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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
`
`Glaucoma: Definition and Associated Risk Factors
`
`Glaucoma comprises a heterogeneous group of chronic, progressive, optic neuropathies characterized by loss of
`retinal ganglion cells and their axons. Glaucoma results in visual impairment and is the second leading cause of
`irreversible blindness worldwide.1,2 Primary open-angle glaucoma (POAG) is the most common type of
`glaucoma, and is estimated to account for approximately 90% of cases of glaucoma in North America.3,4
`Because symptoms of POAG do not manifest until the disease process is already in advanced stages, and
`because the progression of disease occurs gradually over the course of many years, POAG is sometimes referred
`to as the “silent thief of sight.”5
`
`Current management guidelines from the American Academy of Ophthalmology Preferred Practice Pattern cite
`several important risk factors for POAG, including advanced age, African American and Latino/Hispanic
`ethnicity, elevated intraocular pressure (IOP), family history of glaucoma, low ocular perfusion pressure (OPP),
`type 2 diabetes, myopia, and having a thinner central cornea.2
`
`OPP is defined as the difference between arterial blood pressure and the IOP. Although further investigation is
`needed, it is thought that low OPP alters blood flow at the optic nerve head, contributing to glaucomatous
`damage to the optic nerve.2 Importantly, while glaucoma is associated with several risk factors that contribute to
`damage and disease progression, IOP is the only proven modifiable risk factor at this time.3
`
`Burden of Glaucoma
`
`Disease Burden
`
`Globally, glaucoma affects 3.5% of adults 40 to 80 years of age (POAG 3.1% plus angle closure glaucoma
`[ACG] 0.5%).4 With the average age increasing worldwide, the incidence of glaucoma in this population of
`adults is projected to increase by 74% from 2013 to 2040.4 With this increase in prevalence of glaucoma, the
`consequences of glaucoma in terms of vision loss are also expected to grow. Worldwide, the number of people
`experiencing bilateral blindness from primary glaucoma is expected to reach 11.1 million by 2020.6
`Exhibit 1056
`ARGENTUM
`IPR2017-01053
`The increasing burden of glaucoma has important implications for the United States health care system. The
`CDC estimates that in 2015, 2.2 million Americans 40 years and older (about 2% of the population) had
`glaucoma.7 Another estimate suggests that by 2050, the number of people in the United States with POAG aged
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`40 years and older is expected to increase to 7.32 million individuals, a nearly 3-fold increase from the incidence
`of POAG from 2011.8
`
`The prevalence of POAG is highest among individuals of Latino/Hispanic and African heritage.8 In a 2016
`meta-analysis by Kapetanakis et al, researchers estimated the prevalence of POAG among those aged 65 years to
`be 6.4% and 4.0% in patients of African descent and Latino patients, respectively, versus a prevalence of 2.0%
`among those of European descent.9 Moreover, in an adjusted analysis, the risk of developing POAG increases by
`a factor of 2.3 with each advancing decade among Hispanic patients versus a factor of 1.6 among patients of
`African descent, and a factor of 2.0 among those of European descent.9 The Hispanic/Latino population is
`estimated to contribute to the greatest number of individuals with POAG in the United States over the next 4
`decades.8
`
`POAG is characterized by an asymptomatic onset, where patients do not present with symptoms until significant
`visual loss occurs in late stages of the disease. As patients do not have symptoms until visual damage has
`already occurred, many cases remain undiagnosed and untreated.2 The National Health and Nutrition
`Examination Survey published in 2014 found approximately 2.4 million individuals in the United States (2.9%
`of the US population) had undiagnosed and untreated glaucoma, suggesting that 78% of glaucoma was untreated
`and undiagnosed.10 The rate of undiagnosed and untreated glaucoma is estimated to be 85% for blacks, 81% for
`Hispanics, and 73% for non-Hispanic whites.10
`
`Economic Burden
`
`As a chronic and progressive disease, glaucoma poses a substantial burden to the healthcare system.
