FormalPara Key Summary Points

Substantial barriers to long-term therapy with topical intraocular pressure-lowering agents for the treatment of glaucoma exist.

Sustained release therapies currently Food and Drug Administration (FDA) approved for use in the USA include the bimatoprost implant (Abbvie) and travoprost intracameral implant (Glaukos).

Current FDA-approved sustained release therapies have a proven efficacy and safety profile, but there are practical limitations to long-term usage.

Future sustained-release platforms on the horizon offer promise.

Introduction

Glaucoma is a chronic and progressive condition and is a leading cause of irreversible blindness globally [1]. Upon diagnosis, patients necessitate life-long monitoring and treatment [2, 3]. Topical glaucoma medications play a crucial role in the management of glaucoma, with a significant proportion of patients using two or more eye drops concurrently for extended periods [1, 4].

Despite their effectiveness in reducing intraocular pressure (IOP) and slowing glaucoma progression, these medications face several practical limitations. One significant challenge in chronic diseases like glaucoma is poor adherence to therapy, with studies demonstrating that up to 80% of patients with glaucoma and patients with ocular hypertension (OHT) do not adhere to their medication regimen as prescribed [5,6,7]. Nordstrom et al. [8] found that nearly half of the patients diagnosed with glaucoma or patients with suspected glaucoma ceased using their initially prescribed glaucoma medications within 6 months. Barriers to adherence include lack of social support, physical disabilities interfering with handling the medication bottles, forgetfulness, and inconvenient dosages and timing, especially with multiple drops [9, 10].

Moreover, topical glaucoma medications, particularly those containing preservatives, have been linked to ocular surface disease, dry eye disease, conjunctival erythema, and decreased tear production, all of which can significantly impact patients’ quality of life [11, 12]. Economically, some studies have suggested that laser or surgical interventions may be more cost-effective, particularly in early-stage glaucoma or in patients younger than 70 years old [13, 14].

Additionally, compared to glaucoma surgery, topical glaucoma medications have been associated with more fluctuations in the IOP [15, 16], which is a risk factor for glaucoma progression [17]

In recent years, efforts have been made to tackle these challenges and cater to the needs of patients with glaucoma. One promising approach involves the utilization of sustained drug delivery systems, which have the potential to enhance drug delivery and reduce glaucoma progression.

A diverse array of sustained-release glaucoma medications exists, including drug-eluting contact lenses, punctal plugs, conjunctival inserts, intracameral implants such as Durysta® (bimatoprost, Allergan, Irvine, CA, USA), and iDose® TR (travoprost, Glaukos Corporation, Aliso Viejo, California, USA), and intraocular lens-based devices (SpyGlass system, SpyGlass Pharma, Aliso Viejo, California, USA).

A range of indications may exist for the use of intraocular implants in the treatment of OHT and glaucoma. Consideration may be given to social and physical circumstances that preclude consistent eye drop instillation. Presenting IOP and stage of glaucomatous disease may be secondary considerations in these settings, but there are no known contraindications with respect to these factors.

In this article, our focus is on elucidating the potential of intracameral prostaglandin analogue implants, particularly following the recent US Food and Drug Administration (FDA) approval of iDose TR. This article is based on previously conducted studies and does not contain any new studies with human participants or animals performed by any of the authors.

Bimatoprost Implant (Durysta®)

In 2022, the US FDA approved a single administration of the intracameral bimatoprost implant as a sustained-release medication for lowering IOP in patients with glaucoma or OHT. This implant is a small rod-shaped device measuring approximately 200 µm in diameter and 1.1 mm in length. It contains 10 µg of bimatoprost in a biodegradable polymer designed to release the medication slowly and continuously in a non-pulsatile manner over a period of 3 months. This implant is inserted into the anterior chamber either at the slit-lamp or in the operating room.

The approval of the bimatoprost implant was based on the results of two phase III clinical trials (ARTEMIS trials), including 1122 participants. These trials demonstrated the non-inferiority of the bimatoprost implant to topical timolol 0.5% (administered twice daily) in reducing IOP over 12 weeks [18, 19].

