The recent boom in minimally invasive glaucoma surgeries has produced a renewed interest in mechanisms of action and pathology of the outflow system linked to IOP in glaucoma. This has carried over into the pharmaceutical space, with the approvals of 2 novel molecules, latanoprostene bunod (Vyzulta; Bausch + Lomb) and netarsudil (Rhopressa; Aerie Pharmaceuticals). For years, medications have lowered IOP by either suppressing aqueous production or diverting aqueous through the secondary pathway, uveoscleral outflow. Although these types of medications do reduce IOP, they do not address the site of the pathology (decrease in outflow through the trabecular meshwork [TM] and Schlemm’s canal into the distal collector channels). The ramification of traditional mechanisms is, theoretically, further collapse of the TM architecture and therefore further enhanced pathology and decreased outflow. Once the TM flow is decreased, there’s a potential the canal also collapses and thus flow through the distal channel decreases and those channels collapse, creating a vicious cycle. This could also potentially cause of tachyphylaxis and a rise in IOP over time.

New Medications, Trabecular Meshwork, and Outflow

When latanoprostene bunod 0.024% enters the anterior chamber, it is broken down into latanoprost acid (the active prostaglandin analog) and nitric oxide (NO). Nitric oxide inhibits Rho kinase and calcium signaling by activating the upstream soluble guanylate cyclase-cyclic guanosine monophosphate (CGMP) cascade, which in turn increases permeability in the TM to increase aqueous outflow. Studies have shown that there are fewer NO markers in the eyes of patients with primary open-angle glaucoma (POAG). Doganay et al published a study in 2002 that showed 60% less NO in POAG vs control subjects, and Galassi et al in 2004 demonstrated 50% less cGMP levels in POAG vs control.^1,2 Deficiency in NO may play a role in promoting chronic TM cell contraction and elevated IOP. Nitric oxide diffuses into TM cells and causes cell relaxation and decreased IOP.

In the phase 2, dose-ranging VOYAGER study of latanoprostene bunod 0.024% vs latanoprost (Xalatan; Pfizer) 0.005% in patients with OAG or ocular hypertension, latanoprostene bunod demonstrated a mean of 1.23 mmHg greater reduction of IOP compared to latanoprost.³ It is important to remember a mean reduction in IOP is an average of all subjects. Therefore, some patients may have had less than 1.23 mmHg additional reduction of IOP compared to latanoprost 0.005%, but others may have had a significantly greater than 1.23 mmHg better reduction. Further analysis did reveal 42% of patients on 0.024% latanoprostene bunod achieved ≥2 mmHg IOP reduction vs latanoprost 0.005%. Latanoprostene bunod 0.024% also demonstrated a mean reduction in mean diurnal IOP from baseline at day 28 of 9 mmHg vs 7.8 mmHg reduction in the latanoprost 0.005% group.³ This is important because several studies have shown decreased risk of progression for every 1 mmHg reduction in IOP.^4,5 Also, in the single-arm, multicenter, open-label, 12-month JUPITER study in Japanese patients with OAG or OHT, LBN 0.024% reduced mean IOP from 19.6 mmHg to 14.4 mmHg at 1 year (26.5 % mean reduction in IOP from baseline).⁶ This demonstrated a significant reduction of IOP in patients with IOPs averaging in the upper teens, which is important because up to 50% of POAG patients have unmedicated IOPs below 21 mmHg.⁷

In more than 2,000 combined patients in phase 1-2 trials, the 0.02% concentration of netarsudil (Rhopressa; Aerie Pharmaceuticals) administered in the evening was the most efficacious and well-tolerated dosing regimen. ROCKET-1 (3 months),⁸ ROCKET-2 (12 months),⁸ and ROCKET-4 (6 months; NCT02558374) — 3 completed phase 3 clinical trials — compared netarsudil 0.02% administered in the evening to timolol 0.5% administered twice daily. Baseline IOP was higher than 20 mmHg and lower than 27 mmHg in ROCKET-1 and ROCKET-2.⁸ In ROCKET-4, baseline IOP was higher than 20 mmHg and lower than 30 mmHg.⁹

In primary analysis, IOP reductions were similar with netarsudil and timolol in ROCKET-2 and ROCKET-4 among patients who had a baseline IOP below 25 mmHg. In secondary analysis, IOP reductions were similar with the 2 drugs in ROCKET-1 among patients who had a baseline IOP below 25 mmHg and in ROCKET-4 for patients with a baseline IOP below 30 mmHg. In ROCKET-2, IOP reductions with netarsudil were consistent through 12 months of dosing. Netarsudil also has the unique ability to decrease episcleral venous pressure (EVP). A study in 11 patients revealed a 10% reduction in EVP of healthy individuals and 20% reduction in glaucomatous individuals. This is an important mechanism because it is very difficult to reach IOP goals of the lower teens and below due to the back pressure in the venous system, which is often 8-12 mmHg (depending on whether measures in diastole or systole). A drug that can reduce the pressure in the venous system may facilitate IOPs below the lower teens. This also could be why netarsudil worked to reduce IOP at lower starting IOPs compared to timolol in the phase 3 trials. Another important finding from the studies was a high safety profile.

