When treating glaucoma, ophthalmologists have traditionally started with topical therapy, then proceeded to laser trabeculoplasty, and finally considered surgical intervention to obtain the desired reduction in intraocular pressure (IOP). Over the past few years, however, the medical management of glaucoma has seen a tremendous paradigm change. The recent development of novel glaucoma medications, the use of selective laser trabeculoplasty (SLT) as first-line treatment, and adjunctive treatment before and after microinvasive glaucoma surgery (MIGS) have changed the traditional landscape of glaucoma management. There has also been a significant makeover in the comfort of surgical intervention being an option much earlier than ever thought, in large part due to the reduction of complication rates.

With respect to topical therapy, for nearly 2 decades, prescribing a prostaglandin analog (PGA) has been considered first-line therapy for many reasons. Prostaglandin analogs are effective in lowering IOP with once-daily dosing and relatively minimal side effects. Two categories of glaucoma medications, the nitric oxide-donating prostaglandins and Rho kinase inhibitors, challenge this traditional practice. These categories of medications not only are effective in lowering IOP with once-daily dosing with favorable side effect profiles but also work on an undertargeted aspect of aqueous outflow, the trabecular meshwork (TM). It should be noted that bimatoprost, long used as a traditional PGA, does have TM outflow effects, and the FDA labeling does mention this mechanism.¹

New Options

Latanoprostene bunod ophthalmic solution 0.024% (Vyzulta; Bausch + Lomb) was approved by the FDA in November 2017 for the reduction of IOP in open-angle glaucoma and ocular hypertension. This medication has a dual mechanism of action that works on both increasing uveoscleral outflow and enhancing TM outflow in part via a nitric oxide mediator.² Nitric oxide leads to the inhibition of 3 key contractile signals within the TM: Rho kinase activity, intracellular calcium stores, and calcium influx. This signal inhibition leads to TM cell relaxation and increased permeability.^2-4 In the APOLLO and LUNAR phase 3 trials, which compared latanoprostene bunod to timolol, latanoprostene bunod demonstrated a mean IOP reduction of 7.5 mmHg to 9.1 mmHg.^5,6 Furthermore, latanoprostene bunod was found in a phase 2 trial to be statistically superior to latanoprost alone with respect to IOP reduction⁷ with a favorable side-effect profile.⁶

The Rho kinase inhibitors, netarsudil 0.02% ophthalmic solution (Rhopressa; Aerie Pharmaceuticals) and netarsudil 0.02% ophthalmic solution + latanoprost 0.005% ophthalmic solution (Rocklatan; Aerie Pharmaceuticals), are yet another category of novel glaucoma medications. Netarsudil was FDA approved in December 2017, and netarsudil + latanoprost was FDA approved in March 2019 for the reduction of elevated IOP in open-angle glaucoma and ocular hypertension. Netarsudil, dosed once daily, lowers IOP through 3 mechanisms of action: (1) increasing outflow via the TM,8 (2) decreasing production of aqueous humor,⁹ and (3) decreasing episcleral venous pressure.¹⁰ The ROCKET-1 and ROCKET-2 trials demonstrated noninferiority to timolol, with the most common adverse reaction being conjunctival hyperemia.¹¹ Pooled data from the Mercury 1 and 2 trials showed a mean IOP reduction of up to 6.1 mmHg from baseline for netarsudil. Rocklatan contains the PGA latanoprost and netarsudil, thereby including 4 mechanisms of action; those mentioned above for netarsudil plus the benefit of latanoprost yielding outflow via the uveoscleral pathway. More than 60% of patients taking netarsudil + latanoprost achieved an IOP reduction of 30% or more, nearly twice that achieved by latanoprost alone.¹² Patients taking netarsudil + latanoprost were 2 to 3 times more likely to achieve IOPs less than or equal to 14 mmHg to 15 mmHg than latanoprost patients at 3 months.^13,14

