Consistent with the rapid evolution of ophthalmic surgical technologies, 2022 promises to bring an explosive, meaningful introduction of new anterior segment ophthalmic pharmaceuticals to better help our patients. These range from treatment options for dry eye and myopia to infectious corneal ulceration. Below we outline novel medicines that have the potential for paradigm shifts in the management of anterior segment disease.
Cornea and ocular surface
Verkazia (cyclosporine A ophthalmic emulsion, 0.1%, Santen, Osaka Japan) was recently approved by the United States Federal Drug Administration (US FDA) for vernal keratoconjunctivitis (VKC) in both children and adults. VKC is a member of a group of diseases classified under “allergic conjunctivitis” and involves complex interactions between chemokines, adhesion molecules, and other inflammatory modulators. VKC can be difficult to treat and is characterized by chronic, bilateral inflammation of the conjunctiva, with associated ocular redness, mucus discharge, and giant papillae, which may erode the corneal surface and lead to ulceration (shield ulceration).
The formulation of Verkazia consists of a proprietary oil-in-water cationic emulsion, which provides improved ocular bioavailability of topical cyclosporine A compared to previous formulations.2 Cyclosporine A is a calcineurin inhibitor that functions by inhibiting the transcription of interleukin-2, thus inhibiting T-cell activation.3 A blunted T-cell response decreases the allergic inflammation that is present in patients suffering from VKC.
The FDA approval of Verkazia is based on data from the phase 3 VEKTIS study and the phase 2/3 NOVATIVE study. The VEKTIS study showed that cyclosporine A cationic emulsion was well-tolerated and improved keratitis symptomology in children with VKC.4 The NOVATIVE similarly found Verkazia to be safe and effective in children with VKC.5 Verkazia is a novel tool in the treatment of VKC and has the potential to be a first-line therapeutic for VKC.
Reproxalap ophthalmic solution is a small molecule reactive aldehyde species (RASP) inhibitor created by Aldeyra Therapeutics (Lexington, MA) to treat dry eye disease. RASPs constitute a group of molecules that covalently bind to amine and thiol groups on proteins and modify their function to potentiate inflammation through processes that involve the activation of NF-KB, inflammasomes, and Scavenger Receptor.6
To date, reproxalap has shown promising results in clinical trials. The phase 3 ALLEVIATE trial—a double-masked, randomized study—recently demonstrated that reproxalap reduced ocular itching score compared to vehicle acutely one hour following allergen challenge.7
In a longer-term randomized, double-masked, controlled, phase 2b trial, reproxalap decreased signs and symptoms of dry eye disease over 12-weeks of therapy versus vehicle.8 The phase 3 TRANQUILITY trial demonstrated a statistically significant decrease in ocular itching, ocular redness, ocular tearing, and ocular severity score in the reproxalap group compared to vehicle in patients with allergic conjunctivitis.9
Reproxalap has the potential to become the first-in-class therapeutic to treat dry eye disease and allergic conjunctivitis via RASP inhibition. Aldeyra plans to submit a New Drug Application with the FDA in late 2021 or early 2022.10
Tyrvaya (varenicline solution 0.03mg, Oyster Point Pharmaceuticals, Princeton NJ) nasal spray was recently approved by the US FDA for the treatment of dry eye disease (DED). Tyrvaya is the first and only nasal spray for the treatment of DED. Tyrvaya’s exact mechanism of action has not yet been fully elucidated; nonetheless, varenicline pharmacodynamics reveal it to be a potent partial agonist of the alpha2beta4 neuronal nicotine acetylcholine receptor.11
Tyrvaya is postulated to activate the trigeminal parasympathetic pathway, resulting in positive modulation of innervation to the lacrimal glands, Meibomian glands, and goblet cells. This process is thought to increase tear film production and thus reduce the signs and symptoms of DED.12
The safety and efficacy of Tyrvaya was studied in the ONSET-1, ONSET-2, and MYSTIC clinical trials with over 1000 patients enrolled with mild to severe DED.11-13 In these pivotal studies, Tyrvaya recipients had increased tear film production compared to controls. The most common adverse effect was sneezing (82%).13 Tyrvaya is available as of November 2021 and may prove to be especially helpful in patients who do not tolerate eyedrops due to manual dexterity difficulties, ocular surface aversion, and medicamentosa.
