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Open Access 23.04.2024 | Review Article

Recent United States Developments in the Pharmacological Treatment of Dry Eye Disease

verfasst von: David Valdés-Arias, Elyana V. T. Locatelli, Paula A. Sepulveda-Beltran, Simran Mangwani-Mordani, Juan Carlos Navia, Anat Galor

Erschienen in: Drugs

Abstract

Dry eye disease (DED) can arise from a variety of factors, including inflammation, meibomian gland dysfunction (MGD), and neurosensory abnormalities. Individuals with DED may exhibit a range of clinical signs, including tear instability, reduced tear production, and epithelial disruption, that are driven by different pathophysiological contributors. Those affected often report a spectrum of pain and visual symptoms that can impact physical and mental aspects of health, placing an overall burden on an individual’s well-being. This cumulative impact of DED on an individual’s activities and on society underscores the importance of finding diverse and effective management strategies. Such management strategies necessitate an understanding of the underlying pathophysiological mechanisms that contribute to DED in the individual patient. Presently, the majority of approved therapies for DED address T cell-mediated inflammation, with their tolerability and effectiveness varying across different studies. However, there is an emergence of treatments that target additional aspects of the disease, including novel inflammatory pathways, abnormalities of the eyelid margin, and neuronal function. These developments may allow for a more nuanced and precise management strategy for DED. This review highlights the recent pharmacological advancements in DED therapy in the United States. It discusses the mechanisms of action of these new treatments, presents key findings from clinical trials, discusses their current stage of development, and explores their potential applicability to different sub-types of DED. By providing a comprehensive overview of products in development, this review aims to contribute valuable insights to the ongoing efforts in enhancing the therapeutic options available to individuals suffering from DED.

Key Points

Dry eye disease (DED) is a multifactorial condition with a range of symptoms and signs. Effective treatment requires consideration of various underlying causes, including identifying how comorbidities influence DED pathogenesis (i.e., Sjögren’s syndrome aqueous tear deficiency or diabetes-associated neurotrophic keratitis).

This paper discusses novel therapeutic approaches for treating DED, while taking into account the different contributing factors, including inflammation, meibomian gland dysfunction, and neurosensory abnormalities.

1 Introduction

The Tear Film and Ocular Surface Society Dry Eye Workshop II (TFOS DEWS II) defined dry eye disease (DED) as “a multifactorial disease of the ocular surface characterized by a loss of homeostasis of the tear film, and accompanied by ocular symptoms, in which tear film instability and hyperosmolarity, ocular surface inflammation and damage, and neurosensory abnormalities play etiological roles” [1]. The various abnormalities that underlie DED, as described in its definition, spotlight the potential for targeting various aspects of the disease.

Symptoms of DED include pain complaints, frequently characterized as “dryness” but also as “aching,” “tenderness,” “foreign body sensation,” “irritation,” and “burning,” to name a few [2]. Other symptoms include visual complaints (e.g., blurred, fluctuating), redness, and tearing. These various symptoms have been captured in various DED questionnaires, many of which combine different symptoms to arrive at a composite severity score [3, 4]. Symptom diversity reinforces the heterogenic nature of DED, with pain symptoms being driven by nerve activation, either in the presence of normal nerves appropriately responding to their environment (i.e., nociceptive pain) and/or nerve abnormalities that themselves contribute to the generation of ocular pain (i.e., neuropathic pain) [5]. On the other hand, visual complaints, redness, and tearing are generally driven by ocular surface abnormalities, including poor tear film quality, epithelial disruption, and anatomic disturbances, to name a few [6].

The prevalence of DED symptoms in the general population, ranging from 5 to 50%, with an increasing prevalence with older age and in women, warrants the development of targeted therapeutic approaches to treat the various aspects of DED [7]. DED manifestations can have consequences for patients, like reduced quality of life, decreased ability to work and perform daily activities, and impacted mental health [8]. Moreover, DED symptoms also have a negative economic impact on patients, the health care system, and society [9, 10]. As more information arises on the underlying contributors of DED, available interventions are expanding to address symptoms. However, in order to deliver precision-based medicine to patients, it is important to first determine an individual’s underlying DED contributors. Furthermore, despite the availability of several agents to treat DED, there is a need for new solutions that improve on current therapeutics (e.g., agents that target inflammation with minimal side effects) and target novel aspects of disease (e.g., agents that address neurosensory abnormalities, meibomian gland dysfunction [MGD], microbiome alterations, anatomic issues) with the ultimate goal of enhanced patient outcomes.

This review aims to highlight the latest advancements in pharmacological treatments for DED in United States (US). The text will offer insights into a drug’s mechanisms of action, clinical trial findings, current stage, and potential applicability to DED sub-types. Of note, non-pharmacological approaches, such as device-based, surgical, or dietary interventions, among others, fall outside the scope of this article.

2 Methods

A review of the literature was conducted to identify relevant sources, including original articles, randomized clinical trials, meta-analyses, and other reviews that describe innovative therapeutic approaches for DED. We excluded articles in languages other than English and those containing information about drug development specific to countries other than the US. The search was conducted from the PubMed database (https://pubmed.ncbi.nlm.nih.gov, accessed on the 12th of June, 2023) using specific Medical Subject Heading (MeSH) terms: “Dry eye” [All Fields] OR “Dry eye disease” [All Fields] AND “Treatment” [All Fields], limited to publications since 2020. The initial search yielded a total of 6293 articles, of which 24 were included.

3 Dry Eye Disease Sources

3.1 Inflammation

Inflammatory processes have been identified as key contributors to some DED sub-types, including DED in the setting of immune conditions (e.g., Sjögren’s syndrome [SS], graft versus host disease [GVHD]), anatomical abnormalities (e.g., conjunctivochalasis), and allergy (e.g., atopic dermatitis) [11]. Outside of these conditions, tear abnormalities themselves (e.g., hyperosmolarity, low tear production) can contribute to a pro-inflammatory state mediated by T cells, with downstream products including metalloproteinases, tumor necrosis factor-α (TNFα), and other pro-inflammatory cytokines, among others [11, 12]. In the US, most of the available anti-inflammatory therapies for DED target T cells, through various mechanisms [13]. Recently, research has focused on developing more potent T cell inhibitors with fewer side effects (e.g., instillation site reactions) and on focusing on other targets of inflammation.

