Dry eye treatment entering ‘age of abundance’
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A long time ago, in a galaxy far, far away, DED diagnosis and treatment was a spartan affair undertaken by a tiny cadre of Jedi doctors who were pitied by their doctor brothers and sisters if they, and their quest, were acknowledged at all.
Actually, it was 2008 or so in Cleveland, but the whole “galaxy far, far away” thing makes for a much better lede. Still, as fanciful as that may be, it does describe the state of dry eye disease care when people actually started to talk about it. As barren as the DED landscape was in the late aughts, if you go back to the ’80s and ’90s, it is almost like studying those ancient tribes that were cut off from all contact with the developing world; we were cut off from “modern” medicine. These were the times when a DED doc could only direct patients to the pharmacy to buy one of the look-alike, do-nothing tear products on the shelves.
I have described my peers in the early days DED community as the red-haired stepchildren of ophthalmology, alone in a corner of the professional village telling anyone who would listen that DED was real and needed to be treated. What must it have been like for the real pioneers of our subspecialty before folks such as Mark Milner, Marguerite McDonald and I came around? It is astonishing to think about what it must have been like for Mike Lemp who talked about tear osmolarity and its primacy in the process of DED. Or Hank Perry, who published on Demodex and meibomian gland dysfunction (MGD) in the days when “best practice” in blepharitis treatment was insisting on Johnson’s Baby Shampoo and not a generic. Ken Kenyon mused about the commonality in the pathophysiology of DED and other more severe inflammatory diseases such as graft-versus-host disease, anticipating the epiphany that inflammation is the defining element in DED.
Thank heavens they did not despair and abandon their inquiries.
Our landscape is so much different now. Even the over-the-counter artificial tear market is a veritable cornucopia of good options broken down into classes (hypotonic, oil based, gel, etc). Heck, there is a real cutting-edge artificial tear that requires you to know the difference between osmolarity and osmolality (extracellular proteins that affect extracellular fluid movement), Freshkote from Eyevance Pharmaceuticals. Where once we had a single approved medication to treat chronic surface inflammation, Restasis (cyclosporine ophthalmic emulsion 0.05%, Allergan), the addition of Xiidra (lifitegrast ophthalmic solution 5%, Novartis) and Cequa (cyclosporine ophthalmic solution 0.09%, Sun Pharmaceutical) brings us to three immunomodulators. I have long been critical of how Lotemax (loteprednol etabonate ophthalmic suspension 0.5%, Bausch + Lomb) and its stablemates have been handled in the marketplace, so I am thankful that there are two steroids — Eysuvis (loteprednol etabonate ophthalmic suspension 0.25%, Kala Pharmaceuticals) and Flarex (fluorometholone acetate ophthalmic suspension 0.1%, Eyevance Pharmaceuticals) — that have the treatment of DED signs on their labels (and you can still use all of the Lotemax options, too).
And can I just say: in-office procedures! Wuuut? Even with all of the hullaballoo about insurance coverage, can anyone using these technologies envision a world in which we are not using thermal treatments with or without contiguous evacuation of the glands? Not me, man. Keep giving me more. And you know what? That is exactly what is happening in our world. From the spartan options of the ’80s and ’90s, we now live in an age of “more.” Just over the horizon there are even more treatments that are on the cusp of approval that will further expand our ability to treat all of the different types of pathology that we, and our patients, call “dry eye.” Let me highlight a few of the important new medications that are just around the corner.
Anti-inflammatory treatments continue to be a linchpin in our armamentarium. Some newcomers will be familiar. For example, Ocular Therapeutix has launched a trial using Dextenza (intracanalicular dexamethasone) to treat signs and symptoms of DED. Anyone using Dextenza for cataract surgery knows that this works; the trial will provide “on-label” support for prescribers seeking insurance coverage. Ocular Therapeutix is also launching a trial of an intracanalicular cyclosporine A (CsA) insert, another well-known and time-tested medication.
In the more traditional way we think about drug delivery, Novaliq is presently in phase 3 trials with its version of CsA. CyclASol is a water-free formulation of 0.1% CsA, which has shown a rapid onset of significant improvements in both signs and symptoms of DED. It has been well tolerated in trials. The newcomer in this space is reproxalap from Aldeyra Therapeutics. This is a novel RASP inhibitor that shows promise in treating inflammation in a manner that mimics that of steroids, but along a novel pathway. Reproxalap may treat the underlying inflammation of both DED and allergic conjunctivitis, something that would alleviate the challenge we all face in teasing apart these co-conspirators so often present at the same time (shout-out to Dr. John Sheppard for his writing on these).
Targeting the eyelids and the lid diseases that cause DED and other ocular surface inflammatory diseases is where the really cool stuff is happening, at least for me. We all know that evaporative DED driven largely by MGD and related entities constitutes the majority of DED in the U.S. At the moment, we do not have any treatments that are approved for this indication (AzaSite, azithromycin ophthalmic solution from Akorn, is only approved to treat bacterial conjunctivitis). This is about to change. Bausch + Lomb announced that its novel molecule NOV03 (perfluorohexyloctane) demonstrated a significant effect in reducing both symptoms and signs in its pivotal phase 3 trial. If approved, NOV03 will be the first direct MGD treatment available. Competition may come from Azura Ophthalmics and AZR-MD-001, which has been shown to improve tear breakup time, meibum secretion and quality. This medicine, now entering phase 2 trials, appears to promote the breakdown of disulfide bonds in keratin, stimulating meibum production (hat tip: Dr. Laura Periman).
I am most anxiously awaiting the arrival of TP-03, or whatever Tarsus Pharmaceuticals is planning on calling its groundbreaking treatment for Demodex infestation of the lash follicles. This incredibly common problem is a source of lid inflammation and resulting MGD. The phase 2b results show what adds up to essential wipeout of Demodex in the study subjects. Having seen these results, I immediately began having my DED and MGD patients look down at the slit lamp so that I could assess them for the presence of cylindrical dandruff, the pathognomonic sign for Demodex. I am taking names! If the phase 3 trials are as definitive as the phase 2, and there is no reason to expect otherwise, I will have a large list of patients lined up for treatment. This is as exciting today as it was when we were waiting for the arrival of Restasis, our first DED treatment.
We are about to enter an “age of abundance,” something that was inconceivable as recently as 2008. The red-haired stepchildren are now, in many ways, the coolest kids on the block. The force is strong within us, my fellow Jedi Knights.
- For more information:
- Darrell E. White, MD, can be reached at SkyVision Centers, 2237 Crocker Road, Suite 100, Westlake, OH 44145; email: dwhite@healio.com.
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