`Management of glaucoma has direct medical costs (eg, visits to providers, tests, medications, and surgery),
`direct nonmedical costs (eg, home healthcare, and transportation), and indirect costs (eg, loss of productivity for
`both patient and caregiver).2
`
`According to a Prevent Blindness study, the $6 billion spent annually in 2014 on the direct costs of glaucoma
`care is expected to reach $12 billion by 2032, and exceed $17 billion by 2050.11,12
`
`Medicare beneficiaries with glaucoma had higher mean annual total healthcare costs compared with those
`without glaucoma, and more severe cases of glaucoma in Medicare beneficiaries are associated with higher
`direct annual costs. One study found that the mean annual total cost of healthcare per patient was $16,760
`among Medicare beneficiaries aged 65 years and older with glaucoma versus $13,094 for Medicare beneficiaries
`without glaucoma. The cost increased by severity of disease. Those with visual disability had costs of $18,073,
`while those without visual disability had costs of $15,829. In this population, the primary drivers of cost were
`physician services, inpatient care, and prescription medications.13
`
`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
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`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
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`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
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`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
`
`
`Pharmacologic Options for Glaucoma Management
`
`A reasonable objective for initial treatment of patients with POAG is to reduce IOP by 20% to 30% below
`baseline. This target IOP is an estimate of treatment needed to lower the risk of disease progression and protect
`vision. An IOP may be adjusted up or down, as indicated by risk factors present, stage of glaucomatous damage
`or disease severity, and progression or aggressiveness during long-term monitoring. Therefore, management in
`IOP reduction should be individualized to patient needs over the course of disease and is subject to change.2
`
`
`Prostaglandin analogs are considered first-line therapy for POAG. They increase uveoscleral outflow, effectively
`lower IOP, are usually well-tolerated, can be dosed once a day, and also act during the night when IOP levels
`may be more elevated.39 These agents bind to prostaglandin receptors; they alter the expression of matrix
`metalloproteinases (MMPs) and increase uveoscleral outflow, lowering IOP.14
`
`
`Currently, latanoprost is the most prescribed prostaglandin analog in the United States.40 In pivotal phase 3 trials
`of latanoprost conducted in the United States, the United Kingdom, and Scandinavia, latanoprost reduced
`baseline diurnal IOP over 6 months of treatment by a mean of 6.7 mm Hg, 8.5 mm Hg, and 8.0 mm Hg,
`respectively.41 In a later trial evaluating the efficacy of latanoprost compared with placebo in lowering IOP and
`preserving vision, the treatment was evaluated in 516 patients with newly diagnosed open-angle glaucoma
`(OAG). At baseline, 44% of the treatment group and 49% of the control group had IOP levels ≥20 mm Hg. At
`24 months, the mean reduction in IOP was 3.8 mm Hg in the latanoprost-treated group and 0.9 mm Hg in the
`placebo group. At 24 months, visual field preservation was significantly better in patients treated with IOP-
`lowering therapy compared with placebo (HR 0.44; 95% CI, 0.28-0.69; P = .0003). None of the 18 serious
`adverse events observed in the latanoprost-treated group were attributed to the drug.30
`
`
`The IOP lowering activity of prostaglandin analogs and other important classes of therapies used as single
`agents in the treatment of glaucoma is summarized in Table 2.2,19 These agents include the following:
`
`
`Prostaglandin analogs act by increasing outflow through the uveoscleral (unconventional) pathway. Adverse
`events may include conjunctival hyperemia, hyperpigmentation of the iris and eyelashes, increased eyelash
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`growth, blepharopigmentation, and prostaglandin-associated periorbitopathy.14
`
`
`Beta-adrenergic receptor antagonists (beta blockers) reduce IOP by decreasing the production and secretion of
`aqueous humor.14 Potential adverse effects associated with beta-blocker treatment may impair adherence to
`therapy including depression, exercise intolerance, and allergic conjunctivitis or contact dermatitis. Adverse
`effects, such as hypotension, bradycardia, and bronchospasm may limit beta-blocker use in patients with these
`pre-existing conditions, as well as use in patients with chronic obstructive pulmonary disease or asthma.2
`
`
`Alpha-2 adrenergic receptor agonists act on alpha adrenergic receptors, reducing the production of aqueous
`humor by the ciliary body, and increasing uveoscleral outflow to decrease IOP.14 Alpha-2 adrenergic agonists
`are associated with potential adverse effects including allergic conjunctivitis or contact dermatitis and follicular
`conjunctivitis. Additional potential adverse effects include dry mouth and nose, headache, fatigue, or drowsiness
`and hypotension.2
`
`
`Both topical and systemic carbonic anhydrase inhibitors reduce production of aqueous humor by the epithelial
`cells within the ciliary body, thereby reducing IOP.14,17 Both topical and oral carbonic anhydrase inhibitors are
`potentially limited as treatment options for patients with kidney stones, blood disorders and sulfonamide
`allergies. Potential adverse events differ between the use of oral or topical treatments; topical carbonic anhydrase
`inhibitors are associated with allergic dermatitis or conjunctivitis like other agents, as well as corneal conditions.
