Topical medical therapy has been a mainstay of glaucoma treatment for decades. Today’s medications are effective, and some have the convenience of once-daily dosing. In addition, the availability of generic formulations ensures accessibility. However, the initiation of chronic topical therapy comes with the stipulation that patients be adherent with their eyedrop regimen.

Studies show that anywhere from 26% to as much as 80% of glaucoma patients fail to adhere to their prescribed medications consistently over time.¹ Non-adherence is also multifactorial.² The vast majority of these patients are elderly and may have cognitive changes, memory challenges and/or dementia, causing forgetfulness, especially with more complex regimens that require frequent multi-bottle regimen administrations.

Also, patients may not have a sufficient social support system to assist with their ocular and systemic medications. Others may have difficulty with drop instillation; some patients have poor vision and others do not have manual dexterity or hand-eye coordination necessary for proper instillation onto the ocular surface. Additionally, patients may fail to see the benefit of therapy or understand that glaucoma is a disease that can progress with nonadherence, despite lack of symptoms.

Novel treatment options aim to address these limitations in patient adherence to topical therapy while improving quality of life. Sustained-release (SR) drug delivery is an attempt to provide a 100% adherence in therapy without relying on patient responsibility; fortunately, it is now available in the United States.

SUSTAINED RELEASE ARRIVES IN THE UNITED STATES

A number of SR drug delivery platforms for glaucoma medications have been in development. In March 2020, the FDA approved the first SR IOP-lowering implant, Bimatoprost SR (Durysta, Allergan).³ It is a rod-shaped biodegradable polymer-based intracameral implant (Figure 1) that slowly releases bimatoprost into the aqueous humor over 4 to 6 months.⁴ The implant is preloaded on a delivery handpiece and delivered into the anterior chamber through a peripheral corneal injection with a 28-g needle. It is minimally invasive and can be inserted in an office setting.

The implant contains 10 µg of bimatoprost, the total dose of which is similar to the amount contained in a single drop of the ophthalmic bimatoprost 0.01% solution. Currently, the FDA label allows for a single implantation per eye.

Durysta was evaluated in a pair of Phase 3 clinical trials, ARTEMIS 1 and 2.^5,6 Both enrolled subjects with open-angle glaucoma or ocular hypertension; they received either Bimatoprost SR 10 µg or 15 µg at day 1, week 16 and week 32 (fellow eyes received topical timolol 0.5% b.i.d. with a sham injection to maintain masking). Implantation occurred with patients in the supine position under a microscope (specified in the protocol). At the 12-week primary end point analysis, Durysta was deemed non-inferior to twice-daily topical timolol, with mean IOP reductions of 7-8 mm Hg and 6-7 mm Hg, respectively, in the two studies. The planned retreatment at weeks 16 and 32 provided long-term IOP control, with 80% of eyes sustaining controlled IOP to month 12 after the last injection with no further treatments. Factors associated with need for rescue IOP-lowering treatment after a third implant included baseline IOP >25 mm Hg and prior SLT.⁷

Common safety issues included conjunctival hyperemia, foreign-body sensation, eye pain, photophobia and conjunctival hemorrhage. Based on separate analyses, these were suggested to be attributable to the injection procedure itself, with side effects being greatest in the first 2 days after implantation. As principal investigators of the ARTEMIS clinical trials, we had the privilege of early experience with the implant. During the study, we implanted Bimatoprost SR every 4 months (per protocol) for a total of three implants. Eyes were rigorously sterilized, and many of the symptoms felt by patients were likely related to povidone iodine.

In the ARTEMIS pooled data, it was reported that a series of three implants (16 weeks apart) was associated with endothelial cell loss in 5.4% of patients. When data was analyzed 12 weeks after a single implant, endothelial cell loss was reported in 0.9% of patients.

PATIENT EDUCATION AND SELECTION

We recognized the importance of discussing the implantation technique with patients so they know what to expect during and after the procedure. This alleviated a lot of apprehension and made patients more comfortable. We also emphasized to patients how short the procedure was (typically less than 60 seconds) after the eye was prepped and the patient positioned. It was very helpful to inform patients in advance about the irritation from topical anesthesia and povidone iodine, which usually lasts no longer than a day. Finally, it is critical to warn patients of the pressure sensation from the eyelid speculum, as this is probably the most bothersome part of the procedure from the patient’s perspective.

