Current topical treatments for glaucoma have limited efficacy in lowering intraocular pressure (IOP) and/or can produce side effects and tolerability problems. At present, IOP remains the only known modifiable risk factor to delay the progression of glaucoma. The novel IOP-lowering treatment latanoprostene bunod (LBN) is a nitric oxide (NO)-donating prostaglandin F2α analog that is rapidly metabolized in situ to latanoprost acid and butanediol mononitrate, an NO-donating moiety. LBN has a dual action in that it enhances aqueous humor outflow via both the uveoscleral and trabecular meshwork pathways. It is undergoing regulatory review by the Food and Drug Administration (FDA) for the reduction of IOP in patients with open-angle glaucoma (OAG) or ocular hypertension (OHT). In the dose-ranging VOYAGER study, LBN 0.024%, the lower of the most effective concentrations evaluated, demonstrated significantly greater IOP lowering and comparable side effects compared with latanoprost 0.005%. The recent APOLLO phase III clinical study (n=420) found LBN 0.024% demonstrated significantly greater reductions in IOP than timolol 0.5% in patients with OAG or OHT at various time points over 3 months. The same study found the proportion of patients with IOP ≤18 mmHg was significantly greater with LBN 0.024% than with timolol 0.5%. In the LUNAR study (n=420), LBN 0.024% was non-inferior to timolol 0.5% over 3 months’ treatment. LBN treatment also resulted in significantly greater IOP lowering than timolol at all time-points with the exception of the first post-baseline assessment. In JUPITER, a study of 130 subjects with OAG or OHT, LBN 0.024% was safe and well tolerated when used for up to a year, and provided significant and sustained IOP reduction. Further, in CONSTELLATION, a study of 25 patients with OHT or OAG, IOP lowering with LBN 0.024% was consistently lower than baseline during both the diurnal/wake and nocturnal/sleep periods whereas timolol 0.5% reduced IOP only during the diurnal period. In addition, LBN 0.024% treatment resulted in a significantly increased diurnal ocular perfusion pressure versus baseline and nocturnal ocular perfusion pressure versus timolol 0.05%. Similarly, in KRONUS, a single-arm, single-center, open label study of 24 healthy Japanese subjects, LBN 0.024% significantly lowered mean IOP over a 24-hour period. Across these studies, LBN has demonstrated a favorable safety profile and good ocular tolerability. It is hypothesized that LBN’s dual action on the outflow pathways accounts for the improved efficacy when compared with latanoprost and timolol.
Glaucoma, intraocular pressure, nitric oxide, latanoprostene bunod
Robert N Weinreb has been a consultant to Aerie Pharmaceuticals, Alcon, Allergan, Bausch & Lomb, and ForSightV. He has received research grants from Genentech and Quark and research instruments from Heidelberg Engineering, Optovue, Topcon, and Zeiss. Tony Realini has been a consultat to Alcon, Bausch & Lomb/Valeant, Envisia, Inotek, and Smith and Nephew, and received research support from Alcon, Roche, and Aerie. Rohit Varma has been a consultant to Aerie Pharmaceuticals, Allergan, Bausch & Lomb, Genentech, and Isarna. This study involves a review of the literature and did not involve any studies with human or animal subjects performed by any of the authors.
Medical writing assistance was provided by Catherine Amey and James Gilbart at Touch Medical Media, UK with assistance from Michelle Dalton, Dalton & Associates, US.
August 22, 2016 Accepted
September 14, 2016
Robert N Weinreb, Shiley Eye Institute, 415 Campus Point Dr, La Jolla, California 92037, US. E: email@example.com
This article is published under the Creative Commons Attribution Noncommercial License, which permits any noncommercial use, distribution, adaptation, and reproduction provided the original author(s) and source are given appropriate credit
Glaucoma is a multifaceted disorder resulting from damage to the retinal ganglion cells (RGCs) and their axons, causing progressive optic nerve degeneration and leading to irreversible blindness in some patients.1–4 In most cases the condition develops gradually, with peripheral vision loss typically being followed by loss of central vision.5 In the US, in 2011, openangle glaucoma (OAG) affected 2.71 million persons and is estimated to rise to 7.32 million by 2050.6 Globally, glaucoma affected an estimated 64.3 million people (aged 40–80 years) in 2013.7 Given the aging of the world’s population, this number is expected to rise to 76.0 million in 2020 and to 111.8 million in 2040.7
Ocular hypertension (OHT) can be defined as a high intraocular pressure (IOP) without observable optic nerve damage.4 OAG and angleclosure glaucoma are the two predominant types of glaucoma, and are characterized by an elevated IOP.9 Normal tension glaucoma (NTG) is a form of OAG that is prevalent in both Japanese and Western populations.10 While damage to the optic nerve occurs without elevation of IOP in NTG, IOP reduction has been shown to reduce visual field damage in patients with NTG.10
Current treatment options target IOP reduction to delay progressive glaucomatous damage and to delay onset of visual field loss in subjects with OHT; these include topical medications, laser trabeculoplasty, and surgical drainage procedures (micro-invasive glaucoma surgery [MIGS], trabeculectomy, tube shunts).11–13 However, commonly used topical treatments (prostaglandin analogs [PGA], beta blockers, carbonic anhydrase inhibitors, and α2-adrenergic agonists) can be limited by ocular and systemic side effects, allergies, the need for multiple administrations every day, poor adherence/compliance, and an inability to consistently control 24-hour IOP (Table 1). A new molecular entity incorporating both the established prostaglandin F2α (PGF2α) analog, latanoprost acid and a nitric oxide (NO)-donating group (latanoprostene bunod [LBN, BOL-303259-X] Bausch & Lomb Inc. Bridgewater, NJ, USA) is currently under review by the Food and Drug Administration (FDA) in the US as a novel IOP-lowering monotherapy for glaucoma management. This review discusses the dual mechanism of action of this potential new treatment and evaluates the clinical evidence supporting the compound’s efficacy.
