Back in 2003, with the release of an ophthalmic ciclosporine A emulsion (Restasis, then Allergan, now Abvie) in the United States, we saw the start of an exciting new era in the treatment and management of dry eye disease (DED).

Coming alongside reports of experts developing materials and methods to define, diagnose, and monitor the disease, this formulation was the first agent with a specific indication to manage signs of DED.

Ciclosporine A acts as a calcineurin inhibitor affecting T-cells, and its success in improving signs and symptoms highlighted the role of inflammation as part of the pathogenesis of DED.1Having long been used to modulate the immune response in other parts of the body during organ transplantation, its potential use for ophthalmic applications had now been demonstrated.2

Since ciclosporine A’s release to the market, numerous agents have reached clinical trials in the hopes of targeting the underlying causes of DED.

Lifitegrast ( Xiidra, Bausch and Lomb) became the second agent to reach commercialisation with a DED indication in the United States, which did not occur until 2016. Lifitegrast was notably designed from the ground up to be a drug for dry eye.3

In DED, lymphocytes migrating from blood cells to the ocular surface interact with inflamed cells, perpetuating further inflammation through the release of cytokines. Lifitegrast works by blocking this interaction between cells on the ocular surface. The immune cells lower the possibility and intensity of the inflammation signal being propagated on the ocular surface.3

To discover lifitegrast, researchers in the laboratory screened small molecules that were able to bind to the receptor on the ocular surface and outcompete the endogenous molecules found on inflammatory cells. In doing so, they identified a new class of drug molecule known as leukocyte functional antigen 1 (LFA-1) antagonists.3

NEW CICLOSPORINE A FORMULATIONS

Since the success of the original 0.05% ciclosporine product for dry eye, more variants have been developed with different concentrations or vehicles for further improvement.

Cequa (Sun Pharmaceuticals) is one. In contrast to the original emulsion on the market, it is notable for having both a higher concentration at 0.09%, as well as a nanomicellar formulation.4This combination is reported to significantly increase the bioavailability of the drug. 5Other ophthalmic ciclosporine formulations on the market include Ikervis (0.1%, Santen Pharmaceuticals) and Verkazia (0.1%, Santen Pharmaceuticals), with the latter indicated for vernal keratoconjunctivitis. 6

A new water-free formulation of ciclosporine, Vevye (0.1%, Novaliq GmbH, known as CyclASol during development) is currently reporting clinical trial data. As this formulation does not contain any water, it does not require any oils, surfactants, or lubricants to form a usable eye drop. Rather, the formulation uses perfluorobutylpentane as a liquid base.7This type of semi-fluorinated alkane has been reported to be able to solubilise highly hydrophobic drugs, such as ciclosporine, and is non-toxic to the ocular surface. It may even lead to greater bioavailability of the drug compared to other vehicles as it aids in passing the corneal epithelial barrier.8

Clinical trials of this formulation showed improvements in total corneal fluorescein and dryness scores on a visual analogue scale after use two times a day for 29 days, which is reportedly earlier than improvements seen with other formulations.7,9In the Phase 2 study to determine the optimum dose, this formulation was also shown to consistently reduce corneal and conjunctival staining compared with the vehicle alone, or with ciclosporine emulsion (Restasis). 10As more formulations using ciclosporine are released, further information from practising clinicians will hopefully provide insight into which formulation will be most suited for a particular patient, based on their history and presentation.

NOVEL ANTI-INFLAMMATORY TARGETS

Following the lead established by lifitegrast, several first-in-class molecules targeting other parts of the inflammatory cascade are now at various points of development and trial for DED management.

