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Latanoprostene Bunod 0.024% versus Timolol Maleate 0.5% in Subjects with Open-Angle Glaucoma or Ocular Hypertension

The APOLLO Study
Open AccessPublished:February 11, 2016DOI:https://doi.org/10.1016/j.ophtha.2016.01.019

      Purpose

      To compare the diurnal intraocular pressure (IOP)-lowering effect of latanoprostene bunod (LBN) ophthalmic solution 0.024% every evening (qpm) with timolol maleate 0.5% twice daily (BID) in subjects with open-angle glaucoma (OAG) or ocular hypertension (OHT).

      Design

      Phase 3, randomized, controlled, multicenter, double-masked, parallel-group clinical study.

      Participants

      Subjects aged ≥18 years with a diagnosis of OAG or OHT in 1 or both eyes.

      Methods

      Subjects were randomized (2:1) to a 3-month regimen of LBN 0.024% qpm or timolol 0.5% 1 drop BID. Intraocular pressure was measured at 8 am, 12 pm, and 4 pm of each postrandomization visit (week 2, week 6, and month 3). Adverse events were recorded throughout the study.

      Main Outcome Measures

      The primary efficacy end point was IOP in the study eye measured at each of the 9 assessment time points. Secondary efficacy end points included the proportion of subjects with IOP ≤18 mmHg consistently at all 9 time points and the proportion of subjects with IOP reduction ≥25% consistently at all 9 time points.

      Results

      Of 420 subjects randomized, 387 completed the study (LBN 0.024%, n = 264; timolol 0.5%, n = 123). At all 9 time points, the mean IOP in the study eye was significantly lower in the LBN 0.024% group than in the timolol 0.5% group (P ≤ 0.002). At all 9 time points, the percentage of subjects with mean IOP ≤18 mmHg and the percentage with IOP reduction ≥25% were significantly higher in the LBN 0.024% group versus the timolol 0.5% group (mean IOP ≤18 mmHg: 22.9% vs. 11.3%, P = 0.005; IOP reduction ≥25%: 34.9% vs. 19.5%, P = 0.001). Adverse events were similar in both treatment groups.

      Conclusions

      In this phase 3 study, LBN 0.024% qpm demonstrated significantly greater IOP lowering than timolol 0.5% BID throughout the day over 3 months of treatment. Latanoprostene bunod 0.024% was effective and safe in these adults with OAG or OHT.

      Abbreviations and Acronyms:

      ANCOVA (analysis of covariance), BCVA (best-corrected visual acuity), BID (twice daily), CFB (change from baseline), CI (confidence interval), IOP (intraocular pressure), ITT (intent-to-treat), LBN (latanoprostene bunod), LOCF (last observation carried forward), logMAR (logarithm of the minimum angle of resolution), NO (nitric oxide), OAG (open-angle glaucoma), OHT (ocular hypertension), PP (per-protocol), qpm (every evening), SD (standard deviation), TEAE (treatment-emergent adverse event), WOCF (worst observation carried forward)
      Open-angle glaucoma (OAG) is the leading cause of irreversible blindness and affects tens of millions of individuals worldwide.
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      Latanoprostene bunod (LBN, BOL-303259-X) is a novel nitric oxide (NO)-donating prostanoid FP receptor agonist that is rapidly metabolized in the eye into latanoprost acid, an F2α prostaglandin analog, and butanediol mononitrate. Nitric oxide is subsequently released from butanediol mononitrate in conjunction with 1,4 butanediol, an inactive metabolite.
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      A randomised, controlled comparison of latanoprostene bunod and latanoprost 0.005% in the treatment of ocular hypertension and open angle glaucoma: the VOYAGER study.
      Latanoprost acid reduces IOP by increasing aqueous humor outflow primarily through the uveoscleral pathway (“nonconventional” route) via long-term remodeling of the extracellular matrices in the ciliary body.
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      Latanoprostene bunod demonstrated IOP-lowering activity in several preclinical models of OHT, including in rabbits that are known to be insensitive to latanoprost, demonstrating the contribution of NO to the IOP-lowering effect of LBN.
      • Krauss A.H.
      • Impagnatiello F.
      • Toris C.B.
      • et al.
      Ocular hypotensive activity of BOL-303259-X, a nitric oxide donating prostaglandin F2α agonist, in preclinical models.
      Further, a well-controlled phase 2 study in 413 patients with OAG or OHT demonstrated a significantly greater reduction in mean diurnal IOP after 28 days of treatment with LBN 0.024% compared with latanoprost 0.005%.
      • Weinreb R.N.
      • Ong T.
      • Scassellati Sforzolini B.
      • et al.
      A randomised, controlled comparison of latanoprostene bunod and latanoprost 0.005% in the treatment of ocular hypertension and open angle glaucoma: the VOYAGER study.
      The current study was designed to compare the diurnal IOP-lowering effect of LBN ophthalmic solution 0.024% every evening (qpm) (hereafter referred to as “LBN 0.024%”) with timolol maleate ophthalmic solution 0.5% twice daily (BID) (hereafter referred to as “timolol 0.5%”) in subjects with OAG or OHT.