Novel therapies are emerging, yet it is pertinent to highlight the availability of current anti-inflammatory treatments for DED. Two compounds that are currently available are cyclosporine and lifitegrast. There are two available ophthalmic formulations of cyclosporine, a calcineurin inhibitor and immunosuppressive agent [14, 15]. Cyclosporine 0.05% and 0.09%, trialed in adults with DED based on questionnaire scores and clinical features, most robustly increased tear production and less robustly, but still significantly, reduced DED-related symptoms compared to placebo across various trials [14‐18]. Lifitegrast is a lymphocyte function-associated antigen-1 (LFA-1) antagonist whose anti-inflammatory mechanism of action comes from blocking the interaction of LFA-1 with its cognate ligand intercellular adhesion molecule-1 (ICAM-1) [19]. In clinical trials, lifitegrast 5% improved both eye dryness scores and ocular surface signs, including tear production and corneal staining, from baseline compared to vehicle [20‐22]. In terms of available short-term treatment (up to 2 weeks) options, loteprednol etabonate is a topical anti-inflammatory corticosteroid indicated for dry eye flares [23]. Loteprednol etabonate ophthalmic suspension 0.25% was evaluated in clinical trials involving adult participants with ocular discomfort (based on Symptom Assessment in Dry Eye [SANDE]) and signs (non-anesthetized Schirmer tear test [STT], corneal staining, and conjunctival hyperemia) and was found to improve ocular discomfort severity and conjunctival hyperemia compared to vehicle [23, 24] (Table 1). Beyond the abovementioned products, several compounds are currently under investigation or have been recently approved and will be discussed below.

Table 1

Summary of FDA-approved pharmacological treatments for managing various DED categories, including inflammation, eyelid abnormalities, neuropathic conditions, and Neurotrophic Keratitis

Generic name	Trade name	Concentration	Company	Mechanism of action	Dose	Indication	Effect	Approval date
Cyclosporine ophthalmic solution	Vevye	0.1% (1 mg/mL)	Harrow Health, Inc. and Novaliq GmbH	Cyclosporine, a calcineurin inhibitor, is a relatively selective immunomodulatory drug	BID	DED	4 weeks for increases of ≥ 10 mm from baseline in Schirmer wetting [31]	5/2023
	Cequa	0.09% (0.9 mg/mL)	Sun Pharma Industries	As above	BID	DED	3 months for increases of ≥ 10 mm from baseline in Schirmer wetting [115]	8/2018
	Restasis	0.05% (0.5 mg/mL)	AbbVie, Inc.	As above	BID	DED	6 months for increases of ≥ 10 mm from baseline in Schirmer wetting [116]	10/2003
Lotilaner ophthalmic solution	Xdemvy	0.25% (2.5 mg/mL)	Tarsus Pharmaceuticals, Inc.	GABA-gated chloride channel inhibitor inducing paralysis and ultimately causing the organism’s death	BID for 6 weeks	Demodex blepharitis	6 weeks for mite eradication and erythema cure [117]	7/2023
Perfluorohexyloctane ophthalmic solution	Miebo	100%	Bausch + Lomb, Corp.	Forms a monolayer at the air–liquid interface of the tear film, reducing evaporation	QID	Evaporative DED	8 weeks reduction in patient-reported eye dryness score and total CFS score [118]	5/2023
Lifitegrast ophthalmic solution	Xiidra	5% (50 mg/mL)	Bausch + Lomb, Corp.	Inhibits T cell adhesion to ICAM-1 in T cells reducing the secretion of inflammatory cytokines	BID	DED	12 weeks for reduction in patient-reported eye dryness score and inferior CFS score [119]	7/2016
Loteprednol etabonate ophthalmic suspension	Eysuvis	0.25% (2.5 mg/mL)	Alcon Laboratories, Inc.	Corticosteroids that inhibits inflammatory response to a variety of inciting agents	QID for up to 2 weeks	DED	2 weeks for reduction in patient-reported ocular discomfort severity score and conjunctival hyperemia score [120]	10/2020
Cenegermin-bkbj ophthalmic solution	Oxervate	0.002% (20 mcg/mL)	Dompé farmaceutici S.p.A.	Nerve growth factor that supports corneal innervation and integrity	6 times per day at 2-h intervals for 8 weeks	NK	8 weeks for corneal healing [121]	8/2018

BID twice daily (every 12 h), CFS cornea fluorescein staining, DED dry eye disease, FDA Food and Drug Administration, GABA gamma-aminobutyric acid, ICAM-1 intercellular adhesion molecule-1, NK neurotrophic keratitis, QID four times daily

