What's New in the Glaucoma Drug and Surgical Device Pipeline for 2023 and Beyond?

Glaucoma is an incurable optic neuropathy that progresses over time, resulting in permanent loss of peripheral and central vision that may ultimately lead to total blindness. As the second most common cause of blindness overall and the number one cause of irreversible blindness, glaucoma impacts nearly 76 million people worldwide.¹

With an aging population and increased prevalence of risk factors such as diabetes, epidemiologists predict that the number of people affected by glaucoma will nearly double by 2040.¹

The need for innovation and individualization in treating glaucoma has become increasingly apparent as cases continue to rise.

Present therapies cannot reverse the damage caused by glaucoma; therefore, we must identify the disease in its infancy. Early recognition can allow clinicians to mitigate disease progression by managing elevated intraocular pressure (IOP), the leading risk factor for the development of glaucoma and deterioration into more advanced pathology.^2,3

Contemporary therapeutics include eye drops, oral medications, laser treatment, and surgery. Although many patients may benefit from a singular mode of treatment, others may require multiple modalities.²

These increase the permeability of the trabecular meshwork, thus increasing the outflow of aqueous humor from the eye’s anterior chamber.⁴ Examples include travoprost (Travatan Z, Novartis), latanoprost (Xalatan, Pfizer), bimatoprost (Lumigan, Allergan), tafluprost (Zioptan, Théa), and latanoprostene bunod (Vyzulta, Bausch & Lomb).²

Similarly to the prostaglandins, these increase the outflow of aqueous humor from the anterior chamber, although they work by constricting the pupil and ciliary muscle.⁵ Examples include pilocarpine, carbachol (Isopto Carbachol, Alcon), echothiophate (Phospholine Iodide, Pfizer), and acetylcholine (Miochol-E, Bausch & Lomb).²

These target beta-adrenergic receptors to reduce aqueous humor production within the eye. Examples include timolol (Timoptic (Bausch & Lomb), Istalol (Bausch & Lomb), Betimol (Vistakon)), and betaxolol (Betoptic S, Alcon).²

These reduce aqueous humor production and increase its outflow from the anterior chamber. Examples include brimonidine (Alphagan P, Allergan) and apraclonidine (Iopidine, Alcon).²

By inhibiting the action of carbonic anhydrase, which plays a role in producing aqueous humor, carbonic anhydrase inhibitors lower IOP. Examples include brinzolamide (Azopt, Alcon) and dorzolamide.²

This more recently developed class of eye drops reduces IOP by inhibiting the activity of the Rho kinase enzyme, which helps regulate the trabecular meshwork cytoskeleton, leading to increased outflow of aqueous humor.⁶ Additionally, this eye drop class reduces aqueous humor production. Netarsudil (Rhopressa, Aerie) is one example.

These medications work by inhibiting carbonic anhydrase systemically, thus reducing aqueous humor production and decreasing IOP. Examples include acetazolamide (Diamox) and methazolamide (Neptazane).⁷

This in-office procedure uses a high-energy laser to instill minor burns on the trabecular meshwork, which help to increase the outflow of aqueous humor and lower IOP. The two main types of laser trabeculoplasty include argon laser trabeculoplasty (ALT) and selective laser trabeculoplasty (SLT).

ALT uses a non-selective laser, while SLT uses a selective laser which only targets specific cells in the meshwork. Clinicians may use eye drops in conjunction with trabeculoplasty, or the procedure may be an option for patients who do not tolerate or respond well to topical treatments altogether.⁸

A scleral flap is created during this procedure, and a small hole is created in the underlying trabecular meshwork. Sutures are then used to close the flap and maintain the tissue’s stability. Trabeculectomy provides an alternative drainage pathway for the flow of aqueous humor from the eye, encouraging optimal IOP.⁹

Also known as aqueous shunts and glaucoma implants, these work similarly to trabeculectomy by providing an alternate pathway for the exit of aqueous humor. A small tube is inserted into the eye (usually the anterior chamber) and attached to a sub-conjunctival plate, thus redirecting the flow of aqueous humor and lowering IOP.¹⁰

MIGS refers to procedures involving tiny incisions and specialized devices to bypass natural drainage channels, allowing aqueous humor to flow more freely from the eye.¹¹ Its conservative approach gives it an advantage over other more invasive glaucoma surgeries, such as iStent (Glaukos), Streamline (New World Medical), or Hydrus (Alcon) implantation, among others.

Innovation in the treatment of glaucoma is essential to increasing positive patient outcomes. By improving current treatment modalities and establishing novel therapies, challenges like poor patient adherence due to adverse effects, high costs, complicated regimens, strenuous eye drop administration, as well as medication resistance and surgical risks, may be alleviated.