Reproxalap (Aldeyra Therapeutics) is a reactive aldehyde species (RASP) inhibitor.11 Reactive aldehyde species, such as malondialdehyde (MDA) and 4-hydroxy-2nonenal (HNE), are formed as part of the inflammatory cascade, and have been found to be increased in the tears of patients with DED. 12,13 Reproxalap works to competitively bind such species, preventing them from exerting effects on other immune cells and stopping the propagation of further inflammation.11

A Phase 2 trial has been completed and published on the tolerability of two solutions of reproxalap (0.1% and 0.5%) as well as a 0.5% lipid solution, although a vehicle only control arm was not conducted.11 Use of the solutions demonstrably reduced the amounts of MDA levels found in tears and improved symptoms, even within one week. 11 There were greater amounts of discomfort reported by patients using the higher 0.5% concentration solutions, regardless of whether it was a solution or lipid vehicle, prompting the researchers to suggest that the 0.1% solution should move forward, given that this lower concentration was still able to improve both Schirmer’s test and tear osmolarity scores. 11 Researchers have also found that 0.25% reproxalap has a better ocular discomfort score, has less impact on vision and has less incidences of poor taste when compared head-to-head against 5% lifitegrast.16

A transient receptor potential melastatin 8 (TRPM8) receptor agonist (AR-15512) has also been reported for its dry eye effects within the literature. TRPM8 receptors are responsible for detecting tear evaporation and thus stimulating tear production.17Acting as an agonist on these receptors, AR-15512 may induce more tear production, and may reduce discomfort symptoms through production of a cooling sensation on the ocular surface. 17A Phase 2 trial suggested that a 0.003% AR-15512 solution, used two times a day, was associated with an improvement in Schirmer scores, corneal staining, and symptoms within 14 days. 17Unfortunately, for the two co-primary endpoints of anaesthetised Schirmer score at day 28 and symptoms measured using a visual analogue scale, the AR-15512 solutions at different concentrations were not statistically significantly different from the vehicle control.17

Tanfanercept (HanAll BioPharma Co, HBM9036) is another new molecule in clinical trials to manage DED.18 Tumour necrosis factor (TNF) is an inflammatory signalling cytokine throughout the body, and agents to block the interaction of the molecule with its two receptors have been investigated. 18 Tanfanercept has been molecularly engineered to be similar to the TNF receptor 1, and so it can bind any TNF present and prevent its action on the ocular surface. A Phase 2 clinical trial reported results from its use, two times a day for eight weeks, in China. Although there was some evidence of improvement in measures, including inferior and total corneal staining score and Schirmer score, these results have been reported to be not statistically significant compared to the vehicle control. 18 Two other clinical trials with this agent are at various stages in the US.18

NASAL DELIVERY ROUTES IN DRY EYE DISEASE

Not only have researchers developed and investigated new agents in the treatment of dry eye, but also new routes of delivery. The intranasal route has recently been harnessed in commercially released products for dry eye, with the aim to stimulate the trigeminal nerve and parasympathetic pathway to increase aqueous tear production.

Two neurostimulation devices have been released to the market, improving metrics of dry eye such as Schirmer score and lissamine green staining.19The devices either deliver the electrical current stimulus intranasally (TruTear, Allergan) or extra-nasally (iTEAR, Olympic Ophthalmics), and require treatment durations of approximately 30 seconds each time.19

These devices are limited by the practicalities of their use, with users presenting hygiene concerns for the device placed within the nostrils, for example. Other potential complications, while minor, impact their usability and acceptability, such as headaches or dizziness in some proportion of the population, or irritation to the nose or surrounding tissue.19

Varenicline is a novel agent, which attempts to use the same pathways as the electrical nasal stimulation devices using a chemical agent. The drug is a nicotinic acetylcholine receptor antagonist.20 It can bind to numerous nicotinic acetylcholine receptors on neuronal cells and is thought to stimulate basal tear secretion through its activation on the trigeminal nerve within the nasal cavity. 20

Initially used as a smoking cessation aid in the form of an oral tablet, a varenicline nasal spray for the treatment of dry eye was released to the market (Tyrvaya, Oyster Point Pharma) in the United States in 2021.20 This preservative-free spray is intended to be used twice a day. Release of this formulation for DED was supported by multiple clinical trials, where dosages of 0.03mg or 0.06mg per spray compared with a placebo over a period of 28 days or over 12 weeks were investigated for their effects on Schirmer score. 21-23 The results showed that the spray was able to improve tear film production, as measured by the Schirmer score, and that this effect occurred generally within minutes of administration. Further, there was no evidence of a decrease in effectiveness over the course of time out to 12 weeks.23

One of the strongest arguments for treatment of DED through stimulation of nasal structures centres on the rate of ocular side effects and adverse events from other conventional treatments. Ocular irritation, discomfort, stinging or general dislike of using eye drops is a significant factor in participants adherence (or lack thereof ) with ocular eye drop therapy.

