Although diagnostic tools and treatments for glaucoma are advancing, it remains a significant public health issue worldwide. Researchers have found that approximately 4.22 million people in the United States are living with glaucoma, with about 1.49 million experiencing some level of vision impairment.1 The prevalence of glaucoma is 1.62% among individuals aged 18 and older and 2.56% among those aged 40 or older.1
While the characteristics of glaucoma vary significantly across subgroups, all types share similarities that distinguish them from other disease processes. In its simplest form, glaucoma can be described as a progressive optic nerve neuropathy that is associated with corresponding visual field defects.
The most common type of glaucoma continues to be primary open-angle glaucoma (POAG).2 This form is typically bilateral and characterized by an open, normal-appearing anterior chamber angle and elevated intraocular pressure (IOP), without any other underlying disease. A meta-analysis determined that the global prevalence of POAG is 2.4%, with the current estimated global population affected being 68.56 million.2
Pipeline drugs and devices for glaucoma treatment
Traditionally, glaucoma treatment has centered on lowering IOP. However, as researchers gain a deeper understanding of the disease, they are investigating new compounds with diverse mechanisms of action. Some emerging compounds focus on neuroprotection, aiming to preserve retinal ganglion cells essential for visual transmission.
Others seek to enhance ocular perfusion, particularly to the optic nerve. Several studies suggest that neuroprotection and ocular perfusion have the potential to be modifiable factors for slowing glaucoma progression.3,4
Neuroprotection
ST266
ST266 is an intranasal biologic drug derived from culturing amnion epithelial cells obtained from discarded full-term placenta after birth. Intranasal administration allows the drug to pass the blood-brain barrier through the cribriform plate.
In fact, in preclinical studies, the highest concentration of the drug, when administered intranasally, was found in the optic nerve tissue. When ST266 was administered to mice in preclinical studies, it decreased both optic nerve inflammation and RGC loss when compared to a placebo.4
Research has shown that stem cells like ST266 provide neuroprotective effects in glaucoma through the release of various trophic factors. These factors include brain-derived neurotrophic factor, ciliary neurotrophic factor, and platelet-derived growth factor.
The drug has completed phase I clinical trials for glaucoma treatment and is further being studied. While additional research is required, ST266 holds potential as a neuroprotective therapy to prevent retinal ganglion cell (RGC) damage and optic neuropathies.4
Dronabinol
Tetrahydrocannabinol (THC) has been used as a glaucoma treatment in countries around the world. Beyond its IOP-lowering effect, THC demonstrates neuroprotective properties and improves ocular blood flow. Dronabinol, a synthetic form of THC, is legally available in several European countries and is being studied as a glaucoma treatment.
A recent study conducted in the investigator’s laboratory found that a single dose of dronabinol significantly increased optic nerve head blood flow (without compromising its autoregulatory capacity) but had no effect on IOP or ocular perfusion pressure (OPP).5
While the specific MOA of dronabinol warrants further investigation, it has been shown that cannabinoids activate the CB1 receptors, which are known to cause vasorelaxation and decrease vascular resistance.6
IOP lowering
Topical ophthalmic drug delivery device (TODDD)
TODDD is a non-invasive topical device made from a soft hydrogel material, designed to be placed under the upper eyelid. There is no anesthetic, applicators, or tools needed for insertion.
The device measures 20mm in length, 8mm in width, and 1mm in thickness, and enables various drugs to diffuse into the conjunctiva for absorption. Several glaucoma medications, including timolol, brimonidine, and prostaglandin analogs, have shown efficacy when delivered via TODDD.7
TODDD loaded with timolol
In one study, researchers investigated the effects of TODDD loaded with timolol vs. topical timolol drops for reducing IOP in rabbits over a 90-day period. Results demonstrated a 5.5mmHg decrease in IOP (a 37% reduction from baseline) sustained over a 3-month period.8
The same study demonstrated that the systemic absorption of TODDD was less than 0.1ng/mL, whereas 8.49ng/mL in the topical timolol drop group. There was no documented corneal or intraocular irritation in the 90-day period.
TODDD safety and tolerability
To assess safety and tolerability, a study was completed at the New England College of Optometry. In this study, a non-drug-loaded TODDD was placed under the superior lid of 14 people for 4 consecutive weeks. In total, 10 people completed the study, and reported no visual changes or other significant safety findings.
Of note, three of the four people who did not complete the study withdrew within 24 hours, and had device stability issues that became uncomfortable. Results indicate that the device is well tolerated and that compliance can be predicted within the first 24 hours of wear.9
Efficacy and duration of drug release studies are still being completed. However, there was a single human timolol study that demonstrated that one TODDD provided continuous drug release for 180 days.
OTX-TP
Punctal plugs offer an alternative approach for delivering glaucoma medications. OTX-TP is a punctal plug loaded with travoprost, specifically designed to lower IOP.
Researchers assessed both the device’s efficacy and retention, reporting a 100% retention rate after 10 days and an IOP reduction of 5.4 to 7.5mmHg, depending on the time of day. However, by day 30, retention decreased to 42%, with IOP reduction dropping to 14%.10
Ocular perfusion
NCX 470
NCX 470 is an innovative, second-generation nitric oxide-donating prostaglandin analog currently in development. Nitric oxide (NO) has been shown to lower IOP through the conventional pathway as well as increase ONH perfusion. Similarly, NCX 470 may benefit glaucoma patients by enhancing ocular perfusion.
