If there is one thing on which patients and physicians can agree, it’s that eye drops are not ideal. The problems related to eye drop use are numerous and varied. First, the use of eye drops assumes all of the problems inherent with prescription medications, from prescription barriers (e-prescribe misfires and formulary changes) to punitive medication copays and compliance challenges. But eye drops, in particular, are special. Many pharmacists are less familiar with eye drops, so they don’t necessarily understand that a generic eye drop is not identical to the branded drop.

Also, many drops, particularly in the area of glaucoma, exist in inefficient markets where medication prices and copayments, even for generic medications, can vary by hundreds of dollars from one medication to the next and one pharmacy to the next. If you’ve ever had a patient pay more than $100 for generic prednisolone, you know what I mean.¹

In a fantastic series of studies,^2,3 Alan Robin and colleagues demonstrated that eye drops are most often applied outside of the eye, perhaps to the cheek or the eyelid, and that patients are very “generous” when applying these medications, often running out of their drops well before the date on which a prescription can be refilled. Believing this issue to be extremely serious and far-reaching, the American Glaucoma Society and the American Academy of Ophthalmology developed a joint position statement, which had some success in getting Medicare to allow early refills for glaucoma medications based on known and published problems with eyedrop wastage.⁴

And the nail in the coffin? The final problem with topical therapy? The eye simply is not meant to absorb anything. Systemic medications that are taken orally are absorbed by the lining of the stomach. The conjunctiva of the eye was never given such a purpose. We began marinating the surface of the eye, a fragile ecosystem, with active molecules and their preservatives in the hopes of treating eye disease. The unfortunate result has been widespread problems related to allergy, ocular surface disease, and dry eye.⁵ From the standpoint of our patients, these symptoms often are worse than the glaucoma itself, and can result in eye pain, blurred vision, and red eyes (and the accompanying stigma).

SURGICAL ALTERNATIVES

So, if eye drops are insufficient, what are our other options? Data from two prospective, randomized trials^6,7 suggest that laser trabeculoplasty and even trabeculectomy could be considered as alternatives. In the collaborative initial glaucoma treatment study,⁷ IOP control was slightly better with surgery versus eye drops, and there were more localized side effects from surgery, but overall progression rates were the same. In the glaucoma laser trial,⁶ better pressure was achieved with laser, and visual field stability was similar to that attained with drops (timolol).

In 2017, the most popular alternative to eyedrop therapy is selective laser trabeculoplasty (SLT), which is performed approximately 150,000 times annually.^8,9 Laser therapy solves most of the inherent problems with eye drops — including problems with compliance, out-of-pocket costs, and tolerability for topical and systemic eyedrop side effects — and is gentler to the eyes, often avoiding the development of ocular hyperemia, dry eye, and visual fluctuation. Some data suggest that laser trabeculoplasty may help limit IOP fluctuations, and that it works better at night than some eye drops.¹⁰

Based on the above information, I believe laser trabeculoplasty should be the primary therapy for the treatment of glaucoma. The treatment has an exceptionally safe treatment profile, which cannot be said of topical medications.^11,12

In my estimation of phase 3 clinical trials that led to the approval of some of our mainstay topical glaucoma therapies, adverse events ranged from 20% to 40% of those treated. In addition to selective laser trabeculoplasty, argon laser trabeculoplasty remains an option, and micro-pulse laser trabeculoplasty is a viable alternative as well.

For patients with more pronounced glaucoma, micro-pulse transscleral cyclophotocoagulation provides a safety profile similar to, or in some cases, more favorable than, incisional glaucoma surgery, and can be used appropriately to get patients off of medication, or to help them avoid incisional glaucoma surgery.¹³ Although one might not put micropulse cyclophotocoagulation in the category of primary therapy, micropulse transscleral cyclophotocoagulation can serve an important role in some distressed glaucoma patients to help lower IOP and reduce topical medication use, and, in some cases, eliminate the need for eye drops. For example, this therapy can be a homerun for patients who have had prior surgery or have a barrier getting to the operating room and are taking numerous medications to maintain a healthy IOP range. It is my belief that micropulse laser therapy will likely result in happier patients who require fewer or no medications in the long run.

