Glaucoma is a group of eye conditions in which patients present with high intraocular pressure (IOP) due to increased overload of aqueous humor in the anterior chamber, either due to increased production or decreased drainage of fluid. This can result in progressive and irreversible optic neuropathy with significant visual field and vision loss. Those with glaucoma exhibit a pattern of vision loss whereby peripheral vision is lost first, followed by central vision.
Closed angle glaucoma, the rarer and more precipitous form, occurs when the angle for drainage of aqueous humor in the anterior chamber closes abruptly. It can be brought on by pupil dilation in environments such as a dark room or after taking antimuscarinic drugs such as scopolamine and atropine. This condition is treated by urgent surgery while giving treatments such as acetazolamide (carbonic anhydrase inhibitor), mannitol (osmotic diuretic), timolol (BB), and pilocarpine (muscarinic antagonist) in order to decrease IOP and minimize potential complications.
Open angle glaucoma, the more common form, occurs when the angle for drainage of aqueous humor in the anterior chamber is open, but there is either an overproduction of fluid or decreased drainage. The onset of symptoms can linger for a while until peripheral vision loss is first reported. This condition occurs more often in the elderly population (age over 60 years), and chronic IOP-lowering topical drops are used as treatment. Primary open angle glaucoma (POAG), the more common subtype, happens due to an unclear cause, whereas secondary glaucomas can occur due to uveitis, trauma, and corticosteroid use. Risk factors for glaucoma include family history, myopia, and smoking. Glaucoma has also been found to be a risk factor for central retinal vein occlusion.
As of 2020, glaucoma is the world’s leading cause of irreversible blindness and has been associated with a reduced quality of life.
From an epidemiological standpoint, the condition currently affects more than 75 million people globally and over 3 million in the United States. There are more than 42 million people worldwide with precursor glaucoma conditions such as ocular hypertension. In patients suffering from glaucoma, many are treated pharmacologically whereas progressive or advanced cases can be managed with glaucoma surgery including trabeculectomy, glaucoma drainage devices (i.e., tube shunts), and minimally invasive glaucoma surgery (MIGS).
Since 2017, novel therapeutics for the treatment of glaucoma have been aimed at greater efficiency and patient convenience
The global glaucoma therapeutics market was valued at $6.59 billion in 2019, and despite the slowdown due to the pandemic in 2020, it is projected to grow at an annual rate of 6.1% to reach $11.05 billion by 2027; much of this growth is due to the increasing prevalence of patients with glaucoma.
- Muscarinic (M3) agonists (e.g., carbachol, pilocarpine): work through parasympathetics that lower IOP. They contract the ciliary muscle and open the trabecular meshwork to allow for increased drainage. Muscarinic agonists are the oldest known IOP-lowering topical agents and seldom used today.
- Alpha 2 agonists (e.g., apraclonidine, brimonidine): block the sympathetic nervous system through alpha 2-receptors which inhibit the ciliary epithelium from releasing aqueous humor.
- Beta blockers (e.g., timolol, betaxolol, carteolol): block the sympathetic nervous system through beta-receptors which inhibit the ciliary epithelium from releasing aqueous humor.
- Prostaglandin analogs (PGA; e.g., bimatoprost, latanoprost, tafluprost, travoprost): this group vasodilate the canal of Schlemm and increase outflow and drainage of aqueous humor. They are generally well-tolerated, taken once nightly, and are available in generic form. PGA are considered the gold standard first line treatment for treatment of open angle glaucomas.
- Carbonic anhydrase inhibitors (CAI; e.g., oral acetazolamide): These are mild diuretics used to decrease synthesis of aqueous humor. However, these are not often used due to an unfavorable side effect profile.
- Epinephrine: This works through alpha-beta effects. Through its long-term effects it may increase vasoconstriction of the ciliary muscle which can lower production of aqueous humor. However, it may dilate the pupil and increase IOP at first and therefore cannot be used in closed-angle glaucoma.
Although topical IOP-lowering agents are considered first-line treatments, limitations exist with respect to financial cost and patient compliance.
Newer pharmacotherapeutics , drug delivery systems and gene therapies used for the treatment of glaucoma are as follows:
- Vyzulta, Netarsudil (Rhopressa), Durysta
- QLS-101 (Qlaris Bio), MAN-01 (Mannin Research), GB-401
- 3T Ophthalmics/AcuStream, Diopter Corp
- Punctal plug drug delivery system (Mati Therapeutics)
- LipTide (NanoGenics)
- Latanoprost combinations
Drugs Recently Approved by US Federal Drug Administration (2017 – 2020)
Vyzulta, developed by Bausch Health Companies Inc. and approved by the US Federal Drug Administration (FDA) in November 2017, is a combination product composed of a conventional prostaglandin analog added to a nitric oxide (NO) donor. When released in the eye, NO can increase blood supply to the eye and potentially the optic nerve. In combination with the vasodilator effect of the prostaglandin, the NO component relaxes trabecular meshwork and Canal of Schlemm, increasing outflow. Rather than targeting IOP like a conventional topical agent, NO acts at the direct target and point of resistance. Vyzulta has a fairly similar safety profile to prostaglandin analogs with the same side effects and is also taken once nightly, which increases convenience for patients and minimizes risk of complications due to compliance.