      Methods

       Study Objectives and Design

      The APOLLO study (Clinicaltrials.gov identifier: NCT01749904) was a phase 3, randomized, multicenter, double-masked, parallel-group clinical study. The study was composed of 2 phases: an active-controlled 3-month efficacy phase followed by an open-label 9-month safety extension phase. The primary objective of the efficacy phase was to evaluate the noninferiority of LBN 0.024% qpm compared with timolol 0.5% BID with regard to mean IOP reduction at each time point throughout the 3 months of treatment. If LBN 0.024% qpm was determined to be noninferior to timolol 0.5% BID, the secondary objective was to assess the superiority of LBN 0.024% qpm to timolol 0.5% BID. We report results from the efficacy phase of the study; data from the 9-month open-label extension phase will be reported separately. Institutional Review Board/Ethics Committee approval was obtained at each participating site.
      The study was conducted at 45 investigational sites in the United States and Europe and was performed in accordance with Good Clinical Practices (as described by the International Conference on Harmonisation), the Code of Federal Regulations, the ethical principles in the Declaration of Helsinki, Health Insurance Portability and Accountability Act regulations, and other applicable local regulations. All subjects provided written informed consent before the performance of any study procedures.

       Subjects

      The study enrolled men and women aged ≥18 years with a diagnosis of OAG (including pigmentary or pseudoexfoliative OAG) or OHT in 1 or both eyes. Intraocular pressure was assessed once at screening and at 8 am, 12 pm, and 4 pm at baseline to establish eligibility and baseline values. Eligible subjects had an IOP ≥26 mmHg at a minimum of 1 time point, ≥24 mmHg at a minimum of 1 time point, and ≥22 mmHg at 1 time point in the same eye, and IOP ≤36 mmHg at all 3 measurement time points in both eyes at baseline, which occurred after a washout period in those subjects receiving topical hypotensive treatment at the time of enrollment. In addition, subjects were required to have a best-corrected visual acuity (BCVA) of +0.7 logarithm of the minimum angle of resolution (logMAR) units (Snellen equivalent of ∼20/100) or better in either eye.
      Subjects were excluded if they had participated in any clinical trial within 30 days before screening for subjects requiring a washout period or 30 days before baseline (day 0) for subjects not requiring a washout period. Additional exclusion criteria included a known hypersensitivity or contraindications to latanoprost, NO-donating medications, timolol maleate, other β-adrenergic receptor antagonists, or any ingredients in study drugs; central corneal thickness >600 μm in either eye; any condition that prevented reliable applanation tonometry (e.g., significant corneal surface abnormalities) in either eye; and advanced glaucoma (cup-to-disk ratio >0.8 or split fixation) or other significant ophthalmic disease. Subjects requiring treatment with ocular or systemic corticosteroids, or who had an anticipated need to initiate or modify medication that was known to affect IOP (e.g., β-adrenergic antagonists, α-adrenergic agonists, calcium channel blockers, angiotensin-converting enzyme inhibitors, and angiotensin II receptor blockers) during the efficacy phase also were excluded from study participation.

