Recently, there has been a resurgence in creativity in the approach to glaucoma. Not only have there been exciting developments in minimally invasive glaucoma surgery (MIGS) and laser treatment, but pharmaceutical management is also undergoing something of a renaissance with new medications and delivery mechanisms. One of the most promising areas of development in glaucoma therapeutics is the development of new drugs that act on episcleral venous pressure (EVP).
EVP helps to maintain the pressure differential that allows aqueous fluid to egress from the eye; it is a major component of intraocular pressure (IOP) and provides the “floor” below which IOP cannot be lowered. This floor is one of the reasons that glaucoma specialists see diminishing returns from adding second, third, or fourth IOP-lowering medication. It’s also one of the reasons it is so hard to successfully treat patients with normal-tension glaucoma (NTG). With IOP that is already relatively close to the EVP floor in NTG, these patients’ therapeutic window for lowering IOP is extremely narrow with the medications that are currently available.
It has long been recognized that EVP is pathologically elevated in certain forms of glaucoma, such as in pediatric patients with Sturge-Weber syndrome and patients with traumatic carotid-cavernous fistula where the arterial system leaks into the venous system within and behind the eye, raising the pressure. Most topical therapies just don’t work very well in these patients at all. But increasingly, researchers are beginning to suspect that even in patients with primary open-angle glaucoma (POAG), EVP may play a larger role than previously thought.1 Some patients may have a large EVP component to their glaucoma that makes it difficult to lower IOP as much as or as consistently as their doctor would like.
Rho kinase inhibitors were the first class of glaucoma drugs to have an indirect impact on EVP. These drugs primarily act on the conventional trabecular outflow facility, as do cholinergics like pilocarpine and carbachol. But unlike pilocarpine, the rho kinase inhibitor netarsudil (Rhopressa or Rocklatan; Alcon) has a significant IOP-lowering effect on some patients, including those with Sturge-Weber syndrome.2 It is possible that the IOP-lowering effect observed in the patients using rho kinase inhibitors, when other treatments have failed, may be attributable to EVP due to poorly draining or compressed episcleral venous system.
New Drug Targets EVP
A new drug, QLS-111 (Qlaris Bio), was developed to selectively target EVP. QLS-111 is an adenosine triphosphate (ATP)–sensitive potassium channel opener (KATP channels) that relaxes blood vessels within “physiologic” parameters to reduce EVP and therefore IOP. The formulation, which is preservative free, is gentler on the ocular surface. In 2 recently completed clinical trials, QLS-111 successfully met all primary and secondary endpoints.3 The Osprey study was a dose-ranging study in which 3 concentrations of QLS-111 were compared to vehicle control in various dosing regimens. The 0.015% concentration, dosed once daily in the evening, was determined to be most efficacious. In the Apteryx study, QLS-111’s additivity to latanoprost was tested in POAG or ocular hypertension (OHT) patients who were already stable on latanoprost. An additive reduction of 3.2 to 3.6 mmHg was reported in these patients, from a baseline mean IOP of 19.8 mmHg on latanoprost. No clinically relevant adverse events were reported, including no relevant hyperemia when dosed alone and no incremental hyperemia when added to latanoprost.
By lowering the floor for IOP, this new drug has potential to work synergistically with current IOP-lowering drugs, as well as with laser therapy and MIGS, to achieve better outcomes for POAG and OHT patients, for whom current therapies are nowhere near as predictable as physicians would like. It may also prove to be valuable as a first-approved therapy for patients with NTG and Sturge-Weber syndrome, where currently approved therapies are lacking.
It is important that early studies evaluated QLS-111 as an adjunct to latanoprost,3 the most prescribed glaucoma medication in the United States. The additive effects tell us that patients who are stable on a prostaglandin analogue can achieve an even lower target pressure with a complementary drug that acts on a different pathway. Understanding how these drugs work in combination—whether as 2 separate drops or potentially in a fixed combination—is important for clinical practice.
Finally, phase 2 studies have reported excellent safety and tolerability with QLS-111. While hyperemia isn’t sight threatening, it can have a negative impact on compliance. Additional drugs in our armamentarium with fewer side effects would be welcomed.
