Ushering in a New Treatment Paradigm for Glaucoma: Updates on Novel Therapeutics and Disease-Modifying Treatments

USHERING IN A NEW TREATMENT PARADIGM FOR GLAUCOMA: UPDATES ON NOVEL THERAPEUTICS AND DISEASE-MODIFYING TREATMENTS

All of us who take care of patients who have glaucoma are familiar with the statistics. Glaucoma is a leading cause of preventable blindness in the United States.¹ More than 3 million Americans have glaucoma, and the National Eye Institute projects this number will reach 4.2 million by 2030.^1,2 During the past several years, we have seen remarkable innovations in therapies for glaucoma, from pharmaceuticals, surgery, and laser procedures, to implantable devices and new instruments and techniques to deliver them. Yet challenges remain. While most clinicians still rely on topical medications as first-line therapy for primary open-angle glaucoma,³ issues with compliance and adherence often limit their effectiveness.^4-7 In fact, studies have shown that up to 60% of patients with glaucoma are noncompliant or nonadherent with their treatment regimens,^8-12 and adherence continues to drop as the number of medications increases.^5,13,14 Among the challenges are side effects that patients can’t tolerate, forgetfulness, dexterity problems that hamper instillation, access to medications, and high costs.¹⁵ For patients on maximum medical therapy whose IOPs are still inadequately controlled, implantation of various types of devices via microinvasive glaucoma surgery (MIGS) is a newer option to consider, while laser trabeculoplasty and incisional surgery are mainstays.¹⁶ Some promising technologies are on the horizon to deliver therapy in a more consistent and patient-friendly manner. This continuing medical education activity is designed to help clinicians identify and evaluate all available treatments for mild-to-moderate primary open-angle glaucoma, with a goal of individualizing treatment with monotherapy or combination regimens for more effective pressure management.

—Nathan M. Radcliffe, MD, Program Moderator

1. Glaucoma Facts and Stats. Available at: https://www.glaucoma.org/glaucoma/glaucoma-facts-and-stats.php. San Francisco, CA: Glaucoma Research Foundation, 2019.
2. January is National Glaucoma Awareness Month. Glaucoma Research Foundation website. https://www.glaucoma.org/news/glaucoma-awareness-month.php. Last reviewed January 9, 2019. Accessed: December 6, 2019.
3. Whitson JT. Glaucoma: a review of adjunctive therapy and new management strategies. Expert Opin Pharmacother. 2007;8(18):3237-3249.
4. Djafari F, Lesk MR, Harasymowycz PJ, et al. Determinants of adherence to glaucoma medical therapy in a long-term patient population. J Glaucoma. 2009;18(3):238-243.
5. Robin AL, Novack GD, Covert DW, et al. Adherence in glaucoma: objective measurements of once-daily and adjunctive medication use. Am J Ophthalmol. 2007;144(4):533-540.
6. Kass MA, Gordon M, Morley RE, Jr, et al. Compliance with topical timolol treatment. AmJ Ophthalmol. 1987;103(2):188-193.
7. Reardon G, Schwartz GF, Mozaffari E. Patient persistency with topical ocular hypotensive therapy in a managed care population. Am J Ophthalmol. 2004;137(1 Suppl):S3-S12.
8. Freeman EE, Munoz B, West SK, et al. Glaucoma and quality of life: the Salisbury Eye Evaluation. Ophthalmology. 2008;115(2):233-238.
9. Quigley HA, Friedman DS, Hahn SR. Evaluation of practice patterns for the care of open-angle glaucoma compared with claims data: the Glaucoma Adherence and Persistency Study. Ophthalmology. 2007;114(9):1599-1606.
10. Friedman DS, Quigley HA, Gelb L, et al. Using pharmacy claims data to study adherence to glaucoma medications: methodology and findings of the Glaucoma Adherence and Persistency Study (GAPS). Invest Ophthalmol Vis Sci. 2007;48(11):5052-5057.
11. Nordstrom BL, Friedman DS, Mozaffari E, et al. Persistence and adherence with topical glaucoma therapy. Am J Ophthalmol. 2005;140(4):598-606.
12. Schwartz GF, Reardon G, Mozaffari E. Persistency with latanoprost or timolol in primary open-angle glaucoma suspects. Am J Ophthalmol. 2004;137(1 Suppl):S13-16.
13. Robin A, Grover DS. Compliance and adherence in glaucoma management. Indian JOphthalmol. 2011;59 Suppl:S93-S96.
14. Robin AL, Covert D. Does adjunctive glaucoma therapy affect adherence to the initial primary therapy? Ophthalmology. 2005;112(5):863-868.
15. Newman-Casey PA, Robin AL, Blachley T, et al. The most common barriers to glaucoma medication adherence: a cross-sectional survey. Ophthalmology. 2015;122(7):1308-1316.
16. Kalouda P, Keskini C, Anastasopoulos E, Topouzis F. Achievements and limits of current medical therapy of glaucoma. Dev Ophthalmol. 2017;59:1-14.

