To maintain intraocular pressure (IOP) at a steady state, there must be a fine balance between the production of aqueous humor from the processes of the ciliary body, its circulation through the anterior segment of the eye, and its drainage via the conventional (trabecular meshwork) and unconventional (uveoscleral) outflow pathways. In addition, retrograde pressure found at the intersection of aqueous veins and blood-carrying veins, called episcleral venous pressure (EVP), establishes the lowest pressure for IOP, also known as the “floor.” IOP can be reduced to the floor without backflow of blood into the anterior part of the eye. In cases where EVP is elevated, such as in Sturge-Weber Syndrome, or when IOP falls too low, blood will flow back into the eye and become visible in Schlemm’s canal. 

In the Goldmann equation (Figure 1), these parameters can be used to mathematically describe IOP. Current treatment for cases of ocular hypertension or glaucoma, whether with topical eyedrop medications, lasers, or surgical procedures, are all designed to lower IOP by altering aqueous humor production and drainage through the conventional and unconventional pathways. No current treatments selectively target the distal region of the conventional outflow pathway and EVP. Episcleral venous pressure is therefore an attractive therapeutic target, considering that distal outflow and EVP make up 50% to 80% of total IOP.

A crucial step toward developing novel treatment options for ocular hypertension and glaucoma is to identify the key ocular structures and to understand the physiological impact of aqueous humor drainage resistance through the outflow pathways. In glaucoma, current dogma indicates that most of the resistance to aqueous humor drainage occurs at the interface between the trabecular meshwork and the inner wall of Schlemm’s canal. This has stimulated the recent development of numerous microinvasive glaucoma surgery (MIGS) devices as well as therapeutics such as netarsudil (Rhopressa, Alcon) and latanoprostene bunod (Vyzulta, Bausch + Lomb) that target the trabecular meshwork and Schlemm’s canal interface. 

Less studied but critical to aqueous humor drainage is the region distal to Schlemm’s canal that includes the collector channels, aqueous veins, and the deep vascular bed leading into the systemic venous system, which in part constitutes episcleral venous pressure. 

Nearly 3 decades ago, studies performed by Rosenquist et al and a subsequent report by Schumann et al showed that removal of the trabecular meshwork or the outer wall of Schlemm’s canal reduced outflow resistance by up to 50%.^1,2 More recently, longitudinal studies supporting the successful use of MIGS have indicated that, on average, bypassing the trabecular meshwork and Schlemm’s canal reduces IOP to only 13 mmHg to 16 mmHg. Because MIGS device placement does not reduce IOP to EVP levels (8 mmHg to 10 mmHg), the presence of resistance in the distal conventional outflow region must exist. Additionally, laboratory studies with vasodilators (nitric oxide)³ and vasoconstrictors (endothelin 1)⁴ have identified the distal episcleral vasculature as a key component of distal outflow resistance. Together, these data suggest that distal outflow resistance is present and identifying a drug that can target this region and reduce EVP would be a valuable asset to clinicians in treating glaucoma and ocular hypertension.

Over the last decade, ATP-sensitive potassium channel openers have been described as a new class of ocular hypotensive agents.⁵ Researchers at the Mayo Clinic invented a topically administered prodrug called CKLP1 and have shown that it lowers IOP following once-daily dosing in various normotensive and ocular hypertensive preclinical models, resulting in IOP reductions of 20% to 30%.^6,7 CKLP1 is well tolerated and appears to have an excellent safety profile with no side effects after 3 months of treatment in hound dogs.⁸ Evaluation of aqueous humor dynamics has shown that in both normotensive and ocular hypertensive models, CKLP1 lowers EVP, making it a small molecule that can directly target distal outflow.⁹ 

In 2019, Qlaris Bio licensed the program from Mayo Clinic and developed QLS-101, advancing it through preclinical studies, leading to submission of an investigational new drug (IND) application to the US Food and Drug Administration (FDA). Results from clinical trials showed that QLS-101 had promising IOP-lowering potential and was well tolerated with an excellent safety profile. Qlaris Bio then developed an optimized formulation, named QLS-111, to improve efficacy while maintaining the same safety profile. QLS-111, a preservative-free formulation, has demonstrated excellent tolerability in both preclinical studies involving rabbits and dogs, as well as in 2 separate exploratory, investigator-initiated randomized human trials. Qlaris Bio has shown that QLS-111 relaxes ocular vasculature to within normal “physiologic” parameters to lower EVP and IOP without secondary hyperemia. A pair of phase 2 clinical trials of QLS-111 (Osprey and Apteryx) have recently been completed.

