tear film.1 Hyperosmolarity and instability of the tear film lead to inflammation and ocular surface damage, and may cause symptoms of ocular discomfort and visual disturbance.1 The health costs and reduced work productivity associated with DED represent a substantial cost burden, and the disease significantly increases utilization of health care resources.2 Dry eye disease is among the most common reasons for seeking medical eye care, but estimates of prevalence vary widely, ranging from 5% to 33%, in part due to discrepancies in the disease definition used and studied populations.2,3

Over-the-counter medications provide temporary relief of symptoms but prescription medications that address the underlying cause of DED may be needed. Several approved treatments target DED-associated inflammation, but given the heterogeneous nature of DED and limitations with current treatments, there is a need for development of formulations addressing these limitations and treatments with novel targets to expand the range of available treatment options. This review summarizes pharmacotherapies approved in the United States and Europe that target the inflammatory cycle of DED and highlights drugs in development that act on novel targets of this complex disorder. To provide an overview of novel molecules for which peer-reviewed publications were not available, we broadened our sources to include company websites, company press releases, conference presentations, and clinical trial registration databases.

Dry Eye Disease as a Multifactorial Inflammatory Disorder

The core of DED etiology is a vicious inflammatory cycle, where tear film instability and hyperosmolarity trigger an inflammatory cascade leading to ocular surface damage and further loss of tear-film homeostasis (Fig. 1).4 Hyperosmolarity of the tear film may have several causes. When hyperosmolarity results from reduced lacrimal secretions, this is referred to as aqueous-deficient dry eye. Dysfunction or damage to the acinar and ductal epithelium due to inflammation associated with Sjögren syndrome or non-Sjögren syndrome is the most common cause of aqueous-deficient dry eye.2 Other potential causes include damage of the nerve component of the lacrimal functional unit, obstruction of the lacrimal ducts as a result of conjunctival disease, or age-related reduction in tear secretion.2 Some systemic medications—including antihistamines, β-blockers, antispasmodics, diuretics, and select psychotropics—can also reduce tear secretion.2

F1
FIG. 1.:
Vicious inflammatory cycle of dry eye disease. Hyperosmolarity initiates an inflammatory cascade through MAPK and NF-κB activation, leading to helper T-cell maturation and secretion of inflammatory mediators. Inflammation causes apoptosis of the corneal and conjunctival epithelium, further disrupting tear film homeostasis. MAPK, mitogen-activated protein kinase; MMP, matrix metalloproteinase; NF-ĸB, nuclear factor kappa-light-chain-enhancer of activated B cells.

Alternatively, when tear-film hyperosmolarity is caused by excessive evaporation in the presence of a normally functioning lacrimal unit, the resulting type of DED is known as evaporative dry eye,4 which is primarily due to deficiency of the tear-film lipid layer caused by meibomian gland disease (MGD).2,4 Potential causes for MGD include meibomian gland damage, decrease in androgen levels, and androgen receptor insensitivity or blockade.2 Medications—including cis-retinoic acid, pilocarpine, and timolol—and exposure to polychlorinated biphenyls may disrupt the meibomian glands.2 Meibomian gland disease can also be secondary to some skin disorders and conjunctival diseases.2

Due to the cyclical, self-perpetuating nature of DED, many patients fall on a continuum and have features of both aqueous-deficient and evaporative dry eye.

When the cell's adaptive responses fail to compensate for hyperosmolarity, it can result in cellular stress.5 Hyperosmolar stress can trigger a complex inflammatory network, whose major components include the activation of mitogen-activated protein kinases and the nuclear factor kappa-light-chain-enhancer of activated B cells (NF-ĸB) pathway, T-cell maturation, and the secretion of proinflammatory cytokines and matrix metalloproteinases.4 Together, hyperosmolarity and inflammation lead to conjunctival and corneal epithelial cell death, including mucin-producing goblet cells, further increasing tissue damage and inflammation.4 Ocular targets damaged by hyperosmolarity and inflammation in DED include the lacrimal gland, meibomian glands, cornea, conjunctiva, and tear film.4

Current Pharmacologic Options for Treatment

Dry eye disease treatment progresses in a stepwise approach, starting with patient education, environmental modification, and lid hygiene,6 including gentle scrubs that limit the accumulation of lipid by-products and lipolytic bacteria and warm compresses that can soften the secretions in obstructed meibomian glands. However, compliance with lid hygiene is often poor.6 Ocular lubricants are a mainstay of early DED management, but they provide only a palliative solution and do not address the underlying disease mechanisms.6 If the initial steps are inadequate in treating DED, nonpharmacologic devices (e.g., punctal plugs, pulsed light therapy, thermal pulsation, and moisture goggles) may be used in conjunction with prescription medications.6