Glaucoma patients can face a particularly high eyedrop burden when undergoing cataract surgery. Consider, for example, a patient who requires three glaucoma medications preoperatively and will receive three new medications postoperatively (antibiotic, steroid, and NSAID). The compliance burden becomes unbearable. To address this issue in my practice, I use off-label triamcinolone/moxifloxacin (Trimoxi; Imprimis pharmaceuticals) at the time of cataract surgery. The use of intravitreal injections at the time of cataract surgery allows me and my patients to focus on the glaucoma medications postoperatively, and this approach has improved outcomes.

Somewhat surprisingly, I haven’t seen any steroid-related pressure increases, even after more than 800 cases. When combined with microincisional glaucoma techniques, many patients won’t require any glaucoma or cataract medications after surgery, and the experience has given me a glimpse into the benefits of life without drops.

SUSTAINED DELIVERY PLATFORMS IN DEVELOPMENT

For non-cataract patients with glaucoma, there are several exciting treatments options in development that deliver topical medications through sustained delivery platforms.

In 2016, Allergan acquired the ForSight Vision5 sustained delivery platform, the Bimatoprost Ring. This insert is composed of a silicone matrix over an inner polypropylene ring that fits in the fornices of the eye and delivers bimatoprost over a 4-month period.

In a phase 2 study, patients with the Bimatoprost Ring demonstrated an IOP decrease of 3.2 to 6.4 mmHg compared with 4.2 to 6.4 mmHg for the topical timolol group over 6 months.¹⁴ The advantages of this therapy will be its patient-friendly profile, ease of placement for both ophthalmologists and optometrists, and quick reversibility. Nothing encourages patient buy-in like reversibility, and that concept is in good part why patients and physicians are complicit in their eyedrop dependence. Patients who are given this therapy will likely know when the therapy has fallen out of the eye (a rare event from the trial), alleviating some of the pitfalls with punctal plug-related delivery systems.

Intracanalicular therapy has been in development for roughly a decade, and treatment options are finally on the horizon. Ocular Therapeutix is developing OTX-TP (sustained release travoprost) for the treatment of glaucoma and ocular hypertension. OTX-TP is a bio-adsorbable hydrogel insert that resides within the canaliculus and delivers preservative-free travoprost to the ocular surface for up to 90 days. The first of two phase 3 clinical trials began in the fall of 2016. The primary efficacy endpoint will be statistically superior reduction of IOP from baseline with OTX-TP compared with placebo hydrogel vehicle at 2, 6, and 12 weeks following insertion. The therapy contains a compound that will flouress with cobalt blue light, allowing the physician to assess placement during follow up.

Allergan has been working on a sustained-release intracameral bimatoprost platform. Data from the success of these implants, presented at ARVO, suggest that an intracameral injection of the sustained-release bimatoprost implant can reduce IOP in a similar manner as topical bimatoprost 0.03% (likely the most efficacious single agent) and might need to be repeated only every 4 months.¹⁵ This system is currently in phase 3 trials. Envisia Therapeutics has a sustained-release intracameral travoprost delivery system that is currently in phase 2. The ENV515 is a biodegradable PRINT (Particle Replication in Nonwetting Templates) formulation of travoprost. The company reports that it has the potential to lower IOP for more than 6 months with a single dose.

A BRIGHT FUTURE

Despite the excitement of the developing new therapies, there are several barriers to the drop-free practice. One is that patients may initially be hesitant to accept an intra or periocular injection, even if it may lower IOP successfully and has a favorable safety profile. This is partially because we live in a pharmacologically driven culture, and because patients and physicians alike have grown comfortable with the idea of simply discontinuing therapy to eliminate adverse events — something that is more challenging with some sustained-delivery formulations.

Another barrier relates to the amount of time it will take physicians to introduce these therapies to patients, and the added time required to deliver such therapies. It is possible that the financial compensation for the delivery of these therapies will be modest, and in an already overloaded system, this can pose a resource distribution challenge. Finally, the mentality of physicians themselves can have a dramatic impact on the utilization of sustained or drop-free therapies. I often think of this when I consider the compliance of physicians with laser iridotomy in comparison with selective laser trabeculoplasty. Generally speaking, physicians deliver laser iridotomy to nearly 100% of their closed-angle patients, but deliver SLT to only a small fraction of their primary open-angle glaucoma patients. However, comparing the literature of laser iridotomy with selective laser trabeculoplasty is unfair — there is far more data to demonstrate the benefit of laser trabeculoplasty than there is for laser iridotomy. Practice inertia is the only explanation.¹⁶ So, as physicians, our personal belief (rational or not) in therapy will affect the frequency with which we use it.

ARE YOU READY?

