Primary open-angle glaucoma is a condition with a large number of treatment strategies, from drugs to devices to surgical interventions. The most effective drugs are available as generics or will be coming off patent soon. The stability of the therapeutic choices available (there hasn’t been a new class of glaucoma drug in more than 15 years) might lead you to think that it’s a disease that is under control with existing treatments, yet it remains a disease without a cure, a disorder with a significant ocular morbidity, and is the second-leading global cause of blindness. Of the 60 million people with this disease worldwide,Quigley HA, Broman AT. The number of people with glaucoma worldwide in 2010 and 2020. Br J Ophthalmol 2006;90:3:262-267. 15 percent will have a severe degree of permanent visual impairment.
With the host of new therapies that are on the horizon, it’s a good time to peruse the pipeline, take a snapshot of the newest treatment modalities in various stages of development, and also examine issues that will confront efforts at therapeutic progress in the coming years.
Despite its close association with elevated intraocular pressure, glaucoma is a disease manifested at the level of the retinal ganglion cell layer,Chang EE, Goldberg JL. Glaucoma 2.0: Neuroprotection, neuroregeneration, neuroenhancement. Ophthalmology 2012;119:5:979-86. and in any new development strategies, the importance of preserving visual function should be stressed as the ultimate clinical endpoint. This hasn’t been the case so far; in a recent review of the newest surgical procedures, out of 100 clinical trials surveyed, only one used visual function as an endpoint.Coleman AL. Advances in Glaucoma Treatment and Management: Surgery. Invest Ophthalmol Vis Sci 2012; 53:5:2491-2494.
The Glaukos iStent connects the anterior chamber with Schlemm’s canal to facilitate outflow.
Since their introduction to the market in the mid-1990s, prostaglandin analogues have moved to the top of the list for patients with mild to moderately elevated IOP.“Drugs for common eye disorders” Treatment Guidelines in The Medical Letter 2010;8:89:1-8. They are highly effective at reducing IOP via an enhancement of aqueous humor outflow through the uveo-scleral space. A number of other drugs, including b-adrenergic antagonists and carbonic anhydrase inhibitors, are also available. These agents reduce the production of aqueous humor to lower intraocular pressure and, while effective, require b.i.d. or t.i.d. dosing that makes compliance an issue and can significantly compromise therapeutic outcomes. The fourth current class of medications, the a2 adrenergic agonists, also act by decreasing the production of fluid by the ciliary body and enhancing outflow. Combination agents that take advantage of complementary mechanisms of action are also available. In addition, there are several new agents with novel pharmacodynamics in mid- and latestage development that will add to the current arsenal of IOP-lowering compounds.Kaufman PL, Rasmussen CA. Advances in Glaucoma Treatment and Management: Outflow Drugs. Invest Ophthalmol Vis Sci 2012;53:5:2495-2500.
One approach to enhance aqueous humor outflow through the physiological pathway is to use agents designed to relax the tension in the trabecular meshwork. The TM is a tissue that is physiologically similar to muscle in that the tensile status of the myosin-actin complexes within the cells are highly dynamic, and are regulated in large part by the action of Rho GTPase kinase (ROCK).Zhang M, Maddala R, Rao PV. Novel molecular insights into RhoA GTPase-induced resistance to aqueous humor outflow through the trabecular meshwork. Am J Physiol Cell Physiol 2008;295:5:C1057-70. ROCK phosphorylation acts in at least three ways to increase contractile tension in the TM: directly, via phosphorylation of myosin light chain; and indirectly through inhibition of MLC phosphatase and activation of Lim kinases. A couple of ROCK inhibitors (AMA0076, Amakem Therapeutics; AR12286, Aerie Pharmaceuticals) are in clinical development, including testing of combination therapies (AR12286 plus latanoprost). The list of new IOP lowering agents also includes LM7101, a Lim kinase 2 inhibitor (Lexicon Pharmaceuticals).
A different class of agents in development targets adenosine receptors; for example, the adenosine R1 agonist INO-8875 (Inotek) has shown promise in Phase I and Phase II for IOP reduction in patients with ocular hypertension. This compound works by enhancing outflow through the physiological pathway by stimulating the secretion of matrix metalloproteinases, enzymes that mediate connective tissue remodeling of the TM. Several other adenosine receptor-targeted therapies include ACN-1052 (Acorn Biomedical) and CF-101(Can-Fite BioPharma), but unlike the Inotek compound these drugs are aimed at the adenosine A3 receptor. Targeting this signaling pathway reduces IOP by inhibiting aqueous humor production of the ciliary epithelium. These compounds are also formulated for oral rather than topical dosing, a choice that may provide a greater duration of action and less IOP fluctuation.
Two other additions to the development pipeline are in early-phase clinical trials. One of these is a doseranging study of the mixed prostaglandin agonist ONO-9054 (Ono Pharma). Another dose-escalation trial is under way for SYL040012 (Sylentis). The Sylentis compound is an RNAi-based compound designed to target the same b-adrenergic pathway targeted by timolol. Instead of acting as a traditional receptor antagonist however, SYL040012 blocks the pathway by inhibiting biosynthesis of the receptor protein.