Several approved medications in the United States and Europe for the treatment of DED aim to deliver cyclosporine A (CsA) to affected ocular targets. CsA is a cyclic polypeptide that prevents T-cell maturation through binding to cyclophilin and inhibiting the phosphatase activity of calcineurin.7 This immunomodulatory activity has the potential to counteract the vicious inflammatory cycle in DED, but CsA's high hydrophobicity and poor aqueous solubility pose a challenge in delivering the drug to target tissues.8,9 Overall, CsA has been associated with an improved quality of life, improvement in at least some DED symptoms, and reduction in artificial tear use; however, studies of patient satisfaction and adherence show mixed results.10 Very few studies have evaluated efficacy and safety of CsA in the long term, and the optimal duration of treatment with CsA is unclear.10

A preservative-free anionic oil-in-water 0.05% CsA nanoemulsion (Restasis; Allergan, Inc., Irvine, CA) is commercially available in the United States and indicated to increase tear production in patients whose tear production is presumed to be suppressed due to ocular inflammation associated with DED.11,12 This formulation uses castor oil as the CsA solvent, polysorbate 80 as an emulsifier, and carbomer copolymer as a stabilizer.12 In 2 pooled multicenter, randomized, double-masked, phase 3 studies, CsA 0.05% emulsion administered twice daily for 6 months improved mean corneal staining scores (P=0.008) and mean categorized Schirmer’s test values (P≤0.05) from baseline versus vehicle.13 Adverse events (AEs) were reported in 25.3% of patients receiving CsA 0.05% ophthalmic emulsion and 19.5% of patients receiving vehicle.13 The most common AEs were eye burning and stinging, reported in 14.7% versus 6.5% and 3.4% versus 1.4% of patients receiving CsA 0.05% ophthalmic emulsion and vehicle group, respectively; 1.7% of patients in each treatment group discontinued because of eye burning and stinging.13 In an open-label phase 4 study, mean tear film breakup time improved >50% (P<0.001) after 6 months of treatment with CsA 0.05% ophthalmic emulsion. Adverse events were reported in 42.5% of patients, the most common AEs being instillation site burning (7.5%), instillation site pain (7.5%), and eye irritation (5%).14

A cationic 0.1% CsA nanoemulsion (Ikervis; Santen SAS, Évry, France) is commercially available in Europe for treatment of severe keratitis in adult patients with DED that has not improved despite the use of artificial tears.15 Delivery of CsA using cationic nanoemulsion is believed to improve residence time of CsA in target tissues compared with an anionic nanoemulsion; this is potentially due to the electrostatic interactions between positively charged droplets and negatively charged epithelial mucins.12 In a multicenter, randomized, double-masked phase 3 study, treatment with cationic 0.1% CsA nanoemulsion for 6 months improved corneal staining versus vehicle (P=0.037).16 Treatment-related AEs were reported by 37.0% of patients treated with cationic 0.1% CsA nanoemulsion and 21.1% of patients treated with vehicle, and almost all were ocular.16 The most common and only AE that demonstrated numerically increased occurrence in the active treatment group was instillation site pain, which occurred in 29.2% of patients receiving cationic 0.1% CsA nanoemulsion versus 8.9% of patients receiving vehicle.16

A 5% ophthalmic solution of the lymphocyte function-associated antigen 1 (LFA-1) antagonist lifitegrast is approved for treatment of signs and symptoms of DED (Xiidra, Novartis, Basel, Switzerland).17 Lifitegrast interacts with LFA-1 and its binding partner, intracellular adhesion molecule-1, preventing the 2 proteins from forming a complex and thereby inhibiting an inflammatory cascade resulting in T-cell activation and release of proinflammatory cytokines.18 In 2 sequential randomized, double-masked, placebo-controlled, parallel-arm, multicenter, phase 3 studies, treatment with lifitegrast significantly improved corneal and conjunctival staining in the first study, as well as eye dryness as measured on a visual analog scale in the second study, compared with placebo.19,20 Reported AEs were mainly mild to moderate.19,20 Serious AEs were nonocular and considered unrelated to the study.19,20 The most common AE in both studies was instillation site irritation, reported in 24% versus 4% in the first study and 7.8% versus 1.4% in the second study for patients receiving lifitegrast and placebo, respectively.19,20

Despite the increasing availability of pharmacotherapies, there is currently no cure for DED, and ongoing management is needed.6 Lipophilic drugs delivered using ophthalmic emulsions suffer from low penetration into the ocular tissues and may cause eye irritation and vision blurring.21 Current pharmacologic treatments may also have a slow onset of efficacy and overall patient dissatisfaction. Thus, there is an unmet need for DED pharmacotherapies with novel formulation or mechanism of action.