3.1.1 Vevye (Harrow Health, Inc. and Novaliq GmbH)

Vevye is a topical formulation of cyclosporine A (a calcineurin inhibitor that functions primarily by inactivating T cells and their functions) delivered in a novel tear-stabilizing water/preservative-free vehicle (perfluorobutylpentane) [25‐27]. T cells play an essential role in mediating inflammation and amplifying immune responses related to DED [26]. Their diverse mechanisms include the release of a multitude of cytokines, some of which are responsible for cell death, reduced tear production, activation of antigen-presenting cells (APCs), or initiation of the release of matrix metalloproteinases (MMPs) [26, 28]. Correspondingly, higher levels of CD4+ T cells have been reported on flow cytometry from ocular surface wash samples in individuals with DED (diagnosis based on TFOS DEWS II) as compared to healthy individuals [29]. In this study, CD4+ T cell count correlated with Ocular Surface Disease Index (OSDI) (r = 0.28; p = 0.008) and tear break-up time (TBUT) scores (r = −0.31; p = 0.001) [29]. A randomized, double-masked, vehicle-controlled, phase 3 trial evaluated the efficacy of topical Vevye 0.1% (n = 423, administered twice daily) compared to a vehicle (n = 411) in individuals with DED (defined by symptoms, total cornea fluorescein staining [CFS] ≥ 10, and Schirmer 1–10 mm, among other requirements) [30]. After 4 weeks of therapy, dryness assessed with a visual analog scale (VAS) showed improvement from baseline in both groups (−12.2 vs. −13.6, respectively; p = 0.38; range 0–100) [30]. Additionally, the Vevye 0.1% group showed a greater improvement in total CFS assessed with the National Eye Institute (NEI) scale from baseline when compared to the vehicle group (−4.0 vs. −3.6, respectively; p = 0.03; range 0–15) [30]. As seen with previous cyclosporine formulations, ≥ 10 mm improvement in tear production (STT) was more frequently noted in individuals treated with Vevye compared to controls (11% vs 7%; p = 0.05) [31]. The US Food and Drug Administration (FDA) approved the medication on May 30th, 2023 [32]. Given its mechanism of action, Vevye may impact a DED sub-type associated with T cell-mediated inflammation and decreased tear production.

3.1.2 Reproxalap (Aldeyra Therapeutics, Inc.)

Reproxalap is a topical medication that inhibits reactive aldehyde species (RASP) [33]. Malondialdehyde and 4-hydroxynonenal are two RASP molecules, and major ocular biomarkers of oxidative stress [34, 35]. They result from lipid peroxidation and may be relevant molecules in DED pathogenesis due to their high cytotoxicity, ability to upregulate pro-inflammatory signaling cascades, and binding affinity to phosphatidylethanolamine, a component of the tear lipidome involved in retaining moisture on the ocular surface [36, 37]. Elevated levels of these molecules have been reported on the tear film and ocular surface in individuals with DED (defined by symptoms, TBUT ≤ 7 s, and Schirmer ≤ 7 mm, among other requirements) [38]. A randomized, double-blinded, vehicle-controlled, phase 2b trial looked at the efficacy of reproxalap (0.25% and 0.1%, n = 100 in each group, administered daily 4 times per day) compared to a vehicle (n = 100) in individuals with DED (defined by symptoms, TBUT ≤ 5 s, CFS ≥ 2 in ≥ 1 region, and Schirmer 1–10 mm, among other requirements) [33]. After 12 weeks of therapy with reproxalap 0.25%, all symptoms assessed with the Ora Calibra Ocular Discomfort & 4-Symptom Questionnaire (OD4SQ) improved from baseline when compared to reproxalap 0.1% and the vehicle group, especially for dryness (−0.9 vs. −0.6 vs. −0.5, respectively; p = 0.047 for comparison of 0.25% and vehicle; range 0–5) [33]. Additionally, reproxalap 0.25% improved all clinical signs, most robustly nasal CFS, from baseline when compared to reproxalap 0.1% and the vehicle group (−0.3 vs. ~ −0.28 vs. −0.1, respectively; p = 0.03 for comparison of 0.25% and vehicle; range 0–4) [33]. Aldeyra Therapeutics, Inc. submitted a Special Protocol Assessment (SPA) for a new clinical trial on November 16th, 2023, to address FDA feedback and gain regulatory approval [39]. Given its mechanism of action, reproxalap may impact a DED sub-type associated with inflammation, specifically high levels of RASP. However, a limitation in DED is that no current diagnostic tests evaluate ocular surface RASP levels. There are diagnostic tests that qualitatively assess MMP-9 (InflammaDry) but more diagnostics are needed to examine specific pathways of inflammation in an individual patient [40].

3.1.3 Thymosin β4 (RegeneRx Biopharmaceuticals, Inc. and HLB Therapeutics Co. Ltd)

Thymosin β4 is a topical G-actin–sequestering protein that is thought to reduce apoptosis, facilitate wound healing, and diminish inflammation [41]. The exact mechanism remains uncertain; however, it is thought to involve the suppression of nuclear factor kappa B (NF-kB) [42]. NF-kB is a transcription factor central to numerous immunobiological processes, including the regulation of multiple pro-inflammatory cytokines and chemokines associated with aspects of DED [43]. In a DED mouse model (induced by topical instillation of benzalkonium chloride), decreased corneal staining, corneal epithelial cell apoptosis, conjunctival NF-kB activation, and pro-inflammatory cytokine expression were all noted in mice receiving recombinant human thymosin β4 compared to controls [44]. A randomized, double-masked, vehicle-controlled, phase 2 trial looked at the efficacy of topical thymosin β4 0.1% (n = 36, administered twice daily) compared to a vehicle (n = 36) in individuals with DED (defined by symptoms, and CFS ≥ 2, among other requirements) [45]. Symptoms and signs were evaluated before and after exposure to a controlled adverse environment (CAE) chamber. After 28 days of therapy with thymosin β4 0.1%, ocular discomfort graded on a 0–4 scale showed a lower increment of discomfort post-CAE compared to placebo (1.6 vs. 2.2; p = 0.02; range 0–4) [45]. Additionally, thymosin β4 0.1% showed improvement in clinical signs, most robustly CFS in the superior region post-CAE from baseline when compared to vehicle (−0.14 vs. 0.32; p = 0.02; range 0–4) [45]. In October 2022, an SPA request for the fourth phase 3 clinical trial for DED (ARISE-4) was submitted to the US FDA [46]. Meanwhile, an ongoing phase 3 clinical trial (SEER-2) is investigating the potential of this compound for neurotrophic keratitis (NK) [47]. Given its mechanism of action, thymosin β4 may impact a DED sub-type associated with inflammation, specifically high levels of NF-kB. However, limitations are that current tests do not measure levels of NF-kB in tears.