UPDATES ON SELECTIVE LASER TRABECULOPLASTY AND LESS-INVASIVE SURGERY

Alternatives to topical medications as first-line therapy.EARL RANDY CRAVEN, MD Researchers have been studying laser trabeculoplasty, its mechanisms of action, and its impact on the anatomy of the eye, and by extension, glaucoma, for some 40 years, starting with work by Wise and Witter.¹ Further studies by Acott, Samples, and colleagues supported the hypothesis that laser trabeculoplasty causes early cell division by a population of cells in the anterior meshwork, and these new cells then migrate and repopulate the burn sites over a period of weeks.² As research continued, clinicians sought to understand where laser trabeculoplasty would fit in clinical practice. The Glaucoma Laser Trial assessed the efficacy and safety of argon laser trabeculoplasty (ALT) as an alternative to topical medication (timolol) for controlling IOP in patients with primary open-angle glaucoma (POAG).³ After 2 years of follow-up, 44% of the laser-first eyes had controlled IOPs versus 30% of the eyes treated with timolol. These results were somewhat disappointing, as the investigators saw some synechiae in the ALT eyes, and the pressure-lowering in these eyes was not statistically significant. The common thinking was that ALT is more of a second-line therapy for eyes that haven’t responded well to drops. Selective laser trabeculoplasty (SLT) was invented by Latina in the 1990s, and subsequent studies examined its effect inside the eye.^4-6 There seemed to be less evidence of destruction compared with ALT, suggesting that SLT was altering the trabecular meshwork (TM) in a different way. Using eye bank tissue in a test model, SooHoo and colleagues found less thermal concavity damage with SLT than with ALT.⁷ These findings seemed to support what we’d suspected all along, that SLT is less destructive to the meshwork than ALT. The mechanism of action of laser trabeculoplasty has been a subject of much debate, with two primary schools of thought. One is that a mechanical change creates a disruption in the TM, allowing increased aqueous outflow. Another theory suggests a biologic effect from matrix metalloproteinase induction. In other words, once cells are treated with SLT, they alter how they allow aqueous to pass through. Work by Alvarado suggested macrophage migration might have a role in helping to decrease IOP.⁸ An overwhelming body of evidence seems to suggest that SLT may be an effective initial therapy. But can we predict which eyes will have the best outcomes? Pillunat and colleagues looked at preoperative IOP as a predictor of SLT efficacy.⁹ They found that the higher the initial pressures were, the better the response; however, there seems to be a “floor” with SLT. If pressures are 14 mm Hg or less, SLT doesn’t seem to have much effect on the IOP. Hutnik and colleagues compared SLT with ALT in patients treated previously with 360° SLT.¹⁰ They found that the pressure dropped 0.33 mm Hg more, on average, in the SLT group. While that wasn’t statistically significant, they noted a strong trend, in that ALT failed more quickly than SLT. While SLT gained ground as the preferred laser therapy to treat glaucoma, clinicians continued to weigh its value as initial treatment. SLT VERSUS MEDICATIONS AS FIRST-LINE THERAPY Katz and colleagues published results of a study in 2012 in which they randomly assigned 69 patients (127 eyes) to receive SLT or medical therapy with a prostaglandin analogue as initial treatment.¹¹ They found that IOP reduction was similar in both arms after 9 to 12 months of follow up and concluded that these results support the option of SLT as a safe and effective initial therapy in POAG or ocular hypertension (OHT). Probably the most important update on SLT to date is the Laser in Glaucoma and Ocular Hypertension (LiGHT) trial.¹² Investigators in the UK enrolled 718 treatment-naïve patients with POAG or OHT and randomly assigned them to initial therapy with topical antiglaucoma medications or SLT. Objective target IOPs were set according to glaucoma severity using a specific algorithm, as defined by the Canadian work group.¹³ Looking at pressure control at 36 months, the investigators found 74% of patients in the SLT group required no drops to maintain IOP at target. Eyes of patients in the SLT group were within target IOP at more visits (93%) than eyes in the medication group (91%), and no patients in the SLT group required glaucoma surgery to lower IOP versus 11 patients in the medication group. These results suggest that SLT may be disease-modifying and should be considered for initial treatment. SURGICAL OPTIONS When treating glaucoma in the United States, a key factor to consider is whether a patient is ready to have cataract surgery. We might lean toward cataract surgery alone if a patient has a healthy optic nerve head, only slightly elevated IOP (<25 mm Hg), and is using one or no medications. If a patient has mild disease, is using two medications, and you want to give him or her a chance to use fewer medications in the future, or if you want to get more of an IOP reduction than from cataract surgery alone, then you might consider a microinvasive glaucoma surgery (MIGS) at the same time as the cataract surgery. For patients with significant disease, we have several options, including filtration surgery with antimetabolites, tube shunts, deep sclerectomy often with nd:YAG laser goniopuncture and antimetabolites, MIGS, maximum medications, or  multiple combinations. However, safety must be a primary consideration. For example, any of the MIGS procedures can cause pressure spikes. We have to be careful when considering a MIGS option for a patient who has advanced field loss that’s encroaching on fixation. We also must consider how low a pressure a patient can tolerate and how it will affect the visual outcome. For instance, pressures below 10 mm Hg may cause hypotony maculopathy in patients with high myopia, in very young patients with thin, deformable sclera, and in patients with greater retinal nerve fiber layer thickness. Prior cyclophotocoagulation can cause low aqueous production. We must strike a balance between lowering the IOP and the risks involved in doing so. TRABECULAR BYPASS PROCEDURES There are two stents available in the United States designed to bypass the TM and increase the flow of aqueous into the canal of Schlemm. In the United States, these devices are approved for use only in conjunction with cataract surgery. Standalone procedures are approved in Europe and the Middle East. Johnstone described the TM as functioning like a trampoline.¹⁴ During a blink or when the eye moves, the meshwork moves and facilitates the outflow of aqueous into the canal of Schlemm and out through the collector channels. There is some physiologic purpose for having the TM intact, but in some individuals—for instance, those with hereditary glaucoma, people using steroids, and those who have had uveitis—the TM becomes less functioning and perhaps less compliant. In these cases, it is probably better that it be removed rather than bypassed. These are some of the factors to consider when choosing a surgical treatment. The Glaukos stent was the first trabecular bypass device approved by the FDA. While it was shown to be somewhat more effective in lowering IOP than cataract surgery alone,¹⁵ it wasn’t a game-changer for most clinicians. As I was part of the Glaukos study group, I went back through my patients’ charts and analyzed what made the difference for them.¹⁶ I found that visualization and placement of the micro-bypass stent seemed to matter. Patients with correctly placed stents who responded to treatment had a 35% drop in IOP immediately after surgery, and they seemed to sustain pressure reduction (Figure 1).

