Abstract
Glaucoma is the leading cause of irreversible visual loss worldwide, and as yet, there is no cure. The only evidence-based treatment to slow progression is by lowering intraocular pressure (IOP). Despite the development of new topical medications to reduce IOP, the major limitation of eyedrops lies in human and anatomical factors, namely patient compliance and poor bioavailability, making current medical glaucoma treatment ineffective. In this manuscript, we summarise the limitations of traditional topical anti-glaucoma therapy and study current drug delivery systems to lower IOP, with focus on the only two that have made FDA-approval- Durysta and iDose TR. We highlight their limitations and discuss real-world economic challenges that make it prohibitively difficult for these drug delivery systems to be more widely adopted in daily practice. In this perspective, we also introduce gene therapy as a novel therapeutic option to target downstream pathways of IOP regulation, neuroprotection of the optic nerve, and reducing mitochondrial stress to delay the progression of glaucoma. We discuss promising results of gene therapy for glaucoma treatment in in vivo animal models as well. We also explore the concept of novel nanoparticle-based drug delivery systems, which have the advantage of being highly modifiable and customisable, able to incorporate large amounts of cargo while maintaining a high transfection efficacy, and at a fraction of the cost. Lastly, we propose that nanomedicine, in conjunction with gene therapy, offers a promising solution to the aforementioned challenges of current glaucoma therapy, and can herald a new era of sustained glaucoma treatment.
Introduction
Glaucoma is the leading cause of irreversible visual loss worldwide, with global estimates of glaucoma afflicting up to 111.8 million by 2040. The World Health Organisation estimates that 5.2 million cases of irreversible blindness are a result of glaucoma, accounting for 15 % of the total burden of world blindness. Glaucoma is an optic neuropathy, often characterised by elevated intraocular pressure (IOP), leading to progressive death of the retinal ganglion cells (RGCs). There is no cure for glaucoma and as yet, the only evidence-based treatment to halt progression of glaucoma is IOP-lowering therapy. Available treatment to lower IOP includes topical eye drops, laser procedures, minimally invasive glaucoma surgery (MIGS), and glaucoma filtering surgeries or drainage devices. While there have been significant advancements in the surgical management for glaucoma, the mainstay first line treatment for the majority of glaucoma patients is still eyedrops.
Traditional anti-glaucoma eyedrops primarily work by two mechanisms: suppression of aqueous humour production (alpha-agonists, beta-blockers, and carbonic anhydrase inhibitors), or increase in aqueous humour outflow via uveoscleral or trabecular pathways (prostaglandin analogues, pilocarpine). Newer topical medications available on the market include Rho kinase inhibitors, which work via both mechanisms and also by lowering episcleral venous pressure (EVP), selective E-prostanoid subtype 2 (EP2) agonists that increase aqueous humour drainage through both trabecular and uveoscleral pathways without causing significant prostaglandin-associated periorbitopathy syndrome (PAPS), as well as nitric oxide donating prostaglandins that promote actin cytoskeleton rearrangement to improve trabecular outflow.
These advancements in medical therapy for glaucoma have no doubt managed to provide an extensive range of mechanisms of action through which IOP-lowering effects are exerted, and fixed combination options further increase efficacy. However, the major limitation to topical therapy lies in human and anatomical factors. Firstly, patient adherence to the instillation of eyedrops remains one of the biggest challenges in the utility and efficacy of glaucoma eyedrops. Studies on the compliance rate of patients to anti-glaucoma eyedrops have shown that up to 80 % of patients fail to adhere to their prescribed glaucoma treatment regimen. Furthermore, with the use of more complicated regimens (eg. twice or thrice a day dosing), patient compliance to eyedrop instillation drops even further. Secondly, a significant proportion of glaucoma patients also has systemic comorbidities like arthritis, dementia, Parkinson’s disease, which cause functional problems that result in the suboptimal instillation of eyedrops. Thirdly, majority of topical anti-glaucoma eyedrops induce ocular surface damage from preservatives-containing formulations, causing significant ocular discomfort and burning sensation, further reducing patient compliance. Fourthly, topical eyedrops typically have low bioavailability in the conjunctival cul-de-sac. The human conjunctival cul-de-sac has a maximum capacity of 30 μL, and normal eyelid blinking further reduces this capacity to 21–24 μL. Reflex blinking and drainage of tears from the nasolacrimal system again reduces the retention of eyedrops in the conjunctival cul-de-sac. As a result, the bioavailability of eyedrops has been estimated to be 5 %, making this traditional, age old drug delivery system largely wasteful and inefficient.
