Long-term Safety and Efficacy of Latanoprostene Bunod 0.024% in Japanese Subjects with Open-Angle Glaucoma or Ocular Hypertension: The JUPITER Study

Introduction Latanoprostene bunod (LBN) is a novel nitric oxide (NO)-donating prostaglandin F2α analog. We evaluated the long-term safety and intraocular pressure (IOP)-lowering efficacy of LBN ophthalmic solution 0.024% over 1 year in Japanese subjects with open-angle glaucoma (OAG) or ocular hypertension (OHT). Methods This was a single-arm, multicenter, open-label, clinical study. Subjects aged 20 years and older with a diagnosis of OAG or OHT instilled 1 drop of LBN ophthalmic solution 0.024% in the affected eye(s) once daily in the evening for 52 weeks and were evaluated every 4 weeks. Safety assessments included vital signs, comprehensive ophthalmic exams, and treatment-emergent adverse events (AEs). Absolute and percent reductions from baseline in IOP were also determined. Results Of 130 subjects enrolled, 121 (93.1%) completed the study. Mean age was 62.5 years, and mean (standard deviation) baseline IOP was 19.6 (2.9) and 18.7 (2.6) mmHg in study eyes and treated fellow eyes, respectively. Overall, 76/130 (58.5%) and 78/126 (61.9%) subjects experienced ≥1 AEs in study eyes and treated fellow eyes, respectively. In both study eyes and treated fellow eyes, the most common AEs were conjunctival hyperemia, growth of eyelashes, eye irritation, and eye pain. At 52 weeks, 9% of treated eyes had an increase in iris pigmentation compared with baseline based on iris photographs. No safety concerns emerged based on vital signs or other ocular assessments. Mean reductions from baseline in IOP of 22.0% and 19.5% were achieved by week 4 in study and treated fellow eyes, respectively. These reductions were maintained through week 52 (P < 0.001 vs. baseline at all visits). Conclusion Once daily LBN ophthalmic solution 0.024% was safe and well-tolerated in Japanese subjects with OAG or OHT when used for up to 1 year. Long-term treatment with LBN ophthalmic solution 0.024% provided significant and sustained IOP reduction. Trial registration ClinicalTrials.gov identifier, NCT01895972. Funding Bausch & Lomb, Inc. a division of Valeant Pharmaceuticals International Inc.


INTRODUCTION
Open-angle glaucoma (OAG) is associated with progressive visual field damage and visual function loss that can lead to disability and adversely affect health-related quality of life [1][2][3][4]. Ocular hypertension (OHT) is considered a key risk factor for primary OAG, and reducing intraocular pressure (IOP) and maintaining target IOP can delay or prevent the onset of primary OAG in patients with OHT and slow disease progression in patients with glaucoma [5][6][7][8][9][10]. Accordingly, recommended goals of treatment for patients with OAG and those with OHT at risk of developing OAG include maintaining IOP within a target range and achieving stability of the optic nerve/retinal nerve fiber layer status and of visual fields [11,12]. A desirable IOP range should be determined for each patient based on a goal of minimizing the impact of visual field loss on quality of life; the upper limit of this range is considered the ''target pressure'' for achieving the sought after clinical goals. Lowering of IOP by 25% is a well-documented benchmark for slowing the progression of primary OAG, but even more aggressive targets may be appropriate in some patients depending on disease severity and other risk factors [11][12][13].
Topical prostaglandin analogs are potent ocular hypotensive agents with good IOP-lowering efficacy and a favorable safety profile [14,15]. Common ocular side effects of topical prostaglandin receptor agonists include conjunctival hyperemia, elongation and darkening of eyelashes, iris pigmentation changes, and periocular skin hyperpigmentation [16][17][18][19]. While these agents are  [29,30]. Preclinical and clinical studies suggest that both active moieties of LBN (latanoprost acid and NO) contribute to its potent IOP-lowering effect [21,22,29]. In animal models of OHT or glaucoma, LBN  were unable to discontinue contact lens use or other eye drop mediations (e.g., artificial tears) during and 15 min after instillation of study drug and during study visits; had any condition that prevented reliable applanation tonometry; had advanced glaucoma (mean deviation \-12 dB or split fixation) or other significant ophthalmic disease; or had very narrow angles (three quadrants with less than Grade 2), a history of or current angle closure, or congenital or secondary glaucoma. The study also excluded subjects who required treatment with ocular or systemic corticosteroids, or were in need of or expected to require additional topical or systemic treatment for OAG or OHT, or subjects with an anticipated need to initiate or modify medication known to affect IOP (e.g., b-adrenergic antagonists, a-adrenergic agonists, calcium channel blockers, angiotensinconverting enzyme inhibitors, and angiotensin II receptor blockers) during the study.

