Ophthalmology 360’s Editorial Board Member Marguerite McDonald, MD, of NYU and Tulane, gave an exciting look at the dry eye disease treatment pipeline.
Marguerite McDonald, MD, FACS:
The dry eye pipeline. We’re going to review quickly the mechanism of disease and then talk about some of the new things that have been developed for dry eye disease, very exciting stuff.
It’s really important to understand the mechanisms that drive chronic dry eye, and it’s really a vicious cycle. There’s tear film instability that leads to tear hyperosmolarity, that leads to apoptosis, programmed cell death, which leads to inflammation. This is actually shown as a cycle, but it’s really a downward spiral, to be honest. There are all sorts of internal and external factors that impact this cycle. Factors associated with dry eye disease include being a female, dry, drafty environment, high-altitude, pollution, prolonged screen exposure, that is a big one, and diet. Once again, you see the cycle that I just showed you.
However, at the heart of dry eye is inflammation. It is the key driver of the cycle of chronic dry eye disease. The self-perpetuating cycle of inflammation continuously drives chronic dry eye disease. You see there’s a trigger at the very top of the screen there, leading to inflammation, oxidative stress, which leads to reactive oxygen species and reactive aldehyde species, known as RASPs. These are the bad actors that influence the rest of the inflammatory cascade. As I mentioned, these are aldehydes, RASP, that can be triggered by oxidative stress and they are way upstream. They are upstream drivers of the whole dry eye inflammatory cascade.
RASP expression is associated with dry eye disease severity and myeloma and gland damage. Two of the most common RASPs are for 4-HNE and MDA. Here you see on the left, in controlled patients without dry eyes, there’s virtually no 4-HNE. Look at patients with dry eye disease, the difference is enormous and statistically significant. Same with MDA, the controls versus the patients with dry eye disease, statistically significant. If you look at meibomian lipid composition, the aldehyde to wax ester ratio increases with meibomian gland disease severity. You see, if you don’t have MGD in the blue column on the right graph, you have virtually no aldehyde to wax ester ratio. Mild to moderate MGD in the center in the caramel color, and then you see severe MGD. The worse your MGD, the more RASP expression.
The proposed mechanism of action for reproxalap, which is a new drug, it is being studied, it’s in the process of FDA approval, is that oxidative stress causes reactive aldehydes to form. That is exactly where reproxalap acts at the top of the cascade, as you see here.
In the FDA clinical trials, the FDA is very fond of the dry eye chamber, which is basically a little torture chamber for patients. They like it because patients sit in the chamber and the humidity, airflow, temperature are all completely controlled. All the patients are exposed to exactly the same conditions and they’re asked to do visual tasks as well. In a very short period of time, a great deal of information can be obtained.
With reproxalap, the drop, on day 1, four drops were given in the office. On day 2, one drop prior to the chamber, one drop 50 minutes after entry into the chamber. You see here in vehicle in gray, and then the reproxalap group, both groups are suffering. It is not fun to be in this chamber. Their ocular discomfort scores are going up, up, up, up, up. Then you see at 50 minutes, another drop is given, either a vehicle or reproxalap and the scores start to come down. But notice that the vehicle never really improves to baseline. The reproxalap group goes all the way to zero, to baseline. Zero ocular discomfort while they are still in the chamber under these dreadful conditions.
Now, this is not a dry eye chamber. This is reproxalap in a normal clinical trial over 12 weeks. They got 4 drops a day for weeks 1 to 4, two drops a day for weeks 5 to 12. You can see the huge difference in ocular dryness score in favor of reproxalap, and that was statistically significant. You see conjunctival hyperemia, and now this is back to the chamber at 90 minutes, and you see the enormous difference between reproxalap and vehicle, statistically and clinically significant in favor of less conjunctival hyperemia in the reproxalap group.
Now, the safety was studied in more than 1,600 patients. You see that treatment-emergent adverse events that led a patient to drop out occurred in 7% of the 12-week clinical trial patients who were on reproxalap and only 0.7% of the vehicle. In the chambered trials, only 0.5% of patients said that they wanted out in the reproxalap group, they wanted to get out of the chamber, zero in the vehicle group. There were no drug related treatment emergent serious adverse events in either the 12-week clinical trial or the chambered trials. That is well on its way, it’s not approved yet, it’s still in investigational, but we’re all very hopeful. It’s from a company called Aldeyra, and they are working in collaboration with AbbVie.