Figure 1. Patients who responded to treatment with the Glaukos stent had a 35% drop in IOP immediately after surgery.

This led me to try various methods of verifying the placement of the stent to facilitate trabecular outflow. My conclusion was that a broader stent that spans multiple clock hours or multiple stents that can be visualized throughout surgery might result in further pressure reduction. Visualization of the Hydrus microstent is similar to what we see with the Glaukos device. It is inserted through a clear corneal incision and guided through the TM into Schlemm canal. The HORIZON investigators randomly assigned patients to receive a single Hydrus device or no stent after uncomplicated cataract surgery.¹⁷ Medication washout and modified diurnal IOP measurements were repeated at 12 and 24 months. At 12 months, modified diurnal IOP was reduced by 8.5 mm Hg in the Hydrus eyes, and at 24 months, the reduction was 7.8 mm Hg, which is significantly higher than with cataract surgery alone (Figure 2).

Figure 2. At 12 months, modified diurnal IOP was reduced by 8.5 mm Hg in the Ivantis microstent eyes, and at 24 months, the reduction was 7.8 mm Hg.

The newer Glaukos multidirectional device, which consists of two stents, is designed to improve placement of the stent into the canal. In a prospective, randomized, controlled pivotal trial, clinically and statistically greater reductions in IOP without medication were achieved after device implantation with cataract surgery versus cataract surgery alone (Figure 3).¹⁸

Figure 3. In a pivotal trial, clinically and statistically greater reductions in IOP without medication were achieved after implantation of the Glaukos multidirectional stents with cataract surgery versus cataract surgery alone.

Another approach currently being investigated outside the United States is what I call “MIGS ’n’ Meds.” In a study performed in Armenia, two classic Glaukos stents were implanted in each of 39 eyes in standalone procedures.¹⁹ The patients were then prescribed a prostaglandin analogue. Mean IOPs at baseline were 22.2 mm Hg. After 18 months, mean IOPs were 11.8 mm Hg. For patients who want to avoid a trabeculectomy, there’s something to be said for looking at a standalone MIGS plus one medication. With continued improvements in trabecular bypass devices and the potential for FDA approval of standalone procedures, I believe trabecular bypass “MIGS n’ Meds” will be our future. Also in the realm of trabecular bypass procedures are extirpation, which is removal of the TM through goniotomy or trabeculectomy, and canaloplasty, which dilates the canal. In my opinion, trabecular extirpation is indicated for patients who have a less functioning meshwork. Some surgeons use this approach for exfoliative eyes, pigmentary dispersion syndrome, and the like. MIGS IMPLANTS: CREATING A BLEB The Allergan stent is a subconjunctival implant indicated for patients with refractory glaucoma that failed previous surgical treatment and for patients with POAG, pseudoexfoliative  or pigmentary glaucoma with open angles who are not responsive to maximum medical therapy. Reitsamer and colleagues found the gel stent effectively reduced IOP and medication needs over 2 years in POAG that was uncontrolled medically, with an acceptable safety profile (Figure 4).²⁰

Figure 4. The Allergan stent effectively reduced IOP and medication needs over 2 years in POAG that was uncontrolled future.

COMING SOON A device that likely will be approved in 2020 is a microshunt (Santen) originally developed by InnFocus. It was developed by engineer Leonard Pinchuk, using a new biomaterial called poly(styrene-block-isobutyleneblock-styrene) or SIBS, which induces virtually no foreign body reaction in the body and has a low likelihood of fibrosis.²¹ The theory is, if you can place a minishunt into the angle through an external approach, the result will be a better bleb with fewer problems. The FDA trial is awaiting publication. Batlle and colleagues found very good pressure control in a small subset of eyes.²² Our continued search for the perfect treatment for glaucoma continues. Fortunately, we do have some good options and better understanding about what and when we use something. The next generation treatments look promising, as well.