It is understandable that some clinicians may be concerned that educating patients on Bimatoprost SR is challenging or time consuming compared with topical treatment. This sentiment is not uncommon with a first-in-class product representing a paradigm shift from conventional topical treatments. However, in our experience, careful patient selection was key to fruitful discussions of Bimatoprost SR. Once favorable patient profiles are identified, the discussions that ensue tend to flow more naturally.

For example, patients with severe ocular surface disease or poor medication adherence can be good candidates. Those patients may have already received surgical treatments or wish to delay additional surgery. A candid discussion about the implant then follows in which the clinician can present its advantages, favorable safety profile and the comfortable insertion. It is also important to discuss the expected IOP reduction and longevity of effect based on the data from the clinical trials.

IN PRACTICE

At present, many physicians have converted to slit lamp insertion of Bimatoprost SR rather than insertion under a microscope with the patient in the supine position. This change makes the procedure more seamless and less disruptive to patient flow. A lid speculum is still required with slit lamp insertion, however. Having an assistant readily available to stabilize the head of the patient in the slit lamp is also recommended.

In the end, both the supine position under a microscope in a minor procedure room or the sitting position in the slit lamp in an exam lane work equally well. Physicians can choose based on their preference and the logistics of their practice.

Again, the current label allows for a single implantation only per eye. It is imperative that clinicians perform gonioscopy to confirm that the anterior chamber can accommodate the implant (typically an inferior angle greater than 30°) and that eyes with corneal pathology are avoided.

MORE IN THE PIPELINE

Other SR platforms for glaucoma treatment are currently under investigation. These include intracameral implants, surface implants and punctal plugs. Perhaps the next device furthest along in development, behind Bimatoprost SR, is the iDose (Glaukos), which is a titanium intracameral travoprost implant intended for ab interno implantation through the trabecular meshwork (Figure 2). Phase 2 studies compared the iDose at a fast or slow elution rate to topical timolol 0.5% and demonstrated that IOP in both iDose groups remained at 32% below baseline at 12 months.⁸ Phase 3 trials are set for completion in 2023.

The bimatoprost ring (Allergan) is made of a polypropylene core coated with a matrix of silicone and 13 mg of bimatoprost; it is intended to rest on the conjunctival surface within the fornices and comes in various sizes, ranging from 24 mm to 29 mm in diameter.⁹ In Phase 2 trials, mean IOP reduction ranged from 3.2 mm Hg to 6.4 mm Hg, but criteria for non-inferiority to twice-daily topical timolol 0.5% were not met.

A travoprost-eluting punctal plug (OTX-TP, Ocular Therapeutix) has been evaluated as well.^10,11 This is meant to be inserted into the vertical portion of the superior or inferior canaliculus and, once exposed to tears, it conforms to the shape of the punctum. This punctal plug showed clinically meaningful IOP reduction in the 4.5 mm Hg to 5.7 mm Hg range, but it did not match twice-daily timolol 0.5% in Phase 2 studies. Mean IOP reductions of this punctal plug also failed to achieve the primary endpoint in Phase 3 clinical trials. Despite these results, this innovative platform may have potential in the future due to ease of insertion of a punctal plug. This has to be balanced with improved efficacy, retention and longevity.

THE CASE FOR SR IS GETTING STRONGER

Slow-release or drug delivery without drops has been long awaited. There is a general sense of excitement to finally have a breakthrough from the status quo of topical glaucoma medications. SR delivery systems offer many advantages over topical therapy and have the potential to optimize safety, efficacy, tolerability, cost and adherence. They deliver medication over the device’s lifespan, avoiding peak and trough IOP effects associated with topical instillation. With drug delivery to the target tissue, these systems reduce adverse events and improve tolerability and perhaps efficacy. Shifting the responsibility of administration from the patient to the physician also eliminates nonadherence, which limits the effectiveness of topical medication.