       Study Treatments and Assessments

      Baseline data, including demographics, relevant medical and ocular history, and concomitant medications, were recorded at the screening visit. Eligible subjects receiving topical ocular hypotensive treatment at screening were required to discontinue treatment and undergo a washout period before the baseline visit (day 0), varying in duration depending on the IOP-lowering medication used (a minimum of 5 days for miotics and oral/topical carbonic anhydrase inhibitors, 14 days for α and α/β agonists, and 28 days for prostaglandin analogs, β-blockers, and combination drugs including β-blockers). Subjects taking topical β-blockers or prostaglandin analogs at screening were required to participate in a midwashout safety evaluation visit (day −14). Subjects were withdrawn from the study if their IOP was >36 mmHg in either eye at any point during the washout period.
      After baseline IOP measurements, eligible subjects were randomized 2:1 to receive LBN 0.024% qpm and vehicle every morning or timolol 0.5% BID for 3 months. For masking purposes, each treatment was labeled with identical investigational labels and packaged in identical kit boxes. Study drug was dispensed via an Interactive Response Technology system. Randomization schedules were created by a designated unmasked statistician using SAS Version 9.2 (SAS Institute, Inc., Cary, NC). Each subject received study kits containing 4 eye drop bottles and was instructed to instill 1 drop of the study drug from the “night” dosing bottle in the affected eye(s) at approximately 8 pm each day and 1 drop of the study drug from the “day” dosing bottle at approximately 8 am each day (with the exception of the morning of scheduled clinic visits, when the subject instilled the study drug after 8 am in-clinic assessments).
      The study eye was the eye that qualified per inclusion criteria on day 0; if both eyes qualified, then the study eye was the eye with the higher mean diurnal IOP value at day 0 or the right eye if both eyes had the same mean diurnal IOP value. If both eyes of a subject had a diagnosis of OAG or OHT, then both eyes were treated for the duration of the study, even if only 1 eye qualified at day 0.
      After randomization, subjects completed 3 study visits: week 2 (±2 days), week 6 (±3 days), and month 3 (±10 days). At each visit, IOP was measured in both eyes at 8 am, 12 pm, and 4 pm using a Goldmann applanation tonometer. Whenever possible, the same operator measured IOP, and the same tonometer was used at each visit for a given subject.
      Safety assessments included adverse events, vital signs, BCVA (measured using the Early Treatment Diabetic Retinopathy Study standard protocol), conjunctival hyperemia assessment, slit-lamp examination findings, ophthalmoscopy findings, and specular microscopy. The investigator graded conjunctival hyperemia on a scale of 1 to 4 using photographic standards (1 = none, 4 = severe). Slit-lamp findings, ophthalmoscopy findings, and specular microscopy results will be reported separately along with data from the 9-month open-label extension phase.

       End Points

      The primary efficacy end point was the IOP in the subject's study eye measured at 8 am, 12 pm, and 4 pm at each postbaseline visit (week 2, week 6, and month 3). The key secondary efficacy end points were the proportion of subjects with IOP ≤18 mmHg consistently at all 9 time points in the first 3 months and the proportion of subjects with IOP reduction ≥25% consistently at all 9 time points in the first 3 months. Additional secondary end points included the change from baseline (CFB) in IOP measured at 8 am, 12 pm, and 4 pm at each postbaseline visit and the CFB in diurnal IOP (defined as the mean of IOP at 8 am, 12 pm, and 4 pm) at each postrandomization visit. Safety end points during the efficacy phase included BCVA, conjunctival hyperemia assessment, and incidence of ocular and systemic adverse events.