1. Wise J, Witter S. Argon laser therapy for open-angle glaucoma. Arch Ophthalmol. 1979;97:319-322.
2. Acott TS, Samples JR, Bradley JM, et al. Trabecular repopulation by anterior trabecular meshwork cells after laser trabeculoplasty. Am J Ophthalmol. 1989;107(1):1-6.
3. The Glaucoma Laser Trial (GLT). 2. Results of argon laser trabeculoplasty versus topical medicines. The Glaucoma Laser Trial Research Group. Ophthalmology. 1990;97(11):1403-1413.
4. Latina MA, Park C. Selective targeting of trabecular meshwork cells: in vitro studies of pulsed and CW laser interactions. Exp Eye Res. 1995;60(4):359-371.
5. Kramer TR, Noecker RJ. Comparison of the morphologic changes after selective laser trabeculoplasty and argon laser trabeculoplasty in human eye bank eyes. Ophthalmology. 2001;108(4):773-779.
6. Cvenkel B, Hvala A, Drnovsek-Olup B, Gale N. Acute ultrastructural changes of the trabecular meshwork after selective laser trabeculoplasty and low power argon laser trabeculoplasty. Lasers Surg Med. 2003;33(3):204-208.
7. SooHoo JR, Seibold LK, Ammar DA, Kahook MY. Ultrastructural changes in human trabecular meshwork tissue after laser trabeculo­plasty. J Ophthalmol. 2015:2015;476138.
8. Alvarado JA, Katz LJ, Trivedi S, Shifera AS. Monocyte modulation of aqueous outflow and recruitment to the trabecular meshwork following selective laser trabeculoplasty. Arch Ophthalmol. 2010;128(6):731-737.
9. Pillunat KR, Spoerl E, Elfes G, Pillunat LE. Preoperative intraocular pressure as a predictor of selective laser trabeculoplasty efficacy. Acta Ophthalmol. 2016;94(7):692-696.
10. Hutnik C, Crichton A, Ford B, et al. Selective laser trabeculoplasty versus argon laser trabeculoplasty in glaucoma patients treated previously with 360° selective laser trabeculoplasty: a randomized, single-blink, equivalence clinical trial. Ophthalmology. 2019;126(2):223-232.
11. Katz LJ, Steinmann WC, Kabir A, et al.; 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.
12. Gazzard G, Konstantakopoulou E, Garway-Heath D, et al. Selective laser trabeculoplasty versus eye drops for first-line treatment of ocular hypertension and glaucoma (LiGHT): a multicentre randomised controlled trial. Lancet. 2019;393(10180):1505-1516.
13. Damji KF, Behki R, Wang L; Target IOP Workshop participants. Canadian perspectives in glaucoma management: setting target intraocular pressure range. CanJ Ophthalmol. 2003;38(3):189-197.
14. Johnstone MA. Intraocular pressure regulation: findings of pulse-dependent trabecular meshwork motion lead to unifying concepts of intraocular pressure homeostasis. JOcul Pharmacol Ther. 2014;30(2-3):88-93.
15. Craven ER, Katz LJ, Wells JM, Giamporcaro JE; iStent Study Group. Cataract surgery with trabecular micro-bypass stent implantation in patients with mild-to-moderate open-angle glaucoma and cataract: two-year follow-up. J Cataract Refract Surg. 2012;38(8):1339-1345.
16. Craven ER. Ab-Interno Microstent for Glaucoma and Complications of Glaucoma Surgery. Presented at American Society of Cataract and Refractive Surgery; March 25, 2011; San Diego, CA.
17. Samuelson TW, Chang DF, Marquis R, et al.; HORIZON Investigators. A Schlemm canal microstent for intraocular pressure reduction in primary open-angle glaucoma and cataract. Ophthalmology. 2019;126(1):29-37.
18. Samuelson TW, Sarkisian SR Jr, Lubeck DM, et al.; iStent inject Study Group. Prospective, randomized, controlled pivotal trial of an ab interno implanted trabecular micro-bypass in primary open-angle glaucoma and cataract: two-year results. Ophthalmology. 2019;126(6):811-821.
19. Ahmed, II, Katz LJ, Chang DF, et al. Prospective evaluation of microinvasive glaucoma surgery with trabecular microbypass stents and prostaglandin in open-angle glaucoma. J Cataract Refract Surg. 2014;40(8):1295-1300.
20. Reitsamer H, Sng C, Vera V, et al.; Apex Study Group. Two-year results of a multicenter study of the ab interno gelatin implant in medically uncontrolled primary open-angle glaucoma. Graefes Arch Clin Exp Ophthalmol. 2019;257(5):983-996.
21. Pinchuk L, Riss I, Batlle JF, et al. The use of poly(styrene-block-isobutylene-block-styrene) as a microshunt to treat glaucoma. Regen Biomater. 2016;3(2):137-142.
22. Batlle JF, Fantes F, Riss I, et al. Three-year follow-up of a novel aqueous humor microshunt. J Glaucoma. 2016;25(2):e58-e65.

IMPACT OF GLAUCOMA THERAPY ON THE OCULAR SURFACE

Emphasizing the need for novel therapeutics.PREEYA K. GUPTA, MD The Tear Film & Ocular Surface Society Dry Eye Workshop II (TFOS DEWS II) definition of dry eye highlights some of the key areas associated with this disease: loss of homeostasis of the tear film accompanied by hyperosmolarity and inflammation, which lead to damage on the ocular surface.¹ Topping the list of risk factors for dry eye disease are female sex, older age, and meibomian gland dysfunction (MGD).¹ Among the iatrogenic causes of ocular surface disease (OSD), topical medications, particularly those that contain the preservative benzalkonium chloride (BAK), are probably the greatest offenders. Laser vision correction and cataract surgery cause a transient and sometimes longlasting neurotrophic effect, leading to breakdown of the ocular surface. Systemic medications, such as nonsteroidal anti-inflammatory drugs, antihistamines, antihypertensives, and hormone replacement therapies, also increase the risk of dry eyes. What does dry eye have to do with glaucoma? The prevalence of both increases with age. The therapies we prescribe to treat glaucoma induce dry eye disease; and chronic inflammation leads to alteration of the ocular surface anatomy. I’d like to dive a little deeper into OSD and glaucoma, because the literature offers a lot of insight, and I think sometimes, because we’re treating glaucoma, and glaucoma is a blinding disease, we forget about the potential impact of our treatments on the ocular surface. GLAUCOMA DROPS AND THE OCULAR SURFACE Zhang and colleagues reported that as many as 60% of patients using antiglaucoma eye drops have OSD.² They theorized that some OSD might have been preexisting, but in all cases, the medication exacerbated the disease. According to Leung and colleagues, the prevalence and severity of OSD symptoms correlates with the frequency of drop use and BAK exposure.³ They found a two-fold increase in the likelihood of developing OSD with each additional prescribed BAK-containing eye drop. In the early stages of glaucoma, we typically prescribe a topical drop and observe its effect on pressure control. If one drop doesn’t produce the desired response, we often add a second and sometimes even a third agent. This has real consequences for patients who are using these medications. The Table shows a plethora of studies that highlight the various medications we use to treat glaucoma and their negative impact on the ocular surface.²

Not all topical glaucoma medications affect the ocular surface in the same way. Prostaglandin analogues (PGAs) tend to cause more MGD, while alpha-adrenergic agonists have a high ocular allergy rate. Carbonic anhydrase inhibitors can alter the corneal endothelial pump function and lead to corneal thickening. Beta blockers act on the beta receptor of the lacrimal gland and reduce the basal tear turnover rate. They also can alter mucus formation in the tear film, causing increased staining of the cornea and conjunctiva. When we talk about glaucoma, a blinding disease that causes irreversible damage, it’s important to also discuss how some of the medications we use to treat glaucoma can induce irreversible damage to the ocular surface. That’s where meibomian gland-related atrophy and dysfunction come into play. Mocan and colleagues found that 92% of patients using a PGA, compared with 58% of patients using a non-PGA medication, had MGD.⁴ Arita and colleagues reported a higher prevalence of meibomian gland atrophy in patients using glaucoma medications (Figure 1).⁵ While not all patients with meibomian gland atrophy will have issues related to the ocular surface, it’s an important consideration, because once atrophy sets in, it’s irreversible. With decades of therapy, increasing age, and other comorbid risk factors, many of our glaucoma patients are having vision issues as much from their ocular surface disease as from their glaucoma.