Researchers compared the neuroprotective and ocular perfusion effects of NCX 470 using Lumigan as a control. Results indicated that NCX 470 enhanced ocular blood flow and improved retinal cell function in cells affected by ischemia.11 Currently, NCX 470 is in phase 3 clinical trials.
Novel surgical glaucoma treatments
iDose TR
The FDA recently approved iDose TR, an intracameral implant loaded with travoprost, designed to provide up to 3 years of continuous glaucoma therapy. In a phase 2 trial, iDose TR was compared to 0.5% timolol administered twice daily.
Over 3 years, the implant significantly reduced mean baseline IOP, with reductions ranging from 7.3 to 8mmHg in the “slow-eluting” design and 7.6 to 8.8mmHg in the “fast-eluting” design. In the same time period, the timolol group saw a decrease of 7.3 to 7.9mmHg.12
Additionally, by the end of the 3-year period, more patients with the implant achieved IOP control compared to those using timolol (63 to 69% with the implant vs. 45% with timolol). Once its effects diminish, the implant can be replaced with a new one, potentially offering patients prolonged treatment.12
Durysta
Durysta is a biodegradable implant containing 10µg of bimatoprost, designed to lower IOP in patients with open-angle glaucoma and ocular hypertension. In a recent observational study, researchers compared the decrease in the number of topical medications needed to lower IOP in different severities of glaucoma after Durysta was implanted.
They found that patients with mild to moderate glaucoma experienced the greatest reduction in topical medication use at months 1, 3, and 6, while those with severe glaucoma saw the most significant reduction at month 1. These results suggest that while the implant can reduce the need for topical medications for up to a year, its effects may be shorter-lived in patients with severe glaucoma.11
More research is required to determine why the implant is more efficacious in milder forms of the disease. Durysta may cause a decrease in endothelial cells and is only intended to be used once in each eye.13
SpyGlass system
The SpyGlass system is a single-piece intraocular lens (IOL) with two small drug-loaded pads attached at the haptic-optic junction, designed for placement during routine cataract surgery. Preclinical animal studies in rabbits showed no detectable systemic drug exposure or adverse effects, even at doses up to 10 times the maximum intended level, assessed over nine months.14
An initial human trial with 23 patients who had glaucoma or ocular hypertension (OHT) showed a 45% mean IOP reduction across all dosage groups after 3 months.15 Recently, the company received FDA clearance to initiate a randomized, multicenter phase I/II clinical trial to further evaluate the safety and effectiveness of the SpyGlass system compared to standard IOLs combined with topical glaucoma medications.15
Novel glaucoma detection methods
nGoggle
A group of researchers developed the head-mounted nGoggle system, which is a portable steady-state visual evoked potential (VEP) device designed to measure visual field (VF) loss. The device was shown to objectively assess visual function, and was able to identify eyes with glaucomatous loss from control eyes through 3 weekly sessions.
Furthermore, nGoggle’s measurements showed adequate repeatability.16 The portability and objectivity of this device make it a promising tool for glaucoma monitoring; however, additional studies are needed to better understand its accuracy.17
Annexin-5
Annexin-5 is a protein widely expressed in humans and has long served as a marker of early apoptosis in various conditions, including glaucoma, diabetic retinopathy, Alzheimer’s, and Parkinson’s disease.18
Annexin-5 binds to phosphatidylserine, a phospholipid on the cell membrane that becomes exposed on the outer cell membrane during the early stages of apoptosis. When tagged with fluorescent markers, annexin-5 can be visualized through imaging.19
The Detection of Apoptosing Retinal Cells (DARC) project utilizes this method. In a phase I trial, the DARC project found that the number of cells undergoing apoptosis was significantly higher in the glaucoma cohort compared to the control group across all doses, with no major adverse events reported.18
While more research is needed, this approach could potentially offer a real-time, IOP-independent metric for assessing glaucomatous progression.
Gene therapy
Gene therapy has recently become a major focus in treating various diseases, both systemically and in the eye. A notable example is Luxturna by Spark Therapeutics, the first FDA-approved ocular gene therapy, approved in 2019 to treat Leber’s congenital amaurosis type 2.19
Ongoing gene therapy research holds promise for revealing the underlying mechanisms of glaucoma and its progression. Since glaucoma is not caused by a single gene mutation, current gene therapy research aims not only to lower IOP but also to identify genes involved in glaucoma development.20
IOP lowering
Researchers have successfully used gene therapy to increase prostaglandin levels in the anterior chamber of the eye. For instance, a group of researchers introduced a transgene using a recombinant adeno-associated viral vector (rAAV) in normotensive Brown Norway rats.19
They were able to achieve a dose-dependent IOP reduction of 12.6 to 43.2% over 12 months with no adverse effects. This approach increased the expression of COX2 and PTGFR genes, resulting in elevated prostaglandin levels and receptor availability.19
Conclusion
In summary, the evolving landscape of glaucoma treatment emphasizes the importance of innovative approaches that extend beyond traditional IOP-lowering therapies.
As the field of glaucoma research progresses, it is essential to continue exploring these avenues. These new methods are paving the way for more effective therapies that can mitigate vision loss and aid in early detection for millions affected by this debilitating condition.
The integration of neuroprotection, ocular perfusion, and advanced drug delivery systems marks a transformative shift in our approach to glaucoma management, underscoring the need for ongoing research and clinical trials to validate these promising strategies.
