Neurostimulation, neuromodulation offer exciting new approaches for dry eye
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Artificial tears have long been the first option for patients with dry eye disease, but they only offer a partial solution.
Neurostimulation and neuromodulation of tears are newer ways to think about and address issues related to the ocular surface, according to Healio/OSN Board Member Laura M. Periman, MD.
Source: Marjan Farid, MD
“Neuromodulation is an exciting approach to dry eye that harkens to a part of the very definition of dry eye disease — that dry eye includes neurosensory compromise,” she said. “Up until just recently, we did not have the tools for addressing the neurosensory compromise of dry eye disease.”
The main target of these emerging therapies is the lacrimal functional unit, which can be leveraged to stimulate tear production.
“When it’s stimulated, it induces secretion of what we would call a complete tear,” OSN Cornea/External Disease Section Editor Preeya K. Gupta, MD, FACS, said. “It stimulates the lacrimal gland, the meibomian gland and the conjunctival goblet cells.”
This stimulation of natural, complete tears provides much more than artificial tears ever can, Gupta said.
“If you do a chemical analysis of our body’s natural tear, it includes things like antibodies, growth factors, and dozens of other proteins and immune molecules that help to repair the ocular surface,” she said. “The goal of a tear is not just to provide lubrication.”
While achieving these natural tears through neurostimulation is an optimal goal in dry eye treatment, the trigeminal nerve is often poorly understood, even by experts, according to Healio/OSN Board Member Darrell E. White, MD.
“My nickname for the trigeminal nerve, from a pain standpoint, is the ‘highway to hell,’” he said. “There are all kinds of terrible things that happen when the trigeminal nerve is either not working properly or when it’s in some way, shape or form angered by a disease process.”
White said that when treating the nerve, physicians need to understand that it is a two-way highway. It is a complex system that sends information between the eye and brainstem, carrying directions as to how the eye should respond to those signals.
“The connection between the lacrimal functional unit and the brainstem through the trigeminal nerve is always in play, unless you have some sort of process that cuts that connection,” White said. “If you have a neurotrophic cornea because you’ve had surgery and the nerves have been cut, for example, the eye is never going to be normal. You’re always going to be fighting some sort of battle because that line of communication has been cut.”
Although this is an extreme example, White said everyday function depends on a healthy connection between the eye and brain through the trigeminal nerve. That is the system at play in neurostimulation and neuromodulation of tears.
Therapies
The first device to leverage stimulation of the trigeminal nerve was TrueTear (Allergan). The intranasal mechanical device received FDA marketing authorization in 2017.
“Initially, there were some positive results, especially from a research standpoint,” Marjan Farid, MD, OSN Cornea/External Disease Board Member, said. “At first, there was some skepticism that it would only provide a reflex tear that wouldn’t provide real relief for ocular surface disease. But in fact, studies showed us that it really was a good quality tear with all of the components, including the lipid layer, the aqueous layer and the mucous layer.”
For a number of reasons, TrueTear failed to catch on, Gupta said.
“It was a device that you inserted into your nose and stimulated the ethmoidal nerve, which is in the front part of your nose,” she said. “It had some issues with placement and consistency. It relied on the patient to place it in the right spot to stimulate the nerve.”
Allergan ultimately discontinued TrueTear in 2020.
In 2022, Olympic Ophthalmics obtained FDA clearance for the second generation of its device for mechanical stimulation of a small peripheral branch of the trigeminal nerve, the iTear100, which is applied externally.
“It stimulates the trigeminal nerve just below the lacrimal sac by using vibrations that you can tune to different degrees of intensity,” White said. “You’re externally stimulating the trigeminal nerve in order to produce tears.”
In a study published in Translational Vision Science & Technology, researchers evaluated the efficacy and safety of the original iTear device, which was cleared by the FDA in 2020, in patients with dry eye disease. The open-label, single-arm study comprised 101 patients with a Schirmer’s score of 10 mm or less in at least one eye who applied the device at least twice a day for 30 seconds bilaterally. The primary endpoint was the Schirmer’s index, consisting of change from unstimulated to stimulated tear production as measured by Schirmer’s test, at day 30, and the secondary endpoint was change in dry eye disease symptoms at day 30 using the Ocular Surface Disease Index.
At day 30, the mean Schirmer’s index was 9.4 mm, while baseline OSDI improved by an average of 14.4.
Another therapy now available is Tyrvaya (varenicline solution, Oyster Point Pharma), the first approved pharmaceutical method to stimulate the trigeminal nerve.
“The thought was that perhaps the same parasympathetic pathway to stimulate the trigeminal nerve could be triggered chemically through the same nasal passage,” Farid said. “The nasal passage really accounts for a third of our basal secretion of tears. Just breathing through our nose is providing about 30% of tear secretion. With Tyrvaya, we’re able to stimulate that pathway through chemical stimulation of the trigeminal nerve. There’s really nothing else on the market that does that.”