Another drug, acoltremon, an ophthalmic solution which was just FDA approved less than a month ago, is first-in-class for dry eye disease, a completely different category of drug. It’s a very novel topical drug and it stimulates the TRPM8 receptors. I’ll explain what those are. They are on the corneal nerve endings and they regulate basal tear production. There were two phase 3 clinical trials that led to the approval.
Tear secretion is coordinated by the lacrimal functional unit, the LFU. The afferent nerves bring stimulus from the corneal surface back to the trigeminal ganglion to the central nervous system. Then in the light green color, the efferent nerves send a signal back to the goblet cells, the meibomian glands and the lacrimal glands, and that’s how tears are produced.
There are corneal afferent neurons that have very pivotal roles in tear production. The one we are most interested in is the one on the bottom in the green. These are mechanonociceptors and polymodal nociceptors, those are the top 2 in pink and red. They respond to mechanical, chemical or thermal insults, they’re pretty extreme reaction and they produce instantaneous reflexive tears. If you get an eyelash in your eye, extreme heat from a blow dryer or whatever, this is the mechanism by which you get instantaneous reflexive tears. But at the bottom, the cold thermosensory neurons, they detect very small reductions in temperature associated with the interblink tear evaporation to produce basal tears. Believe it or not, between blinks, our eyeballs are cooling off.
On the left you see the cold thermoreceptor detects this very, very tiny change in temperature between blinks and that triggers the lacrimal functional unit to start producing more basal tears. On the right, the reflexive tear response is shown. This is a mechanism that responds to extreme temperature and irritation, as I said, and produces excessive tearing.
The TRPM8 receptors regulate basal tear production, as you see here. Cold hits the corneal surface and sets off the afferent and efferent neurons to produce more tears.
There were two clinical trials, as I mentioned, pivotal trials that led to the approval. Here you see, it’s the classic active versus its own vehicle, acoltremon versus vehicle. Patients were given either 1 of them twice a day on day 1, they were examined again on day 7, 14, 28, and day 90.
Acoltremon met the primary endpoint in both pivotal studies, rapid and consistently high rates of response through day 90. COMET-2 and COMET-3, you see acoltremon versus vehicle. In the proportion of subjects who achieved a 10 mm or greater increase from baseline and unanesthetized Schirmer’s scores on day 14, which is an insanely high bar to hit. We all know if your Schirmer’s gets 2 mm better, that might be enough to get you back into your contact lenses. But anyway, this is a pretty dramatic response to drug. On the right, the pooled analysis shows even at day 1, there was a statistically significant difference between active acoltremon and the vehicle. At every single time point, day 1, day 7, day 14, day 28, and day 90, there was a statistically huge, statistically significant, difference in favor of acoltremon.
Here you see, this is just spread out in greater detail here. Sustained all the way through day 90, there’s no tachyphylaxis, the effect of the drug does not wear off.
The SANDE scores, the psychometric testing, the reduction in misery, discomfort, was met in COMET-2 statistically significantly, and it was numerically greater in COMET-3 with acoltremon. Not quite statistically as significant, but a strong trend. The pooled analysis shows that by day 14, day 28, and day 90, there was a statistically significant difference when you pool COMET-2 and COMET-3, in favor of acoltremon.
Total corneal staining reduction, you see the same pattern in COMET-2 and 3 in the pooled analysis, a big statistically significant improvement in corneal staining reduction as early as 1 week and clinically and statistically significant change from baseline and total corneal staining. Conjunctival staining, same pattern, COMET-2, COMET-3 and pooled analysis, statistically significantly in favor of acoltremon as early as week 1 and sustained through the end of the study.
There was a 50% incidence of installation site burning and stinging. However, 98% of the subjects said it was mild; 86% said the sensation lasted 1 minute or less, 0.7% of the patients discontinued any COMET study due to burning or stinging. It’s very common, but very mild. As you can see, acoltremon led to rapid and sustained increase in tear production and it was very well tolerated.
Now, I’m going to mention a new punctal plug, it’s been out for about a year, a year and a half. We know there are classic punctal plugs that have been around forever, but they are problematic; 50% improvement in symptoms after you put in plugs, which is great, but about 40% of plugs are lost, 9% of patients experience epiphora, 10% require removal because of irritation from the plugs against the corneal surface. Canaliculitis can be found fairly commonly, actually, in 8% of patients. There are other issues like pyogenic granuloma, and this was according to a report from the AAO.