Novel Pharmacotherapies and Ongoing Clinical Trials

OTX-101 0.09% (CEQUA, Sun Pharmaceutical Industries, Inc., Cranbury, NJ), a nanomicellar formulation of CsA, was approved in 2018 to increase tear production in patients with keratoconjunctivitis sicca.22 Nanomicelles are amphiphilic molecules that self-assemble into a water-soluble outer shell and hydrophobic core that encapsulates lipophilic molecules such as CsA.23 Their small size (approximately 10 to 80 nm) allows for easy diffusion through scleral aqueous pores.8 In a head-to-head preclinical study in New Zealand white rabbits, OTX-101 showed increased concentration over time compared with 0.05% CsA ophthalmic emulsion in key ocular tissues, including an increase by a factor of 2.2 and 1.8 in the cornea and superior bulbar conjunctiva, respectively.24 The efficacy and safety of OTX-101 were evaluated in a phase 2b/3 and a phase 3 randomized, double-masked, vehicle-controlled study.25,26 In the phase 2b/3 study, treatment with OTX-101 0.09% for 84 days significantly improved total conjunctival staining versus vehicle as early as day 42 (P=0.048) and through day 84 (P=0.008).25 Total corneal staining was improved in the OTX-101 0.09% versus vehicle group at day 28 (P=0.015) and day 84 (P<0.001), and the percent of eyes with ≥10-mm increase from baseline in Schirmer’s scores at day 84 was significantly improved versus vehicle (P=0.007). Adverse events were reported in 52 (34.2%) patients in the OTX-101 0.09% group and 51 (33.6%) patients in the vehicle group, and most ocular AEs were mild or moderate in severity. The most common AE was instillation site pain in 23 (15.1%) patients receiving OTX-101 0.09% and 5 (3.3%) patients receiving vehicle. Additional AEs included eye irritation and increased lacrimation, each reported in 3 (2.0%) and 1 (0.7%) patients receiving OTX-101 0.09% and vehicle, respectively.25 In the phase 3 study, total conjunctival staining was significantly improved in the OTX-101 versus vehicle group as early as day 56 (P<0.001) and through day 84 (P=0.007), whereas the percent of eyes with complete corneal clearing was significantly improved versus vehicle as early as day 28 (P=0.04) and through day 84 (P=0.02).26 The percent of eyes with increase in Schirmer’s score ≥10 mm from baseline at day 84 was significantly improved versus vehicle (P<0.001). A total of 151 (40.6%) patients in the OTX-101 0.09% group and 91 (24.5%) patients in the vehicle group reported AEs, most of which were mild in severity.26 Most common AEs included instillation site pain—mostly mild in severity—in 90 (24.2%) and 16 (4.3%) patients receiving OTX-101 0.09% and vehicle, respectively; as well as conjunctival hyperemia in 30 (8.1%) and 19 (5.1%), and blepharitis in 5 (1.3%) and 0 patients receiving OTX-101 0.09% and vehicle, respectively.26

A number of pharmacological therapies for DED are in development (Table 1). A CsA nonaqueous solution (CyclASol; Novaliq, Heidelberg, Germany) in development for the treatment of moderate to severe DED uses semifluorinated alkanes to eliminate the need for water, oils, surfactants, or preservatives.27,28 The efficacy and safety of 0.05% and 0.1% cyclosporine aqueous solution were evaluated in patients with moderate to severe DED versus vehicle and an open-label cyclosporine 0.05% ophthalmic emulsion arm in an exploratory phase 2 study.27 There was a significant (P≤0.05) improvement in total corneal staining versus cyclosporine 0.05% ophthalmic emulsion arm in patients receiving 0.05% cyclosporine nonaqueous solution at 4 weeks of treatment but not at subsequent time points. Patients receiving 0.1% cyclosporine nonaqueous solution showed significant (P≤0.05) improvement in total corneal staining at 4 and 12 weeks but not at 16 weeks of treatment versus cyclosporine 0.05% ophthalmic emulsion. Adverse events were reported in 23.5% to 35.3% of patients, depending on treatment received and all were rated mild to moderate in intensity. Adverse events possibly related to study treatment led to discontinuation in 2 patients, of whom 1 was receiving cyclosporine nonaqueous solution 0.05% and experienced mild or moderate eye pain. Most common AEs were visual acuity–related, reported in 3.9%, 7.8%, 1.9%, and 7.5% of patients receiving cyclosporine nonaqueous solution 0.05% and 0.1%, vehicle, and cyclosporine ophthalmic emulsion 0.05%, respectively. Blurred vision, instillation site pain, and conjunctivitis were each reported in 1 (2.0%) patient receiving cyclosporine nonaqueous solution 0.1%.