At the 2021 American Academy of Ophthalmology meeting, Farid presented a study that explored the impact of Tyrvaya on signs and symptoms of dry eye disease; 758 patients with a Schirmer’s score of less than 10 mm received either 0.03 mg or 0.06 mg of Tyrvaya or a vehicle control twice daily for 28 days. The primary endpoint of the study was the percentage of patients with at least 10 mm change in Schirmer’s score from baseline.
At week 4 of the study, 47% of patients in the 0.03 mg group and 49% of patients in the 0.06 mg group met the primary endpoint compared with 28% of patients in the control group (both P < .001). The mean change in Schirmer’s score was 11.3 mm and 11.5 mm in each group, respectively.
Farid said the goal of treatment with Tyrvaya is to restore the homeostasis of the tear film by improving the patient’s own natural production of tears.
“Over time, you’re going to see an improvement in the tear film balance,” she said. “The downstream effects of tear film dysfunction and even the inflammatory cycle that happens downstream for patients with dry eye disease can be improved if homeostasis is restored. If you can reach these patients upstream, before they go into the inflammatory cycle, you can change the course of the disease by restoring that tear film balance.”
In her practice, Farid said she uses Tyrvaya in patients who present with dry eye symptoms and tear film dysfunction. This includes patients in an earlier dry eye state who are demonstrating rapid tear breakup time.
“My practice also includes a lot of severe patients who have tried a lot of different things, so I may even try Tyrvaya in the late stages of disease as well,” she said. “If at any point you restore that regular tear film activation, you can help. I’ve had so many patients that have been frustrated with previous therapies come back and say that nothing else works as well for them as this new therapy.”
For patients with mild to moderate dry eye, Gupta said Tyrvaya might be the only prescription medication needed for symptom relief. However, the spray can also be used as an adjunct to other traditional topical immunomodulator eye drops, such as cyclosporine or lifitegrast.
“We’re able to add another complementary mechanism to the treatment of the dryness,” Gupta said. “If someone is already on cyclosporine or lifitegrast, Tyrvaya is something that can be added and works on a different pathway. In my own clinical practice, it has shown synergistic effects.”
While the initial prescribing guidance left something to be desired, White said clinical experience has shown that Tyrvaya has benefits across a wide variety of patients.
“To whom should we be offering this drug? Is it a last-resort drug, or is it the kind of thing you could use as the very first thing a patient receives?” White said. “In our office, we played around with that, and we’re actually using it both ways. We use it in patients who still have symptoms despite being on three medications and undergoing intense pulsed light therapy, for example. We also started using it as the first treatment instead of putting people on over-the-counter artificial tears.”
White said it is possible that Tyrvaya has broader benefits relating to that basic information flow across the trigeminal nerve.
“It’s changing the nerve conduction, nerve impulses and nerve flow,” he said. “It’s difficult to show that and to prove that, but people are getting more relief than we would have expected when they use it as a first-line treatment.”
Farid said there has been some encouraging early evidence that triggering the trigeminal pathway may lead to improvements in corneal nerve health. Oyster Point, which has since been acquired by Viatris, initiated a trial exploring the efficacy of varenicline for the treatment of neurotrophic keratopathy in 2021.
“This is the same varenicline solution at a slightly different dose,” Farid said. “Essentially, you’re again triggering and restoring that homeostasis of the tear film regularly so you can improve corneal nerve health.”
Neuromodulation
While interventions such as Tyrvaya and iTear are specifically neurostimulation therapies, Periman said the next wave of innovation could come from treatments known as neuromodulators.
“Neuromodulation is where we can target specific receptors of the corneal nerves on the ocular surface to create an effect,” she said. “In the case of Aerie Pharmaceuticals' TRPM8 agonist, AR-15512, you are specifically stimulating that receptor.”
AR-15512 was the focus of a phase 2b study published in The Ocular Surface in which patients received 0.0014% AR-15512 (121 patients), 0.003% AR-15512 (122 patients) or vehicle (126 patients) twice daily for 12 weeks. Signs and symptoms of dry eye disease were assessed, including the primary endpoints of change from baseline in ocular discomfort and anesthetized Schirmer’s score at day 28.
Treatment with 0.003% AR-15512 was associated with early, sustained improvement in unanesthetized Schirmer’s score at day 1 and day 14, with patients demonstrating improvements in ocular surface staining and hyperemia. Additionally, there were improvements in dry eye symptom assessment, ocular discomfort, eye dryness and other quality of life measures.