`Potential systemic treatment-related effects of oral carbonic anhydrase inhibitors include depression, anorexia,
`blood disorders, gastrointestinal upset, and adverse events related to kidney function (eg, renal calculi, serum
`electrolyte imbalance).2
`
`
`Direct and indirect cholinergic agonists are direct agonists of parasympathetic receptors in the ciliary muscle
`where they induce contractions that expand the trabecular meshwork and dilate Schlemm’s canal, acting on the
`conventional pathway to decrease aqueous humor outflow resistance.14,17 However, these agents are used less
`frequently due to adverse events including, pupil constriction, eye pain, brow ache, and reduced night vision.14
`
`
` Although single agents have demonstrated relative IOP reductions near the target IOP (20%-30% reduction from
`baseline), individual agent IOP-lowering efficacy differs. In a meta-analysis comparing IOP-lowering agents, the
`degree of IOP lowering demonstrated by single agents varied with peak and trough drug levels. The most
`substantial IOP reductions were achieved with prostaglandin analogs where relative IOP lowering was
`demonstrated from 28% to 33%. Beta-blockers reduced IOP by 20% to 27%, alpha-adrenergic receptor agonists
`reduced IOP by 18% to 25%, and carbonic anhydrase inhibitors reduced IOP by 17% to 22%.42 As available
`single agents may require additional IOP-lowering to achieve IOP targets, treatment regimens that include
`adjunctive therapy are designed with different classes of medications for optimal IOP reduction.43
`
`
`Use of combination therapies in patients with glaucoma is often required to achieve adequate control of IOP. For
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`instance, a retrospective analysis of 16,486 patients with glaucoma who were using a prostaglandin analog
`showed that within 24 months of starting this therapy, 36% required 1 or more adjunctive therapies and 82% of
`them had started adjunctive therapy with a beta-blocker within 12 months of initiating prostaglandin analog
`treatment. Initial adjunctive therapies included a fixed-dose combination product in 28% of patients. Overall,
`42% of patients required adjunctive therapy within 30 days.38
`
`
`Fixed combinations of IOP-lowering medications have been shown to be more effective than the individual
`components and offer the advantages of enhanced convenience, improved adherence, reduced exposure to
`preservatives, and a possible lower cost. Additionally, some combinations are better tolerated than
`monotherapy.36 However, a disadvantage of fixed-combinations of IOP-lowering medications is that there is no
`option for adjusting the strength of individual medications within the combination.
`
`
`Therapeutic Pipeline for Lowering IOP
`
`Several IOP-lowering agents are in development to address the unmet therapeutic needs of patients with
`glaucoma, including the need for agents with new mechanisms of action, with better efficacy and with
`acceptable tolerability, as well as patient convenience. Key information about these agents is summarized below.
`
`Trabodenoson Alone and in Combination
`
`With Latanoprost
`
`Trabodenoson is a highly selective adenosine A1-receptor agonist with a novel mechanism of action. It enhances
`the outflow of aqueous humor by upregulating MMP-2 expression in the trabecular meshwork, resulting in
`remodeling of the extracellular matrix in that tissue, lowering outflow resistance and IOP. Across 144 patients
`with OHT or POAG enrolled in the trial, trabodenoson was well-tolerated at 4 doses tested (ie, 50 mcg, 100
`mcg, 200 mcg, and 500 mcg daily) and reduced IOP significantly at the 500 mcg dose compared with placebo at
`all time points (9 am, 10 am, 12 pm, 4 pm, and 8 pm) tested on day 28 (mean intra-day IOP reduction: 1.15 mm
`Hg with placebo vs 4.1 mm Hg with trabodenoson 500 mg, P <.05).44 However, the first pivotal phase 3 trial of
`trabodenoson for treatment of POAG or OHT failed to meet the primary endpoint of superiority in reduction of
`IOP compared with placebo. Also notable, in a phase 2 trial of trabodenoson in combination with latanoprost,
`the combination failed to outperform latanoprost alone in IOP reduction.45
`
`
`Netarsudil Alone and in Combination
`
`With Latanoprost
`
`Netarsudil is a member of a new class of IOP-lowering agents that inhibits Rho-kinase and norepinephrine
`transport. Through these mechanisms, netarsudil increases aqueous humor outflow through relaxation of the
`trabecular meshwork, decreases the production of aqueous humor, and decreases episcleral venous pressure.