Polihexanide 0.08% is a monotherapy for treating Acanthamoeba keratitis, developed by SIFI SpA (Catania, Italy). Acanthamoeba keratitis is a rare, vision-threatening, notoriously difficult-to-treat, parasitic infection commonly associated with soft contact lens use and contaminated water sources.14
Polihexanide is an antiseptic polymer with dermatological and ophthalmological applications.14 It has antimicrobial effects and is used in contact solutions to inhibit fungal colonization.15 Polihexadine has also demonstrated a good tolerability and safety profile.16 Polihexanide 0.02% has been used to treat Acanthamoeba keratitis; however higher concentrations may be necessary to treat patients who have infections deeper in the corneal stroma.16
SIFI announced that it has recently completed a phase 3 trial on the use polihexanide 0.08% monotherapy for Acanthamoeba keratitis. The study achieved its primary endpoint of clinical resolution over a timeframe 12 months.15-17 SIFI plans to file for drug approval in Europe in early 2022.17 In the USA, the FDA has given polihexanide 0.08% an orphan drug designation.15-17 SIFI will soon initiate the regulatory process with the FDA.17 If successful, polihexanide 0.08% will be the first FDA-approved monotherapeutic topical drug for Acanthamoeba keratitis.18
The global pediatric myopia epidemic continues to worsen, and there are currently several studies looking into halting myopic disease progression.19 While myopia cannot be reversed, the ultimate treatment goal is to keep halt myopia disease progression as a means to mitigate the occurrence of vision-threatening complications from myopic degeneration (e.g., macular atrophy, staphyloma, choroidal neovasculrization, retinal detachment).19 Of specific interest is the use o low-dose atropine eye drops for the treatment of myopia described below.19
MicroPine (atropine ophthalmic solution, Eyenovia, New York, New York) is a microdose formulation of atropine currently under investigation for the treatment of progressive myopia in children.20 It is used with a proprietary Optejet drug delivery system.20 The Optejet is a handheld device that sprays medication to coat the eye at the push of a button.20 This novel drug delivery mechanism delivers a smaller 8 µL dose to the cornea, versus the standard drop of 40µl.20 This is intended to reduce drug waste and exposure to preservatives.20 The Optejet is also connected to Bluetooth, so medication adherence can be monitored electronically.20,21
MicroPine is currently undergoing the phase 3 CHAPERONE trial to determine the efficacy of microdosed atropine (0.01% and 0.1%) versus placebo for pediatric progressive myopia.20-22 The study is still recruiting participants and will follow them over the course of 36 months. The study’s primary outcome measure is the proportion of study eyes that show less than a 0.5 diopter spherical equivalent of myopic progression compared with baseline. The study is scheduled for completion in 2025.20-22
The novel pharmaceuticals discussed above have the potential to significantly alter the management of major anterior segment diseases with the hopeful improvement in patient outcomes. Eyecare professionals can look forward to the evolution of treatment algorithms based on the potential afforded by these upcoming therapeutics.
- Bonini S, Coassin M, Aronni S, Lambiase A. Vernal Keratoconjunctivitis. Eye. 2004;18: 345-351
- FDA approves Verkazia for vernal keratoconjunctivitis. Healio Ophthalmology. Published 2021. https://www.healio.com/news/ophthalmology/20210624/fda-approves-verkazia-for-vernal-keratoconjunctivitis
- Cohen DJ, Loertscher R, Rubin MF, Tilney NL, Carpenter CB, Strom TB. Cyclosporine: A new immunosuppressive agent for organ transplantation. Ann Intern Med. 1984;101(5):667-682. doi:10.7326/0003-4819-101-5-667
- Leonardi A, Doan S, Amrane M, et al. A Randomized, Controlled Trial of Cyclosporine A Cationic Emulsion in Pediatric Vernal Keratoconjunctivitis: The VEKTIS Study. Ophthalmology. 2019;126(5):671-681. doi:10.1016/j.ophtha.2018.12.027
- Bremond-Gignac D, Pasquale A, Doan S, et al. Safety and Tolerability of Topical Cyclosporine A Cationic Emulsion in Patients With Active Severe Vernal Keratoconjunctivitis (VKC) in Pediatric Patients: Pooled Results of the NOVATIVE and VEKTIS Trials. Investigative Ophthalmology and Visual Science.