3.1.4 Licaminlimab (Oculis Holding AG)

Licaminlimab is a topical single-chain antibody fragment that binds and inhibits the activity of human TNFα [48]. Primarily produced by macrophages, TNFα is a crucial cytokine that regulates immune responses, contributes to tissue degeneration and cell proliferation, and can influence the regulation of proinflammatory molecules, like NF-kB and mitogen-activated protein kinases, closely involved with DED pathogenesis [49, 50]. Elevated levels of TNFα messenger ribonucleic acid (mRNA) have been reported on conjunctival brush cytology in individuals with SS as compared to a non-SS DED and a control non-DED group [51]. A randomized, double-masked, vehicle-controlled, phase 2 trial evaluated the efficacy of topical licaminlimab 60 mg/mL (n = 69, administered daily 3 times per day) compared to a vehicle (n = 65) in individuals with DED (defined by symptoms, and hyperemia ≥ 1 in ≥ 2 quadrants, among other requirements) [48]. After 4 weeks of therapy with licaminlimab 60 mg/mL, ocular discomfort assessed with the SANDE questionnaire showed a significant improvement from baseline when compared to the vehicle group (−7.9 ± 1.45 vs. −3.6 ± 1.49; p = 0.04; range 0–100) [48]. Additionally, clinical evaluation of total CFS assessed in five regions showed improvement in both licaminlimab 60 mg/mL and the vehicle group (−1.1 vs. −1.4, range 0–20) [48]. An ongoing phase 2b clinical trial (RECOVER) is investigating the potential of this compound for DED [52]. Given its mechanism of action, licaminlimab may impact a DED sub-type associated with high levels of TNFα, but again, this metric cannot be currently measured using available diagnostic testing.

3.1.5 Tanfanercept (HanAll Biopharma Co. Ltd)

Tanfanercept is a topical solution made of a modified TNF receptor 1 (TNFR1), specifically from the TNFα binding fragment, that is able to block TNFα and its activity [53]. As previously mentioned, TNFα is a cytokine that plays a central role mediating the inflammatory cascade that contributes to the pathogenesis of multiple diseases, including DED, which suggest its downregulation as a potential treatment [54]. In a mouse model of DED (induced by subcutaneous injections of scopolamine hydrobromide and a controlled environmental chamber), topical tanfanercept suppressed inflammatory cytokines in corneal and lacrimal gland samples, in addition to improving goblet cell counts and corneal erosion scores [53]. A randomized, double-blinded, vehicle-controlled, phase 2 trial evaluated the efficacy of topical tanfanercept 0.25% (n = 50, administered twice daily) compared to a vehicle (n = 50) in individuals with DED (defined by symptoms, CFS ≥ 2 in ≥ 1 region, and Schirmer 1–10 mm, among others) [55]. Symptoms and signs were evaluated before and after exposure to a CAE chamber [55]. After 8 weeks of therapy all symptoms assessed with the OD4SQ improved from baseline in both groups, especially for discomfort (approximate change −1.30 vs. −1.26; p = 0.46; range 0–5) [55]. Additionally, for the change from pre- to post-CAE after 8 weeks, there was improvement on inferior CFS assessed with the Ora Calibra Corneal and Conjunctival Fluorescein Staining Scale in both groups (−0.61 ± 0.11 vs. −0.54 ± 0.11; p = 0.65; range 0–4) as well as in Schirmer test scores (1.87 ± 0.62 vs. 1.28 ± 0.62 mm; p = 0.50) [55]. On May 19, 2023, after completion of the clinical trial VELOS-3, HanAll Biopharma Co. Ltd projected intentions to advance into the next study, schedule to begin in 2024 [56]. Given its mechanism of action, tanfanercept may improve symptoms and signs in a DED sub-type characterized by high levels of TNFα.

3.1.6 SkQ1 (Essex Bio-Technology Ltd)

SkQ1 is a topical synthetic mitochondria-targeted antioxidant that functions to suppress reactive oxidative species (ROS) generation, oxidative stress propagation and increase intrinsic antioxidant defense [57]. ROS elevations can lead nuclear acids, lipids, and proteins to undergo irreversible oxidative modifications and elevate proinflammatory cytokine expression [57]. Higher levels of lipid oxidative stress markers have been observed in tear and conjunctival brush cytology of individuals with SS compared to healthy controls [58]. These levels were also correlated with worse tear stability and staining scores in SS [58]. As the primary source of ROS (~ 90%) is mitochondria, the SkQ1 molecule composition includes the naturally occurring antioxidant plastoquinone conjugated with the transport molecule triphenyl phosphonium, to enable cellular penetration and accumulation within the mitochondria [57, 59]. A randomized, double-blinded, vehicle-controlled, phase 2 trial evaluated the efficacy of SkQ1 (1.55 μg/mL vs. 0.155 μg/mL, n = 30 in each group, administered daily 2 times per day) compared to a vehicle (n = 31) in individuals with DED (defined by symptoms, CFS ≥ 2 in ≥ 1 region, and Schirmer 1–10 mm, among others) [60]. Symptoms and signs were evaluated before and after exposure to a CAE chamber [60]. After 29 days of therapy with SkQ1 1.55 μg/mL, symptoms of grittiness assessed with the OD4SQ improved post-CAE from baseline when compared to SkQ1 0.155 μg/mL and the vehicle group (−0.50 ± 0.90 vs. −0.40 ± 1.10 vs. 0.00 ± 1.17; range 0–5) [60]. Interestingly, post-CAE total CFS (assessed with the Ora Calibra Corneal and Conjunctival Fluorescein Staining Scale) improved from baseline in all groups (−0.70 vs. −1.23 vs. −0.95; range 0–20) [60]. After acquisition of SkQ1 from Mitotech on October 13th, 2022, Essex Bio-Technology is focused on completing the transfer of knowledge related to the drug and addressing potential risks with regulators before resuming clinical trials [61]. Given its mechanism of action, SkQ1 may impact a DED sub-type with high levels of ROS, but again, this metric cannot be currently measured using available diagnostic testing.

