Glaucoma therapeutic update

The high-profile progress in treating age-related macular degeneration in recent years has taken some of the spotlight from another great threat to ocular health: primary open-angle glaucoma (POAG).

It’s now 15-plus years past the arrival of once-daily prostaglandin analogue therapy, and with a large number of the available treatment strategies one might think that the outlook for patients with glaucoma was positive. Yet, it remains a disorder that results in significant ocular morbidity and is a leading global cause of blindness. Of the 60 million to 80 million people affected by this disease worldwide,Quigley HA, Broman AT. The number of people with glaucoma worldwide in 2010 and 2020. Br J Ophthalmol. 2006;90:262–267. 15% are destined to suffer a severe degree of permanent visual impairment. A survey of the newest in diagnosis and therapy of POAG is an idea whose time has come.

Among the newest therapeutic approaches to IOP reduction are several agents designed to relax the tension in the trabecular meshwork. Inhibitors of rhokinase (AMA0076, Amakem Therapeutics; AR-12286, Aerie Pharmaceuticals) are in clinical development including testing of combination therapies (AR-12286 plus latanoprost). The list of new IOP-lowering agents also includes LM7101, a Lim 2 kinase inhibitor (Lexicon Pharma).

Another new class of agents in development is those targeting adenosine receptors; the adenosine R1 agonist INO-8875 has shown promise in phase I and phase II trials for IOP reduction in ocular hypertension. This compound works by enhancing outflow similar to the kinase inhibitors and prostaglandin analogues.

Several other adenosine receptor- targeted therapies include ACN- 1052 (Acorn Biomedical) and CF-101 (Can-Fite BioPharma). Both of these compounds target the adenosine A3 receptor and act to reduce aqueous humor production. These are formulated for oral rather than topical dosing, a choice that may provide a greater duration of action and less IOP fluctuation.

Treatments for POAG focus on reduction in IOP, the major risk factor associated with the disease. One aspect of IOP that has been thought to play a role in progression of disease is the natural diurnal patterns that occur in different patients.Chang EE, Goldberg JL. Glaucoma 2.0: neuroprotection, neuroregeneration, neuroenhancement. Ophthalmology. 2012;119:979-986. Office visit assessments provide a single measure of IOP, and it has been known for some time that the pressure can vary significantly over the course of the day. Several IOP-monitoring devices are on the horizon, each designed to provide a continuous measure of pressure fluctuations. One approach uses implantable microsensors that can transmit pressure data to a handheld external device (Implandata Ophthalmic Products). Another implantable device (iSense, AcuMEMs) is also in development.

Take-Home Message
A survey of the newest in diagnosis and therapy of primary open-angle glaucoma reveals a focus on treatments for the reduction of IOP

 

An alternative technology employs a contact lens with an embedded strain gauge (Triggerfish; Sensimed AG) to record continuous, 24- hour IOP measures. Using this device, a recently published study showed a nocturnal peak in IOP, via a correlation to the device output signals, occurs in about 70% of all patients with diagnosed or suspected POAG.Mansouri K, Liu JH, Weinreb RN, Tafreshi A, Medeiros FA. Analysis of continuous 24-h intraocular pressure patterns in glaucoma. Invest Ophthalmol Vis Sci. 2012 Nov [Epub ahead of print] Considering the known limitations of current IOP measurement techniques as well as the potential impact of a temporal mismatch between therapy and symptoms, these continuous measurement technologies could have a significant impact on therapy of POAG going forward.

trabecular micro-bypass stentFigure 1 In June, the FDA approved a trabecular micro-bypass stent (iStent, Glaukos) for use with cataract surgery. (Image courtesy of Glaukos)

A growing trend in IOP-lowering strategies is the use of surgical implants to create or enhance aqueous outflow pathways. Several new such implantable devices either have arrived or are on the horizon. For example, a trabecular micro-bypass stent (iStent, Glaukos) was approved by the FDA in June 2012 for use in patients undergoing cataract surgery who also have mild-to-moderate ocular hypertension.http://www.accessdata.fda.gov/ cdrh_docs/pdf8/ p080030a.pdf Accessed Nov. 29, 2012. This device is a titanium tube that bypasses the trabecular meshwork and provides a direct connection between the anterior chamber and Schlemm’s canal. By limiting the stent to patients undergoing cataract surgery, this indication minimizes additional surgical procedures. Long-term follow-up will include a 5-year monitoring of patients from completed studies.

There are several other devices in late-stage development, each with its own unique approach to the engineering challenge of increasing aqueous outflow. One microstent (Hydrus, Ivantis) is designed to act much like a cardiac stent; it is placed in the canal of Schlemm and maintains a patent canal that can mediate aqueous outflow.

Another device (Cypass, Transcend Medical) is a thin polymer tube that creates a new outflow pathway when inserted under the scleral spur into the supraciliary space. The device has gained approval in Europe (CE Mark) and is being tested in several ongoing clinical trials in the United States as well. A different kind of implantable treatment is the stent from AqueSys, a gelatin tube that is a thin rod in its dehydrated form, but when inserted becomes hydrated and soft to form a path for aqueous humor outflow. This device is distinguished from others currently in development in that it has been targeted to patients whose condition has been refractive to other surgical procedures; in addition, the ab initio surgical technique may cause less trauma than other surgical procedures.

To address the issue of patient compliance, a number of products are targeting improvements in drug delivery. Depot forms of prostaglandin analogues, such as punctum plugs (Ocular Therapeutix and QLT Inc.), have already shown positive data in the clinic and are poised to move closer to approval in the near future. Another delivery vehicle that is a variant of the contact lens, designed to reside under the lid rather than on the cornea, is in development by Amorphex Therapeutics. This device can theoretically deliver any number of drugs in a continuous, slow-release fashion, but it is likely that prostaglandin analogue delivery for glaucoma would be an early test candidate in clinical trials.

microstentFigure 2 One microstent (Hydrus, Ivantis) is designed to act much like a cardiac stent; it is placed in the canal of Schlemm and maintains a patent canal that can mediate aqueous outflow. (Image courtesy of Ivantis)

opening is created through the iris rootFigure 1 An opening is created through the iris root with the tip of the inserter. The microstent (CyPass, Transcend Medical) is deposited into the supraciliary/suprachoroidal space by retracting the inserter guidewire. (Image courtesy of E. Randy Craven, MD)

Another approach to depot drug delivery is use of polymerized collagen gels (Euclid Systems), a biodegradable matrix that has been shown to be capable of slow release of latanoprost in vitro. Perhaps a bit further into the future we can expect to see nanoparticle-based depot delivery from companies such as Liquidia Technologies and Icon Bioscience. IOP lowering remains the primary aim in glaucoma treatment, and the addition of these and other new therapies should pave the way for improved prognoses for patients with POAG.