Figure 1. Some glaucoma medications may permanently damage the meibomian glands.

Histologically, patients who have OSD and are using topical antiglaucoma medications experience increased conjunctival inflammation. The corneal epithelial cells become devitalized and have difficulty recovering. Over time, BAK can lead to neurotrophic corneas. As a result, we often see patients in our clinics who have been using topical medications for many years and are now reporting blurry vision but no pain. When we look at the tear film, reduced tear breakup time is common, in part because of MGD and hyperosmolarity, which is a key mechanism that drives OSD and dry eye in particular. That leads to a signaling cascade to create chronic inflammation on the surface. BARRIERS TO COMPLIANCE: SIDE EFFECTS While our current glaucoma medications cause dry eye and MGD, we’re also challenged to manage patients who cannot or will not adhere to the regimen we prescribe.^6,7 Some of our elderly patients are hampered by poor dexterity,⁸ and frequently when the drops are working, they’re causing side effects that patients can’t tolerate.⁹ I often ask colleagues, “If you had to take a multivitamin every night, how many of you would take it?” Typically, only about 25% would comply. Now, think about prescribing eye drops for patients who can’t relate the medication to their glaucoma, because it starts in the periphery of their vision, and you’re telling them to use an eye drop that will irritate their ocular surface over time. We’re creating a situation where compliance is not rewarded. We need to be cognizant of that fact. The literature certainly confirms that noncompliance exists,^10-12 and I think all of us in clinical practice concur. If we ask ourselves, “Do patients have to be 100% compliant?” The answer is yes. Patients who are not compliant have visual field progression (Figure 2).¹⁰ Therefore, we need therapies that take concerns about compliance out of the picture.

Figure 2. Patients who are not compliant have visual field progression.

BARRIERS TO COMPLIANCE: COST AND ACCESS When prescribing or recommending a medication to our patients, many extraneous factors are involved, such as insurance coverage and what’s happening at the pharmacy (pharmacists are often incentivized to make certain substitutions). And the question remains: Is the patient actually getting the medication that you prescribed? Patients may have a high copay and may not be able to afford the drug. If they do get the medication, they may stop using it because of the side effects. There’s also a cost to the practice when we prescribe eye drops.  We must take the time to explain how to use them and the importance of compliance. Clinicians and staff will need to field phone calls from patients related to side effects, and, of course, we’re all familiar with the phone calls and staff time required to obtain prior authorizations. We have had some advances in our traditional glaucoma therapies. Preservative-free formulations of topical medications are available, and many more patients today are undergoing selective laser trabeculoplasty. We also have an entirely new category, microinvasive glaucoma surgery, which is an option in the United States for patients who are having cataract surgery. We’re trying to rely less on topical drops, or if we’re using drops, we’re trying to use those that are friendlier to the ocular surface. Despite these advances, we need more options. We need therapies that work at the target site of activity and deliver medication without topical toxicity, which I truly believe is a huge issue as it relates to compliance. Our next-level treatment needs to take that into consideration. We need novel drug delivery platforms to improve patient care and reduce the blindness burden from glaucoma.

1. Craig JP, Nichols KK, Akpek EK, et al. TFOS DEWS II definition and classification report. Ocul Surf. 2017;15(3):276-283.
2. Zhang X, Vadoothker S, Munir WM, Saeedi O. Ocular surface disease and glaucoma medications: A clinical approach. Eye Contact Lens. 2019;45(1):11-18.
3. Leung EW, Medeiros FA, Weinreb RN. Prevalence of ocular surface disease in glaucoma patients. J Glaucoma. 2008;17:350-355.
4. Mocan MC, Uzunosmanoglu E, Kocabevoglu S, Karakaya J, Irkec M. The association of chronic topical prostaglandin analog use with meibomian gland dysfunction. J Glaucoma. 2016;25(9):770-774.
5. Arita R, Itoh K, Maeda S, et al. Effects of long-term topical anti-glaucoma medications on meibomian glands. Graefes Arch Clin Exp Ophthalmol. 2012;250(8):1181-1185.
6. Fechtner RD, Godfrey DG, Budenz D, Stewart JA, Stewart WC, Jasek MC. Prevalence of ocular surface complaints in patients with glaucoma using topical intraocular pressure-lowering medications. Cornea. 2010;29(6):618-621.
7. Friedman DS, Quigley HA, Gelb L, et al. Using pharmacy claims data to study adherence to glaucoma medications: methodology and findings of the Glaucoma Adherence and Persistency Study (GAPS). Invest Ophthalmol Vis Sci. 2007;48(11):5052-5057.
8. Hennessy AL, Katz J, Covert D, et al. A video stud of drop instillation on both glaucoma and retina patients with visual impairment. Am J Ophthalmol. 2011;152(6):982-988.
9. Sherwood MB, Craven ER, Chou C, et al. Twice-daily 0.2% brimonidine-0.5% timolol fixed-combination therapy vs monotherapy with timolol or brimonidine in patients with glaucoma or ocular hypertension: a 12-month randomized trial. Arch Ophthalmol. 2006;124(9):1230-1238.
10. Stewart WC, Konstas AG, Pfeiffer N. Patient and ophthalmologist attitudes concerning compliance and dosing in glaucoma treatment. J Ocul Pharmacol Ther. 2004;20(6):461-469.
11. Patel SC, Spaeth GL. Compliance in patients prescribed eyedrops for glaucoma. Ophthalmic Surg. 1995;26(3):233-236.
12. Konstas AG, Maskaleris G, Gratsonidis S, Sardelli C. Compliance and viewpoint of patients in Greece. Eye(Lond). 2000;14 Pt 5:752-756.