3.1.7 Summary

As above, many different aspects of inflammation including T cell activation, ROS generation, and cytokine-mediated inflammation have been noted in individuals with various sub-types of DED. Various compounds that target these aspects of inflammation have shown promising results in the developmental stage (reproxalap, thymosin β4, licaminlimab, tanfanercept, SkQ1) while Vevye has already secured approval. The success of precision-based DED therapies highlights a gap in the capabilities of our diagnostic tools, particularly in accurately identifying involved inflammatory profiles. Future research dedicated to advancing diagnostic technologies is the key to offering tailored treatment to individuals.

3.2 Eyelid Abnormalities: Demodex Blepharitis and Meibomian Gland Dysfunction

Demodex blepharitis and MGD are prevalent ocular conditions that can contribute to DED symptoms and signs [62, 63]. Demodex infestation, with cylindrical dandruff as its pathognomonic presentation, is a common cause of anterior blepharitis (with staphylococcal and seborrheic blepharitis as other variants) [63]. Two species of Demodex mites (folliculorum and brevis) can colonize human eyelash follicles, with the frequency of colonization increasing with age and impaired immunity [64]. While the pathophysiology is not fully understood, chronic Demodex infestation can lead to symptoms (e.g., itching, pain) and signs (e.g. hyperemia) that can be bothersome to patients and negatively impact quality of life [62]. MGD is another common eyelid condition whose hallmark is functional or structural abnormalities involving the superior and inferior meibomian glands (MG) [65]. MGD can present with functional alterations in the quality or quantity of meibum, or with structural abnormalities presenting as MG atrophy or orifice blockage (e.g., keratinization), all of which can impact tear film composition and contribute to discomfort [65]. Recent advances in the field have evaluated compounds that target these conditions.

3.2.1 Lotilaner (Xdemvy, Tarsus Pharmaceuticals, Inc.)

Lotilaner is a topical medication that belongs to the isoxazoline class and exhibits an anti-parasitic effect [62]. When gamma-aminobutyric acid (GABA) molecules activate GABA-gated chloride channels (GABACls), a chloride influx hyperpolarizes the cell membrane [66]. This process generates inhibitory potentials in the invertebrate’s nervous system that allows for muscular relaxation [66]. Isoxazolines are non-competitive GABACls inhibitors that depolarize the cell membrane by preventing the chloride influx, leading to paralysis and eventual death of the organism [67]. The contribution of Demodex to DED and MGD is not fully understood, but the organism can induce a host inflammatory response and may contribute to MG orifice obstruction [68]. A randomized, double-masked, phase 3 trial evaluated the efficacy of topical lotilaner (n = 203, administered twice daily) compared to a vehicle (n = 209) in individuals with Demodex blepharitis (defined by mild or greater upper eyelid margin erythema, > 10 collarettes present on the upper eyelid, and mite density > 1.5 mites per lash between upper and lower eyelid margins) [69]. After 43 days of therapy with lotilaner 0.25%, clinical signs assessed through slit-lamp examination and epilation showed improvement when compared to the vehicle group, including reduction to ≤ 2 lashes with collarettes (56.0% vs. 12.5%; p < 0.0001), mite eradication (51.8% vs. 14.6%; p < 0.0001), and resolved palpebral erythema (31.1% vs. 9.0%; p < 0.0001) [69]. The US FDA approved the medication for the treatment of Demodex blepharitis on July 25th, 2023 [70]. The Ersa phase 2a clinical trial designed to evaluate the drug’s efficacy in treating MGD has concluded, and ongoing examination of the data is currently taking place [71]. Given its mechanism of action, lotilaner may improve symptoms and signs in DED sub-types associated with Demodex blepharitis.

3.2.2 Perfluorohexyloctane (Meibo, Bausch + Lomb Corp.)

Perfluorohexyloctane is a topical medication belonging to the group of semifluorinated alkanes, and it can stabilize the tear film by enhancing the lipid layer of the tear, resulting in evaporation reduction [72]. MGD caused by MG inflammation, blockage, or dropout can lead to meibum qualitative modifications and/or lipid deficiencies [63]. These events create instability of the tear film, culminating in evaporative DED [63]. Accordingly, meibum quality grades have been reported to correlate negatively to TBUT and positively to corneal staining scores in individuals with obstructive MGD (defined by symptoms, clinical signs of MGD including gland obstruction, plugging, turbid secretions, and eyelid margin inflammation, among others) [73]. A randomized, double-masked, saline-controlled, phase 3 trial evaluated the efficacy of topical perfluorohexyloctane (n = 311, administered daily 4 times per day) compared to a hypotonic saline solution (n = 309) in individuals with DED (defined by symptoms, TBUT ≤ 5 s, total CFS 4–11, and Schirmer ≥ 5 mm, among other requirements) [74]. After 8 weeks of therapy with perfluorohexyloctane, symptoms assessed with the VAS showed a greater improvement from baseline when compared to hypotonic saline solution for dryness (−29.5 vs. −19.0; p < 0.001; range 0–100) and burning/stinging (−22.1 vs. −13.7; p < 0.001; range 0–100) [74]. Additionally, perfluorohexyloctane also improved clinical signs, most robustly the total CFS assessed with the NEI grading scale (−2.3 vs. −1.1; p < 0.001; range 0–15) [74]. The US FDA approved the medication on May 18th, 2023 [75]. Given its mechanism of action, perfluorohexyloctane may impact a DED sub-type associated with MGD and evaporative DED.