T1
TABLE 1.:
Pharmacologics in Development for Dry Eye Disease Treatment

TOP1630 (TopiVert, London, United Kingdom) is a narrow spectrum kinase inhibitor (NSKI) in development for the treatment of DED.29 Unlike inhibitors targeting a single kinase, NSKIs are designed to selectively target several kinases to overcome the redundancy in inflammatory pathways.30,31 In a phase 2, randomized, double-masked, placebo-controlled, parallel-arm study, 4 weeks of treatment with TOP1630 led to significant improvement from baseline versus placebo in symptoms of grittiness (P=0.0374), foreign body sensation (P=0.0213), and eye pain (P=0.0292).32 Significant improvement was also noted in the objective sign of total (conjunctival and corneal) lissamine green staining (P=0.0349). There was no consistent significant change in other objective signs, including corneal fluorescein staining, tear-film breakup time, the Schirmer’s test, and conjunctival and lid margin redness. A total of 5 AEs were reported in 4 (12.9%) patients receiving TOP1630—reduced visual acuity, blurred vision, vitreous floaters, instillation site pain, and procedural pain. A total of 5 AEs were reported in 4 (13.3%) patients receiving placebo—reduced visual acuity, eye discharge, instillation site pain (in 2 patients), and instillation site discomfort. All reported AEs were mild to moderate in severity.32

SYL1001 (Sylentis, Madrid, Spain) is a short interfering RNA (siRNA) in development for treating the signs and symptoms of DED.33 The siRNA targets the transient receptor potential cation channel subfamily V member 1 (TRPV1), involved in facilitating pain sensation and modulation of inflammation.34 By silencing expression of TRPV1, treatment with the siRNA aims to prevent eye discomfort resulting from stimulation of corneal nerve endings after corneal epithelial damage.34 In a randomized, double-masked, placebo-controlled phase 2 study, SYL1001 1.125% significantly decreased ocular pain compared with placebo (P<0.05) as measured on a visual analog scale.34 Adverse events were reported in 10% of patients receiving SYL1001 1.125% and 15% of patients receiving placebo (n=20 for each treatment group). The most common AE in the SYL1001 1.125% group was ocular pruritus in 10% of patients versus 0 patients receiving placebo.

Thymosin β4 (Tβ4), a peptide involved in wound and dermal repair through downregulation of NF-κB mediated inflammation, promotion of cell survival, and stem cell maturation and migration, is currently under development for the treatment of DED (RGN-259; RegeneRx, Rockville, MD).35 In a randomized, double-masked, placebo-controlled phase 2 study, treatment with Tβ4 significantly improved ocular discomfort (P=0.0141) and total corneal staining (P=0.0108) versus vehicle.36 No AEs or discontinuations were reported.36 A follow-up randomized, double-masked, placebo-controlled phase 2 study evaluated patient response to the controlled adverse environment (CAE) challenge after 28 days of treatment with Tβ4 0.1% or vehicle.35 The study did not meet its primary endpoints of significant improvement in ocular discomfort or inferior corneal staining after CAE exposure, but ocular discomfort on day 28 of treatment was significantly improved versus vehicle (P=0.0244). Adverse events were reported in 5.6% and 13.9% of patients randomized to Tβ4 0.1% or vehicle, respectively. All AEs reported in the Tβ4 group were mild and included eye pain in 2.8% each of patients receiving Tβ4 and vehicle, blurred vision in 2.8% versus 0 patients receiving Tβ4 versus vehicle, and hordeolum in 2.8% versus 0 patients receiving Tβ4 versus vehicle.35