Hence, long-term sustained release and delivery of topical anti-glaucoma medication remains an attractive alternative to eyedrops, whilst avoiding the morbidity of surgical options. Chong et al. have shown that up to 75 % of glaucoma patients were willing to accept an alternative form of IOP-lowering treatment through 3-monthly subconjunctival injections rather than daily eyedrop use, and 86 % of these patients were willing to accept this alternative treatment even at a higher cost. This review aims to summarise the current Food and Drug Administration (FDA)-approved sustained drug delivery systems for glaucoma, their indications for use, their shortcomings, and also introduce a glimpse into the future directions currently being sought and developed in an effort to deliver long-term sustained IOP lowering.
Current sustained drug delivery systems for glaucoma
In recent years, there have been much research into non-topical sustained release glaucoma drug delivery systems (DDS), but few have made it to FDA-approval and commercialisation to market. Glaucoma DDS can be largely divided into intraocular and extraocular systems ( Fig. 1 ) , including drug-eluting punctal plugs, conjunctival fornix inserts, contact lenses, intracameral implants, and intraocular lens implants. Of these numerous devices currently undergoing research, some have reached clinical trials, but only 2 have obtained FDA-approval and made it to market: Durysta (Allergan, Irvine CA, USA) and iDose TR (Glaukos Corporation, Aliso Vjejo, California, USA).
Of those that have reached clinical trials but yet to attain FDA approval, few have shown good sustained IOP-lowering effects. These include the Latanoprost Punctal Plug Delivery System (L-PPDS) (Evolute, Mati Therapeutics, Austin, TX, USA), the bimatoprost ocular insert (Allergan, Dublin, Ireland), the topical ophthalmic drug delivery device (TODDD) (Amorphex Therapeutics, Andover, MA, USA), OTX-TP and OTX-TIC (Ocular Therapeutix, Bedford, MA, USA), a nanoliposome containing latanoprost (POLAT-001) , and a bimatoprost-loaded intraocular lens SpyGlass (SpyGlass Pharma). ( Table 1 ) .
| Drug delivery system | Company | Current/completed phase | Route of administration | Clinical Trial ID | Material | Active drug | Proposed duration of action |
|---|---|---|---|---|---|---|---|
| Latanoprost Punctal Plug Delivery System ( L -PPDS) | Evolute, Mati Therapeutics, Austin, TX, USA | 2 | Punctal plug | NCT02014142 | Silicone | Latanoprost | 4 weeks |
| Bimatoprost ocular insert | Allergan, Dublin, Ireland | 2 | Forniceal ring | NCT02537015 | Inner polypropylene support ring with an outer silicone matrix | Bimatoprost | 6 months |
| Topical ophthalmic drug delivery device (TODDD) | Amorphex Therapeutics, Andover, MA, USA | 1 | Superior forniceal implant | N.A | Soft elastomeric material | Timolol | 6 months |
| ENV515 Travoprost XR | Envisia Therapeutics, Morrisville, NC, USA | 2 | Intracameral | NCT02371746 | Biodegradable poly(esteramide) (PEA) polymer using PRINT technology | Travoprost | 6 months |
| OTX-TP | (Ocular Therapeutix, Bedford, MA, USA) | 3 | Punctal plug | NCT02914509 | Hydrogel | Travoprost | 3 months |
| OTX-TIC | Ocular Therapeutix, Bedford, MA, U.S.A | 3 | Intracameral | NA | Hydrogel | Travoprost | 3 months |
| POLAT-001 | Peregrine Ophthalmic Pte Ltd, Singapore | 2 | Subconjunctival injection | NCT02466399 | Liposomal carrier | Latanoprost | 3 months |
| SpyGlass | SpyGlass Pharma | 1/2 | Attachment to intraocular lens | NCT06120842 | Drug-eluting pads | Bimatoprost | 3 years |
Despite promising results on sustained IOP-lowering with good tolerability and side effect profile for these aforementioned drug delivery systems, they have been slow to attain FDA-approval. In stark contrast, surgical innovation in glaucoma in the family of minimally invasive glaucoma surgical devices (MIGS), have expediently obtained FDA approval, completed robust clinical trials, and have been globally adopted into clinical practice with exponential speed. The first FDA-approved MIGS device, the Trabectome (Neomedix Corporation, Tustin, CA) came onto the market in 2004, and in the next 15 years, multiple MIGS devices have rapidly emerged into the market and obtained FDA approval and are now in widespread clinical use. Such devices include Glaukos Corporation’s iStent in 2012, New World Medical’s Kahook Dual Blade in 2015, Allergan’s XEN Gel Stent in 2016 and Ivantis Inc.’s Hydrus Microstent in 2018. The evolution of MIGS has revolutionised the treatment paradigm of glaucoma, offering a less invasive treatment option to manage early glaucoma, whilst avoiding the surgical morbidity of traditional incisional surgeries such as trabeculectomies.
