EXTENDED EDITION
Cornea
November 2021
by Liz Hillman
Editorial Co-Director
It’s not the first time the trigeminal nerve pathway or even intranasal delivery received approval as a treatment for dry eye, but clinicians are excited nonetheless about the October 2021 FDA approval of varenicline (TYRVAYA, Oyster Point Pharma), a nasal spray for the signs and symptoms of dry eye disease.
According to Oyster Point Pharma, the varenicline nasal spray is “believed to bind to cholinergic receptors to activate the trigeminal parasympathetic pathway, resulting in increased production of basal tear film as a treatment for dry eye disease.” The company shared that the mean change in Schirmer’s scores among patients treated with TYRVAYA vs. vehicle in the two clinical trials was 11.7 mm and 11.3 mm and 3.2 mm and 6.3 mm, respectively.
It might be the first and only nasal spray approved for this indication, but preceding it was a similar concept with a different mode of action. TrueTear, which was pulled from the market by Allergan in 2020 just 2 years after its launch, also operated based on stimulation of the trigeminal nerve pathway to increase production of a complete tear film. TrueTear, however, was an intranasal neurostimulator, which used randomly generated micro-electrical impulses to drive the reaction. Vincent de Luise, MD, also mentioned the iTEAR device (Olympic Ophthalmics), still on the market, which stimulates the nasal nerve externally to increase tear production.
Anat Galor, MD, said she thinks there is a place for TYRVAYA in the dry eye space.
“It’s such a big market, I do think there is space for everyone,” she said, noting that there is a subset of patients who might find intranasal delivery of therapy beneficial, such as those who have difficulty with drops (administering them or the topical effects).
“There are people who are sensitive to eye drops; … they find it attractive to have tearing without the local site reaction,” she said.
“We know there is a trigeminal pathway that can activate a tearing response from stimulation of the anterior ethmoidal nerve in the nose. It’s obvious; we saw a rapidly increasing tear lake,” she continued.
John Sheppard, MD, said the trigeminal nerve stimulation pathway is familiar to him, working on development of TrueTear with Allergan.
“It worked beautifully,” he said, providing full stimulation of the lacrimal functional unit, which produced real tears with natural proportions of oil, mucin, aqueous, proteins, and other beneficial components.
Targeting this pathway with TrueTear had its challenges though, such as patient acceptance, lack of insurance coverage, and a significant cohort of patients who didn’t like the tingling sensation the device caused, Dr. Sheppard said. Thus, despite what Dr. Sheppard called “tremendous intellectual investment, large amounts of investigational time, and magnificent short- and long-term results,” this neurostimulation approach was not a commercial success.
It, however, established the viability of afferent trigeminal stimulation for varenicline.
Dr. Sheppard called the results from the Phase 3 clinical trial exciting, noting that it produced excellent sign and symptom improvements and is thought to produce a classic physiologic tripartite tear film. Dr. Sheppard also said a significant subset of patients who don’t like drops or who have issues with drop delivery, tremors, arthritis, poor depth perception, those who are already on other drops, or who don’t want to use drops for aesthetic purposes will accept intranasal delivery. He said patients are familiar with nasal sprays, such as those for allergies, which may increase acceptance as well.
Dr. Sheppard described TYRVAYA as not only a novel pathway but a novel delivery system. “It’s dually innovative in this regard,” he said.
Other novel pathways in the pipeline
While targeting the production of natural tears for dry eye through the trigeminal pathway is novel, there are other pharmaceuticals in development that are targeting unique pathways and/or specific indications as well. The following is not an exhaustive list.
Tavilermide (Mimetogen Pharmaceuticals, Allergan): This is, according to Dr. de Luise, a first-in-class nerve growth factor mimetic that has been shown to stimulate production of goblet cells. Tavilermide has completed enrollment for its randomized, double-masked, placebo-controlled Phase 3 trial evaluating two concentrations.
NOV03 (perfluorohexyloctane, Novaliq): Dr. de Luise said this novel topical semi-fluorinated alkane is being developed to specifically treat dry eye associated with MGD, preventing excessive tear evaporation and potentially restoring tear film balance. Based on the clinical development progress for NOV-03, Novaliq expects to file a New Drug Application (NDA) to the FDA in 2022.
