Dry eye intranasal spray stimulates the trigeminal nerves

August 17, 2020

Novel route of administration and mechanism of action promotes tear film homeostasis

OC-01, a selectove nicotinic acetylcholine receptor (nAChR) agonist, is being developed to treat the signs and symptoms of dry eye disease. The parasympathetic nervous system, commonly referred to as the “rest and digest” system, controls tear film homeostasis partially via the trigeminal nerve, accessible within the nose. This novel treatment uses the parasympathetic nervous system to promote natural tear film production and restore tear film homeostasis.

An estimated 34 million adults in the United States have dry eye disease1—a chronic, progressive, and multifactorial condition that requires comprehensive treatment. In the last 15 years, eyecare practitioners have continued to hone their ability to diagnose and characterize dry eye. Treatments have expanded beyond palliative options to include nutritional guidance and supplements, topical and oral prescription medications, and in-office procedures.

A new potential development for patients, OC-01 intranasal spray (varenicline, Oyster Point Pharma), is one step closer to becoming a viable option as the company looks to file a new drug application (NDA) in the second half of this year. OC-01 is a highly selective nicotinic acetylcholine receptor (nAChR) agonist that activates the trigeminal nerve in the nasal cavity to stimulate natural tear film production. If approved, OC-01 would be the first dry eye treatment to achieve improvement in signs and symptoms in the same clinical trial, in addition to achieving primary and secondary endpoints.

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Activating the trigeminal nerve

In dry eye disease, the loss of tear film homeostasis triggers a vicious cycle that involves inflammation and cellular damage as both sequellae of disease as well as primary components contributing to progression, which in turn leads to further tear film destabilization. Among current medications for dry eye disease, most focus on modulating the inflammatory part of the cycle, reducing inflammation to promote better tear film production.

However, if the eye could produce a healthy natural tear film that is not compromised by inflammation and cell damage, ocular surface health could be more easily maintained. The tear film’s natural composition includes not only the muco-aqueous and lipid layers but also a complex mixture of more than 1,500 different proteins, nerve, and epidermal growth factors for healing, and anti-inflammatory and antimicrobial components. 2,3 There is no substitute for natural tears and a healthy, natural tear film, both of which protect and lubricate the eye, improving ocular comfort and helping to maintain consistently clear vision.

The goal of OC-01 treatment is to restore tear film homeostasis, preventing the vicious cycle of dry eye disease from the beginning or continuing by stimulating the eye to produce more natural, healthy tears. The trigeminal nerve was chosen as the mechanism for this process because this large cranial nerve which transmits sensation from the nose to the brain is one of the critical sentinel structures to regulate basal tear production.

In a study conducted by the Pfugfelder laboratory at Baylor School of Medicine, it was shown that anesthetizing the nasal mucosa resulted in a 34 percent reduction in basal tear film production, implicating this pathway in both acute and resting tear production.4,5 The sensory input is conducted through the trigeminal nerve via the nasal cavity, stimulating this nerve pathway to innervate goblet cells, meibomian glands, and the lacrimal gland, all of which triggers the production of natural, complete tears.3,6

Related: 5 essential truths to treating dry eye disease

The trigeminal nerve’s ophthalmic zone extends over the eyes and forehead and down the bridge and tip of the nose via the nasociliary branch, making nasal access most expedient. Delivered in a preservative-free nasal spray, OC-01 stimulates the nerve to release transmitters, which in turn trigger the physiologic function of natural tear production.

In addition to approaching dry eye disease from a different underlying mechanism, pharmacologic nasal spray stimulation of the trigeminal nerve presents an interesting delivery method from a practical standpoint. It may be beneficial for patients who have difficulty using eye drops because of contact lens use, aesthetics, ocular discomfort, or preservative toxicity. Furthermore, patients who use eye drops for other conditions, such as for glaucoma, often don’t want to add yet another eyedrop to their regimen.

Note that Allergan has ceased production of its neurostimulation device TrueTear.

Phase 3 data

The recently concluded Phase 3 study of OC-01, called the ONSET-2 trial, has yielded positive results.7 Among a study population of 758 subjects at 22 centers in the U.S., subjects using OC-01 nasal spray twice a day for 4 weeks showed statistically significant improvements in dry eye signs and symptoms. What’s more, the improvements were demonstrated in patients with all stages of dry eye disease—mild, moderate, and severe.

Related: Consider the role of corneal nerves in dry eye disease

The baseline criteria for dry eye diagnosis was a Schirmer’s score 10 mm and an Ocular Surface Disease Index (OSDI)23. Subjects could have an eye dryness score (EDS) ranging from 0 to 100. Using the National Eye Institute Scale, corneal fluorescein staining was rated 0 to 3 for each of the eye’s five regions; subjects needed a baseline score 2 in at least one corneal region or a total for all regions 4.