FOCUSING ON SUSTAINED-RELEASE DRUG DELIVERY

Researchers aim to address long-standing glaucoma treatment challenges with new devices.ROBERT N. WEINREB, MD The development of sustained-release drug delivery devices is a rapidly emerging area in the field of glaucoma. Current development programs, almost all of which are utilizing the proven efficacy of the prostaglandin analogues, aim to demonstrate long-lasting efficacy, reduce side effects, and improve patients’ adherence to treatment. Investigators are looking at two major approaches to overcome this challenge. One involves applying devices to the ocular surface through, for example, a contact lens-like ring or intracanalicular implant. The second requires intracameral injection. Most of these studies are currently in phase 2, and keep in mind, none of the devices I discuss here have FDA approval. DELIVERY TO THE OCULAR SURFACE The travoprost sustained-release device (Ocular Therapeutix) is administered as an intracanalicular depot through the punctum and is designed to deliver the medication to the ocular surface for up to 90 days. One of the benefits with this device is that the depot can be visualized with a blue light (Figure 1). This is important, because one of the issues with any of the intracanalicular devices is that, like a punctal plug, they can fall out. If a patient is being treated for dry eye, and a punctal plug falls out without the patient’s knowledge, that’s not so critical. If a patient with glaucoma is depending on an intracanalicular device for IOP control and it falls out, undetected, that can have significant consequences.

Figure 1. The travoprost sustained-release depot can be visualized using a blue light source with a yellow filter.

In a phase 2 study, comparing the travoprost depot to timolol and a placebo plug, the average pressure reduction over 3 months with the travoprost depot was similar to what was observed with topical travoprost (Figure 2).¹ A phase 3 clinical trial, which enrolled more than 554 patients with ocular hypertension or primary open-angle glaucoma, failed to meet the primary endpoint of significant superiorityin the reduction of IOP.² An argument might be made that the use of this device could improve adherence.

Figure 2. Average IOP reduction over 3 months with the travoprost depot was consistent with the reduction observed with topical travoprost.

Another product, an L-shaped punctal plug with a latanoprost core (Mati Therapeutics), is designed to create unidirectional flow into the tear film and, therefore, reduce systemic absorption. Phase 2 studies showed a 20% reduction in IOP at 3 months with 92% retention.³ The device is implanted in the canaliculus, and although it is cosmetically invisible, it is detectable clinically (Figure 3).

Figure 3. A punctal plug delivery system by Mati Therapeutics is inserted in the canaliculus.

The bimatoprost sustained-release ring was developed by ForSight Vision and acquired by Allergan. The periocular ring is inserted into the conjunctival cul-de-sac and rests under the eyelid (Figure 4). The ring must be replaced by a clinician once the drug is depleted every 3 to 6 months.

Figure 4. This sustained-release ring is formulated with bimatoprost and rests under the eyelids.

In a phase 2 study, 130 patients were randomly assigned to treatment with timolol or the bimatoprost ring.⁴ Patients in the bimatoprost ring group experienced a mean reduction from baseline IOP of 3.2 to 6.4 mm Hg compared with 4.2 to 6.4 mm Hg for the timolol group over 6 months. The bimatoprost ring is not inferior to timolol. One potential advantage is that the prostaglandin analogues have sustained pressure-lowering over 24 hours in comparison to timolol, which lowers pressures during the day but not during the night. What’s more, adherence to a drop regimen is poor, particularly when compared with a medication that is in the eye for 3 months or longer. INTRACAMERAL DRUG DELIVERY A number of intracameral devices are currently in development. The travoprost extended-release biodegradable implant (Envisia Therapeutics) and a latanoprost free-acid implant (PolyActiva) are in phase 1/2 trials. There are preliminary safety data from a phase 2 trial of the travoprost intracameral implant (Glaukos; Figure 5)⁵ and a phase 3 trial is underway. Ocular Therapeutix has a travoprost implant in phase 1 trials.

Figure 5. Investigators reported preliminary safety data for the travoprost intracameral implant.

Allergan has a first-in-class bimatoprost sustained-release biodegradable implant designed to lower IOP for at least 4 months (Figure 6). The implant is supplied in a preloaded single-use applicator and is deposited within the anterior chamber using a 28-gauge needle.

Figure 6. This first-in-class implant is designed to lower IOP for at least 4 months.