The ideal lacrimal occlusion device would be biocompatible, reversible, repeatable, safe, and have a low complication rate. There is Lacrifill, which is a cross-linked hyaluronic acid, and it comes in a pre-filled injector with enough gel to actually treat and occlude the lower and upper canaliculi. The cannula tip is placed in the inferior punctum and the syringe plunger is squeezed and the Lacrifill gel is inserted, and it flows through the punctum into the lacrimal sac. If you see the gel extruding from the upper punctum, you know that both the upper and lower puncta have been blocked.
This is just a little video, and it’s comfortable, the patient’s really experience no discomfort of any kind. There you see it.
If you compare Lacrifill to another intracanalicular hydrogel plug called Form Fit, you see that the results are very, very good. This was a non-inferiority study. Lacrifill definitely improved anesthetized Schirmer scores at both 3 months and 6 months. The ocular surface disease index, the psychometric test, was very, very favorable for Lacrifill and not inferior to Form Fit. Same with corneal fluorescein staining, statistically significant differences.
The DEWS III report from TFOS recently came out in June of 2025, and they said, “The study concluded that the cross-linked hyaluronic acid filler is a safe, well-tolerated, and effective method to treat dry eye disease by canalicular occlusion. Clinically and statistically significant improvements in signs and symptoms of dry eye were sustained through 6 months.” It does eventually dissolve, but it lasts at least 6 months.
Now, chronic epithelial defects are very common in severe dry eye and amniotic membranes are often used. There is a relatively new one that has 3 layers of amniotic membrane, and this is a natural stimulus for the orderly release of growth factors and cytokines as the cells attach to it. It’s very easy to handle because it’s 3 times as thick as a normal amniotic membrane. In a study of severe dry eye patients, if you look at post-procedure best corrected vision in patients who had an initial best corrected less than 20/25, as you see these 16 patients, they all had a dramatic improvement in best corrected vision after the Biovance 3L amniotic membrane from Versea.
Ocubio is a new company, which is an offshoot from a team at Bascom Palmer, and they are providing qualified autologous serum eye drops. We all know autologous serum eye drops are great for dry eye but they are an enormous hassle. Finding a place to do it, a licensed laboratory that will do it under sterile conditions. As a matter of fact, these drops are produced under FDA-registered blood center supervision. The concentrations are 20% or 50%, and there’s some great things about it. First, the blood can be drawn at Quest Diagnostics, which are, there are thousands of them across the country, or the company will send a licensed phlebotomist to the patient’s home to draw the blood. It is shipped to the company, they process it, and the eye drops can be stored frozen for up to 6 months. Patients use a bottle a week at room temperature or chilled. The enormous advantage of being able to take highly purified autologous serum eye drops that do not require refrigeration, this is huge.
There is the BrightMEM. It is a novel corneal allograft that promotes re-epithelialization of the corneal epithelium. It’s a completely, completely new way to treat impaired corneal healing, including severe dry eye. It requires the placement of minimally manipulated donor corneal tissue. It’s actually made from Descemet’s membrane, so we’re taking tissue from the back of the eye to help the front of the eye. It’s a new foundation for the ocular surface, capable of supporting native limbal epithelial stem cells. It’s not investigational. You can get it through a company called Brightstar Therapeutics. It’s also distributed by their partner eye banks. There’s a surgical procedure code that you see here for anterior lamellar keratoplasty.
It’s used in many indications. Here in particular, we’re talking about chronic epitheliopathy, severe dry eyes, diabetes, contact lens overuse. It’s clear, it’s collagenase resistant, it protects against stromal melting. Turns out, the anterior Descemet’s membrane resembles limbal basement membrane.
Here’s the procedure. It’s called BMAK. Here’s the graft pre-trephination. There’s a superficial keratectomy, the second picture on the top row, that the surgeon performs. The punched button is placed on the cornea. The end of the top row, the fluid is wicked away from the interface. First picture on the bottom row, removal of the stromal button, leaving only Descemet’s. You smooth and dry the graft, put a little fiber and glue at the edges, and here you see an eye with the contact lens in place, post-op.
It’s been enormously helpful. Over 250 BMAK procedures have been performed for a variety of indications by over 90 surgeons. The percent that were fully healed is 91.6%. Takes a little time, mean time to healed is 34.5 days. However, percent healed if over 6 months, 98%. Enormously, enormously successful. It’s optically clear and it is a wonderful new addition to our armamentarium for severe dry eye.
There you have it. Thank you for your attention.
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