In this regard, these drug delivery systems for glaucoma have been slower to achieve widespread clinical use, and we will discuss some of the reasons why. For the purposes of this review, we will focus on the only two FDA-approved medical DDS currently on the market: Durysta and iDose TR.
Durysta (Allergan, Irvine CA, USA)
Durysta is a 10 mcg bimatoprost implant that was first approved by the FDA in March 2020 for the treatment of eyes with primary open angle glaucoma (POAG) or ocular hypertension (OHT). Durysta is the first sustained-release glaucoma therapy to be approved for the treatment of glaucoma, reducing dependence on topical eyedrops. It is an intracameral implant made of biodegradable polymers that release bimatoprost in a controlled non-burst, steady-state manner over 90 days.
Animal studies on the controlled release of Durysta showed that 80.5 % of the 15 ug bimatoprost implant was released by day 51, and 99.8 % was released by day 80, whilst constantly achieving a concentration 4400 times that of topical dosing at the iris-ciliary body. Phase I/II trials have also shown that the IOP-lowering effects of Durysta lasts beyond the 90 days that bimatoprost is released, as up to 28 % of POAG patients had sustained IOP-lowering effects lasting up to 2 years after a single administration of Durysta. The ARTEMIS 1 and 2 studies also showed similar IOP-lowering effects at 1 year post-administration of Durysta. These longer term IOP-lowering effects of Durysta are not well established, but some mechanisms postulated include the significant upregulation of matrix metalloproteinase 1 (MMP1) and downregulation of fibronectin, which only occurs upon high concentrations of bimatoprost in the anterior chamber. This may then promote sustained tissue remodelling of aqueous outflow pathways such as in the trabecular meshwork (TM), and explain the sustained IOP reduction beyond the duration of intracameral drug availability.
Durysta is indicated for eyes with POAG and OHT, and contraindicated in angle closure eyes, eyes with active or suspected intraocular or periocular infections, corneal endothelial cell dystrophies eg Fuchs endothelial dystrophy, previous corneal transplantations, or a unicameral eye. This is largely attributable to the movement of the intracameral implant causing damage to the corneal endothelial cells, or migrating to the posterior segment in a unicameral eye.
The most common side effects from Durysta use include conjunctival hyperaemia, corneal endothelial cell loss, and inflammatory reactions (keratitis, iritis, vitritis). The risk of endothelial cell loss increases with repeated procedures, with estimates of endothelial cell loss of 5 % at 20 months. It is noteworthy that even though some study protocols involve repeat injections of Durysta in one eye, it is contraindicated for repeat use in the same eye in the official Durysta prescription insert.
iDose TR (Glaukos Corporation, Aliso Vjejo, California, USA)
The iDose TR is a trabecular meshwork implant containing 75 µg of preservative-free travoprost that was first approved by the FDA in December 2023 for the intracameral use in the treatment of POAG and OHT.
