New and Upcoming Developments in Glaucoma Treatment

Dec 22, 2021
19 min read

As a glaucoma specialist, I struggle with the daily emotional task of diagnosing patients with an irreversible form of vision loss, inevitably at times feeling a heavy burden of explaining the grave nature of this sight-threatening disease. Having no curative treatment to reverse the optic neuropathy in glaucoma is the crux of managing patients with this condition.

The situation as it stands

Glaucoma is the second most common cause of blindness overall and the leading cause of irreversible blindness worldwide. As life expectancy grows, the incidence and prevalence of those diagnosed with glaucoma will continue to grow. Currently, in the United States, 1.9% of the population has been diagnosed with glaucoma, and in patients aged > 80, the prevalence is 7.7%.1 In addition to the varying glaucomatous etiologies and stages, there is a significant need for more individualized treatment modalities in the management of glaucoma.

The challenges

Management of glaucoma patients presents a spectrum of challenges ranging from poor medication regimen adherence (both due to multiple medication phenomenon and side effect profiles) to secondary or worsening ocular surface disease from chronic topical preserved medications to the need for novel treatments and more targeted mechanisms of action. Amazingly, the glaucoma world is currently racing forward with technological advances and significant therapeutic growth, with the following on the horizon to provide more tools to treat these patients.

Compliance—on the ocular surface front

While benzalkonium chloride (BAK) is necessary for preservation of sterility in topical ophthalmic solutions in a multidose vial (most glaucoma topical medications), it is one of the key perpetrators of ocular surface disease, particularly dry eye disease.2 It can cause several signs and symptoms, including conjunctival hyperemia and inflammation, tear film instability, burning, tearing, foreign body sensation, and pain.

Whereas a majority of glaucoma patients are on at least one topical glaucoma medication, ocular surface disease from chronic BAK preservative is inevitable and found in up to 40% of glaucoma patients.3-4 This in turn leads to intolerance of certain topical glaucoma medications and non-adherence to medications needed to curb disease progression.

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Figure 1

On the horizon is a preservative-free multidose vial of Latanoprost, formulated by TearClear (Boston, MA). As of 24 August 2021, TearClear filed an investigational new drug (IND) application for TC-002 latanoprost ophthalmic solution 0.005%. The goal is to create a safe and effective formulation of latanoprost in a multidose vial that will capture the preservative before it leaves the bottle and reaches the ocular surface. This would allow BAK to remain in the bottle, preserving the eye drop's sterility but not allowing it to get the ocular surface.

Latanoprost is currently and has been the most common glaucoma medication prescribed as a first line of treatment, most likely due to its ease of access being both generic and affordable, and due to its efficacy being at least as effective—and in some studies superior—to the gold standard of beta-blocker timolol.5-7 Having a preservative-free version of this medication could be significant in the likelihood of compliance and tolerance of this medication. Additionally, if this formulation can then be applied to other glaucoma medications, common ocular side effects can be circumvented.

Compliance—polypharmacy and multiple medications

It is known that the more drugs a patient has to take, and the longer patients have to take them, the less likely they are to get every dose. One study defined non-adherence to glaucoma medications as missing ≥5% of the prescribed pressure-lowering eye drops and found that 30% of patients reported non-adherent over nine years.8 Some other studies show that up to 25% of patients on monotherapy alone miss >25% of their doses of medication.9 Adherence is crucial to the management of glaucoma and preventing progression, and therefore alternatives to daily medication administration are essential in glaucoma treatment.

The current debate in glaucoma management concerns first-line topical medication versus selective laser trabeculoplasty (SLT). Since the 2019 publication of the pivotal LIGHT trial in the Lancet, SLT has become the first-line therapeutic modality for many glaucoma patients. The LIGHT study demonstrated improvement in quality of life, cost efficiency, and maintenance of IOP over 36 months; it demonstrated superiority to topical medications as first-line treatment.10

In 2017, direct selective laser trabeculoplasty (DSLT) was proposed as an alternative to SLT via gonioscopy; DSLT demonstrated the same efficacy of SLT without eye discomfort secondary to gonioscopy and rotation of the lens during the procedure.11 Although being applied directly through a more dispersive scleral tissue, DSLT demonstrated targeted application of energy to the trabecular meshwork with less energy (efficacy achieved at 0.3mJ/spot).

