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Current Therapeutic Options and Treatments in Development for the Management of Primary Open-Angle Glaucoma
Jeffrey M. Liebmann, MD, FACS, and Jeannie K. Lee, PharmD, FASHP

Current Therapeutic Options and Treatments in Development for the Management of Primary Open-Angle Glaucoma

Jeffrey M. Liebmann, MD, FACS, and Jeannie K. Lee, PharmD, FASHP
Current Management Options and Unmet Needs
Within the eye, the balance between the production of aqueous humor in the ciliary tissue and outflow of aqueous humor out of the eye through the conventional (ie, the trabecular meshwork and Schlemm’s canal) and the unconventional (ie, uveoscleral) pathways functions to maintain an IOP of approximately 10 to 21 mm Hg.14-18 Current therapies are aimed at either enhancing the outflow of aqueous humor via the unconventional or uveoscleral pathway, or by decreasing the production of aqueous humor.19 Although muscarinic cholinergic agonists may enhance outflow of aqueous humor through the trabecular meshwork by contracting the ciliary muscle, these agents are used infrequently as they may cause blurry vision and myopia and are subject to adherence challenges (they may be administered up to 4 times daily).3,14,20 As a result, in practice, there is a lack of agents that target the conventional pathway.3,20 Existing mechanisms are illustrated in Figure 1.19 Although several mechanisms for IOP-lowering are available, no treatment is available to repair or regenerate optic nerve damage in patients with glaucoma. The goal of POAG management is to lower IOP, since elevated IOP is the only known modifiable risk factor for progressive disease leading to blindness.20,21 However, lowering IOP may not be sufficient to prevent vision loss, highlighting the need for new agents with new mechanisms of action and perhaps more effective IOP lowering.1

Management of glaucoma includes control of IOP to a target pressure of at least a 25% reduction which has been shown to slow progression of POAG. However, an IOP target sufficient to reduce IOP by more than 25% may be selected if there is more severe optic nerve damage, damage is increasing rapidly, or the patient has the risk factors indicated previously. A higher IOP target may be acceptable for patients who do not tolerate treatments or have a limited life expectancy.2 Of note, approximately one-third to one-half of patients with POAG do not have elevated IOP—a condition known as normal tension glaucoma (NTG).1,22 NTG is characterized by ocular damage and vision loss at statistically normal intraocular pressure levels (maximum IOP <21 mm Hg). Treatment for patients with NTG also aims to reduce IOP; a 30% reduction of IOP in patients with NTG was shown to slow the rate of visual field progression.23,24 However, patients with NTG may have difficulty achieving substantial IOP reductions given their low baseline IOP. Additional IOP-lowering is a challenge for patients with NTG in comparison to patients with elevated IOP.23

The usual steps for treating glaucoma include the use of instilled medications (eye drops). If pharmacologic treatment is not sufficiently effective, surgical procedures may be required; these include laser surgery (trabeculoplasty or cycloablation), traditional surgery (trabeculectomy), or other procedures (eg, shunts or canaloplasty).25 As indicated previously, available instilled ophthalmic preparations used in clinical practice are limited to agents that reduce IOP either through reduction of aqueous humor production or by facilitating aqueous humor drainage (uveoscleral outflow). Although muscarinic agonists indirectly target the conventional outflow pathway by contracting the ciliary muscle to widen and promote outflow through the trabecular meshwork/Schlemm’s canal, as of this writing, there are no agents directly targeting the conventional outflow pathway or agents that impact both conventional and unconventional pathways.3,14,20 As of this writing, there are no available agents targeting both conventional and unconventional outflow pathways for IOP lowering.3,14

Management With IOP-Reducing Therapy
It is well-established that management with IOP-reducing pharmacologic therapy reduces the risk of glaucoma onset in patients with ocular hypertension (OHT) and use of pharmacologic and surgical therapies reduces the risk of disease progression and vision loss in patients with glaucoma.20 In the 1636-patient Ocular Hypertension Treatment Study (OHTS), topical ocular hypotensive medication was effective in delaying or preventing onset of POAG over 60 months of follow-up (POAG incidence was 4.4% in the treatment group vs 9.5% in the observation group; HR 0.40; 95% CI, 0.27-0.59; P <.001).26 Similarly, 48-month results of the Early Manifest Glaucoma Treatment study demonstrated a 49% risk of visual field progression in the control group versus a 30% risk of progression in the treatment group, corresponding with a treatment difference of 19% (95% CI, 7%-23%; P = .004).27 Results of the Ocular Hypertension Treatment Study and the Early Manifest Glaucoma Treatment study suggested a 10% risk reduction for every 1 mm Hg reduction in IOP.28,29 More recently, in a follow-up analysis of data reported by Garway-Heath et al, it was estimated that each 1 mm Hg reduction in IOP reduced the risk of visual field deterioration by approximately 19%.30,27 Results of several landmark randomized multicenter clinical trials demonstrating effects of IOP lowering in patients with POAG are summarized in Table 1.20,23,26,27,30-33

IOP-lowering therapy is also effective at delaying progression of disease in patients without elevated IOP (NTG). NTG is characterized by ocular damage and vision loss at statistically normal IOP levels.23,24 In the Collaborative Normal Tension Glaucoma Study, 140 patients with NTG received IOP-lowering medical or surgical treatment in 1 eye. When IOP was lowered by 30% (the treatment target in this study), the treated eyes had a slower rate of visual field progression than untreated eyes.23

Unmet Needs in Glaucoma Therapy
As indicated above, most pharmacologic agents that lower IOP act by either reducing aqueous humor production or by increasing outflow/drainage of aqueous humor from the eye primarily through the uveoscleral pathway.2,14 There is an unmet need for tolerable treatments that target the conventional (trabecular meshwork/Schlemm’s canal) outflow pathway, and for therapies that target both conventional and unconventional outflow pathways. The trabecular meshwork tissue is diseased in glaucoma presenting increased resistance to aqueous outflow, and is therefore responsible for elevated IOP in POAG.17,34 Current therapies do not target the conventional outflow pathway, leaving a potentially important modality for IOP reduction largely unused.34

Evaluation and treatment of IOP can be complicated by variability of IOP between eyes as well as diurnal and nocturnal variations. IOP tends to rise at night when individuals are supine, and peaks around 5:30 am. Therefore, daytime office measurements may underestimate IOP levels, and may miss spikes in IOP.24 With treatments administered during the morning hours, nocturnal IOP elevations may be uncontrolled, which may result in overestimation of treatment efficacy, uncontrolled IOP elevation, and an increased risk of glaucomatous damage.

Another unmet need is the challenge of adherence in patients receiving complex glaucoma treatment regimens.35 When a second prescription was added to an IOP-lowering regimen, prescription refills were delayed or decreased.36,37 Adherence is expected to be better for simple regimens.36 In one study of patients newly initiating prostaglandin therapy for glaucoma, 25% of patients received 1 or 2 prescription fills of adjunctive therapy added on to prostaglandin therapy. Of these patients, slightly more than one-fourth (26%) continued therapy with a different agent, and the remaining 74% discontinued therapy entirely.38 In order to improve adherence to IOP-lowering therapy, there is a need for novel effective agents with simple treatment regimens (ie, once-daily dosing and single agent) for the management of glaucoma, especially in the population ineffectively managed with combination therapies.36 Patients may potentially achieve more consistent effects of treatment, and overall greater effectiveness in glaucoma management with convenient regimens.35

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