The most common adverse effect experienced by participants using the varenicline nasal spray, in contrast, has been sneezing, which occurred in over 80% of participants using the drug spray, compared with only 22% of participants in the placebo group.24 This sneezing symptom tended to occur relatively rapidly after spray instillation and was generally rated to be mild in severity. Additionally, it was not unexpected given the nasal branch of the trigeminal nerve was being stimulated.24

The second most common adverse event included cough or throat irritation, both of which occurred in less than 20% of participants in the drug arm compared with approximately 1% in the placebo arm.24

Importantly, the rates of ocular adverse events, which include reduced visual acuity, conjunctival hyperemia, eye irritation, and eye pain, were all low and less than 5% for participants receiving the active drug.24

Examination of the rates of treatment discontinuation, as part of the clinical trial, were also used by the authors to argue for the potential advantage of this mode of drug delivery. Across the three major treatment trials of varenicline, 93.5% of participants completed the trials, which compares favourably to the approximate 80% who completed the ciclosporine ophthalmic emulsion trials, and the 91% of participants who completed the lifitegrast ophthalmic solution trials.24

A second nicotinic acetylcholine receptor agonist, simpinicline, which has been used in gastrointestinal disorders, has also recently published data on its nasal delivery to help with stimulating basal tear secretion.25In a Phase 2 clinical trial testing various delivered doses of the drug nasally once a day (0.11 mg, 0.55 mg, or 1.1 mg), improvements in Schirmer scores and symptoms were found, often within five minutes of the spray being used. 25

Now, with literature to support the effect on dry eye of two nicotinic acetylcholine receptor agonist agents, this class of molecule delivered via the nasal route is gathering evidence as a viable means for dry eye treatment that warrants further study.25

NEW AGENT FOR MEIBOMIAN GLAND DYSFUNCTION

An agent recently approved by the US Food and Drug Administration (FDA) for the treatment of symptoms associated with meibomian gland dysfunction (MGD) is perfluorohexyloctane (Miebo, Bausch and Lomb). It is also available within Europe. Clinical trials conducted in the United States, Germany, and China have reported that when the agent was used four times a day, improvements in patient symptoms and total corneal fluorescein score in patients with evaporative dry eye disease were found.26-31

These studies have followed participants across eight weeks of treatment using a saline control group, and enrolled patients with evidence of dry eye symptoms, corneal staining, and MGD.27-29,31 The formulated drops consisted entirely of perfluorohexyloctane, with no additions of water. As such, there was no requirement to include any preservatives.30

The mechanism of action of the drug has not been fully elucidated. However, it is thought that the drug can spread rapidly over the ocular surface and prevent evaporation by localising to the air-tear interface and serving as an additional barrier.27

Some studies have also suggested that the agent may reduce corneal surface temperature sufficiently to stimulate tear production and blinking, without evoking enough of a sensation to be perceived as discomfort.32

Due to its amphipathic nature, perfluorohexyloctane is also able to dissolve lipids. This points to a potential role in dissolving and facilitating the removal of thickened meibum secretions on meibomian gland orifices and further stabilising the tear film lipids.26 However, while most of the human trials have reported on the ability of the agent to improve corneal surface damage and dry eye symptoms, most have not reported measures of tear film stability. 33 One study, which reported tear break-up time and meibomian gland score, did not show any significant change for either measure over the course of 57 days of treatment. This suggests the need for further investigation to understand the overall mechanism of action of these drops in patients with MGD.31,33

CONCLUSIONS

There are numerous agents at various stages of development and trials specifically targeting DED. New agents that can target parts of the inflammatory cascade, stabilise the tear film, or stimulate tear production have all been released to the market recently and highlight the avenues through which researchers and companies are aiming to tackle the condition.

There are also many other molecules, which have been announced by companies, and there are registered ongoing clinical trials that have not yet published in the peer-reviewed literature.

With all of this underway, it will be interesting to see how the dry eye therapeutic landscape changes over the near term. As more agents become available commercially, clinicians and patients will have an expanded repertoire of potential therapeutic options, and greater hopes for improving the signs and symptoms of patients with DED.

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