Historically, mild to moderate glaucoma has been managed primarily with medical therapy. The approach for patients who required additional intraocular pressure (IOP) lowering but who were not candidates for invasive surgical intervention was simply to add another topical medication. This led to patients on 3 or 4 different classes of IOP-lowering therapy, often all as individual drops, creating challenges with adherence issues as well as tolerability and systemic safety concerns. Evidence suggests that, among current options, each new drop confers only about 4% further IOP reduction, compared to a much more substantial 24% reduction from the initial topical therapy, typically with a prostaglandin analog (PGA).1 More complex regimens increase the likelihood of poor adherence,which may contribute to the diminishing effects of additional drops.2 However, that paradigm is shifting, thanks to advancements in laser and surgical options, as well as new topical therapies with unique mechanisms of action.
Patients also now have the option for laser as a first-line therapy. The Laser in Glaucoma and Ocular Hypertension (LiGHT) trial clearly demonstrated that starting initial management of glaucoma with selective laser trabeculoplasty (SLT) may be better for patients because it is more cost-effective3 and more likely to reduce the need for incisional glaucoma surgery.4 But SLT doesn’t work for everyone and it doesn’t last forever, which means most glaucoma patients will still need topical therapy at some point.
PGAs remain a mainstay of topical therapy, offering a combination of high efficacy and a low rate of systemic side effects. PGAs increase aqueous humor outflow, predominantly through the uveoscleral pathway, which some believe is preferable to suppressing the production of aqueous humor, the eye’s natural circulatory system and the source of nutrients for all the avascular tissues of the anterior segment, including the cornea, lens, and trabecular meshwork (TM).
When both laser and a PGA do not provide enough pressure lowering, treatment options include standalone MIGS, adding 1 of the 3 classes of aqueous suppressants, or adding an agent that increases outflow through the TM, such as a rho kinase (ROCK) inhibitor. ROCK inhibitors have been wonderfully effective as incremental therapy, although the side effect profile has significantly hindered longer-term use.
New Topical Options
The success of ROCK inhibitors points to a promising area of ongoing research for medical therapy—topical agents with new and complementary mechanisms of action that can help clinicians maximize pressure lowering while minimizing the number of drops per day a patient must manage. One such agent in late-stage clinical development is QLS-111 (Qlaris Bio). Another outflow-enhancing drug, it works primarily by reducing episcleral venous pressure (EVP). EVP, a significant component of IOP, is the back pressure from the episcleral veins and collector channel systems that are distal to the TM. It must be overcome for aqueous humor to flow out through the TM pathway.5
QLS-111 is an ATP-sensitive potassium channel opener, a class of drugs that preclinical work suggests can modulate distal outflow.6 The drug met all primary and secondary endpoints in two phase 2 studies, with mean IOP lowering of 3.7 mmHg from baseline.7 A once-daily evening dose of the 0.015% concentration of the drug was determined to be the most effective regimen. One of the studies also showed strong additive efficacy with latanoprost, as patients already using this PGA experienced an additional 3.2 mmHg to 3.6 mmHg reduction in IOP when QLS-111 was added.7 If the efficacy, safety, and tolerability seen so far are confirmed in larger phase 3 trials, QLS-111—a preservative-free topical agent compatible with all current therapies—could represent a valuable new option for the treatment armamentarium.
Sustained-Release and Other Novel Formulations
Another fruitful development is sustained-release (SR) drugs that can reduce or eliminate the need for patient compliance with daily drop instillations. Among the first generation of SR implants, the bimatoprost SR implant (Durysta; AbbVie) is relatively short-acting in its currently approved single-implant form. The SR travoprost implant (iDose TR; Glaukos) is longer lasting but also more invasive because it is surgically implanted into the TM instead of the anterior chamber. There are insurance hurdles to clear for access to these implants, but even with these shortcomings, procedural pharmaceuticals have a role to play and will likely have an even greater role as second-generation implants with refillable designs or greater drug capacity come to market. Despite the excitement around SR, the fact is that most newly diagnosed glaucoma patients still receive a topical eye drop to start.
Another promising development is a cream that provides transdermal delivery of travoprost (GLK-311; Glaukos). A topical cream might avoid some of the instillation challenges that patients face with traditional eye drops. If GLK-311 proves capable of delivering a sufficient dose of travoprost to the target ocular tissues, that would represent a very exciting advancement. Contact lens delivery of glaucoma therapies is also under investigation, but a cream would be much easier to use than a contact lens, particularly for older patients.
The Greatest Challenge
The greatest barrier to developing disease-interrupting treatments is a full understanding of the pathophysiology of glaucoma, which remains the leading cause of preventable blindness worldwide. Lowering IOP has been successful in slowing the progression of glaucoma, without knowing the pathogenic molecular mechanisms that cause elevated IOP in the first place. Until such a discovery is made, glaucoma treatments will remain palliative. Optimism remains that someday underlying disease mechanisms will be better understood, along with treatments to interrupt them. With one gene therapy already available in ophthalmology (Luxturna; Spark Therapeutics), it is not a stretch to imagine gene therapies for glaucoma. However, even if the pathogenic mechanism for glaucoma is identified, topical therapies and laser eye surgery to lower IOP will remain necessary to manage the incremental care of glaucoma patients for decades to come. GP
References
1. Johnson TV, Jampel HD. Intraocular pressure following prerandomization glaucoma medication washout in the HORIZON and COMPASS trials. Am J Ophthalmol. 2020;216:110-120. doi:10.1016/j.ajo.2020.04.008
2. Robin AL, Covert D. Does adjunctive glaucoma therapy affect adherence to the initial primary therapy? Ophthalmology. 2005;112(5):863-868. doi:10.1016/j.ophtha.2004.12.026
3. Gazzard G, Konstantakopoulou E, Garway-Heath D, et al. Selective laser trabeculoplasty versus eye drops for first-line treatment of ocular hypertension and glaucoma (LiGHT): a multicentre randomised controlled trial. Lancet. 2019;393(10180):1505-1516. doi:10.1016/S0140-6736(18)32213-X
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. Sit AJ, Aihara M, Khawaja AP, et al. Clinical implications of lowering episcleral venous pressure in the management of glaucoma and the use of rho kinase inhibitors. Surv Ophthalmol. 2025;70(5):918-929. doi:10.1016/j.survophthal.2025.03.003
6. Roy Chowdhury U, Millar JC, Holman BH, et al. Effect of ATP-sensitive potassium channel openers on intraocular pressure in ocular hypertensive animal models. Invest Ophthalmol Vis Sci. 2022;63(2):15. doi:10.1167/iovs.63.2.15
7. Wirostko B, Brandano L, Htoo T, et al. QLS-111 significantly lowers IOP in phase 2 studies, Osprey and Apteryx, as monotherapy and adjunctive therapy with excellent safety and tolerability. Presented at: World Glaucoma Congress; June 25-28, 2025; Honolulu, Hawaii.