`Netarsudil statistically lowers IOP in patients and is dosed once daily. A 29-day study randomly assigned 298
`patients with POAG or OHT to single-agent latanoprost 0.005%, single-agent netarsudil 0.02%, or 1 of 2
`concentrations of combinations of the 2 agents (ie, netarsudil 0.01%/latanoprost 0.005% or netarsudil
`0.02%/latanoprost 0.005%). At day 29, reductions in mean diurnal IOP were 1.9 mm Hg greater for netarsudil
`
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`0.02%/latanoprost 0.005% versus latanoprost and 2.6 mm Hg greater versus single-agent netarsudil 0.02% (P
`<.0001, both comparisons). Conjunctival hyperemia was observed in approximately 40% of patients receiving
`either strength of the combination treatment, 40% of patients receiving single-agent netarsudil, and 14% in the
`latanoprost-only group.46
`
`
`The fixed-dose combination netarsudil 0.02%/latanoprost 0.005% has been further studied in a 90-day phase 3
`trial and a 12-month phase 3 registration trial. In the 90-day trial, the primary efficacy endpoint, statistical
`superiority of the combination over each component as a single agent, was achieved. Combination
`netarsudil/latanoprost dosed once daily lowered IOP by 1 to 3 mm Hg more than monotherapy with either
`netarsudil or latanoprost throughout the study. About 10% of patients in each arm discontinued. In patients
`receiving netarsudil/latanoprost, more than half (55%) of patients experienced mild hyperemia, the most
`common adverse event. There were no serious adverse events.47,48
`
`
`Interim 3-month findings of the 12-month phase 3 study also indicate significantly greater reductions in IOP
`with netarsudil/latanoprost than with either treatment used alone at 2 weeks, 6 weeks, and 3 months of follow-up
`(P <.0001). Moreover, 44% of patients receiving netarsudil/latanoprost achieved IOP levels 15 mm Hg or lower,
`versus 23% of patients receiving netarsudil and 25% of patients receiving latanoprost (P <.0001). Conjunctival
`hyperemia was observed in 53% of patients receiving the combination therapy versus 41% of patients receiving
`netarsudil alone and 14% of patients receiving latanoprost alone. No serious drug-related adverse events were
`observed.48 Preliminary 1-year results of this trial were reported on July 19, 2017. Results of the 1-year efficacy
`endpoint were similar to results at the 90-day efficacy endpoint, with 60% of patients receiving
`netarsudil/latanoprost achieving a mean IOP of 16 mm Hg or lower. Secondary endpoints of IOP measurements
`at certain time intervals also exceeded reductions of IOP of both latanoprost 0.05% and netarsudil 0.02% by a
`range of 1 to 3 mm Hg.49 In terms of safety, the most common side effect with netarsudil/latanoprost was
`conjunctival hyperemia, present in 60% of patients, 70% of which were mild. Other adverse events, such as
`conjunctival hemorrhages and cornea verticillata were also consistent with the 90-day safety findings.49
`
`
`Latanoprostene Bunod
`
`Mechanism of Action
`
`Latanoprostene bunod (LBN) has a novel dual mechanism of action lowering IOP by acting on both of the major
`pathways for aqueous humor outflow, as shown in Figure 2.50 When LBN is topically administered to the eye, it
`is hydrolyzed by endogenous esterases into latanoprost acid, the active component of latanoprost, and butanediol
`mononitrate, which breaks down into nitric oxide (NO) and inactive 1,4-butanediol.39,50-52 This is illustrated in
`Figure 3.39,51,52
`
`
`Latanoprost acid increases the outflow of aqueous humor by reducing resistance through the uveoscleral
`pathway, by enhancing MMP expression, and remodeling extracellular matrix in the ciliary muscle and sclera.50
`The unique NO component of LBN has an additional important effect on the conventional outflow pathway and
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`adds a new mechanism of action to available treatment options unique from that of latanoprost and other
`prostaglandin analogs.50
`
`
`Nitric oxide is an endogenous signaling molecule with a wide range of physiological functions including its
`well-known role as a mediator of smooth muscle relaxation and vasodilation. Generation of NO by nitric oxide
`synthases (NOS) leads to activation of soluble guanylate cyclase (sGC), resulting in increased levels of cyclic
`guanosine monophosphate (cGMP) and activation of protein kinase G. Resulting effects on cyclic nucleotide
`gated channels, protein kinases, and other molecules lead to actin cytoskeletal rearrangement and thus cell
`relaxation culminating in physiological outcomes.53