Rhopressa, developed by Aerie Pharmaceuticals and approved by the FDA in December 2017, is a rho-kinase inhibitor that targets the trabecular meshwork. It acts on the meshwork by altering structural rigidity and allowing greater flexibility; consequently, this allows increased fluid outflow through the trabecular meshwork into the Canal of Schlemm. The drug also lowers episcleral venous pressure, which is the pressure of the vessels into which aqueous fluid flows. As opposed to other glaucoma drugs which lower IOP at a proportional level (i.e., 20%), Rhopressa tends to lower IOP by a constant 4-6 mmHg regardless of the starting pressure and therefore works more effectively in low tension glaucoma.
Durysta, developed by Allergan and approved by the FDA in March 2020, is a dissolved prostaglandin implant. This first-of-its-kind therapeutic is used to reduce IOP in patients with open angle glaucoma. An injection of Durysta is given every four months and is injected into the anterior chamber between the cornea and iris to release bimatoprost directly into the eye. Through its method of injection, the drug can circulate in the eye at higher concentrations rather than acting at the surface of the eye and potentially exerting systemic effects. Initial studies have shown that one implant can reduce eye pressure for a period of 15 weeks. Additionally, for patients who have received three injections, they have shown a higher maintenance and control of IOP after one year from their last injection than those who were taking a PGA alone.
Pipeline Drugs in Clinical Trials
QLS-101, developed by Qlaris Bio, is an investigational drug currently being tested in clinical trials for use in reducing IOP in patients with glaucoma. It is a topically administered drug that acts as a prodrug of levcromakalim, an ATP-sensitive potassium channel modulator. QLS-101 can lower IOP and increase outflow through vasodilating the vasculature downstream from the trabecular meshwork and decreasing episcleral venous pressure, similar to the mechanism of action of Rhopressa.
The drug has shown to be well-tolerated and effective in decreasing IOP in preclinical animal studies across mice, dogs, rabbits, and human eye explants. As of April 2021, Qlaris has achieved investigative new drug (IND) approval within a period of 18 months following its $25 million funding and started to enroll its first human patient participants in a Phase ½ trials comparing QLS-101 to timolol to further study the drug’s safety and efficacy profile. Future clinical trials are also planned to evaluate the use of QLS-101 in normal-tension glaucoma and Sturge-Weber Syndrome related glaucoma.
MAN-01, developed by Mannin Research and Q BioMed, is a new small molecule drug in topical form that is used to treat POAG. The drug acts directly on the Canal of Schlemm and has been shown in animal studies to reduce IOP. Both companies are currently completing the IND approval process and are planning for a phase I proof of concept trial in late 2021.
GB-401 (Graybug Vision)
GB-401, developed by Graybug Vision, is an inactive prodrug for a beta-receptor inhibitor in an intravitreal formation. Preclinical trial results from February 2020 have shown an increased encapsulation efficiency and drug levels over the course of three months with no signs of ocular toxicity. The drug is currently being submitted for IND approval and the company is planning on starting additional trials in the second half of 2021.
Drug Delivery Systems
Engineered drug delivery systems and implants utilized in the ophthalmic space are used to target a specific region in the eye or to provide a controlled release of the given drug. Although these are somewhat classified as devices rather than drugs, we’ll touch on a few including Diopter, 3T Ophthalmics, Punctal, Accustream, and LipTide (mentioned under gene therapy).
The Diopter drug delivery system integrates contact lenses worn by patients with drug eluting devices embedded with FDA-approved drugs used for glaucoma. During preclinical animal studies it was found that the effects on IOP lasted longer for the Diopter than conventional eye drops.
Punctal Plug Delivery System
This system, developed by Mati Therapeutics, is designed to be placed in the punctum during an outpatient procedure by an ophthalmologist or optometrist. The technology is able to deliver a number of ophthalmic drugs over specified time periods. As of now, latanoprost is the only glaucoma drug being tested in clinical trials in conjunction with the Punctal Plug drug delivery system.
3T Ophthalmics is developing an episcleral implant that is designed to be inserted for subconjunctival implantation. It is intended to be used for extended release of various ophthalmic drugs for up to two years. The technology has been used in animal trials and has been determined to be effective in providing direct drug delivery to ocular tissues involved in glaucoma.