Patient Selection

How should these new medications be used? Latanoprostene bunod and netarsudil + latanoprost are 2 of the most effective medications available, with once-daily dosing and minimal systemic side effects. These medications can be seen as first line for highly elevated IOPs as well as IOPs that are already within normal-to-low range.^13,15 They can be ideal for patients who have difficulty using medications with multiple doses to simplify the regimen and for those patients with cardiovascular disease who cannot tolerate the systemic side effects of other classes like beta blockers or alpha agonists. Netarsudil, in contrast, would be ideal for those patients who are concerned about iris color change or periorbitopathy that can be seen with PGAs, as well as patients with uveitis, with macular edema, or for whom PGAs are not effective. Netarsudil, which has IOP reductions closer to the timolol range, would be an excellent adjunctive agent, before introducing medications with more frequent dosing regimens. That these medications work at the level of improving TM outflow is quite novel. Perhaps by maintaining the function and contractility of the TM, atrophy of this intricate system may be curtailed, thereby maintaining the long-term functionality of the TM.

Compounding

Yet another reason the medical management of glaucoma is changing is the recent introduction of compounding pharmacies, such as Ocular Science and Imprimis Pharmaceuticals. Such pharmacies offer up to 4-molecule fixed-ratio combination medications for glaucoma. Although fewer data are available for compounded medications than for currently available brand-name medications, compounded medications have potential benefits. These benefits include increased tolerability, given the decreased amount of the preservative benzalkonium chloride used and options for preservative-free formulations; improved adherence, given fewer medications to administer; and the potential for decreased cost, considering added copays for multiple medications. Compounded formulations provide more options for patients while potentially improving adherence, tolerability, and affordability.

A New First-Line Therapy

Paradigm shifts have also been occurring in determining when to introduce SLT therapy, which indirectly affects medical management. Instead of waiting to introduce this modality as a second, third, or even fourth-line form of treatment, many ophthalmologists are introducing SLT as a first-line agent. The many benefits of introducing SLT as first-line therapy include avoiding the side effects of topical medications, obviating the question of patient adherence, aiding in the simplification of the topical regimen, improved efficacy when used first line,¹⁶ and documented effects on the contralateral eye.¹⁷ In fact, efficacy of SLT may help glaucoma surgeons determine the potential for success with future angle-based MIGS procedures by helping to identify the location of blockage within the outflow system. As such, if SLT is effective, blockage is likely within the TM. If SLT is ineffective, the obstruction may be outside the TM, in Schlemm’s canal, or more distal. This information is invaluable when determining which MIGS procedure to perform. Furthermore, SLT can be performed after angle-based MIGS procedures to enhance the outflow via the TM.¹⁸

With the therapeutic and diagnostic benefits of novel glaucoma medications and the introduction of SLT as a first-line treatment, the medical management of glaucoma has changed. This change in paradigm highlights the importance of TM outflow in the long-term, effective management of glaucoma. GP