3.2.3 AZR-MD-001 (Azura Ophthalmics, Pty Ltd)

AZR-MD-001 is a topical medication containing selenium sulfide and is believed to be an agent with keratostatic properties that reduce keratin synthesis by slowing keratinocyte proliferation and turnover, preventing hyperkeratinization of the MG ducts, as well as keratolytic properties that promote the effective release of blockages [76]. As mentioned earlier, MGD has various etiologies, including structural abnormalities of MG secondary to aging that can lead to evaporative DED [65, 77]. Concordantly, a negative correlation with age was found in the mean length of the upper (r = −0.485, p < 0.05) and lower MG (r = −0.533, p < 0.001), as well as in the percentage area of MG acini of the upper (r = −0.592, p < 0.05) and lower MG (r = −0.357, p < 0.05) [78]. These findings were obtained through the assessment of infrared meibography images within a healthy population [78]. A randomized, double-masked, vehicle-controlled, phase 2 trial evaluated the efficacy of AZR-MD-001 (0.5% and 1.0%, n = 82 and n = 83. respectively, administered twice daily) compared to a vehicle (n = 80) in individuals with MGD (defined by symptoms, TBUT < 10 s, CFS < 3, Schirmer > 5 mm, MG secretion ≤ 12 on 15 glands, and meibography score < 4, among others) [79]. After 3 months of therapy, symptoms assessed with the OSDI questionnaire showed significant improvement from baseline with both AZR-MD-001 concentrations when compared to vehicle (−7.3 vs. −6.1 vs. −3.8; p < 0.0001; range 0–100) [79]. Additionally, improvement of MGD signs were significant with AZR-MD-001, including in the MG yielding liquid secretion assessed through individual expression of five glands per three regions (4.2 vs. 3.2 vs. 2.4; p < 0.0001; range 0–15) and MG secretion assessed through visual evaluation of meibum quality from baseline when compared to vehicle (10.5 vs. 8.1 vs. 6.0; p < 0.0001; range 0–45) [79]. On April 20th, 2023, Azura Ophthalmics announced intentions to advance to phase 3 clinical trials [80]. Given its mechanism of action, AZR-MD-001 may improve symptoms and signs in a DED sub-type associated with hyperkeratinization of the MG ducts.

3.2.4 Summary

These data highlight that eyelid abnormalities, whether in the form of Demodex overgrowth, poor meibum quality leading to tear instability, or keratinization of the MG orifices, can contribute to DED symptoms and signs. Several compounds that target these abnormalities are being investigated (AZR-MD-001) and/or have been approved (lotilaner, perfluorohexyloctane). We anticipate that the use of these agents in the “real world” will provide much needed data on the impact that targeting these abnormalities has on DED-associated morbidity.

3.3 Neuropathic

Neuropathic ocular pain (NOP) is a DED sub-type in which peripheral and/or central nerve hypersensitivity contributes to symptoms. Individuals with NOP often present with symptoms out of proportion to DED signs, and report a specific symptom profile of “burning” pain, with increased sensitivity to triggers such as wind, light, temperature change, and odor [81]. There are no gold-standard diagnostic criteria for NOP, but suggestive features include the symptoms profile noted above, a history of pain that started < 3 months after a surgical procedure, co-morbidities such as fibromyalgia and migraine, and/or altered corneal sensation. In addition, findings that suggest central nervous system (CNS) contributions to NOP include persistence of ocular pain after placement of topical anesthesia, cutaneous allodynia (e.g., pain to light touch around the eye), and/or pain radiation to sites beyond the eye [82, 83]. However, more diagnostic tools are needed to evaluate nerve function and help identify when neuropathic mechanisms contribute to DED symptoms. Meanwhile, challenges to be considered with respect to therapeutics relate to the location of nerve abnormalities. Topical therapies are more likely to impact those with peripheral nerve abnormalities that contribute to NOP, while individuals with central abnormalities are less likely to respond to a topical approach [83, 84]. In this context, companies are studying topical therapies that modulate pain via modulation of peripheral nerve function. A challenge is identifying which patient populations are most likely to benefit from this approach.

3.3.1 AR-15512 (Alcon Laboratories, Inc.)

AR-15512 is a topical medication that acts as an agonist of transient receptor potential melastatin 8 (TRPM8) chemicals and cold-sensitive thermoreceptors responsible for stimulating trigeminal tear production [85]. TRPM8, located in corneal and conjunctival nerves, is a cation channel activated when it senses hyperosmolarity or tear evaporative cooling [85, 86]. Reduced corneal nerve density has been noted in some individuals with DED (especially in those with immune-mediated DED such as SS), and as such, it is hypothesized that these individuals also have less TRPM8, and may thus not respond appropriately to hyperosmolarity or cooling [87, 88]. A randomized, double-masked, vehicle-controlled, phase 2b trial evaluated the efficacy of topical AR-15512 (0.003% and 0.0014%, n = 122 and n = 121, respectively, administered daily 2 times per day) compared to a vehicle (n = 126) in individuals with DED (defined by symptoms, total CFS 2–15, and Schirmer 2–10 mm, among other requirements) [89]. After 12 weeks of therapy with AR-15512 0.003%, ocular discomfort assessed with a VAS showed greater improvement from baseline when compared to the AR-15512 0.0014% and the control group (−20.6 vs. −13.3 vs. −13.6, respectively; p = 0.028; range 0–100) [89]. Additionally, the AR-15512 0.003% group significantly improved tear production assessed with Schirmer from baseline to day 14 when compared to the AR-15512 0.0014% group and the control group (19.7 vs. 15.7 vs. 6.0 mm, respectively; p < 0.0001) [89]. Alcon plans to submit a New Drug Application (NDA) to the US FDA in 2024 [90]. Given its mechanism of action, AR-15512 may impact a DED sub-type associated with nerve dysfunction and lower nerve density.

3.3.2 Tivanisiran (Sylentis, S.A.)

Tivanisiran is a topical synthetic small interfering RNA (siRNA) that inhibits Transient Receptor Potential Vanilloid 1 (TRPV1) mRNA by enabling degradation of the molecule [91]. TRPV1, located in afferent nociceptive neurons among other tissues, is a cation channel that acts as a transducer of noxious stimuli into electrical impulses and is involved in inflammatory processes [91]. TRPV1 can be activated by corneal damage, hyperosmolarity, or inflammatory mediators [91]. Correspondingly, higher TRPV1 protein levels have been reported in rats with DED (created by exorbital gland excision) compared to sham rats, from samples of the anterior eye segment and trigeminal ganglia [91, 92]. A randomized, double-masked, vehicle-controlled, phase 2 trial looked at the efficacy of topical tivanisiran (0.75% and 0.375%, n = 21 in each group, administered once daily) compared to a vehicle (n = 24) in individuals with DED (defined by symptoms, TBUT < 10 s, CFS ≥ 1, and Schirmer < 10 mm, among other requirements) [93]. After 10 days of therapy, symptoms assessed with the OSDI questionnaire showed a significant reduction from baseline in all groups (−16.5 vs. −16.2 vs. −17.6, respectively; p < 0.05; range 0–100) [93]. Additionally, tivanisiran 0.75% improved clinical signs, most robustly TBUT, from baseline when compared to tivanisiran 0.375% and vehicle (1.67 vs. 0.0 vs. 0.08; p < 0.05) [93]. The FYDES study, a phase 3 trial assessing the safety of tivanisiran in individuals with DED, has concluded, and data analysis is currently taking place [94]. Given its mechanism of action, tivanisiran may impact a DED sub-type associated with peripheral nerve abnormalities.