Unsatisfactory adherence to topical treatment regimens leads to fluctuating IOP measurements, increasing the risk or expediting the advancement of vision loss.¹² Unstable pressures may also make it more difficult for clinicians to assess the efficacy of therapy.

Moreover, the development of new therapeutic approaches has the potential to provide additional avenues to patient management for those who cannot benefit from modern methods. Innovative therapies can help to reduce the burden on healthcare systems and improve the overall quality of life for patients and their families.

IOP measurements are critical to monitoring disease severity and guiding treatment plans for glaucoma patients. Because most IOP peaks occur at night or in the early morning, standard in-office methods are limited in their ability to accurately assess these peaks and fluctuations throughout patients’ daily lives.¹³ Wearable and intraocular technology may soon offer a solution.

The FDA-approved Triggerfish (Sensimed) employs a microsensor embedded in a soft, oxygen-permeable contact lens. The device utilizes two sensing-resistive strain gauges to monitor circumferential variations at the corneoscleral junction continuously.

These allow it to record fluctuations in the ocular dimensions, which researchers believe correspond to changes in intraocular volume and IOP. The Triggerfish can record measurements in any patient position, allowing it to be worn throughout the day and overnight.

Although further research is needed to determine the full efficacy of this device prior to becoming commercially available in the United States, its potential to provide valuable data on pressure fluctuations offers an optimistic outlook for glaucoma patients.¹⁴

Another promising prospect in continuous IOP monitoring for glaucoma patients is the Eyemate-SC (Implandata). The device is implanted into the ciliary sulcus as a stand-alone procedure or during other glaucoma surgeries. It utilizes a wireless intraocular transducer with eight temperature and pressure sensors, and using an external handheld display, patients may view their IOP readings on demand.

In a 2021 study investigating the safety and reliability of the device in 24 open-angle glaucoma (OAG) patients undergoing simultaneous non-penetrating glaucoma surgery (NPGS), the Eyemate-SC proved successful in continuous IOP monitoring and showed no severe complications, malfunctions, or implant migration at 6 months, proving itself to be another potential leap in the advancement of glaucoma management.¹⁵

The prevalence of virtual reality (VR) has increased immensely in recent years, continuously shaping our lives by offering new ways to interact with technology and the world around us. The management of glaucoma is no exception.

Visual field perimetry is vital in preserving eyesight and ensuring optimal treatment outcomes.¹⁶ With its advancements, VR has the potential to revolutionize the diagnosis and treatment of glaucoma through its application in visual field testing.

The Olleyes VisuALL is a headset-based visual field perimeter making waves in the world of glaucoma management. The headset features two displays, one for each eye, allowing it to individually assess both eyes with a similar test duration to other perimeters. Unlike conventional visual field units, the VisuALL enables clinicians to test patients in any position, which is especially valuable for those that use wheelchairs or are unable to tolerate traditional instruments.¹⁶

Furthermore, the headset facilitates adjustable fixation through gaze tracking and self-monitoring, eliminating the need for staff supervision. Instructions and feedback from the device reduce the likelihood of patient error, and the immersive experience may increase patient compliance.¹⁷ 

The VisuALL can also assess near and far visual acuity, color vision, contrast sensitivity, extraocular motility, and ptosis, with additional tests currently in development.¹⁸ These advantages enhance the likelihood of obtaining viable visual field results, all while optimizing evaluations through an ergonomic and user-friendly experience.

Researchers are continually working to develop new eye drops for glaucoma treatment, hoping to improve efficacy, reduce side effects, and provide better patient adherence. Many new glaucoma drops aim to strengthen current medications, while others work through entirely new mechanisms.

In December of 2022, the FDA approved Iyuzeh (latanoprost ophthalmic solution, 0.005%) for patients with open-angle glaucoma (OAG) or ocular hypertension (OHT). Indicated for the reduction of elevated intraocular pressure (IOP), Iyuzeh (Thea Pharma) is the first and only preservative-free formulation of latanoprost currently available in the US. Multiple trials in both the US and Europe have demonstrated both its tolerability and efficacy in lowering IOP without the use of preservatives, including benzalkonium chloride (BAK). As preservatives have been routinely linked to an exacerbation of ocular surface disease that can often present in glaucoma patients, this formulation reduces not only intraocular pressure but potentially the incidence of ocular surface symptoms.¹⁹ The recommended dosage of one drop in the affected eye(s) once daily in the evening may reduce IOP for a full 24 hours. In addition, this solubilized and stabilized version of latanoprost does not require storage at refrigerated temperatures.