The iDose TR comprises of 3 main components: a scleral anchor for attachment to the trabecular meshwork, a titanium reservoir containing preservative-free travoprost, and a nanoporous Ethylene Vinyl Acetate (EVA) membrane through which the travoprost is delivered in a sustained release manner. This preservative-free travoprost is approximately 25,000 times more concentrated than the travoprost in the 0.004 % ophthalmic eyedrop formulation. Coupled with the sustained release mechanism through the EVA membrane, the iDose TR has been shown to gradually elute travoprost over a duration of 6–12 months or even longer. iDose TR maintains consistent mean travoprost levels above the efficacious dose at all time points across 2 years with 50 % remaining travoprost at 1 year and 16 % at 2 years. A 12-month prospective study also showed that it demonstrated non-inferiority in terms of IOP-lowering effects compared to topical timolol over 12 months.
iDose TR is indicated for eyes with POAG and OHT, and like Durysta, is also contraindicated in eyes with active or suspected intraocular or periocular infections, corneal endothelial cell dystrophies, previous corneal transplantations, or a unicameral eye. Although not an absolute contraindication, iDose TR is used with caution in eyes with angle abnormalities including angle closure, likely because of the use of a scleral anchor to the trabecular meshwork necessitates good angle anatomy and adequate space at the iridocorneal angle in such eyes.
The most common side effects of the iDose TR have been shown to be mild and transient, including transient rise in IOP, dry eyes, conjunctival hyperaemia, and iritis. Of note, over 12 months, the use of the iDose TR did not result in statistically significant change in central corneal thickness (CCT) or loss of endothelial cell count ≥ 20 % from baseline.
A significant advantage of both Durysta and iDose-TR compared to topical prostaglandin use is that Durysta and iDose TR mitigate the undesired extraocular side effects of prostaglandins. Even though there have been new classes of anti-glaucoma medications developed recently as mentioned above, the prostaglandin analogues still have unparalleled IOP-lowering effects with a once-a-day dosing, and are hence still often the first-line anti-glaucoma medication physicians choose to start. Prostaglandin associated periorbitopathy (PAPS) has since been well-recognised as a clinical and cosmetic concern resulting from long-term use of prostaglandin analogues, that is characterised by deepening of the upper eyelid sulcus (DUES), upper lid ptosis, flattening of the lower eyelid bags (FLEBS), and inferior scleral show. PAPS has been shown to be a clinically significant phenomenon that leads to treatment non-compliance and Durysta and iDose-TR effectively eliminate this concern since the drug is delivered intracamerally and studies show minimal to undetectable drug levels in non-target extraocular tissues.
In spite of attainment of FDA-approval, the sustained drug delivery systems have been relatively slow to penetrate into clinical practice. There may be several reasons for this resistance to widespread adoption. The wholesale acquisition costs for Durysta and iDose TR are USD $1950 and USD$13,950 respectively per implant. Comparatively, the generic price of a bottle of timolol maleate 0.25 % is USD $9.85 and that of a bottle of latanoprost is USD $19.12. This means that the cost of a 2-year supply of latanoprost (USD $458.88) is still 4 times cheaper than a single Durysta implant and 30 times cheaper than the cost of a single iDose TR implant. Even though the pricing of pharmaceutical medications is a complex issue complicated by the roles of government subsidies, commercial health insurance providers and retail pharmacies, until the cost of current sustained-release implants like Durysta or iDose TR is brought down markedly, it is unlikely that these implants would be economically accessible to the majority of the world’s glaucoma population. The one time use approval by the FDA for both drug delivery devices poses a challenge to the company marketing strategy when ophthalmologists have other relatively more familiar options available in the form of MIGS and lasers to replace one or two medications. As such, only few insurance policies have included the use of intracameral implants in the treatment of glaucoma under their coverage- for example, Molina Healthcare and Cigna. However, these insurers require patients to have an inadequate response, intolerance, or contraindication to at least two prostaglandin analogues and at least two additional anti-glaucoma therapies before allowing the claim of intracameral implants. This prompted the American Academy of Ophthalmology (AAO) to write an open letter to relax the requirements and improve accessibility of intracameral implants to the average glaucoma patient.
The clinical positioning of a drug delivery system within the glaucoma treatment algorithm is clear. Ideally it will replace the use of eyedrop with the convenience of a repeatable outpatient procedure to top up on a 6 monthly or annual basis. Its role in glaucoma management is more uncertain as a one-time use drug delivery system. To our knowledge, these drug delivery systems have not yet found a robust place in common glaucoma management algorithm guidelines (eg. AAO or European Glaucoma Society (EGS) guidelines). Glaukos is exploring the possibility of a refillable device, which would extend the shelf life of the implanted device, but with the requirement to bring the patient into the operating theatre to perform the procedure, the cost benefit analysis needs to make sense.