The ability to lower the floor of IOP by reducing distal outflow resistance and EVP should enable combination therapy with other classes of IOP-lowering agents, such as prostaglandin analogues, beta blockers, carbonic anhydrase inhibitors, alpha agonists, and rho kinase inhibitors. Additionally, QLS-111 may enhance MIGS procedures, enabling further IOP reduction of the “floor.” Advancing our understanding of the distal outflow pathway, its contribution to resistance, and the development of EVP-targeting molecules like QLS-111 represents the future of drug development for lowering IOP in patients with ocular hypertension and glaucoma. GP

Michael P. Fautsch, PhD, is the Joseph E. and Rose Marie Green Professor of Visual Sciences at the Mayo Clinic in Rochester, Minnesota, where he conducts and oversees research into ATP-sensitive potassium channel openers that have been found to lower IOP by reducing distal outflow resistance and EVP. He is the chair of the Scientific Advisory Board for Qlaris Bio. Dr. Fautsch can be reached at fautsch@mayo.edu.

Barbara M. Wirostko, MD, FARVO, is an adjunct professor of ophthalmology at the John A. Moran Eye Center, University of Utah, in Salt Lake City. She is chief medical officer and cofounder of Qlaris Bio and cofounder and medical director of MyEyes. Dr. Wirostko can be reached at barbara.wirostko@hsc.utah.edu.

References

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2. Schuman JS, Chang W, Wang N, de Kater AW, Allingham RR. Excimer laser effects on outflow facility and outflow pathway morphology. Invest Ophthalmol Vis Sci. 1999; 40:1676-1680.

3. Chang JY, Stamer WD, Bertrand J, et al. Role of nitric oxide in murine conventional outflow physiology. Am J Physiol Cell Physiol. 2015;309(4):C205-C214. doi:10.1152/ajpcell.00347.2014

4. McDonnell F, Dismuke WM, Overby DR, Stamer WD. Pharmacological regulation of outflow resistance distal to Schlemm’s canal. Am J Physiol Cell Physiol. 2018;315(1):C44-C51. doi:10.1152/ajpcell.00024.2018

5. Roy Chowdhury U, Dosa PI, Fautsch MP. ATP sensitive potassium channel openers: a new class of ocular hypotensive agents. Exp Eye Res. 2017;158:85-93. doi:10.1016/j.exer.2016.04.020

6. Roy Chowdhury U, Viker KB, Stoltz KL, Holman BH, Fautsch MP, Dosa PI. Analogs of the ATP-sensitive potassium (K_ATP) channel opener cromakalim with in vivo ocular hypotensive activity. J Med Chem. 2016;59:6221-6231. doi:10.1021/acs.jmedchem.6b00406

7. 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;63:15. doi:10.1167/iovs.63.2.15

8. Roy Chowdhury U, Kudgus RA, Holman BH, et al. Pharmacological profile and ocular hypotensive effects of cromakalim prodrug 1, a novel ATP-sensitive potassium channel opener, in normotensive dogs and nonhuman primates. J Ocul Pharmacol Ther. 2021;37(5):251-260. doi:10.1089/jop.2020.0137

9. Roy Chowdhury U, Rinkoski TA, Bahler CK, et al. Effects of cromakalim prodrug 1 (CKLP1) on aqueous humor dynamics and feasibility of combination therapy with existing ocular hypotensive agents. Invest Ophthalmol Vis Sci. 2017;58:5731-5742. doi:10.1167/iovs.17-22538