PDP-716 (0.35% brimonidine tartrate) from Visiox may become the first once-daily brimonidine eye drop to enter the market for the treatment of glaucoma. The eye drop utilizes patented TearActTM fine resin technology, which provides a slow, consistent, and sustained release for all-day IOP maintenance, simplifying eye drop regimens and improving patient compliance. The biopharmaceutical company recently submitted a New Drug Application (NDA) and is seeking FDA approval.²⁰

NCX 470 is a novel nitric oxide (NO)-donating bimatoprost eye drop developed by Nicox, which looks promising in advancing glaucoma treatment. The eye drop works by leveraging the robust IOP-lowering effects of NO with prostaglandin analogs.²¹ 

In its recently completed initial Phase 3 trial, NCX 470 proved well-tolerated and superior to latanoprost 0.005% in IOP reduction at a concentration of 0.1%. It is undergoing its second phase 3 trial, intended to demonstrate long-term safety through 12 months.²²

CKLP1, an ATP-sensitive potassium channel opener, is an emerging drop that boasts an unprecedented mechanism of action, lowering episcleral venous pressure (EVP) 1:1 with IOP reduction, rivaling numbers currently only achieved through glaucoma surgery. The drop has yet to be tested on humans but appears optimistic in potentially decreasing the need for surgical intervention.¹⁷

QLS-111 is an innovative drop developed by Qlaris Bio, which utilizes ATP-sensitive potassium channels to lower IOP by selectively targeting EVP. It works by relaxing vessels of the vascular and vascular-like tissues distal to the trabecular meshwork, increasing the rate of aqueous humor outflow. It is currently undergoing Investigational New Drug (IND)-enabling studies.²³

Ocular implants have emerged as promising alternatives to traditional eye drops in glaucoma treatment. Developers have created these products to provide a continuous, controlled release of medication within the eye, eliminating the need for daily eye drop administration and improving patient compliance.²⁴ Furthermore, advancements in surgical techniques continue to pave the way toward improved patient outcomes.

One such technique in the glaucoma treatment pipeline is the Glaukos iDose, a tiny titanium implant designed to release travoprost into the anterior chamber continuously. Once implanted, a scleral anchor holds the iDose in the trabecular meshwork.

Over a 1 year course of clinical trials, the implant maintained stable and sustained IOP reductions without serious adverse events. The creators of the iDose constructed it to be removed and potentially replaced as its therapeutic effect wears off, offering the possibility of long-term dropless therapy.²⁵

Another exciting advancement in glaucoma surgery is the Sight Sciences Sion, a device used to excise trabecular meshwork during surgical procedures manually. The Sion features a bladeless design that removes tissue without cutting. Instead, it grasps the unwanted tissue as it is maneuvered through Schlemm’s canal, improving patient safety and ease of use.²⁶

Despite decades of research, the exact mechanisms underlying glaucoma remain elusive. Current therapies rely on achieving and sustaining optimal IOP.²⁷ However, recent advances in our understanding of glaucoma pathogenesis and technological breakthroughs have led to exciting new therapeutic avenues, increasing the probability of treating the disease at its root.

Although gene-based glaucoma therapy is still in its infancy, ongoing research highlights how it may open new avenues in treatment development. A 2023 study found that ophNdi1 gene therapy enhances mitochondrial function in retinal ganglion cells (RGC).

This finding is relevant to glaucoma and other neurodegenerative diseases associated with impaired mitochondrial function. Further, ophNdi1 therapy employs viruses to access dysfunctional cells and deliver genetic code related to improved mitochondrial action, allowing the cells to generate sufficient energy to support healthy eyesight.²⁸

Like gene therapy, harnessing the power of cellular machinery offers another approach to developing novel glaucoma treatments. In a recent study, scientists used gene editing techniques to develop glaucoma in mice and revealed how deletion of the ANGPT1 gene might lead to primary congenital glaucoma.

Using this information to manipulate cell signaling pathways, they administered a recombinant ANGPT1-mimetic that was shown to blunt IOP elevation and improve the overall function of RGCs in both ANGPT1 deficient and healthy mice, demonstrating the potential power of cell-based therapies across different etiologies of glaucoma.²⁹

As the incidence of glaucoma continues to increase globally, the need for innovation in managing and treating the disease becomes persistently apparent.

With expanding understanding of glaucoma’s underlying pathological processes, more effective treatments continue to grow on the horizon, shining light on a brighter future through 2023 and beyond for patients worldwide.