In the 2-year phase 1/2 APOLLO trial, 75 patients with open-angle glaucoma received various doses of the bimatoprost sustained-release implant (6 μg, 10 μg, 15 μg, or 20 μg) in the study eye and topical bimatoprost 0.3% once daily in the fellow eye.⁶ Over 16 weeks, mean IOP reduction from baseline in the bimatoprost sustained-release implant group ranged from 7.2 mm Hg to 9.5 mm Hg, depending on dose, compared with 8.4 mm Hg in topically treated eyes. At 24 months, 28% of patients had not required any additional treatment after a single implant administration. Sustained effects through 24 months were reported for all dose cohorts and were not dose dependent. In two 20-month phase 3 studies (ARTEMIS 1 and 2), patients were randomized to receive a bimatoprost sustained-release  implant dosed every 4 months for a total of three administrations or twice daily timolol 0.5% eye drops. One study has recently completed, and the other is ongoing, but the primary database lock phase 3 results showed that bimatoprost sustained-release implant met the primary endpoint of noninferiority to topical timolol in the primary efficacy period through week 12. In addition, after receiving three implants over 8 months, more than 80% of patients had probability of sustained IOP lowering with no additional treatment needed for at least a year.⁷ The results, in my opinion, were nothing short of stunning and transformative. More than 20 years ago, my laboratory at the University of California San Diego, in collaboration with Paul Kaufman, MD, at the University of Wisconsin, investigated the extracellular matrix of the ciliary muscle, which is integral with the uveoscleral outflow pathway.⁸ In particular, the effect of prostaglandins in altering the extracellular matrix was studied. One aspect of our studies evaluated the release of a group of substances within the outflow pathway called metalloproteinases. We observed that prostaglandins alter these substances, and we concluded that these observations supported the hypothesis that increased metalloproteinase production by ciliary muscle cells has a role in increasing uveoscleral outflow facility after administration of topical prostaglandins. Would this explain how this implant has such a great effect? One possibility is extracellular material is being washed out. The muscle is being altered, which is creating a sustained effect on uveoscleral outflow. This remains to be determined. SUMMARY We currently have two major forms of sustained delivery. One is largely products that deliver medication to the external surface of the eye, whether it’s a ring, an intracanalicular implant, or a punctal plug. The other is the intracameral approach, which, to me, is most impactful. Besides lowering IOP, these devices have the potential to reduce ocular surface disease. Both types of drug delivery will improve adherence. Sustained drug delivery is arriving, and new classes, molecules, and mechanisms will be arriving in the coming months to years. Many new avenues and interactions with existing therapies have yet to be explored. There’s no question that they will be disease-modifying or paradigm-changing.

1. Ocular Therapeutix reports on topline results of phase 2b glaucoma clinical trial [press release]. Bedford, MA: Ocular Therapeutix; October 22, 2015. https://www.businesswire.com/news/home/20151022006614/en/Ocular-TherapeutixTM-Reports-Topline- Results-Phase-2b. Accessed December 11, 2019.
2. Ocular Therapeutix announces topline results of phase 3 clinical trial of OTX-TP for the treatment of glaucoma [press release]. Bed­ford, MA: Ocular Therapeutix; May 20, 2019. https://ocutx.gcs-web.com/news-releases/news-release-details/ocular-therapeutixtm-announces-topline-results-phase-3-0. Accessed December 11, 2019.
3. Varma DK. Sustained-release drug delivery is closer than you think! Glaucoma Today. 2018;6:58-60. http://glaucomatoday. com/2018/06/sustained-release-drug-delivery-closer-than-you-think/. Accessed December 11, 2019.
4. Brandt JD, DuBiner HB, Benza R, et al. Long-term safety and efficacy of a sustained-release bimatoprost ocular ring. Ophthalmology. 2017;124(10):1565-1566.
5. Glaukos Corporation’s iDose Travoprost achieves sustained IOP reduction and favorable safety profile in 12-month interim cohort [press release]. San Clemente, CA: Glaukos Corporation; January 10, 2018. http://investors.glaukos.com/investors/press-releases/ press-release-details/2018/Glaukos-Corporations-iDose-Travoprost-Achieves-Sustained-IOP-Reduction-and-Favorable-Safety- Profile-in-12-Month-Interim-Cohort/default.aspx. Accessed December 11, 2019.
6. Lewis RA, Christie WC, Day DG, et al.; Bimatoprost SR Study Group. Bimatoprost sustained-release implants for glaucoma therapy: 6-month results from a phase I/II clinical trial. Am J Ophthalmol. 2017;175:137-147.
7. Allergan Announces Positive 3-Month Topline Results from Second Phase 3 Study of Bimatoprost SR (Sustained-Release) Implant for Lowering Intraocular Pressure (IOP) in Patients with Open-Angle Glaucoma or Ocular Hypertension [press release]. January 9, 2019. www.allergan.com/News. Accessed January 17, 2020.
8. Weinreb RN, Toris CB, Gabelt BT, Lindsey JD, Kaufman PL. Effects of prostaglandins on the aqueous humor outflow pathways. Surv Ophthalmol. 2002;47(Suppl 1):S53-S64.

MAKING A CASE FOR A SUSTAINED-DELIVERY DRUG IN GLAUCOMA THERAPY

A case-based roundtable discussion. This 55-year-old patient with untreated open-angle glaucoma had initial pressures of 26 mm Hg. The visual field glaucoma hemifield test (Figure 1) appears to be within normal limits in the left eye. The right eye has a small borderline inferior defect and some corresponding thinning of the retinal nerve fiber layer superiorly.

Figure 1. OCT and visual fields suggest glaucoma.

The patient had been using latanoprost for 2 years, and as shown in Figure 2, some punctate epitheliopathy of the cornea is present. As a glaucoma specialist, I see corneas like this one every day, but Dr. Gupta, maybe you would tell me something else is happening.

Figure 2. The patient developed dry eye and blurred vision after 2 years of prostaglandin analogue therapy.