References

1. Stamer WD, Piwnica D, Jolas T, et al. Cellular basis for bimatoprost effects on human conventional outflow. Invest Ophthalmol Vis Sci. 2010;51(10):5176-5181.
2. Dismuke WM, Mbadugha CC, Ellis DZ. NO-induced regulation of human trabecular meshwork cell volume and aqueous humor outflow facility involve the BKCa ion channel. Am J Physiol Cell Physiol. 2008;294(6):C1378-C1386.
3. Bausch + Lomb, Inc. VYZULTA prescribing information. 2018.
4. Dismuke WM, Lang J, Overby D, Staer WD. Concentration-related effects of nitric oxide and endothelin-1 on human trabecular meshwork cell contractility. Exp Eye Res. 2014;120:28-35.
5. Weinreb RN, Sforzolini BS, Vittitow J, Liebmann J. Latanoprostene bunod 0.024% versus timolol maleate 0.5% in subjects with open-angle glaucoma or ocular hypertension: the APOLLO study. Ophthalmology. 2016;123(5):965-973.
6. Medeiros FA, Martin KR, Peace J, Sforzolini BS, Vittitow JL, Weinreb RN. Comparison of latanoprostene bunod 0.024% and timolol maleate 0.5% in open-angle glaucoma or ocular hypertension: the LUNAR study. Am J Ophthalmol. 2016;168:250-259.
7. Weinreb RN, Ong T, Scassellati Sforzolini B, Vittilow JL, Singh K, Kaufman PL; VOYAGER study group. A randomised, controlled comparison of latanoprostene bunod and latanoprost 0.005% in the treatment of ocular hypertension and open angle glaucoma: the VOYAGER study. Br J Ophthalmol. 2015;99(6):738-45.
8. Kazemi A, McLaren JW, Kopczynski CC, Heah TG, Novack GD, Sit AJ. The effects of netarsudil ophthalmic solution on aqueous humor dynamics in a randomized study in humans. J Ocul Pharmacol Ther. 2018;34(5):380-386.
9. Wang RF, Williamson JE, Kopczynski C, Serle JB. Effect of 0.04% AR-13324, a ROCK and norepinephrine transporter inhibitor, on aqueous humor dynamics in normotensive monkey eyes. J Glaucoma. 2015;24(1):51-54.
10. Kiel JW, Kopczynski CC. Effect of AR-13324 on episcleral venous pressure in Dutch belted rabbits. J Ocul Pharmacol Ther. 2015;31(3):146-151.
11. Serle JB, Katz LJ, McLaurin E, et al; ROCKET-1 and ROCKET-2 Study Groups. Two phase 3 clinical trials comparing the safety and efficacy of netarsudil to timolol in patients with elevated intraocular pressure: Rho kinase elevated IOP treatment trial 1 and 2 (ROCKET-1 and ROCKET-2). Am J Ophthalmol. 2018;186:116-127.
12. Asrani S, McKee H, Scott SS, Lewis R, Kopczynski C, Heah T. Pooled phase 3 efficacy analysis of a once-daily fixed-dose combination of netarsudil 0.02% and latanoprost 0.005% in ocular hypertension and open-angle glaucoma. Poster presented at: 13th European Glaucoma Society Congress, Florence, Italy, May 19-22, 2018.
13. Brubaker JW. PO074: Once-daily fixed-dose combination of netarsudil 0.02% and latanoprost 0.005% in ocular hypertension/open-angle glaucoma: 12-month data from Mercury-1. Poster presented at: Annual Meeting of the American Glaucoma Society, New York, New York; March 2, 2018.
14. Walters T. PO073: Once-daily fixed-dose combination of netarsudil 0.02% and latanoprost 0.005% in ocular hypertension or open-angle glaucoma, the Mercury-2 study. Poster presented at: Annual Meeting of the American Glaucoma Society, New York, New York; March 2, 2018.
15. Araie M, Sforzolini BS, Vittitow J, Weinreb RN. Evaluation of the effect of latanoprostene bunod ophthalmic solution, 0.024% in lowering intraocular pressure over 24 h in healthy Japanese subjects. Adv Ther. 2015;32(11):1128-1139.
16. Freitas AL, Ushida M, Almeida I, et al. Selective laser trabeculoplasty as an initial treatment option for open-angle glaucoma. Arq Bras Oftalmol. 2016;79(6):417-421.
17. Rhodes KM, Weinstein R, Saltzmann RM, et al. Intraocular pressure reduction in the untreated fellow eye after selective laser trabeculoplasty. Curr Med Res Opin. 2009;25(3):787-96.
18. Lubeck D. MIGS: Restoration of Normal Outflow Aqueous Pathways with ABiC. Digital supplement to Cataract & Refractive Surgery Today sponsored by Ellex, March 2018. Available at https://crstoday.com/articles/migs-restoration-of-normal-outflow-aqueous-pathways-with-abic/migs-restoration-of-normal-outflow-aqueous-pathways-with-abic-2/ .

Samantha Dewundara, MD, is a glaucoma and cataract surgeon at Virginia Eye Consultants in Norfolk, Virginia. She reports no related disclosures.

Constance Okeke, MD, MSCE, is the lead glaucoma specialist and cataract surgeon at Virginia Eye Consultants in Norfolk, Virginia. She reports no relevant disclosures. Reach her at iglaucoma@gmail.com or www.drconstanceokeke.com .