New Delivery Systems
One of the greatest hurdles in controlling IOP by means of medical treatment in glaucoma patients is that of compliance: The combination of the chronic nature of treatments, the lack of symptoms and the age of the affected population is a recipe for poor compliance. Recent estimates suggest that 60 percent of patients fail to maintain a daily medication regimen.Rossi GC, Pasinetti GM, Scudeller L, Radaelli R, Bianchi PE. Do adherence rates and glaucomatous visual field progression correlate? Eur J Ophthalmol 2011;21:4:410-414. One approach to this problem is to take the task out of the hands of the patient by employing sustained-release or other depot forms of existing drugs. A number of strategies employing this approach to drug delivery are currently in development.
Depot forms of effective drugs such as the travoprost punctal plugs (Ocular Therapeutix) are currently in clinical trials. In a recent Phase II study presented at the 2011 meeting of the American Glaucoma Society, German researcher Norbert Pfeiffer, MD, found that the travoprostcontaining plugs provided a sustained IOP lowering effect of at least 6. mmHg that persisted for two months. Another delivery vehicle is a variant of the contact lens and is designed to reside under the lid rather than on the cornea. This device is in development at Amorphex Therapeutics, and can deliver drugs to the eye in a continuous, slow-release fashion; it is particularly easy to place or exchange if needed. Polymerized collagen gels (Euclid Systems) are a biodegradable matrix suitable for depot delivery, as demonstrated for slow release of latanoprost in vitro. (Devore DP, et al. IOVS 2011;52:ARVO E-Abstract 3421) Perhaps a bit further into the future we can expect to see nano-particle based depot delivery of drugs from companies such as Icon Bioscience.
IOP Monitoring Devices
Diurnal variations of IOP have been thought to play an important role in progression of disease for some time. Office visit assessments provide a single measure of IOP, so they cannot provide a comprehensive picture of daily IOP fluctuations. The arrival of continuous monitoring devices designed to provide a roundthe- clock IOP measurement is a welcome step forward.
A number of different technologies in development can provide continuous IOP monitoring. One approach uses implantable micro-sensors that transmit pressure data to a handheld external device (Implandata Ophthalmic Products). Another implantable device, the iSense (AcuMEMs), is also in development. Both the Implandata and AcuMEMs systems would be implanted during cataract surgery or another surgery to allow access to the anterior chamber. An alternative technology employs a contact lens with an embedded strain gauge (Triggerfish; Sensimed AG) to record continuous 24-hour changes in ocular surface tension. While this metric is distinct from a true measure of IOP, it provides an indirect means to monitor the fluctuations associated with IOP. Using this device, a recently published study showed a nocturnal peak in tension occurs in about 70 percent 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] These continuous measurement devices will likely have a significant impact on therapy of POAG going forward.
Surgical approaches to reducing IOP remain an important treatment option in glaucoma therapy, but an expanding alternative to laser-based surgery that can effectively address the compliance issue is the use of implantable stents and other devices that improve the function of aqueous outflow. With few exceptions, these devices are implanted in patients during cataract surgery (similar to the IOP devices listed above) and so are relatively low-risk. Several such implantable devices are either new to the market or in late-stage development, and each employs its own unique approach to the engineering challenge of increasing outflow. The Hydrus microstent (Ivantis) is designed to act much like a cardiac stent; it’s placed in the canal of Schlemm and maintains a patent canal that can mediate aqueous drainage. In a recently reported trial, the patients receiving the device maintained an IOP of 21 mmHg or less without medication for six months. Another device in development is the Cypass (Transcend Biomedical), a thin polymer tube that creates a new outflow pathway when inserted under the scleral spur into the supraciliary space. A different kind of surgically implantable treatment is the stent from AqueSys. The device is a gelatin tube that is a thin rod in its dehydrated form, but when inserted becomes hydrated and soft in order to form a path for aqueous humor outflow.
The newest addition to the list of approved implants is the Glaukos iStent, which was approved by the Food and Drug Administration in June 2012. http://www.accessdata.fda.gov/ cdrh_docs/pdf8/p080030a.pdf Accessed 29 November 2012. This device is a titanium tube which bypasses the TM and provides a direct connection between the anterior chamber and Schlemm’s canal. In multiple clinical trials the device was shown to decrease IOP to a greater extent than cataract surgery alone and, in doing so, provide a longterm solution to compliance issues for patients with ocular hypertension. The iStent indication limits it to patients undergoing cataract surgery, however, which reduces the number of eligible patients but also minimizes the need for additional surgical procedures. Long-term follow-up of the iStent will include five-year monitoring of patients from completed studies for safety issues such as bestcorrected acuity loss, endophthalmitis, retinal detachment, choroidal hemorrhage and aqueous misdirection. It’s interesting to note that while the efficacy endpoint for the iStent is reduction in IOP, it’s the safety assessment of the device that will tell the real story, since any glaucoma therapy should have, as an ultimate goal, the minimization of decremental loss of visual function.