       Statistical Analysis

      The sample size estimate was based on a noninferiority test of the difference between LBN 0.024% versus timolol 0.5% with respect to IOP in the per-protocol (PP) population, assuming a standard deviation (SD) of 3.75 mmHg, a power of 90%, a 2-sided α = 0.05, and a noninferiority margin of 1.5 mmHg. The SD was based on data from a phase 2b study of LBN 0.024% and the timolol arm of a phase 3 study.
      • Higginbotham E.J.
      • Olander K.W.
      • Kim E.E.
      • et al.
      Fixed combination of latanoprost and timolol vs individual components for primary open-angle glaucoma or ocular hypertension: a randomized, double-masked study.
      To account for potential dropouts and protocol violations, 393 subjects were to be randomized to the LBN 0.024% and timolol 0.5% treatment groups in a 2:1 ratio.
      The primary efficacy analysis was performed using analysis of covariance (ANCOVA) in the intent-to-treat (ITT) population, which comprised all randomized subjects who instilled at least 1 dose of study drug and had at least 1 postbaseline IOP assessment. In the ANCOVA model, treatment was a variable and time-matched baseline mean IOP was a covariate. Missing data were inputted using the last observation carried forward (LOCF) method. The 2 treatment groups were compared for each time point by visit, and the least squares mean of each treatment group, the difference in the least squares mean (LBN 0.024%−timolol 0.5%), and the 2-sided 95% confidence interval (CI) for the difference were obtained. Noninferiority was determined if the upper limit of the CIs for the difference did not exceed 1.5 mmHg at all 9 time points and did not exceed 1.00 mmHg for ≥5 of the 9 time points. If noninferiority was determined, superiority at each time point was demonstrated if the upper limit of the 95% CI did not exceed 0 mmHg at all 9 time points. To supplement the primary analyses, the ANCOVA was repeated for the PP population (i.e., all subjects in the ITT population who remained in the study through month 3 with no missing postbaseline IOP assessments and no major protocol violations). In addition, the primary analysis was repeated on the ITT population using the worst observation carried forward (WOCF) method.
      If noninferiority of LBN 0.024% to timolol 0.5% was shown, secondary end points analyzed were based on the ITT population with LOCF, with supportive analyses performed using the PP population. The proportion of subjects with IOP ≤18 mmHg at all time points in the first 3 months and the proportion with IOP reduction ≥25% at all time points in the first 3 months were summarized categorically. Percent reduction from baseline was calculated as 100*(baseline mean IOP − postbaseline mean IOP)/baseline mean IOP. For each key secondary end point, the 2-sided 95% CI around the difference in proportions (LBN 0.024%−timolol 0.5%) was calculated, and the P value was determined using Pearson's chi-square test. An ANCOVA of CFB in IOP was performed with fixed-effect terms for treatment and baseline for the specified postbaseline time points at week 2, week 6, and month 3. In addition, an ANCOVA of CFB in mean diurnal IOP was performed with fixed-effect terms for treatment and diurnal baseline IOP at each postbaseline visit. The CFB in IOP was summarized using descriptive statistics, and within-treatment group paired t tests were performed for the CFB mean IOP at each time point of each visit.
      Safety analyses were based on the safety population, which included all randomized subjects who instilled at least 1 dose of the study drug. Ocular treatment-emergent adverse events (TEAEs) were summarized for study eyes, treated fellow eyes, and nontreated fellow eyes separately by treatment group. Nonocular (systemic) TEAEs were summarized using discrete summaries at the subject and event level, respectively, using the Medical Dictionary for Regulatory Activities coding of the system organ class and preferred term for each treatment group. Treatment-emergent adverse events were summarized by relationship to study drug and severity. Systolic and diastolic blood pressure and heart rate were summarized by visit using descriptive statistics. Other safety data presented in this article, including BCVA and conjunctival hyperemia, were described separately for study eyes, treated fellow eyes, and nontreated fellow eyes and summarized using descriptive statistics (BCVA) or categorically (conjunctival hyperemia).
      All CIs, statistical tests, and P values were reported as 2-sided and assessed at the 5% significance level. Continuous data were summarized using descriptive statistics (number, mean, SD, median, minimum, and maximum). All statistical analyses were performed using SAS software (SAS Institute, Inc.) version 9.2 or higher.