Incorporating New Drugs Into Practice

Using these outflow drugs early in the disease process may allow for the greatest potential benefit. Latanoprostene bunod has reduced IOPs in my patients who have been on generic latanoprost and whose IOPs have fluctuated, who were not at target, or who were poor responders. The key is keeping these patients using 1 bottle and 1 medication (latanoprostene bunod is not a combination drop).

When evaluating our own switches from generic latanoprost to latanoprostene bunod, we have found a more significant additional reduction of IOP when switching over to latanoprostene bunod in patients where there was not a significant initial response to latanoprost (25% or less). Therefore I recommend paying attention to the percentage of reduction you achieve when starting a patient on latanoprost, and if you don’t achieve 25% to 30% reduction, consider switching to latanoprostene bunod. The tolerability profile of latanoprostene bunod is also similar to latanoprost and clinically I have not seen a significant increase in adverse events (including hyperemia) when switching to latanoprostene bunod. I have also seen a benefit using it as an initial treatment. In these “virgin eyes” we usually see a 30% reduction of IOP, but have often been surprised with 35% to 40% reduction, depending on starting IOP and type of glaucoma. My hope is that by starting early in the disease and increasing spaces within the TM, we might be halting further progression of the TM collapse, and might even help keep the canal and distal channels patent long term, thus changing the course of the disease.

Netarsudil has also filled a significant void. I have found it extremely helpful in those patients who are already on a PGA and need additional reduction of IOP. Since netarsudil has multiple mechanisms of action, including relaxation of TM and reduction of EVP, I have seen patients with medicated IOPs in the middle to lower teens achieve IOP reduction to 10 mmHg or even single digits. In fact, I have had a few patients avoid incisional surgery by adding Rhopressa to their regimen. Lowering IOP to the lower teens is often difficult for the aqueous suppressants, because the EVP can range from 8 mmHg to 12 mmHg. We have seen netarsudil provide an opportunity to achieve those low target IOPs, again likely due to its effect on lowering EVP.

Because netarsudil is dosed in the evening, patients can easily add it to a PGA. When IOPs are below 20 mmHg and the patient is already on a PGA, I often reach for netarsudil as my adjunct medication. I find netarsudil also valuable as a first line for patients with normal-tension glaucoma when IOPs may be in the lower teens to begin with, for those who cannot tolerate a PGA, and for those with a secondary glaucoma in one eye (to avoid PGA related adverse events). Netarsudil has no systemic side effects, based on the phase 3 trials, which therefore makes it much easier to select over a beta blocker when adding to a PGA.

A New Drug in the Mix

Recently, the combination of netarsudil and latanoprost (.02%/.005%) was approved by the FDA (Rocklatan; Aerie Pharmaceuticals). This will also likely change paradigms for many providers. Being able to combine a PGA with netarsudil in 1 drop provides a powerful option for IOP reduction, while addressing the diseased TM. The phase 3 trials of the netarsudil-latanoprost combination (MERCURY-1 and MERCURY-2 trials) demonstrated statistically superior IOP reduction over latanoprost and netarsudil at every measured time point.^10,11 More than 60% of patients taking the combination drug in the 2 MERCURY studies achieved an IOP reduction of 30% or more, which was 2 times more than the latanoprost-alone group. More importantly, nearly twice as many patients taking the combination reached 16 mmHg or lower and nearly 3 times as many reached 14 mmHg or lower compared to latanoprost. This significant difference in percentage of patients reaching 14 mmHg or less is likely due to the netarsudil component. In fact, similar percentages of patients reached 14 mmHg or less in the netarsudil group compared to the latanoprost-only group. This may be explained by the fact netarsudil works well at lower IOPs. Hyperemia was the most common ocular adverse event, as seen in the Rocket Rhopressa studies, and therefore educating patients ahead of time that hyperemia can occur, reminding them it is not permanent, it can fluctuate, and will not affect vision will prepare them for the possibility.