CyclASol (cyclosporine, Novaliq): While cyclosporine formulations are not unique for dry eye treatments, this formulation is designed to increase time on the ocular surface by using a smaller, more physiologic droplet size profile, Dr. de Luise said. Unfortunately, the results of its second Phase 3 trial symptom scores did not reach significance.
Reproxalap (Aldeyra): This reactive aldehyde species inhibitor is being evaluated for inflammatory ocular surface diseases. It is currently in Phase 3 randomized placebo-controlled multicenter trials. Dr. Sheppard said this compound has a steroid-like effect without the steroid side effects. He thinks it “will be a real game changer for us since reproxalap appears to be effective for both allergy and dry eye patients.”
RGN-259 (thymosin beta 4, ReGenTree): This drop is intended to target dry eye and neurotrophic keratopathy as a synthetic copy of a naturally occurring 43-amino acid peptide, according to Dr. de Luise. It promotes corneal epithelial cell migration, reduces inflammation and apoptosis, and accelerates regeneration and repair, he said, adding that it’s being developed as a single unit dose. It is in Phase 3 trials.
SkQ1 (Mitotech): As a “free-radical scavenger,” Dr. de Luise described this compound as targeting oxidative stress that is associated with inflammatory dry eye. It is in Phase 3 trials.
OCS-02 (Oculis): This anti-TNF alpha antibody fragment formulation could become among the first topical biologics for dry eye disease and anterior uveitis, if approved. The company has completed two proof-of-concept Phase 2 trials.
With many different drugs in development, targeting different pathways and indications related to dry eye, Dr. Galor said the needs are complimentary.
“One need is to have better anti-inflammatory agents. It’s been a big deal with instillation site reaction especially for cyclosporine, so having one that doesn’t have that profile is exciting, and that’s the target that Novaliq is going for,” she said. “There are other compounds that I have been following. Novartis is developing a TRPV1 antagonist, targeting corneal nerves. … It’s aiming for ‘Can I make some of the pain go away?’ in patients who have inappropriate pain or neuropathic pain.
“The important thing to remember is that dry eye is an umbrella term, and it’s a constellation of signs and symptoms; no one product is going to take the entire constellation of dry eye,” she said. “The idea is to try to individualize therapy and figure out what approaches make sense based on what factors are contributing to the disease. I think that’s where the field is going. Having these newer products is going to help us do that.”
Dr. Sheppard said that “it’s really in the marketplace where we find out whether these drugs are truly approved in the court of patient acceptance. The FDA data tells you a lot, but post-approval clinical prescription data and growth of market share is proof in the pudding.” In general, with so much diversity in terms of target mechanisms in dry eye, he said it will be good for patients to have more choices in dry eye drugs and delivery strategies.
“There are probably 50 drugs somewhere in pipeline for dry eye, and at most 5% make it to the marketplace,” Dr. Sheppard said. “This is a huge commitment by scientists, clinicians, pharmaceutical corporations, and investors. Nevertheless, we have a growing demographic of dry eye patients who need a variety of approaches, so this is quite a worthwhile effort.”
About the physicians
Anat Galor, MD, MPSH
Assistant Professor of Clinical Ophthalmology
Bascom Palmer Eye Institute
Miami, Florida
John Sheppard, MD, MMSc, FACS
President
Virginia Eye Consultants
Norfolk, Virginia
Vincent de Luise, MD
Assistant Clinical Professor of Ophthalmology
Yale University School of Medicine
New Haven, Connecticut
Relevant disclosures
de Luise: None
Galor: Oyster Point Pharma, Novartis, Novaliq, Oculis, Tarsus
Sheppard: Aldeyra, Allergan, Mimetogen Pharmaceuticals, Mitotech, Novaliq, Olympic Ophthalmics, Oyster Point Pharma, ReGenTree
Contact
de Luise: vdeluisemd@gmail.com
Galor: AGalor@med.miami.edu
Sheppard: jsheppard@cvphealth.com