KPI-121, in development for the temporary relief of signs and symptoms of DED, is a novel formulation of loteprednol etabonate designed to improve loteprednol delivery through the mucus layer of the tear film (INVELTYS, Kala Pharmaceuticals, Waltham, MA).37,38 Loteprednol etabonate is a corticosteroid whose molecular structure allows for rapid degradation, retaining potent anti-inflammatory activity while reducing the risk of known ocular side effects of corticosteroids, such as increased intraocular pressure and cataract formation, thus facilitating its use to treat a number of ocular inflammatory conditions.39,40 Efficacy and safety of KPI-121 for treating inflammation and pain after cataract surgery were demonstrated in 2 phase 3 randomized, double-masked, vehicle-controlled studies.37 Preliminary results suggest that treatment with KPI-121 0.25% significantly improves the DED objective sign of conjunctival hyperemia at day 15 versus vehicle (P<0.0001 for both studies).41 Improvement in the DED symptom of ocular discomfort at day 15 versus vehicle was statistically significant in the first study (P<0.0001) but not the second (P=0.1298). Most common AEs in the first study included instillation site pain in 28 (6.1%) patients each in the KPI-121 and vehicle groups, as well as eye irritation in 5 (1.1%) and 7 (1.5%) patients receiving KPI-121 and vehicle, respectively. In the second study, most common AEs were instillation site pain in 26 (5.7%) and 20 (4.4%) patients receiving KPI-121 and vehicle, respectively, as well as blurred vision in 1 (0.2%) and 6 (1.3%) patients receiving KPI-121 and vehicle, respectively. A third phase 3 study is currently ongoing with preliminary results to be reported in late 2019.38

ADX-102 (Reproxalap; Aldeyra Therapeutics, Lexington, MA), in development for the treatment of dry eye, is believed to act by sequestering reactive aldehyde species, small molecules with cytotoxic and proinflammatory activity generated from membrane lipid modification by reactive oxygen species in a process known as lipid peroxidation.42–44 Preliminary results from a phase 2b randomized, double-masked, vehicle-controlled study suggest that 12 weeks of treatment with ADX-102 0.25% results in significant improvement from baseline versus vehicle in symptoms of ocular dryness, overall ocular discomfort, and stinging (P<0.05 for all assessments), but without statistically significant improvement in ocular nasal zone fluorescein staining (P<0.1).45 Conversely, ADX-102 0.1% significantly improved ocular nasal fluorescein staining from baseline at week 12 versus vehicle (P<0.05) but did not significantly improve ocular symptoms (P-value not reported). No safety concerns and only predominantly mild instillation site irritation were observed. Discontinuations were reported in 3%, 12%, and 1% of patients receiving ADX-102 0.1%, 0.25%, and vehicle, respectively.

Lacritin is a protein component of tears secreted by acinar cells in the lacrimal gland.46,47 In New Zealand white rabbits, lacritin promotes basal tear secretion shortly after administration and after 2 weeks of treatment as measured by the anesthetized Schirmer’s test.48 In cell culture, lacritin promotes human corneal epithelial cell proliferation.49 Proteomics approaches have also detected lacritin in meibomian gland secretions, and suggest that levels of the protein are depleted in tears from patients with DED compared to control individuals.50,51 A phase 2 randomized, double-masked, placebo-controlled study is evaluating the efficacy and safety of a lacritin formulation (Lacripep; TearSolutions, Charlottesville, VA) in patients with dry eye due to primary Sjögren syndrome with an estimated completion in June 2019.52

Challenges of Pharmacotherapy Development for Dry Eye Disease

Despite numerous promising candidates in the pipeline, drug development for DED has been characterized by low success rate and relatively few compounds reaching the approval stage.53,54 This could be due to challenges unique to DED, including the heterogeneity of the patient population in terms of causes and clinical presentation, and the lack of correlation between symptoms and objective signs of the disease.53–55 When designing clinical trials, monitoring several objective signs of the disease is recommended because it may most accurately represent the disease state.53 Clinical trial inclusion and exclusion criteria should be carefully selected, with a clear delineation of whether aqueous-deficient dry eye, evaporative dry eye, or both are included.54

CONCLUSIONS

Several approved treatments deliver drugs to ocular targets to treat the underlying inflammatory pathophysiology of DED. In the United States, there are three Food and Drug Administration–approved pharmacologic options for treating DED. CsA has been shown to be effective in the treatment of DED, and the most recently approved nanomicellar CsA formulation of OTX-101 is designed to improve CsA bioavailability in target ocular tissues, potentially improving efficacy and tolerability of treatment. Future pharmacotherapies for DED with novel targets are the focus of ongoing research, and a number of promising treatment options are in the pipeline.

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                                        Keywords:

                                        Keratoconjunctivitis sicca; Dry eye disease; Nanomicelles; OTX-101; Cyclosporine

                                        Copyright © 2019 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the Contact Lens Association of Opthalmologists.