3.3.3 Summary

These findings underscore the existence of NOP resulting from nerve dysfunction or the transmission pain signals. Innovative topical therapies, such as AR-15512 and tivanisiran, designed to modulate peripheral nerve function, exhibit promise in addressing nerve abnormalities associated with DED. Further research is warranted to fully elucidate their effectiveness and long-term safety.

3.4 Neurotrophic Keratitis

NK is a neurodegenerative corneal disorder characterized by impaired corneal sensation due to trigeminal nerve damage or dysfunction [95]. This condition negatively impacts corneal epithelial health as the cornea relies on a delicate balance of neurotrophic factors such as substance P, calcitonin gene-related peptide, norepinephrine, acetylcholine, neurotensin, and vasoactive intestinal polypeptide, secreted by corneal nerves [96]. The disruption of this balance, which is frequently caused by corneal denervation due to surgery (e.g., refractive), procedures (e.g., pan retinal photocoagulation), infections (e.g., herpes), metabolic disorders (e.g., diabetes), or central mechanisms (e.g., stroke), can result in a cascade of consequences, including impaired corneal reflex arc activation, increased susceptibility to corneal ulcers, and vision loss [97]. The hallmark of NK is decreased corneal sensation, often measured in the clinic with the use of a cotton tip, dental floss, or tissue paper. NK severity is further graded from 1 to 3 (1: punctate epithelial disruption; 2: persistent epithelial defect; 3: stromal melt and/or perforation) [98]. Given the importance of nerve derived growth factors in epithelial maintenance, one approach to targeting epithelial abnormalities in NK is to replenish missing growth factors. Autologous serum tears (AST) contain a rich concentration of these essential neurotrophic growth factors, offering the possibility of nerve regeneration, which may help alleviate corneal pain [99]. Clinical trials have evaluated the effectiveness of AST drops in treating ocular surface diseases, including NK, which has been found to improve ocular surface sign and decrease symptoms [100, 101]. Efforts to develop targeted therapies for this condition are progressing, with recent evaluations yielding encouraging results.

3.4.1 Cenegermin (Dompé farmaceutici S.p.A.)

Cenegermin, a topical recombinant human nerve-growth factor (rhNGF), aims to promote corneal healing by replenishing missing growth factors [102]. Corneal nerves originating by the fifth cranial pair play a crucial role in maintaining corneal homeostasis and facilitating healing [98, 102]. Impairment of these nerves can lead to a diminished sense of the cornea, weakened protective blinking and tearing reflexes, epithelial abnormalities, and impaired healing [102, 103]. Not surprisingly, individuals with NK from a variety of causes often have lower corneal nerve density compared to controls [104, 105]. In a similar manner, individuals with ipsilateral trigeminal damage caused by neurosurgical intervention have lower corneal nerve density on the side of injury than the non-damaged side [106]. A randomized, double-masked, vehicle-controlled, phase 2 trial looked at the efficacy of cenegermin (20 mg/mL and 10 mg/mL, n = 52 in each group, administered daily 6 times per day) compared to a vehicle (n = 52) in individuals with grade 2–3 NK on one eye (defined by reduced corneal sensitivity of the cornea both inside the corneal lesion and in at least one quadrant outside of it, among other requirements) [107]. After 8 weeks of therapy with cenegermin, corneal healing was significantly better when compared to vehicle (74% vs. 74.5% vs. 43.1%; p = 0.001; defined by < 0.5 mm diameter residual defect when stained with fluorescein) [107]. Additionally, cenegermin-treated lesions were smaller as compared to baseline when compared to vehicle (76% vs. 58.4% vs. 26.2%; p = 0.102) [107]. Cenegermin has also been found to improve epithelial abnormalities in individuals with grade 1 NK, as shown in an uncontrolled multicenter, prospective, open-label phase 4 trial [108]. The US FDA approved the medication on August 22th, 2018 [109]. Given its mechanism of action, cenegermin may impact the DED sub-type associated with NK.

3.4.2 Topical Insulin

Insulin is an endocrine hormone that regulates diverse processes, including metabolic regulation, cell growth, migration, and proliferation [110]. Naturally present in tears, insulin activates various receptors (insulin-like growth factor receptors type 1 and 2 [IGF-1/2R], insulin receptor [INSR]), as well as signaling pathways (WNT/β-catenin pathway, phosphatidylinositol 3-kinase [PI3K]/Akt/mTOR signaling pathway) that are implicated in epithelial and neural corneal repair mechanisms [110]. Deficient insulin signaling in the cornea, as observed in diabetic conditions, can compromise its structural integrity and lead to various pathologies, including NK [111, 112]. Consistently, lower epithelial cell and corneal nerve density have been reported in individuals with type 1 diabetes mellitus when compared to healthy controls [113]. A retrospective, observational, single-center study looked at the efficacy of topical insulin (1 IU/mL, n = 21, administered daily 4 times per day) in individuals with grade 2–3 NK (defined by reduced or absent corneal sensation, corneal damage resistant to standard treatment, and clinical history of disorders associated with trigeminal innervation dysfunction) [114]. Between 7 and 45 days after initiating insulin therapy, complete re-epithelialization of the corneal lesion was observed in 90% of the individuals (n = 19) [114]. The mean number of days to achieve this outcome was significantly lower in individuals with grade 2 NK compared to those with grade 3 NK (18 ± 9 vs. 29 ± 11 days, respectively; p = 0.025) [114]. Two active investigations (NCT05692739 and NCT06017362) on ClinicalTrials.gov are evaluating topical insulin’s efficacy in treating DED, while another one (NCT05321251) examines its potential for NK. Given its mechanism of action, insulin may impact the DED sub-type associated with deficient insulin signaling.