As previously mentioned, a single administration of Durysta is allowed per eye, which limits its practicality in the treatment of a chronic disease like glaucoma. However, Durysta still offers clinicians and patients a profoundly different approach to medication delivery than the currently available topical treatments. It is an appropriate alternative for certain patients, such as those with progressive glaucoma from non-adherence to topical agents and those wishing to delay incisional surgery.

Adverse effects, such as ocular surface disease, are also minimized with SR therapy as a result of drug delivery to the targeted tissue, while reducing off-target tissue exposure to active and inactive ingredients.¹²

In the current COVID-19 pandemic and social-distancing era, Durysta also enables patients to avoid routine visits or surgery and can be another tool in individualizing care for some patients to ensure IOP control in the interim. Overall, these advantages allow for more precise delivery of glaucoma care and may indeed transform the treatment paradigm. OM

REFERENCES

1. Olthoff CM, Schouten JS, Van De Borne BW, et al. Noncompliance with ocular hypotensive treatment in patients with glaucoma or ocular hypertension: An evidence-based review. Ophthalmology (Rochester, Minn). 2005;112:953-961.e7.
2. Tsai JC. A comprehensive perspective on patient adherence to topical glaucoma therapy. Ophthalmology. 2009;116:S30-S36.
3. Durysta. Package insert. Allergan, Inc; 2020.
4. 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.
5. Craven ER, Walters TR, Christie WC, et al. Phase 3 evaluation of bimatoprost sustained-release implant in patients with glaucoma or OHT: results at primary database lock. Paper presented at: 2019 Annual Meeting of the American Academy of Ophthalmology; October 12-15, 2019; San Francisco. Abstract PA054.
6. Medeiros FA, Walters TR, Kolko M, et al. Phase 3, randomized, 20-month study of bimatoprost implant in open-angle glaucoma and ocular hypertension (ARTEMIS 1). Ophthalmology. June 13, 2020.
7. Khouri AS, Medeiros FA, Robinson MR, et al. Predictive Factors for Long-Term IOP Lowering After Bimatoprost Implant 10-µg Administration in Phase 3 ARTEMIS Studies. Poster presented at: 2020 Annual Meeting of the American Academy of Ophthalmology; November 14-17, 2020. Poster PO176.
8. Glaukos corporation. Randomized study comparing two models of a travoprost intraocular implant to timolol maleate ophthalmic solution, 0.5%. ClinicalTrials.gov . March 8, 2019. https://clinicaltrials.gov/ct2/show/NCT03519386
9. Brandt JD, Sall K, DuBiner H, et al. Six-month intraocular pressure reduction with a topical bimatoprost ocular insert: results of a phase II randomized controlled study. Ophthalmology. 2016;123:1685-1694.
10. BioSpace. Ocular TherapeutixTM announces toppling results of phase 3 clinical trial of OTX-TP for the treatment of glaucoma. News release. May 20, 2019. https://www.biospace.com/article/releases/ocular-therapeutix-announces-topline-results-of-phase-3-clinical-trial-of-otx-tp-for-the-treatment-of-glaucoma 20121025_qlt_shows_positive_efficacy_trends_from_data_in_plug_combinations_in_phase_2_studies_for_glaucoma_using_latanoprost_punctal_plug_delivery_system/
11. Business Wire. Ocular TherapeutixTM reports on topline results of phase 2b glaucoma clinical trial. News release. October 22, 2015. https://www.businesswire.com/news/home/20151022006614/en/Ocular-TherapeutixTM-Reports-Topline-Results-Phase-2b
12. Seal JR, Robinson MR, Burke J, et al. Intracameral sustained-release bimatoprost implant delivers bimatoprost to target tissues with reduced drug exposure to off-target tissues. J Ocul Pharmacol Ther. 2019;35:50-57.

About the Authors

Khelly Shah, MD, is a PGY3 ophthalmology resident at Rutgers New Jersey Medical School in Newark, N.J.

Albert S. Khouri, MD, is the director of the Glaucoma Service and also the director of resident education at Rutgers New Jersey Medical School.

Disclosures: Dr. Shah has no financial disclosures.

Dr. Khouri reports financial relationships with Aerie, Allergan, Bausch + Lomb, Glaukos, NJ Health Foundation and Optovue.