Study Treatments and Assessments
Baseline data were recorded at Visit 1. Subjects undergoing treatment with an IOP-lowering medication were required to undergo a washout period, with the length of the washout dependent on the type of medication used (a minimum of 5 days for miotics and oral/topical carbonic anhydrase inhibitors, 14 days for sympathomimetics, and 28 days for topical prostaglandin analogs, b-blockers, and combination drugs with b-blockers). A mid-washout visit (Visit 2) was scheduled for those requiring washout longer than 2 weeks. Any subject with a mean/median IOP exceeding 36 mmHg in either eye at any point during the washout period was withdrawn from the study. Safety assessments included treatmentemergent adverse events (AEs), vital signs, corrected decimal VA, conjunctival hyperemia assessment, slit-lamp examination findings, ophthalmoscopy findings, photographs of the irides, eyelids, and eyelashes, visual field assessment, gonioscopy, and pachymetry. VA was measured at baseline and all study visits using a decimal VA chart. The investigator graded conjunctival hyperemia prior to slit-lamp examination and IOP measurement on a scale of 1-4 using photographic standards (1 = none, 4 = severe). Photographs were taken using a slit-lamp mounted digital camera at Visits 3 (Day 0) and 16 (week 52), and were evaluated at the end of the study to assess any changes. Iris pigmentation was graded using four categories (1 = no increase, 2 = undecided, 3 = possible increase, and 4 = clear increase) by an independent reviewer, whereas any change in eyelid pigmentation or eyelashes was evaluated by the investigator and reported as an AE.
IOP was assessed at screening, the mid-washout visit (if applicable), baseline, and at each post-baseline study visit in both eyes at 10 AM ± 30 min using a Goldman applanation tonometer. For each patient, IOP was measured by the same operator using the same tonometer at each visit whenever possible.

Endpoints
Efficacy endpoints were absolute IOP values and reduction from baseline (RFB) in IOP. Safety endpoints included AEs, vital signs, corrected decimal VA, conjunctival hyperemia assessment, slit-lamp examination, ophthalmoscopy, photographs, visual field assessment, gonioscopy, and pachymetry.

Statistical Analysis
The sample size of 130 subjects was not based on power considerations for testing any hypothesis and was assumed to provide sufficient data to study the safety profile of LBN 0.024% QD over 52 weeks using descriptive statistics.
Treatment adherence was defined as the percentage of prescribed instillations received (based on diary card entries).
Safety analyses were based on the safety population, which included all subjects who received at least one dose of study drug. Treatment-emergent AEs were coded using Medical Dictionary for Regulatory Activities, version 16.0 and summarized by severity and relationship to study drug. Treatment-emergent ocular AEs were summarized for study eyes and treated fellow eyes, and treatment-emergent non-ocular AEs were summarized at the subject level by system organ class and preferred term.
Vital sign measurements and visual acuity were summarized using descriptive statistics.
Conjunctival hyperemia was categorized as none, mild, moderate, and severe, with the number and percentage of subjects in each category presented by visit. The number and percentage of subjects having C1 hyperemia and C1 moderate or severe hyperemia were also presented by visit. Iris photographs from Visits Efficacy analyses were based on the safety population (all subjects who received at least 1 dose of study drug). The absolute IOP, RFB in IOP, and mean percent change from week 4 through week 52 were summarized for study eyes and treated fellow eyes at each visit using descriptive statistics and discrete summaries (proportion of subjects with RFB in IOP C5 and C10 mmHg; proportion of subjects with RFB in IOP at each visit categorized into: B-5, -4 to 0, 1-4, 5-9, 10-14, and C15 mmHg). In addition, a paired t test was performed on the RFB at each visit.
In general, continuous variables were summarized by sample size, mean, standard deviation (SD), median, minimum, and maximum. Summaries for discrete variables included the tabulation of frequencies and percentages. All statistical analyses were performed using the SAS software (SAS Institute, Cary, NC, USA) version 9.2 or higher.