Furthermore, while these drug delivery implants provide prolonged IOP lowering effect, the fact that these trabecular meshwork-based drug delivery systems cannot be used in patients with angle closure immediately removes a large proportion of patients who would benefit from such technologies. Primary angle closure glaucoma (PACG) accounts for nearly half of all the primary glaucomas, and is especially prevalent in Asian populations, carrying a 2.5-fold risk of blindness compared to POAG. Hence, a safe and effective sustained drug delivery system that can ideally be repeatedly delivered to both open and angle closure eyes is desirable and yet to be achieved.
The potential for gene therapy in IOP control
In recent years, research into gene therapy as a new therapeutic approach in ophthalmology has gained traction, with research in inherited retinal diseases leading the way. Gene therapy of retinal diseases began with the discovery and identification of RPE65 variants and their association with Leber’s congenital amaurosis (LCA). The RPE65 gene encodes for a protein that is crucial for the normal functioning of the visual photoconduction cascade, and early animal studies showed that RPE65 gene knockout mice models had similar disease phenotypes as patients afflicted with LCA. RPE65 gene replacement resulted in improvement in visual function in animal model, which then led to Phase 1, 2 and 3 studies in humans using adeno-associated viral vectors (AAVs). Promising results then led to the development of the FDA-approved subretinal voretigene neparvovec therapy for RPE65-associated LCA called Luxterna, the first FDA-approved gene therapy for ophthalmology. Such gene editing provides more permanent solutions by correcting the genetic pathology causing the pathogenic phenotype.
Glaucoma, unlike such inherited retinal diseases, is a heterogenous group of eye diseases that involve multiple genetic loci, with early onset glaucoma exhibiting Mendelian inheritance whilst the more common adult onset glaucoma being inherited as complex traits. Despite the identification of many genes that contribute to the pathogenesis of glaucoma, no FDA approved treatment has yet been borne out of these genetic findings. On the other hand, studies into the genetic basis of the homeostasis of aqueous humour regulation, or even RGC protection, have led to the identification of few select genes that can be targeted more easily.
Gene therapy for glaucoma can be grossly divided into gene therapies targeting aqueous humour production (AQP 1 and 2 and Adrb 2), uveoscleral outflow (COX-2, PTFGR, and MMP-2), conventional trabecular meshwork outflow (myocilin, MMP-1, MMP-3, Rock 1 and 2), optic nerve neuroprotection (BDNF and PEDF), as well as mitochondrial dysfunction (Ndi1 and SOD2). ( Table 2 ) For example, PACG and POAG eyes were shown to have a significant increase in AQP 1 and 2 expression in the iris and reduced aqueous osmolality compared to non-glaucomatous eyes. One pre-clinical study in an OHT mice model used AAVs (ShH10 serotype) to deliver CRISPR-Cas9 vectors via intravitreal injections to disrupt the AQP1 gene. The authors demonstrated a significant reduction of IOP in treated eyes compared to controls and fellow non-treated eyes, and with no evident off-target effects (eg. increase in corneal or retinal thicknesses). Another example involving the use of the CRISPR-CasRx tool to mediate disruption of Rock 1 and 2 genes reported both a lowering in IOP as well as reduced loss of RGCs. Other studies on neuroprotective gene therapy used AAV vectors to induce upregulation of BDNF in mice and rat models with high IOP showed success in preventing RGC loss. Gene therapy targeting improvement of mitochondrial function has also shown promise in recent years. AAV-mediated ND1 therapy in RGCs reduced reactive oxygen species (ROS) and hence improved mitochondrial function, and also significantly increased basal and maximal ATP production in lamina cribosa cells, protecting these cells from oxidative stress. Other studies used AAV-mediated SOD2 therapy show attenuation of oxidative stress and improvement of mitochondrial dysfunction of in RGCs. These pre-human studies show exciting and promising results, which may herald a new era of treatment modalities to achieve sustained IOP control.