A review of the current therapeutic options available and in development suggests that over the next few years, we will have several pharmacologic and laser therapies available to decrease our dependence on eye drops in the treatment of glaucoma. The question then remains, are physicians and patients ready to move away from drops? GP

References

1. Thomas K. 20 States Accuse Generic Drug Companies of Price Fixing. The New York Times. Dec. 15, 2016. Available at: https://www.nytimes.com/2016/12/15/business/generic-drug-price-lawsuit-teva-mylan.html . Last accessed Feb. 9, 2017.
2. Sleath B, Blalock S, Covert D, Stone JL, Skinner AC, Robin AL, et al. The relationship between glaucoma medication adherence, eye drop technique, and visual field defect severity. Ophthalmology. 2011;118(12):2398-2402.
3. Hennessy AL, Katz J, Covert D, Kelly CA, Suan EP, Robin AL, et al. A video study of drop instillation in both glaucoma and retina patients with visual impairment. Am J Ophthalmol. 2011;152(6):982-988.
4. American Glaucoma Society AAO and AGS Joint Position Statement on Glaucoma Eye Drop Availability. Revised January 2014. Available at http://www.americanglaucomasociety.net/patients/position_statements/glaucoma_eye_drop_availability . Last accessed Feb. 9, 2017.
5. Saade CE, Lari HB, Berezina TL, Fechtner RD, Khouri AS. Topical glaucoma therapy and ocular surface disease: a prospective, controlled cohort study. Can J Ophthalmol. 2015;50(2):132-136.
6. Glaucoma Laser Trial Research Group. The Glaucoma Laser Trial (GLT) and glaucoma laser trial follow-up study: 7. Results. Am J Ophthalmol. 1995;120(6):718-731.
7. AGIS Investigators. The Advanced Glaucoma Intervention Study (AGIS): 11. Risk factors for failure of trabeculectomy and argon laser trabeculoplasty. Am J Ophthalmol. 2002;134(4):481-498.
8. Pham H, Mansberger S, Brandt JD, Damji K, Ramulu PY, Parrish RK. Argon laser trabeculoplasty versus selective laser trabeculoplasty. Surv Ophthalmol. 2008;53(6):641-646.
9. Ramulu PY, Corcoran KJ, Corcoran SL, Robin AL. Utilization of various glaucoma surgeries and procedures in Medicare beneficiaries from 1995 to 2004. Ophthalmology. 2007;114(12):2265-2270.
10. Katz LJ, Steinmann WC, Kabir A, Molineaux J, Wizov SS, Marcellino G; SLT/Med Study Group. Selective laser trabeculoplasty versus medical therapy as initial treatment of glaucoma: a prospective, randomized trial. J Glaucoma. 2012;21(7):460-468.
11. Tojo N, Oka M, Miyakoshi A, Ozaki H, Hayashi A. Comparison of fluctuations of intraocular pressure before and after selective laser trabeculoplasty in normal-tension glaucoma patients. J Glaucoma. 2014;23(8):e138-143.
12. Aptel F, Musson C, Zhou T, Lesoin A, Chiquet C. 24-hour intraocular pressure rhythm in patients with untreated primary open angle glaucoma and effects of selective laser trabeculoplasty. J Glaucoma. Epub ahead of print: Dec 13, 2016.
13. Micropulse versus continuous wave transscleral diode cyclophotocoagulation in refractory glaucoma: a randomized exploratory study. Aquino MC, Barton K, Tan AM, Sng C, Li X, Loon SC, Chew PT. Clin Exp Ophthalmol. 2015;43(1):40-46.
14. Brandt JD, Sall K, DuBiner H, Benza R, Alster Y, Walker G, et al. Six-month intraocular pressure reduction with a topical bimatoprost ocular insert: results of a phase II randomized controlled study. Ophthalmology. 2016;123(8):1685-1694.
15. Perera S, Lewis RA, Christie WC, et al. Bimatoprost sustained-release implants for glaucoma therapy: 12-month interim results from a phase 1/2 clinical trial. Invest Ophthalmol Vis Sci. 2016;57:e-abstract 4280.
16. Caprioli J. The tube versus trabeculectomy study: why its findings may not change clinical practice? Am J Ophthalmol. 2011;151(5):742-744.

Dr. Radcliffe is Clinical Assistant Professor in the Department of Ophthalmology at NYU Langone Medical Center and a surgeon at the New York Eye Surgery Center. He is also the special guest editor for this inaugural issue of Glaucoma Physician.