Once-daily topical bimatoprost 0.01% has been shown to reduce mean diurnal IOP by approximately twice as much as nocturnal IOP [20, 21]. However, a recent multicenter study by Weinreb et al. [22] demonstrated that a single administration of intracameral bimatoprost significantly reduced both diurnal and nocturnal IOP, with reductions of 2.6 and 2.1 mmHg, respectively, leading to a reduction in 24-h IOP fluctuations.

Although the level of bimatoprost in the blood becomes undetectable within 4.5 months after intracameral injection, its IOP-lowering effect may persist longer. One study reported that after a single bimatoprost injection, IOP remained controlled in 40% of patients at 12 months and in 28% of patients at 24 months [23]. The exact mechanism underlying this prolonged IOP-lowering effect is not fully understood. However, it is hypothesized to be due to its effect on episcleral venous outflow [24, 25] or changes in matrix metalloproteinase production, leading to remodeling of the trabecular meshwork and ciliary body extracellular matrix, thereby reducing resistance to aqueous outflow [26, 27].

One advantage of targeted delivery of the bimatoprost implant is the reduced exposure of the ocular adnexa to prostaglandin, which may help mitigate periorbitopathy and eyelash hypertrichosis associated with topical prostaglandin analogues [28].

The main limitation of the bimatoprost implant is that it is FDA approved for a single use only because of the risk of adverse corneal events. In the ARTEMIS II trial, none of the patients had worsening of endothelial cell loss after the first or the second intracameral 10 µg bimatoprost injections. However, after the third 10 µg bimatoprost injection, approximately 6% of patients experienced worsening endothelial cell loss, and the implant had to be removed in around 3% of patients during the 20-month follow-up period [19]. At the 20-month follow-up visit, the mean endothelial cell density in the 10 µg bimatoprost group was 5% lower than the baseline values, compared to 1% lower in the topical timolol group [19].

Another limitation may be the efficacy of the implant in patients with severe glaucoma. A recent study found that while the bimatoprost implant successfully reduced the glaucoma medication burden in patients with mild to moderate glaucoma for up to 6 months, its effectiveness in reducing medication burden in patients with severe glaucoma was only sustained for 1 month [29].

Travoprost Implant (iDose® TR)

The FDA has recently approved the use of the travoprost intracameral implant (iDose TR) for the management of glaucoma. This implant consists of a biocompatible titanium reservoir (approximately 0.5 mm in diameter and 1.2 mm in length) preloaded in a single-dose inserter. The implant is designed to provide a slow, sustained release of preservative-free travoprost (75 µg) controlled by the thickness of a nanoporous ethylene vinyl acetate (EVA) membrane (Fig. 1). There are two implant designs, the fast-eluting (FE) and slow-eluting (SE) models, which differ only in the thickness of the EVA membrane. It is noteworthy that the SE is the commercially available model, while the FE model is reserved for research purposes. The implant is surgically inserted into the trabecular meshwork and secured to the sclera via a 0.6-mm-long anchor (Fig. 1).

Fig. 1
figure 1

Design of the travoprost intracameral implant (iDose® TR). Printed with permission from Glaukos Corporation

Full size image

In their phase II trial, Berdahl et al. [30] investigated the long-term safety and efficacy of two designs of the implant (single implantation) compared to topical timolol 0.5% ophthalmic solution (used twice daily). They observed a significant reduction in mean baseline IOP over 3 years, with reductions ranging from 7.3 to 8 mmHg in the SE design and 7.6–8.8 mmHg in the FE design, compared to 7.3–7.9 mmHg in the timolol group. Additionally, throughout all follow-up visits, a higher percentage of patients in the implant groups (63–69% at 3 years) achieved IOP control while using the same or fewer medications compared to the timolol group (45% at 3 years), with favorable safety profile observed in the implant groups.