`
`
`The NO-sGC-cGMP signaling pathway appears to control physiological IOP via regulation of aqueous humor
`outflow. In the healthy human eye, NOS are present in the trabecular meshwork, Schlemm’s canal, uveal
`vascular endothelium, the ciliary body, and nerve fibers in the limbus cornea and lens epithelium.53 In patients
`with POAG, markers for NO are decreased in aqueous humor, suggesting lower NO levels may contribute to
`increased IOP.53 There is some evidence that low-level NO signaling may have neuroprotective effects in
`glaucoma, and may also act by regulating episcleral blood flow.53 The glaucoma medication nipradilol, which is
`not available in the United States, has an NO-donating effect in addition to its alpha and beta receptor blocking
`activity, and reduces retinal ganglion cell death compared with a control when administered to rats with
`experimentally damaged optic nerves.53,54
`
`
`NO is thought to mediate its IOP-lowering effects by activation of the sGC/cGMP/protein kinase G pathway as
`described previously in other tissues. This, in turn, promotes rearrangement of the actin cytoskeleton resulting in
`decreased cell contractility and volume in the trabecular meshwork and Schlemm’s canal. These changes alter
`the physical properties of the trabecular meshwork and Schlemm’s canal cells, resulting in an increase in
`conventional outflow and lower IOP.50
`
`
`Preclinical Studies of LBN
`
`LBN reduced IOP by 17% in wild-type mice and by 0.45 mm Hg to 1.23 mm Hg in an FP-receptor knockout
`mouse model insensitive to the action of prostaglandin analogs.55 In a canine model of glaucoma, LBN
`decreased IOP by 44% from baseline versus latanoprost, which reduced IOP by 27%.56 In nonhuman primates
`with elevated IOP, reduction of IOP was greater with LBN (31%-35% depending on dose) than with latanoprost
`(25.8%).56 Additionally, in a rabbit model, LBN reduced the hypertensive response induced by injecting
`hypertonic saline intravitreously, while the same dose of latanoprost was without effect.56 These results, in part,
`formed the rationale for clinical trials of LBN, which are discussed in the next section.
`
`
`Latanoprostene Bunod Key Clinical Trials
`
`The clinical development program for LBN is summarized below. Results of key efficacy evaluations of LBN
`are summarized in Table 3.39,50,51,57-59
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`4/22/2018
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`Phase 1 Trial of LBN
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`KRONUS was a phase 1, single-center, open-label clinical study in 24 healthy Japanese male volunteers treated
`for 14 days with LBN 0.024% administered once every evening. Subjects had their 24-hour IOP profiles
`assessed in a sleep lab at baseline and after 14 days of dosing. LBN significantly reduced IOP at all evaluated
`time points (P <.001), with a mean 24-hour reduction of 3.6 (standard deviation = 0.8) mm Hg (27%) from
`baseline. Common adverse events included mild punctate keratitis and ocular hyperemia.60
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`Phase 2 Trials of LBN
`
`VOYAGER was a phase 2, multicenter, randomized, controlled, investigator-masked, dose-finding trial in 413
`patients with OAG or OHT. Patients were randomly assigned to LBN 0.006% (n = 82), LBN 0.012% (n = 85),
`LBN 0.024% (n = 83), LBN 0.040% (n = 81), or latanoprost 0.005% (n = 82). Each treatment was administered
`once daily in the evening for 28 days. Efficacy for LBN was dose-dependent, plateauing at the 0.024% and
`0.040% doses.57 At the primary efficacy endpoint of day 28, treatment with LBN 0.024% resulted in a mean
`IOP reduction of 9.00 mm Hg compared with a 7.77 mm Hg reduction with latanoprost treatment, for a
`statistically significant treatment difference of 1.23 mm Hg (P = .005).57 LBN 0.024% was also associated with
`significantly greater reductions in diurnal IOP compared with latanoprost on days 7 (P = .033) and 14 (P =
`.015).57
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`At all follow-up visits over the 29-day assessment period, a significantly greater proportion of patients treated
`with LBN 0.024% achieved a mean diurnal IOP of ≤18 mm Hg compared with patients receiving latanoprost (P
`≤.046). A significantly greater proportion of patients within the LBN 0.040% treatment group achieved a mean
`IOP of ≤18 mm Hg measured during visits on day 7 and day 28 compared with patients in the latanoprost group
`(P = .007 and P = .039, respectively), as shown in Figure 4.5