In 2022, Aerie announced that the first participant had undergone dosing in the phase 3 COMET-3 study of AR-15512 for the treatment of dry eye disease. About 460 subjects, who will receive 0.003% AR-15512 or vehicle twice daily for 3 months, are expected to be enrolled in the study. The primary endpoint is tear production measured by unanesthetized Schirmer’s score. The company ultimately hopes to file a new drug application for AR-15512 with the FDA in 2024.
“The effect, at least in the phase 2 data, was immediate increased tear production,” Periman said. “TRPM8 stimulation also has a central nervous system mechanism that dampens pain signals for improved tear production and less pain.”
Periman said this is just one example of what is on the horizon.
“You’ll be able to orchestrate that neurosensory component of healthy homeostatic tear production with elegance and precision rather than waiting for inflammation to go down and hoping the system comes back online,” she said. “I think it will be a targeted, specific adjunctive approach that will be helpful for patients that don’t have sufficient relief with prior medications and strategies.”
White said the neuropathic connection between the ocular surface and the brain is likely to be fertile ground for research in the near future. Some of the currently available treatments have already shown benefits in corneal pain.
“Altering the information flow across the trigeminal nerve is a very promising area for research purposes,” he said. “We have had success with patients who had pure neurogenic pain where there was no relief given with topical anesthetic, but there was relief that was received through stimulation of the trigeminal nerve with TrueTear.”
In 2022, the National Eye Institute’s Anterior Segment Initiative Ocular Surface Innervation Consortium committed more than $50 million over 5 years to eight research projects to examine different aspects of corneal pain and sensation. Research areas include understanding neural control of the ocular surface and evaluating how ocular surface nerves and immune cells communicate to encourage neuro-immune homeostasis.
“These studies are looking at how these systems work, how communication works and how this highway of information going back and forth between the eye and the brain actually functions. Once we understand how it functions, then we can hopefully have a better understanding of what happens when it’s dysfunctional,” White said.
“We have a couple of things that are nibbling around the edges of this great unknown, but as a specialty, we’ve only just received acknowledgement from the National Eye Institute that this is a big deal,” he said. “I think they’ve identified the right people who can do the research and give us the basic science answers from which we should be able to leap forward.”
- References:
- Aerie Pharmaceuticals announces first participant dosed in the COMET-3 study of AR-15512 for the treatment of dry eye disease. https://investors.aeriepharma.com/news-releases/news-release-details/aerie-pharmaceuticals-announces-first-participant-dosed-comet-3. Published Aug. 1, 2022. Accessed Feb. 6, 2023.
- ASI Ocular Surface Consortium. https://www.nei.nih.gov/about/goals-and-accomplishments/nei-research-initiatives/anterior-segment-initiative/asi-ocular-surface-innervation-consortia. Updated Nov. 2, 2022. Accessed Feb. 6, 2023.
- Farid M, et al. ONSET-2 phase 3 trial of OC-01 (varenicline solution) nasal spray for the treatment of the signs and symptoms of dry eye disease. Presented at: American Academy of Ophthalmology meeting; Nov. 12-15, 2021; New Orleans.
- Ji MH, et al. Trans Vis Sci Tech. 2020:doi:10.1167/tvst.9.12.23.
- Olympic Ophthalmics announces FDA clearance and availability of its next-generation iTear100 neurostimulation device, expanded patent portfolio, and further clinical studies. https://www.globenewswire.com/en/news-release/2022/03/30/2412901/0/en/Olympic-Ophthalmics-Announces-FDA-Clearance-and-Availability-of-Its-Next-Generation-iTEAR100-Neurostimulation-Device-Expanded-Patent-Portfolio-and-Further-Clinical-Studies.html. Published March 30, 2022. Accessed Feb. 6, 2023.
- Oyster Point Pharma announces enrollment of first subject in the OLYMPIA phase 2 clinical trial of OC-01 (varenicline) nasal spray for patients with neurotrophic keratopathy. https://www.biospace.com/article/releases/oyster-point-pharma-announces-enrollment-of-first-subject-in-the-olympia-phase-2-clinical-trial-of-oc-01-varenicline-nasal-spray-for-patients-with-neurotrophic-keratopathy/. Published June 21, 2021. Accessed Feb. 6, 2023.
- Wirta DL, et al. Ocul Surf. 2022;doi:10.1016/j.jtos.2022.08.003.
- For more information:
- Marjan Farid, MD, of Gavin Herbert Eye Institute at the University of California, can be reached at mfarid@uci.edu.
- Preeya K. Gupta, MD, FACS, of Triangle Eye Associates in Cary, North Carolina, can be reached at preeyakgupta@gmail.com.
- Laura M. Periman, MD, of Periman Eye Institute in Seattle, can be reached at dryeyemaster@gmail.com.
- Darrell E. White, MD, of SkyVision Centers in Westlake, Ohio, can be reached at dwhite@healio.com.
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