While current therapies, surgeries and the growing list of devices focus on lowering IOP as the path to successful glaucoma therapy, there have also been some advances in more direct approaches to treatment and prevention of the glaucomatous neuropathology that leads to visual loss. A key point in understanding the pathology underlying POAG is that while lowering IOP shows a strong correlation with minimizing disease progression, the connection is not absolute: Patients with normal pressures can show visual field loss, while the visual fields in others with high IOPs may remain intact. Increasingly, then, the focus of clinicians and researchers has turned to addressing the pathological consequences of the disease.
A growing body of evidence suggests that many of the drugs that are used to treat elevated IOP also have neuroprotective effects.Shih GC, Calkins DJ. Secondary neuroprotective effects of hypotensive drugs and potential mechanisms of action. Expert Rev Ophthalmol 2012;7:2:161–175. For example, there is ample evidence that inflammatory cytokines from neighboring microglia are important contributors to retinal degeneration, and recent studies suggest that a2 adrenergic agonists can minimize cytokine release, perhaps through activation of brain-derived neurotrophic factor or other neurotrophic pathways.Lambert WS, Ruiz L, Crish SD, Wheeler LA, Calkins DJ. Brimonidine prevents axonal and somatic degeneration of retinal ganglion cell neurons. Mol Neurodegener 2011;6:1:4.,Saylor M, McLoon LK, Harrison AR, Lee MS. Experimental and clinical evidence for brimonidine as an optic nerve and retinal neuroprotective agent: An evidence-based review. Arch Ophthalmol 2009;127:4:402-406.,Gao H, Qiao X, Cantor LB, WuDunn D. Upregulation of brain-derived neurotrophic factor expression by brimonidine in rat retinal ganglion cells. Arch Ophthalmol 2002;120:6:797-803., A clinical study in patients with normal-tension glaucoma has suggested that brimonidine (Alphagan) has an effect beyond lowering IOP.Krupin T, Liebmann JM, Greenfield DS, Ritch R, Gardiner S, for the Low-Pressure Glaucoma Study Group. A randomized trial of brimonidine versus timolol in preserving visual function: Results from the low-pressure glaucoma treatment study. Amer J Ophthalmol 2011;151:4:671-681. Similarly, b-adrenergic antagonists, prostaglandin F2a agonists and carbonic anhydrase inhibitors all have established neuroprotective actions that may provide a therapeutic benefit beyond their IOP-lowering action.,Boltz A, Schmidl D, Weigert G et al. Effect of latanoprost on choroidal blood flow regulation in healthy subjects. Invest Ophthalmol Vis Sci 2011;527:4410-4415., Kniep EM, Roehlecke C, Ozkucur N et al. Inhibition of apoptosis and reduction of intracellular pH decrease in retinal neural cell cultures by a blocker of carbonic anhydrase. Invest Ophthalmol Vis Sci 2006;47:3:1185-1192.,
Interest in neuroprotection is evident from clinical studies of the glutamate receptor antagonist memantine, animal studies of other glutamate antagonists and experimental trials with other drugs with known neuroprotective effects.Osborne NN. Recent clinical findings with memantine should not mean that the idea of neuroprotection in glaucoma is abandoned. Acta Ophthalmol 2009;87:4:450-4.,Beidoe G, Mousa SA. Current primary open-angle glaucoma treatments and future directions. Clin Ophthalmol 2012;6:1699-707., Promising animal studies suggest other avenues of addressing the goal of neuroprotection. For instance, the tumor necrosis factor-a (TNF-a) inhibitor Etanercept has been shown to effectively prevent RGC loss in a rodent glaucoma model.Roh M, Zhang Y, Murakami Y, Thanos A, Lee SC, et al. (2012) Etanercept, a widely used inhibitor of tumor necrosis factor-a (TNF-a), prevents retinal ganglion cell loss in a rat model of glaucoma. PLoS ONE 7:7:e40065. The established association between retinal degeneration seen in POAG, b-amyloid deposition and the more global neurodegeneration of Alzheimer’s disease may provide a route for basic scientific advances as well as new clinical approaches. Guo L, Salt TE, Luong V, Wood N, Cheung W et al. Targeting amyloid-beta in glaucoma treatment. Proc Natl Acad Sci U S A 2007;104:33:13444-9. One compound that has shown the ability to reduce b-amyloid (Merz Pharmaceuticals GmbH), is currently the subject of clinical trials to assess the safety of a topical formulation (NCT01714960) at clinicaltrials.gov.
Overall, the dual-action nature of many current glaucoma therapies seems to be a serendipitous consequence of redundant ocular signaling physiology, but it’s likely that future approaches will focus on the mitigation of the retinal pathology that’s the hallmark of open-angle glaucoma. Whatever the route to neuroprotection, this one-two punch of reduced IOP and diminished retinal cell loss is a goal that is in sight, and would be a major step forward in preserving visual function in patients with POAG.
Dr. Abelson is a clinical professor of ophthalmology at Harvard Medical School and senior clinical scientist at the Schepens Eye Research Institute. Dr. David is head of glaucoma, Mr. Shapiro is the vice-president of retina, and Dr. McLaughlin is a medical writer at Ora Inc.