Other Innovations
Several companies are working to reduce the burden on patients of adhering to glaucoma medication regimens by developing other drug-delivery approaches. The Laser in Glaucoma and Ocular Hypertension (LiGHT) Trial4 and the 5-year Horizon trial5 have both recently demonstrated that patients maintained better visual field outcomes when the burden of topical administration has been reduced, even when IOP levels are the same. Although these studies evaluated laser and surgical approaches, they add to the evidence that reducing the number of topical drops needed—whether that reduction is achieved via laser, surgery, or more effective delivery of medications—could provide more consistent pressure reduction and minimize IOP fluctuations,6 thereby leading to better outcomes.
Glaucoma specialists already have the Durysta (AbbVie) and iDose TR (Glaukos) implants that release IOP-lowering medications slowly over time. Glaukos is working on a longer-lasting version of iDose,7 as well as transdermal delivery of glaucoma medications with iLution, currently in phase 2 trials. Mediprint Ophthalmics is developing a 3D-printed bimatoprost-eluting contact lens; the Spyglass IOL would deliver bimatoprost intraocularly for multiple years after cataract surgery.8 Other manufacturers are working on biodegradable implants that release IOP-lowering drugs.
Other innovations that are on the way include the introduction of more combination drops (which limit the number of bottles and instillations) and more preservative-free (PF) options for glaucoma therapy. Not only can PF versions of established glaucoma medications help patients who are allergic to many of the current drugs, but limiting surface toxicity is also beneficial for any patient who will be on chronic drops for this lifelong disease.
A long-term goal, and one for which research is still in the very early stages, is neuroprotection or neuro-regeneration. Just as in other neurodegenerative diseases like Parkinson’s or Alzheimer’s disease, the underlying problem in glaucoma is retinal ganglion cell death, not IOP. The goal would be to protect the optic nerve with a neuroprotective agent or repair it with a neuroregenerative agent, but these outcomes are much harder to study. The route to neuroprotection may come through a better understanding of genetics and epigenetics and the development of polygenetic risk scores and targeted gene therapies.
This is an exciting time in glaucoma. Identifying targets beyond pressure lowering, overlapping mechanisms of action for lowering pressure that can have a synergistic effect, and less toxic and/or less frequent dosing can all be helpful to our glaucoma patients. GP
References
1. Selbach JM, Posielek K, Steuhl KP, Kremmer S. Episcleral venous pressure in untreated primary open-angle and normal-tension glaucoma. Ophthalmologica. 2005;219(6):357-361. doi:10.1159/000088378
2. Kaufman AR, Elhusseiny AM, Edward DP, Vajaranant TS, Aref AA, Abbasian J. Topical netarsudil for treatment of glaucoma with elevated episcleral venous pressure: A pilot investigation in sturge-weber syndrome. Eur J Ophthalmol. 2023;33(5):1969-1976. doi:10.1177/11206721231159694
3. Htoo T. First-in-class EVP-lowering therapies for glaucoma. Presented at: 2025 Glaucoma 360 New Horizons Forum; February 7, 2025; San Francisco.
4. Gazzard G, Konstantakopoulou E, Garway-Heath D, et al. Laser in Glaucoma and Ocular Hypertension (LiGHT) trial: six-year results of primary selective laser trabeculoplasty versus eye drops for the treatment of glaucoma and ocular hypertension. Ophthalmology. 2023;130(2):139-151. doi:10.1016/j.ophtha.2022.09.009.
5. Montesano G, Ometto G, Ahmed IIK, et al. Five-year visual field outcomes of the HORIZON trial. Am J Ophthalmol. 2023;251:143-155. doi:10.1016/j.ajo.2023.02.008
6. Wirostko B, Johnson C, Sanchez G, et al. Diurnal fluctuation of IOP before and after selective laser trabeculoplasty. Poster 917 P3.115. Presented at: European Glaucoma Society Congress; June 1-4, 2024; Dublin.
7. Glaukos announces positive clinical updates for its iDose sustained-release procedural pharmaceutical platform. News release. January 14, 2025. Accessed February 18, 2025. https://investors.glaukos.com/investors/news/news-details/2025/Glaukos-Announces-Positive-Clinical-Updates-for-its-iDose-Sustained-Release-Procedural-Pharmaceutical-Platform/default.aspx
8. SpyGlass completes Tigris trial enrollment. Glaucoma Physician. November 20, 2024. Accessed February 18, 2025. https://www.glaucomaphysician.net/news/2024/spyglass-completes-tigris-trial-enrollment/