Subjects ranged in age from 22 to 95 years with a mean age of 58.8. Women were 76 percent of the subjects. The racial breakdown was 83.1 percent white, 12 percent black or African American, 3 percent Asian, and 1.2 percent Native American or Alaskan. About 13 percent were of Latinx ethnicity. The mean baseline Schirmer’s test with anesthesia was 5.1 mm. The mean baseline EDS was 58.6 mm.

The multicenter, randomized, double-masked, vehicle-controlled clinical trial evaluated 2 treatment arms—1.2 mg/ml and 0.6 mg/ml concentrations— compared to vehicle (n=246, 260, 252, respectively). Schirmer’s score improvement at 4 weeks was selected as the primary endpoint. Secondary endpoints included mean change in Schirmer’s score at 4 weeks, visual analog EDS in both controlled adverse environment (CAE) chamber and clinic at 4 weeks, mean changes in EDS at 1 and 2 weeks, and the mean change in inferior corneal staining score at 4 weeks.

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Schirmer’s score improvement: The primary endpoint of gaining >10 mm was achieved by 44 percent of patients receiving the 0.6 mg/ ml dose of OC-01 and 47 percent of patients using 1.2 mg/ml, compared to 26 percent of patients in the control group. For the secondary endpoint of mean change in Schirmer’s score at 4 weeks, the 0.6 mg/ml dose group was 11.0 mm, the 1.2 mg/ml dose group was 11.2 mm, and the control group was 5.9 mm.

Visual analog EDS: Mean changes in EDS were statistically significant compared to control for the 0.6 mg/ml dose group at Week 2, although not at Week 4 with the observed data (with imputation for missing data, the 0.6 mg/ml dose is statistically significant), and was statistically significant for the 1.2 mg/ml dose group at Week 2 and Week 4. Neither group reported significant EDS improvement in the controlled adverse environment (CAE) chamber, a metric that was difficult to acquire because many patients did not meet the health criteria for CAE.

Corneal staining: At 4 weeks, the inferior fluorescein corneal staining scores favored OC-01 but were not significantly better for OC-01 compared to control. During ONSET-2, no serious adverse events were reported. The most common side effect was transient sneezing, which patients experienced in about half of the administrations, mostly within 1 minute of use. Of study patients using OC-01, 9 (1.7 percent) stopped the study because of treatment- emergent adverse events related to the drug.

Related: Lactoferrin levels can diagnose dry eye disease

Potential addition to toolkit

If approved, OC-01 could help a broad range of dry eye patients. It would also provide ODs with a novel tool that stimulates the trigeminal nerve to trigger production of more natural tears—a distinctive mechanism of action and delivery method that is complementary to our current arsenal of dry eye therapies.

References

1. Paulsen AJ, Cruickshanks KJ, Fischer ME, Huang G-H, Klein BEK, Klein R, Dalton DS. Dry eye in the beaver dam offspring study: prevalence, risk factors, and health-related quality of life. Am J Ophthalmol. 2014 Apr;157(4):799-806.

2. Klenkler B, Sheardown H, Jones L. Growth factors in the tear film: role in tissue maintenance, wound healing, and ocular pathology. Ocul Surf. 2007 July;5(3):228-239.

3. Willcox MD, Argü eso P, Georgiev GA, Holopainen JM, Laurie GW, Millar TJ, Subbaraman LN, Uçakhan OO, Jones L. TFOS DEWS II tear film report. Ocul Surf. 2017 Jul;15(3):366-403.

4. Heigle TJ, Pflugfelder SC. Aqueous tear production in patients with neurotrophic keratitis. Cornea. 1996 Mar;15(2):135-138.

5. Gupta A, Heigle T, Pflugfelder SC. Nasolacrimal stimulation of aqueous tear production. Cornea. 1997 Nov;16(6):645-648.

6. Bron AJ, de Paiva CS, Chauhan SK, Bonini S, Gabison EE, Jain S, Knop E, Markoulli M, Ogawa Y, Perez V, Uchino Y, Yokoi N, Zoukhri D, Sullivan DA. TFOS DEWS II pathophysiology report. Ocul Surf. 2017 Jul;15(3):438-510.

7. Oyster Point Pharma press release. Oyster Point Pharma Announces Positive Results in ONSET-2 Phase 3 Trial of OC-01 Nasal Spray for the Treatment of the Signs and Symptoms of Dry Eye Disease. Available at: https://investors. oysterpointrx.com/news-releases/news-release-details/ oyster-point-pharma-announces-positive-results-onset-2- phase-3. Accessed 7/28/20.

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