Pathophysiology of glaucoma
Increased IOP raises risk for glaucoma, which is characterized by RGC damage and death that results in changes to the optic nerve head and the visual field. IOP is affected by the balance between aqueous humor (AH) secretion and its subsequent drainage through the trabecular meshwork (TM) and the uveoscleral outflow pathway.5,14–17 AH is secreted into the anterior chamber via the ciliary epithelium and returns to the vasculature through the TM into Schlemm’s canal, draining into collector channels, aqueous and episcleral veins; or it is drained via the uveoscleral route. Recent laboratory studies show cyclic IOP changes, possibly prompted by a reduction in pressure-dependent drainage, alter this aqueous outflow.18 At least 75% of the resistance to AH outflow in humans is localized within the TM, predominantly in the juxtacanalicular portion; in glaucoma, this tissue is altered leading to elevated IOP.16 In addition to IOP, other risk factors affecting the development and/or progression of glaucoma include older age, African ancestry or Hispanic ethnicity, larger optic nerve cup-to-disc ratios, thinner central corneas, family history of glaucoma, diabetes, myopia, history of migraine headaches, and lower ocular perfusion pressure.19,20
Current medical treatments for glaucoma
Topical ocular hypertensive medications which lower IOP have been the mainstay for first-line treatment of OHT and OAG to even before large, population-based clinical studies identified IOP as a modifiable risk factor. The Ocular Hypertension Treatment Study evaluated 1,636 individuals with an IOP of 24–32 mmHg in one eye and 21–32 mmHg in the fellow eye who were randomized to observation or to topical ocular hypotensive medication.21 Early treatment of OHT to lower IOP decreased the cumulative incidence of OAG at a median follow up of 13 years (16% versus 22% overall; p=0.009).
The Early Manifest Glaucoma Trial was a randomized clinical trial that included 255 patients aged 50–80 years (median, 68 years) with early glaucoma, visual field defects (median mean deviation, -4 dB), and a median IOP of 20 mmHg.11 These signs were mainly identified through a population screening. The patients were randomized to no initial treatment or to treatment. The treated patients had laser trabeculoplasty and started receiving topical betaxolol twice daily in eligible eyes. Follow-up visits included tonometry and computerized perimetry every 3 months and fundus photography every 6 months. The results suggest that a reduction of 1 mmHg could be correlated with an approximate 10% decrease in risk for glaucoma progression over a 4–6 year period.11,12 There are five major classes of topical medications currently approved for the treatment of elevated IOP designed to either reduce the production of ocular fluid or facilitate its outflow (Table 1).22–24Until the pathophysiology of glaucoma is better understood, there is little likelihood other therapeutic targets will become a more central component of glaucoma management. Each of these classes of drugs has its own advantages and drawbacks (Table 1). The α2-adrenergic receptor agonists, for instance, decrease the production of aqueous by the ciliary body and act on uveoscleral outflow, but can cause fatigue, high blood pressure or anxiety. While the β-blockers reduce AH secretion to lower IOP, and although rarely cause ocular side effects, may cause respiratory and cardiac side effects.22,23 Also, unlike the cholinergics, β-blockers do not affect pupil size. As miotics, the cholinergic agents target the conventional outflow pathway indirectly, by inducing ciliary muscle contraction that expands the TM and dilates Schlemm’s canal, reducing outflow resistance; however, they are not used widely due to local side effects.25
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Glaucoma, intraocular pressure, nitric oxide, latanoprostene bunod