3.4.3 Summary

These findings demonstrate how NK can arise from reduced growth factors or deficient insulin signaling, among other causes. While cenegermin offers an established approach to corneal and nerve repair, the potential of topical insulin, currently under investigation, has a promising utility for ocular surface disorders, particularly in diabetic patients. Understanding the full extent of these benefits requires further investigation across a diverse range of patients with NK.

4 Conclusion

DED, an umbrella term encompassing multiple etiologies, remains a prevalent and challenging condition impacting millions globally. However, the field is experiencing the emergence of innovative solutions (Fig. 1). Recent studies have provided valuable insights into the diverse intricated mechanisms that contribute to the manifestation of DED. In response to this knowledge, several novel drugs are currently in development, highlighting the possibility of more targeted and precise treatment. While some compounds have shown success and have been approved, a crucial need persists to develop improved diagnostic tools to accurately identify the various sub-types of DED, particularly within the inflammatory and neuropathic categories. Additionally, although significant progress has been made in understanding and treating DED, investigating long-term safety is needed to ensure optimal patient outcomes, as well as further research exploring possibilities for disease prevention. Finally, standardizing the methodology and study design for DED drug research is crucial. This ensures improved reliability, facilitates cross-study comparisons, and contributes to a more systematic evaluation of drug efficacy and safety. Such standardization will empower health practitioners to make well-informed decisions for their patients.

Acknowledgements

We express our gratitude to the funding sources outlined below for their invaluable support. The figure was created using BioRender.com, and we appreciate their contribution to visualizing our research.

Declarations

Funding

This work was supported by the National Institutes of Health (NIH) Center Core Grant P30EY014801, a Research to Prevent Blindness Unrestricted Grant (GR004596) to Bascom Palmer Eye Institute, Department of Veterans Affairs, Veterans Health Administration, Office of Research and Development, Clinical Sciences R&D (CSRD) I01 CX002015 (Dr. Galor), Biomedical Laboratory R&D (BLRD) Service I01 BX004893 (Dr. Galor), Department of Defense Gulf War Illness Research Program (GWIRP) W81XWH-20-1-0579 (Dr. Galor) and Vision Research Program (VRP) W81XWH-20-1-0820 (Dr. Galor), and National Eye Institute R01EY026174 (Dr. Galor) and R61EY032468 (Dr. Galor). The content is solely the responsibility of the authors and does not necessarily represent the official views of any funding organization.

Conflict of Interest

David Valdés-Arias, Elyana V.T. Locatelli, Paula A. Sepulveda-Beltran, Simran Mangwani-Mordani, Juan Carlos Navia, and Anat Galor declare that they have no conflicts of interest that might be relevant to the contents of this article.

Ethics Approval

Not applicable.

Data Availability

Not applicable.

Code Availability

Not applicable.

Author Contributions

DVA designed the study, performed the literature search and data analysis, and drafted and critically revised the paper. EVTL and PASB performed the literature search and data analysis, and drafted and critically revised the paper. SMM and JCN designed the figure. AG conceptualized and designed the study, performed the literature search and data analysis, and drafted and critically revised the paper.

Not applicable.

Open Access This article is licensed under a Creative Commons Attribution-NonCommercial 4.0 International License, which permits any non-commercial use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by-nc/4.0/.

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Titel: Recent United States Developments in the Pharmacological Treatment of Dry Eye Disease
verfasst von: David Valdés-Arias
Elyana V. T. Locatelli
Paula A. Sepulveda-Beltran
Simran Mangwani-Mordani
Juan Carlos Navia
Anat Galor
Publikationsdatum: 23.04.2024
Verlag: Springer International Publishing
Erschienen in: Drugs
Print ISSN: 0012-6667
Elektronische ISSN: 1179-1950
DOI: https://doi.org/10.1007/s40265-024-02031-6

Live-Webinar "Urologie und Sexualmedizin in der Praxis"

Springer Medizin

Abstract

1 Introduction

2 Methods

3 Dry Eye Disease Sources

3.1 Inflammation

3.1.1 Vevye (Harrow Health, Inc. and Novaliq GmbH)

3.1.2 Reproxalap (Aldeyra Therapeutics, Inc.)

3.1.3 Thymosin β4 (RegeneRx Biopharmaceuticals, Inc. and HLB Therapeutics Co. Ltd)

3.1.4 Licaminlimab (Oculis Holding AG)

3.1.5 Tanfanercept (HanAll Biopharma Co. Ltd)

3.1.6 SkQ1 (Essex Bio-Technology Ltd)

3.1.7 Summary

3.2 Eyelid Abnormalities: Demodex Blepharitis and Meibomian Gland Dysfunction

3.2.1 Lotilaner (Xdemvy, Tarsus Pharmaceuticals, Inc.)

3.2.2 Perfluorohexyloctane (Meibo, Bausch + Lomb Corp.)

3.2.3 AZR-MD-001 (Azura Ophthalmics, Pty Ltd)

3.2.4 Summary

3.3 Neuropathic

3.3.1 AR-15512 (Alcon Laboratories, Inc.)

3.3.2 Tivanisiran (Sylentis, S.A.)

3.3.3 Summary

3.4 Neurotrophic Keratitis

3.4.1 Cenegermin (Dompé farmaceutici S.p.A.)

3.4.2 Topical Insulin

3.4.3 Summary

4 Conclusion

Acknowledgements

Declarations

Funding

Conflict of Interest

Ethics Approval

Informed Consent

Data Availability

Code Availability

Author Contributions

Consent to participate

Consent for publication

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