The FDA approval was based on the results of two multicenter randomized controlled trials (GC-010 and GC-012). Sarkisian et al. [31] present the 12-month results of the first of the two pivotal trials (GC-010) in the April issue of Ophthalmology and Therapy. The study compared the travoprost implant (SE and FE models) to a group of patients receiving topical timolol 0.5%. Patients included in the study were either phakic with no visually significant cataract or pseudophakic with uncomplicated cataract surgery. Although the study was initially powered for 3-month non-inferiority in IOP reduction (primary outcome), the results at 6, 9, and 12 months are noteworthy. The study demonstrated non-inferiority to timolol through 12 months, with a significant reduction in mean IOP after SE-travoprost implantation ranging from 5.5 to 8.5 mmHg over a 12-month follow-up period. Additionally, 81% of patients were glaucoma medication-free at 12 months. The implant showed high tolerability and a favorable safety profile, with most adverse ocular events associated with the surgical implantation being mild and transient. One concern associated with the implantation of intracameral implants, in general, is the potential exacerbation of endothelial cell loss. This may stem from alterations in aqueous humor dynamics, direct contact between the implant and corneal endothelium, or medication-induced endothelial toxicity. Although none of the SE-travoprost group experienced endothelial cell loss exceeding 20% compared to baseline values, longer follow-up and evaluation of endothelial cell count in a larger set of patients would provide more comprehensive insights [31]. Moreover, it should be noted that the device is relatively large and requires a surgical skillset for proper insertion to avoid inadvertent injury to surrounding ocular structures.

The device is designed to be replaced with a new one once its effect wears off, potentially providing a prolonged drop-free experience. A recent presentation at the American Academy of Ophthalmology annual meeting showed successful 12-month results in 32 patients who underwent replacement of iDose TR implants [32]. However, it is important to consider that a trip to the operating room is required for implantation, extraction, or replacement of the device, which may not be optimal for all patients. Therefore, implantation at the time of the cataract surgery may be more practical.

Several studies have shown that prostaglandin analogues have been associated with better medication adherence compared to other glaucoma medication classes, probably because of their convenient once-daily dosing [8, 33]. Hence, future implant designs may consider the ability to load the implant with multiple classes of glaucoma medications, potentially offering better IOP reduction and making it more suitable for patients with advanced stages of glaucoma, who are usually on multiple medications. Another future thought is integrating the implants with an IOP-monitoring device. Future studies could also explore the IOP-lowering effect of the iDose implant when used alongside cataract surgery, compared to that of cataract surgery only.

Pipeline Sustained-Release Glaucoma Medications

Various devices are currently being investigated for sustained release of glaucoma medications. SpyGlass system (SpyGlass Pharma, Aliso Viejo, California, USA) is an innovative implant that is designed to be implanted at the time of routine cataract extraction. It is composed of a single-piece hydrophobic acrylic intraocular lens (IOL) with two small drug-eluting pads attached to the haptic-optic junction. Using conventional phacoemulsification techniques, a surgeon implants the IOL into the capsular bag through a standard 2.4-mm incision. These drug-eluting pads are positioned outside the visual axis and designed to slowly release bimatoprost for a duration of 3 years. Preclinical animal studies have demonstrated significant IOP reduction without detectable systemic exposure or drug-related adverse events. In a recent human trial involving 23 patients with glaucoma or OHT, promising results were observed with a 45% mean reduction in IOP across all dosage groups at 9 months. Recently, the company announced that they have received clearance from the FDA to start a randomized multicenter phase I/II clinical trial to evaluate the safety and effectiveness of the SpyGlass system compared to a control group receiving standard IOLs with topical glaucoma medications [34].

Other devices in the pipeline include intracameral travoprost implants such as travoprost XR (ENV515) (Alcon) and OTX-TIC (Ocular Therapeutix), and intracameral sustained-release latanoprost (latanoprost FA SR, PolyActiva, Parkville VIC. Australia).

Conclusion

Sustained-release glaucoma medications have the potential to significantly enhance the medical management of glaucoma. By reducing the topical therapy burden, these delivery systems can reduce the adverse events related to the ocular surface and facilitate more consistent and sustained IOP control. This advancing field holds the promise of improving treatment outcomes and enhancing the overall care of patients with glaucoma.