DR. GUPTA: Chronic use of topical medications, specifically those containing benzalkonium chloride (BAK), can absolutely lead to punctate staining and other forms of ocular surface disease. Certainly, in this patient, I’d want to look at the meibomian glands and the other ocular surface structures. DR. RADCLIFFE: In terms of management, what happens when a patient with good pressure control on monotherapy develops dry eye? How do you proceed? DR. CRAVEN: When a patient is having problems with topical medications, I would discuss selective laser trabeculoplasty (SLT). Evidence shows that it’s effective at reducing pressures when they are in the mid-20s without treatment.¹DR. GUPTA: I appreciate that Dr. Craven suggested a nonpharmacologic therapy. I often see patients who are using several medications, perhaps for many years, and who have meibomian gland disease and are frustrated by poor vision. Sometimes our knee-jerk reaction is to add cyclosporine or lifitegrast, or to advise them to use tears six times a day or add other therapies. In these cases, we need to pause and determine what’s driving the ocular surface disease. I often send my patients back to the glaucoma doctor and recommend SLT or something else to avoid adding another medicine. DR. WEINREB: How do you all feel about nonpreserved products and products with alternative preservatives?DR. CRAVEN: I think it’s reasonable to try those products, because some patients do better with them. It’s not an absolute guarantee, though. Some of my patients who are using preservative-free products still have meibomian gland dysfunction that doesn’t seem to resolve. DR. WEINREB: Dr. Radcliffe, do you ever use nonpreserved products? DR. RADCLIFFE: I have mixed feelings about them. I would say this case is atypical, because a once-a-day prostaglandin analogue usually carries a modest preservative load. I’ve been impressed with the meibomian gland dysfunction, which is present in up to 92% of patients using prostaglandin analogues.² I think getting these great drugs inside of the eye instead of on top of or around the eye might be the key to avoiding some of these topical side effects. What’s your experience with preservative-free drops? DR. WEINREB: Some patients still are averse to SLT, and a preservative-free product provides an alternative. But I agree that patients who have epitheliopathy often continue to have epitheliopathy, even when they’re using a preservative-free medication or one with an alternative preservative to BAK. DR. GUPTA:One of the issues with preservative-free products is that they can be cost-prohibitive. I may want to prescribe this alternative therapy that will be less toxic to the ocular surface, but sometimes it becomes financially unfeasible for patients to pay so much for a medication annually. DR. WEINREB: It’s also inconvenient, because preservative-free drops come in small, one-time-use vials that need to be refrigerated, which is difficult if someone is traveling, for example. DR. CRAVEN: When I was in the Middle East, I had the opportunity to use the Ivantis microstent and the Glaukos mulitdirectional stent as a primary treatment, which is off-label in the United States. I think that would be a good option for a patient like this. Patients tolerate it well, and I was surprised at how well it works as a primary treatment in eyes that are similar to this patient’s. DR. RADCLIFFE: We don’t always use our therapies in the right order here in the United States. We started with laser as a last resort, but it probably does very well, early on. Perhaps that’s the same with how we’re using microinvasive glaucoma surgery (MIGS). In this case, the patient is getting older, has dry eyes, and improved after SLT. His pressure is good for a few years, and then it pops back up, as can happen occasionally after SLT. As I explain to patients, sometimes SLT lasts for 10 years, sometimes it doesn’t work at all. In this case, it wore off after a few years, and we see some progression (Figure 3).  

Figure 3. The patient underwent SLT, but the effect id not persist. It lasted 2 years.

While the visual fields appear reasonably full, the retinal nerve fiber layer has changed from normal thickness to borderline. The IOP has increased to 23 mm Hg, and the OCT is showing progression. Where would you take this patient next? DR. GUPTA:To me, a sustained-delivery medication would be ideal in this case; however, we don’t have the option of an FDA-approved sustained-release implant at this time. When a medication can be delivered over several months, the risk for topical toxicity is eliminated, as is the risk for nonadherence to a regimen that may require patients to instill drops frequently throughout the day. DR. CRAVEN: I agree that this patient is a perfect candidate for a sustained-release medication. If that’s available, I would consider it. DR. RADCLIFFE: Let’s think about the different options for sustained delivery. We have rings and plugs that sit on the surface of the eye, and we have intracameral options. How would your conversation go with that patient? What might you recommend? DR. CRAVEN: The data show stronger efficacy with the intracameral device,³ and this patient needs pressure reduction. I’d probably discuss that option with the patient first. If the patient isn’t interested in that, then I might discuss the external methods, if they’re available. If standalone MIGS were available, that would be a good discussion at this point, and I might even discuss a trabeculectomy. So much of what I would discuss would depend on the individual patient’s circumstances—what my greatest concern is, the status of the other eye, family history, and various other associated factors. DR. RADCLIFFE: Dr. Weinreb, how would you proceed? DR. WEINREB: This patient has early glaucoma. There was loss in an area of retinal nerve fiber layer that corresponded to a small change in the visual field. There’s been a small amount of progression. The rate isn’t rapid, so there’s no urgency in dropping the pressure significantly. SLT is an option. In the LiGHT trial,¹ treatment-naive patients did quite well with SLT compared with drop treatment. I suspect a quarter of the patients had SLT repeated over the 3 years, and it seemed to be effective. Restarting topical therapy, using a preservative-free medication or a different type of preserved medication, is a reasonable choice. Many of the new medications that we’re using today, although effective, just beat up the ocular surface. I’m always looking at my patients and thinking, what can I do for their ocular surface. It’s a big problem. I agree that sustained-delivery of antiglaucoma medications will be transformative for us and for our patients. I would keep standalone MIGS in the background for this patient. It’s still a surgical procedure, and being a surgical procedure, there is the potential, albeit very small, for complications. DR. RADCLIFFE: I tell my patients that I don’t repeat SLT frequently. I think they need to hear that to understand that they’re not being sentenced to a lifetime of biennial SLT treatments, but I agree, this patient is a great candidate for repeat SLT. I also agree that we have many great potent therapies, but this patient needs a great, extremely well-tolerated, potent therapy. I’m not sure we have a perfect medication for him, but an intracameral implant will be ideal, once available. That said, I believe this patient would be a wonderful candidate for an the Glaukos micro-bypass stent if he is ready for cataract surgery. Otherwise, I would repeat the SLT.

1. Gazzard G, Konstantakopoulou E, Garway-Heath D, et al. Selective laser trabeculoplasty versus eye drops for first-line treatment of ocular hypertension and glaucoma (LiGHT): a multicentre randomised controlled trial. Lancet. 2019;393(10180):1505-1516.
2. Mocan MC, Uzunosmanoglu E, Kocabeyoglu S, et al. The association of chronic topical prostaglandin analog use with meibomian gland dysfunction. J Glaucoma. 2016;25(9):770-774.
3. Lewis RA, Christie WC, Day DG, et al.; Bimatoprost SR Study Group. Bimatoprost sustained-release implants for glaucoma therapy: 6-month results from a phase I/II clinical trial. Am J Ophthalmol. 2017;175:137-147.