Subjects
A total of 151 subjects were screened. Of these, 130 subjects were enrolled and 121 (93.1%) completed the study. Reasons for study discontinuation included AEs (n = 4), withdrawal of consent (n = 4), and investigator decision (n = 1).
The mean (SD) age of the study population was 62.5 (18.9) years (range 39-81 years); the median age was 64.0 years. A slightly higher percentage of subjects was female than male (56.9% vs. 43.1%), and all subjects were Japanese. The majority of subjects (90.0%) were on prior IOP-lowering medication at screening and required a washout. In all but four subjects, both eyes qualified for treatment. Treatment-related ocular AEs were those categorized as possibly, probably, or definitely related to treatment AE treatment-emergent adverse event, LBN latanoprostene bunod a Reported as an AE (see Table 2  No treatment-related changes in blood pressure or heart rate were observed from baseline through week 52. Two subjects had vital sign measurements that were associated with AEs (mild hypertension) considered to be not or unlikely related to study drug.
Mean decimal VA at baseline was 1.11 in the study eye and 1.13 in the treated fellow eye. For all post-baseline study visits, the mean decimal VA ranged from 1.10 to 1.13 for the study eye and 1.10-1.15 for the treated fellow eye.   (4.8%) of treated fellow eyes. There were no changes in the number of eyes with these findings at any study visit, and no notable results from visual field assessment, gonioscopy, or pachymetry.

Efficacy
The mean (SD) IOP at each visit from baseline to week 52 for the study eye and the treated fellow eye for all subjects is shown in Fig. 2, and the RFB in IOP from baseline to each study visit is shown in Fig. 3

DISCUSSION
This multicenter, open-label study in Japanese subjects with OAG or OHT was designed to evaluate the long-term safety and IOP-lowering efficacy of LBN ophthalmic solution 0.24% QD. The study treatment duration of 12 months is  Standard deviations at each timepoint ranged from 2.31 to 3.00 mmHg. IOP intraocular pressure the longest reported with LBN 0.024% to date, and adds to a growing body of clinical data with this novel compound [22, [32][33][34][35]. Safety was assessed regularly throughout the study using a comprehensive battery of prospective ocular and non-ocular clinical evaluations along with AE monitoring. The combined findings of the safety evaluations confirmed the long-term safety and tolerability of LBN 0.024%. Over the one-year treatment period, there were no discontinuations due to AEs. The most common AEs were cosmetic and typical of topical prostaglandin analog use [36,37], including conjunctival hyperemia and eyelash growth.
Conjunctival hyperemia, mostly mild, was reported as an AE in 17-18% of treated eyes and was consistent with the rates of hyperemia determined by proactive investigator assessments at each study visit using photographic standards (range 17-20% of treated eyes). It should be noted that investigator-identified hyperemia was present before treatment initiation in about one of every six eyes. After the first 4 weeks of LBN treatment, the prevalence of investigator-identified hyperemia increased to 1 out of every five eyes, but remained generally stable, even showing a slight decline over the remaining 48 weeks. Iris hyperpigmentation is another well-recognized side effect of topical prostaglandin analogs [18,38] with apparently cosmetic-only implications, based on current understanding [19,39]. In the current study, iris hyperpigmentation was reported as an AE in 4% of treated eyes, and, at 1 year, an increase in iris pigmentation was noted in 9% of treated eyes and a possible increase was noted in another 14% based on iris photographs. Iridial pigmentation changes have also been reported with latanoprost in clinical studies with Japanese subjects [40][41][42][43]. These studies found the incidence of iris pigmentation to increase in proportion to duration of latanoprost treatment, with reported frequencies at 1 year ranging from 51.6% [42] to 58.2% [43] based on slit-lamp biomicroscopy, a rate much higher than that found in the current study with LBN. However, another 1-year study of latanoprost in 124 Japanese patients with primary OAG or OHT reported iris hyperpigmentation in only ten patients [44].
Reducing IOP is the primary modifiable factor in managing patients with, or at risk for, glaucoma. Expert consensus guidelines suggest that gold standard pharmacologic glaucoma therapy is defined by the long-term control of IOP with no induction of tachyphylaxis or tolerance [45]. Tachyphylaxis