BLOG: Low-tension glaucoma — Is there another (and better) solution?

BySavak Sev Teymoorian, MD, MBA

The more the scientific community tries to understand glaucoma, the only fact that gets clearer is that it is more complicated than we thought. The hope of all this work is to one day better understand the underlying process in order to either prevent or minimize the effects of the disease process. However, the main question for providers of care today is the same: What can we do to treat our patients?

Glaucoma is not really a single disease but rather an umbrella term we use to define a group of disease processes that have a similar end pathway in which patients have optic nerve damage with associated visual field changes. We know that despite all the complexities that are involved, the reduction of IOP remains the only modifiable factor that has been shown to work. This is supported by numerous, well-respected glaucoma studies that providers use to give evidence-based care. Until there is a better understanding of the various processes occurring and, more importantly, the different methods for treatment, the goal at this time is to reduce IOP.

For most cases of glaucoma, the practice of bringing IOP down makes sense because the level appears high. This becomes an issue with patients who have low-tension glaucoma (LTG) because their IOP already appears to be low. This becomes a source of frustration for both the provider and patient. Patients don’t understand how what they once thought were “normal pressures” are now too high. Providers are left scratching their heads as what to do next with these patients when pressures are low but the patients’ glaucoma continues to worsen.

What is known from the LTG studies is the only modifiable risk factor remains the IOP despite lower initial pressures. This does, however, raise a dilemma for providers because bringing a patient’s pressure down is not a simple task. Not only are the pressures as low as can be with current non-surgical methods, but also the process of having to go lower is not a benign process. To truly get to lower, single-digit IOPs, surgical intervention is needed. The difficulty is the small range of target pressures that need to be attained, usually around 7 mm Hg to 10 mm Hg, without inducing hypotony. If pressures are too low post-surgically, then devastating complications can occur that significantly decrease visual acuity. A good analogy is that providers are like pilots and patients are passengers on a plane. Just as pilots like a large landing strip when arriving at their destination, providers want a wider range of IOP to safely take care of patients. In those with LTG, the landing strip is small and danger exists in the form of blindness if we don’t land properly for our patients.

So, then, what’s the solution for these progressing LTG patients who are on maximal medical therapy when we don’t want to take on the risks of surgical intervention? One possible solution is suggested when we take another look at the Goldmann equation, which identifies the components that determine IOP.

IOP = (F/C) + EVP, where F = rate of aqueous formation, C = facility of outflow, and EVP = episcleral venous pressure

Our current medical treatment options focus on the first half of the equation with either F or C in one form or the other. The untouched part of this equation is the EVP. Until now we didn’t have a way to reduce it through the use of eye drops. The exciting development, however, is that it appears there can be a way to alter the EVP. Research done in animal models with AR-13324, also known as Rhopressa from Aerie Pharmaceuticals, has shown that this agent can reduce EVP. This is now one of the theorized mechanisms of action (MOA) for the Rocket studies underway for the evaluation of AR-13324 in humans. If this molecule does reduce EVP, then it is not surprising to see the new results from the second phase 3 Rocket study that were revealed. These results show non-inferiority of AR-13324 to timolol with the primary endpoint of IOP less than 25 mm Hg. At lower IOPs based on the Goldmann equation, EVP (which is generally a constant number) represents a larger proportion of what determines the IOP.

The reduction of EVP from AR-13324 may not be the only MOA that helps LTG patients. It also increases the outflow through the trabecular meshwork and reduces the production of aqueous humor. The combination of these MOAs makes this molecule the only triple-action drug as compared with all the other commercially available eye drops.

Although we are still trying to completely understand the disease processes, we know that glaucoma patients have some form of trabecular meshwork dysfunction. Improving the malfunctioning meshwork would also help in achieving lower IOPs. AR-13324 has shown in cultured human trabecular meshwork cells to have anti-fibrogenic activity. This would provide another additional benefit that has not been available before now.

There are a few more factors that make the use of AR-13324 even more appealing. This relates to patient dosing compliance. The methods of these studies have its use as a once-daily medication, which is comparable to the current gold standard in glaucoma care — prostaglandin analogues — and much better than other second-line agents. The triple-therapy is achieved with a once-a-day eye drop. The other benefit is that there appear to be no major systemic side effects, with the most frequently reported adverse event being a mild-grade conjunctival hyperemia, which is also seen with current prostaglandin analogues. This prevents concerns of possibly developing cardiac or pulmonary complications that are seen with other classes of glaucoma drops and are much more common in aging glaucomatous patients.

The combination of these many factors provides hope that AR-13324 will finally provide both patients and physicians a safe and effective approach to help patients with LTG without having to revert to surgical interventions. Most importantly, this will improve the quality of life for our patients.

References:

Aerie Pharmaceuticals conference call. Accessed Sept. 16, 2015.

Kiel JW, et al. J Ocul Pharmacol Ther. 2015;doi:10.1089/jop.2014.0146.

Levy B, et al. Am J Ophthalmol. 2015;doi:10.1016/j.ajo.2015.01.026.

Pattabiraman PP, et. al. Effects of Rho kinase inhibitor AR-13324 on actin cytoskeleton and TGF2- and CTGF-induced fibrogenic activity in human trabecular meshwork cells. http://files.shareholder.com/downloads/AMDA-29CD43/0x0x813064/FD162265-D9B2-455B-9502-A35E3A956EFC/Aerie-Duke_fibrosis_poster__AOPT_2015.pdf.

Disclosure: Teymoorian reports he is a consultant for Aerie Pharmaceuticals.