Access to New Medications

Access to any new medication can be difficult. We have adopted authorization services such as PARx and CoverMyMeds, which have helped ease the burden for our staff, but we often still have to fill out prior authorization (PA) forms. Proper documentation that the medications has novel mechanisms of action, that there is no generic equivalent, and that the medication is bringing the IOP down to target can help get PAs accepted. Unfortunately, even with a PA, the cost can be higher than generic medications or even other brand names. We created a nonbranded form that lists the objective differences between a generic and a brand name and explains why keeping the IOPs stable throughout the day and in between days is important. This helps patients to better decide if they want to spend the money on the drops we as providers recommend. We also educate staff about the reasons we ask them to take extra steps to get these medications.

Conclusion

Glaucoma is undergoing a renaissance of sorts. Mechanism of action has become a more important distinction in deciding which treatment to employ. With the introduction of 3 new pharmaceutical products within the last 2 years, we as providers not only have more options to treat, but in turn, have to be more active in determining how we want to bring the IOP down.

Understanding how different medications work together is now more important than ever. Does it make more sense to add two aqueous suppressants together or better to add two outflow drugs together? What about mixing these new outflow drugs with an aqueous suppressant? What is the benefit of these TM relaxing medications pre or post SLT? How do we use these new medications in the context of a MIGS procedure? Does the relaxation of the TM actually help an angle-based procedure work better, especially if we start the medication early in the disease? Can we truly limit the patient’s topical medication burden to just one bottle, if they need to be on drops, with the help of SLT and/or MIGS, even for the more advanced cases? These are questions that are yet to be answered, but I am excited to start the process of figuring them out. GP

References

1. Doganay S, Evereklioglu C, Turkoz Y, Er H. Decreased nitric oxide production in primary open-angle glaucoma. Eur J Ophthalmol. 2002;12(1):44-48.
2. Galassi F, Renieri G, Sodi A, Ucci F, Vannozzi L, Masini E. Nitric oxide proxies and ocular perfusion pressure in primary open angle glaucoma. Br J Ophthalmol. 2004 Jun; 88(6): 757-760.
3. Weinreb RN, Ong T, Sforzolini BS, et al; 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):738-745.
4. Chauhan BC, Mikelberg FS, Balaszi AG, LeBlanc RP, Lesk MR, Trope GE; Canadian Glaucoma Study Group. Canadian Glaucoma Study: 2. risk factors for the progression of open-angle glaucoma. Arch Ophthalmol. 2008;126(8):1030-1036.
5. Garway-Heath DF, Lascaratos G, Bunce C, Crabb DP, Russell RA, Shah A; United Kingdom Glaucoma Treatment Study Investigators. The United Kingdom Glaucoma Treatment Study: a multicenter, randomized, placebo-controlled clinical trial: design and methodology. Ophthalmology. 2013;120(1):68-76.
6. Kawase K, Vittitow JL, Weinreb RN, et al. Long-term safety and efficacy of latanoprostene bunod 0.024% in Japanese subjects with open-angle glaucoma or ocular hypertension: the JUPITER study. Adv Ther. 2016;33(9):1612–1627.
7. Sommer A, Tielsch JM, Katz J, et al. Relationship between intraocular pressure and primary open angle glaucoma among white and black Americans. The Baltimore Eye Survey. Arch Ophthalmol. 1991;109(8):1090-1095.
8. Serlea 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.
9. Business Wire. Aerie Pharmaceuticals reports positive Rocket 4 six-month topline safety and efficacy results for Rhopressa (netarsudil ophthalmic solution) 0.02% [press release]. https://www.businesswire.com/news/home/20170412006000/en/ . Published April 12, 2017. Accessed May 7, 2019.
10. Asrani SG, Kopczynski CC, Heah T. A 3-month interim report of a prospective, double-masked, randomized, multicenter, active-controlled, parallel-group 12-month study assessing the safety and ocular hypotensive efficacy of PG324 ophthalmic solution compared to netarsudil ophthalmic solution, 0.02%, and latanoprost ophthalmic solution, 0.005%, in subjects with elevated intraocular pressure. Abstract/presentation 7. Presented at: the American Glaucoma Society Annual Meeting, Coronado, Colorado, March 2-5, 2017.
11. Walters TR, Ahmed IIK, Lewis RA, et al; MERCURY-2 study group. Once-daily netarsudil/latanoprost fixed-dose combination for elevated intraocular pressure in the randomized phase 3 MERCURY-2 study. Ophthalmol Glaucoma. 2019. [In press]

Inder Paul Singh, MD, practices at The Eye Centers of Racine and Kenosha, Wisconsin. He reports relevant consulting and/or research funding from Bausch + Lomb, Aerie Pharmaceuticals, Allergan, and Sun Ophthalmics. Reach him at ipsingh@amazingeye.com