- Mandell KJ, Clark D, Chu DS, Foster CS, Sheppard J, Brady TC. Randomized Phase 2 Trial of Reproxalap, a Novel Reactive Aldehyde Species Inhibitor, in Patients with Noninfectious Anterior Uveitis: Model for Corticosteroid Replacement. J Ocul Pharmacol Ther. 2020;36(10):732-739. doi:10.1089/jop.2020.0056
- Clark D, Cavanagh B, Shields AL, Karpecki P, Sheppard J, Brady TC. Clinically Relevant Activity of the Novel RASP Inhibitor Reproxalap in Allergic Conjunctivitis: The Phase 3 ALLEVIATE Trial. Am J Ophthalmol. 2021;230:60-67. doi:10.1016/j.ajo.2021.04.023
- Clark D, Tauber J, Sheppard J, Brady TC. Early Onset and Broad Activity of Reproxalap in a Randomized, Double-Masked, Vehicle-Controlled Phase 2b Trial in Dry Eye Disease. Am J Ophthalmol. 2021;226:22-31. doi:10.1016/j.ajo.2021.01.011
- Reproxalap meets endpoints in phase 3 allergic conjunctivitis trial. Published online 2021. https://www.healio.com/news/ophthalmology/20210427/reproxalap-meets-endpoints-in-phase-3-allergic-conjunctivitis-trial
- Aldeyra Therapeutics Achieves Statistical Significance for Primary Endpoint and All Secondary Endpoints in Phase 3 INVIGORATE Clinical Trial of Reproxalap in Allergic Conjunctivitis. Published 2021. https://www.businesswire.com/news/home/20210427005379/en/Aldeyra-Therapeutics-Achieves-Statistical-Significance-for-Primary-Endpoint-and-All-Secondary-Endpoints-in-Phase-3-INVIGORATE-Clinical-Trial-of-Reproxalap-in-Allergic-Conjunctivitis
- Mihalak KB, Carroll FI, Luetje CW. Varenicline is a partial agonist at α4β2 and a full agonist at α7 neuronal nicotinic receptors. Mol Pharmacol. 2006;70(3):801-805. doi:10.1124/mol.106.025130
- Oyster Point Pharma Announces FDA Approval of TYRVAYATM (varenicline solution) Nasal Spray for the Treatment of the Signs and Symptoms of Dry Eye Disease. Published 2021. https://www.multivu.com/players/English/8955851-oyster-point-pharma-fda-approval-tyrvaya/
- Park B. Tyrvaya Nasal Spray Approved for Dry Eye Disease. Monthly Prescribing Reference. Published 2021. https://www.empr.com/home/news/tyrvaya-nasal-spray-approved-for-dry-eye-disease/
- Auran J, Starr M, Jakobiec F. Acanthamoeba Keratitis: A Review of the Literature. Cornea. 1987;6(1):2-26.
- Szkołuda P, Karpi TM. Polyhexanide (PHMB) – properties and applications in medicine. Eur J Biol Res. 2020;10(3):225-231. doi:10.5281/zenodo.3956819
- Papa V, van Der Meulen I, Rottey S, et al. Ocular safety of high doses Polyhexanide (PHMB) in healthy volunteers. Investigative Ophthalmology and Visual Science. Published 2017. https://iovs.arvojournals.org/article.aspx?articleid=2642044
- Acanthamoeba keratitis monotherapy meets endpoint in phase 3 study. Healio Ophthalmology. Published 2021. https://www.healio.com/news/ophthalmology/20211020/acanthamoeba-keratitis-monotherapy-meets-endpoint-in-phase-3-study
- SIFI Announces Positive Topline Results of the Pivotal Phase III Study of Polihexanide for the Treatment of Acanthamoeba Keratitis. Published 2021. https://www.prnewswire.com/news-releases/sifi-announces-positive-topline-results-of-the-pivotal-phase-iii-study-of-polihexanide-for-the-treatment-of-acanthamoeba-keratitis-301402496.html
- Porter D. Myopia Control in Children. American Academy of Ophthalmolgy. 2020. https://www.aao.org/eye-health/treatments/myopia-control-in-children
20. Eyenovia Pipeline: MicroPine (Myopia). https://eyenovia.com/pipeline/mydriasis/
21. Eyenovia Technology. https://eyenovia.com/technology/
22. Microdosed Atropine 0.1% and 0.01% Ophthalmic Solutions for Reduction of Pediatric Myopia Progression. https://clinicaltrials.gov/ct2/show/NCT03942419