Acustream, developed by Kedalion Therapeutics, is another drug delivery system and was designed to deliver a relatively smaller amount of drug to ocular tissues with the same efficacy as when conventionally administered. From a 2018 phase one study, a similar pharmaceutical effect in reducing IOP was found between a 30 µL dose of latanoprost and a 9 µL dose (70% dose reduction) of the same drug using the AcuStream technology.
Alternative Drug Therapies
To date, almost all available therapies available for glaucoma aim to target IOP. However, glaucoma can progress in the face of the approved treatments currently available on the market due to other causes and risk factors such as underlying genetic defects. As a novel basis for therapeutics of the future, gene therapy can be used to individualize treatment and improve the quality of life for those with glaucoma.
Gene therapy involves injecting genetic material into the eye such as viral vectors, potentially integrated into stem cells, that can carry the DNA or RNA into the target cells and targeting specific targets, and silencing genes that contribute to the progression of glaucoma. In this way, gene therapy can also improve convenience for patients as a one-time treatment serving as a long-term therapeutic. Gene therapy has garnered lots of attention in recent years and NanoGenics is currently developing a platform called LipTide for its use in glaucoma treatment.
LipTide-ECP-105, is a dual product developed by NanoGenics, a Scottish biotech company specializing in gene therapy. LipTide is a peptide-lipid molecule that mimics a viral particle, consisting of a lipid core and surrounding peptides that target cells. It is injected under the conjunctiva and has the capability to deliver gene therapy in differing payloads to the posterior eye as it acts directly on the optic nerve.
Used with the LipTide drug delivery system, the ECP-105 has shown to improve outcomes during the trabeculectomy procedure for glaucoma patients. It can increase time for the bleb (surgical opening in a trabeculectomy) to remain open while decreasing scarring. Per Dr. Alan Walker, CEO of NanoGenics, this new drug delivery system will “offer real hope to millions of patients undergoing surgery for their glaucoma, giving them and their doctors more confidence that the surgery will be more successful.”
As much as certain eye drops can be lifesaving and salvage sight in a person with glaucoma, it has its downsides. Compliance and comfortability for patients, especially the elderly patients affected, are also of major concern. In addition to skipping dosages, patients may run out of medication due to failed attempts of administration or patients with cognitive impairment may find the process complex with the multiple medications needed for glaucoma alone.
Furthermore, resulting ocular surface disease can decrease the efficacy of trabeculectomies performed on those with glaucoma. Polymer-based technologies are being explored as substitutes for topical eye formulations and address the compliance and convenience concerns associated with the topical agents.
Hydrogel is a non-surgical and non-drug alternative treatment for glaucoma. Hydrogel is a relatively novel product and is considered to be the glaucoma treatment of the future. It works through an injection of a biodegradable polymer composed of hyaluronic acid and vinyl sulfone groups that form a viscous hydrogel, a crosslinked water-absorbing molecule that creates a pathway for the aqueous humor to drain and exit the eye. Although it has not undergone human trials, it is postulated that injection would be performed as an outpatient procedure by ophthalmologists during regular visits.
Latanoprost: Variations and Integrations
Latanoprost, one of the conventional prostaglandin analogs used for glaucoma treatment, is being used in multiple new formations currently being tested in clinical trials. Among these are two aforementioned drugs, latanoprostene bunod 0.24%, otherwise known as Vyzulta, and fixed-dose combination netarsudil 0.02% - latanoprost 0.005%, otherwise known as Rhopressa. Another application of the drug is the latanoprost FA SR Ocular Implant made by Polyactiva, which is a degradable polymer implant technology used to administer latanoprost.
The market for devices used in glaucoma treatment has been growing over the last decade and is projected to grow by more than two-fold by 2025. Besides the aforementioned drug delivery systems and SLT device, here’s a sneak peek list of some of the devices used in glaucoma treatment. A more in-depth analysis will follow in the future.·
- Mercury Multi-Pressure Dial (MPD) – Equinox
- Excimer Laser Trabeculostomy
- Beacon Shunt
- Sensory Delivery Procedure (Telemedicine Portable Pressure Quantifier)
- Multicenter Ab-interno Glaucoma Study Investigating Canaloplasty (MAGIC)
- Standalone OMNI Surgical System for Open-Angle Glaucoma (OMNIgl)
- ELT and SLT Laser treatment
- Hydrostent (Horizon Trial)
- Implants: AcuStream and 3T ophthalmics
Innovations in therapeutics and cutting-edge devices used for glaucoma treatment are leading to an exciting time in ophthalmology for both affected patients and their providers. With more combination drugs being approved and more drug delivery devices progressing through clinical trials, new branded drugs and devices used for glaucoma can hopefully provide a higher quality of life for those affected in a safer, more efficient, convenient way, and at a reasonable price.
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