Figure 2 demonstrates gonioscopic selective laser trabeculoplasty and path of the laser beam versus direct selective laser trabeculoplasty without a gonioscopic lens with a laser beam.

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Figure 2: Diagram from Belkin M, et al. Non-contact direct selective laser trabeculoplasty: light propagation analysis. Biomed Opt Express.2020;11(6):2889–2904.

Compliance—sustained released devices

Another category of new technologies that offer a better potential for compliance is sustained-release devices that can be added to our repertoire of adjunctive glaucoma treatments for patients with poor adherence to medications.

(i) Mediprint Ophthalmics

LLT-BMT1, a contact lens printed with bimatoprost using MediPrint’s proprietary contact lens printing process, is currently undergoing clinical trials. Their SIGHT-1, safety profile and initial efficacy in phase I and IIa, showed 100% tolerability in five patients and lower hyperemia than bimatoprost topically, as well as good efficacy in a single dose. SIGHT-2 phase IIb clinical trial to assess efficacy dosing, and SIGHT-3 phase III are in the planning phases.

Figure 3, below, illustrates MediPrint’s technology of layered medication printing on contact lenses.

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Figure 3

Mati Therapeutics

The platform Evolute consists of a translucent L-shaped latanoprost polymer matrix surrounded by silicone that is inserted into the nasolacrimal duct. This polymer can be seen by the naked eye only by everting the lower eyelid. This device will slowly elute medication at a consistent rate. They are currently in a phase II clinical trial.

In phase I the translucent L-shaped latanoprost punctal plug was found to be comfortable. It was also associated with a 20% lowering from baseline IOP over a 3-month period, and in two separate clinical trials, it had a retention rate of 92% and 96%, respectively.

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Figure 4:

Ocular Therapeutix

Their platform includes a dissolving intracanalicular depot of travaprost. The plug is invisible to the patient, but is fluorescent at the slit lamp. The prostaglandin analogue is encapsulated in polylactide microparticles in a resorbable hydrogel rod. When it comes into contact to the tear film, the rod will swell in the canaliculus and hydrolysis of the microparticles will release the drug into the tear film. Phase I safety showed no hyperemia and retention up to 90 days was 48%.

They are currently in phase II study, 73 patients randomly assigned to two groups to receive either the travoprost plug with twice daily artificial tears or timolol 0.5% twice daily with placement of a drug-free punctal plug. At 90 days, there was a 4.5 to 5.7 mm Hg reduction from baseline IOP in patients who had the travoprost punctal plug, which was clinically meaningful.

However, the control group had a placebo plug in the punctum and therefore the timolol had longer contact with the surface of the eye, possibly allowing for the more significant IOP reduction of 6.4-7.6 mmHg.


Figure 5:

Novel and more targeted approaches

With a larger bank of knowledge on a microscopic and molecular level, technologies can now target specific tissues and areas in which the pathology of glaucoma stems from an effect.

Transforming Growth Factor β (TGFβ)

Transforming Growth Factor β (TGFβ), a signaling molecule in the inflammatory pathway, that communicates between cells resulting in inflammation and fibrosis in several disease states has been demonstrated to be in higher levels in the aqueous humor of those patient’s eyes with open angle glaucoma. The increase in this factor has been seen to lead to scarring of the trabecular meshwork drainage system.

A team at the University of Birmingham in the UK have focused on stopping this pathway, and have found in a preclinical model that a novel low molecular weight dextran-sulphate, ILB® can normalize the matrix in the eye and therefore potentially lower the IOP.

In the preclinical experimental model, they found that daily subcutaneous injections of ILB significantly reduced extracellular matrix levels of TGFB within the eye’s trabecular meshwork, normalized the IOP and prevented degeneration of retinal neurons.12 Being able to target specific molecules along the pathological process of glaucoma may allow us in the future to reverse damage caused by this disease. Currently being studied as a subcutaneous injection, a project is also in the works to formulate it into a topical gel.

The role of TGFB in glaucoma pathology is represented by Figure 6.