      Results

       Subjects

      Subjects were enrolled from January 31, 2013, to April 30, 2014. Of 679 subjects screened, 420 were randomized to treatment with LBN 0.024% (n = 286) or timolol 0.5% (n = 134). A total of 418 randomized subjects instilled at least 1 dose of study drug and comprised the safety population (n = 283 LBN 0.024%, n = 135 timolol 0.5%); 1 subject did not have any recorded postbaseline IOP readings; thus, 417 subjects were included in the ITT population (n = 284 LBN 0.024%, n = 133 timolol 0.5%). One subject randomized to LBN received timolol and therefore was included in the timolol 0.5% safety population and the LBN 0.024% ITT population. The PP population included 272 subjects (n = 192 LBN 0.024%, n = 80 timolol 0.5%). Overall, 387 subjects (92.6%) in the safety population (92.9% [263/283] of the LBN 0.024% group, 91.9% [124/135] of the timolol 0.5% group) and 387 subjects (92.8%) in the ITT population (93.0% [264/284] of the LBN 0.024% group, 92.5% [123/133] of the timolol 0.5% group) completed the 3-month treatment. For the 30 subjects in the ITT population who discontinued the study (n = 20 LBN 0.024%, n = 10 timolol 0.5%), reasons for discontinuation included adverse events (n = 4 in each group), withdrawal of consent (n = 6 LBN 0.024%, n = 1 timolol 0.05%), failure to follow required study procedures (n = 2 in each group), investigator decision (n = 1 LBN 0.024%, n = 2 timolol 0.5%), lost to follow-up (n = 1 LBN 0.024%), and other reasons (n = 6 LBN 0.024%, n = 1 timolol 0.5%).
      Subjects in the ITT population had a mean age of 64.2 years, were of predominantly European or African ancestry, and were of non-Hispanic/non-Latino ethnicity. Treatment groups were comparable with regard to demographics (Table 1) and baseline eye characteristics (Table 2). More than two thirds of subjects (71.9%) were taking topical IOP-lowering medication at screening or had used IOP-lowering medication 30 days before screening and participated in a medication washout.
      Table 1Subject Demographics (Intent-to-Treat Population)
      LBN 0.024% (n = 284)Timolol 0.5% (n = 133)Total (N = 417)
      Age, yrs
       Mean (SD)64.7 (10.3)63.1 (11.2)64.2 (10.6)
       Median (min, max)65.0 (22, 88)64.0 (23, 83)65.0 (22, 88)
      Age group, n (%)
       <65 yrs138 (48.6)67 (50.4)205 (49.2)
       ≥65 yrs146 (51.4)66 (49.6)212 (50.8)
      Gender, n (%)
       Male118 (41.5)56 (42.1)174 (41.7)
       Female166 (58.5)77 (57.9)243 (58.3)
      Race, n (%)
       White217 (76.4)108 (81.2)325 (77.9)
       Black or African American64 (22.5)24 (18.0)88 (21.1)
       Asian1 (0.4)1 (0.8)2 (0.5)
       Other2 (0.7)02 (0.5)
      Ethnicity, n (%)
       Hispanic or Latino30 (10.6)13 (9.8)43 (10.3)
       Non-Hispanic and non-Latino254 (89.4)120 (90.2)374 (89.7)
      LBN = latanoprostene bunod; SD = standard deviation.
      Table 2Baseline Eye Characteristics (Study Eyes, Intent-to-Treat Population)
      LBN 0.024% (n = 284)Timolol 0.5% (n = 133)
      Mean (SD) diurnal IOP, mmHg26.7 (2.5)26.5 (2.4)
      Corneal thickness, μm
       Mean (SD)546.3 (31.7)549.6 (31.1)
       Median548.7550.7
       Range409.0–598.7461.0–597.0
      Sphere (D)
       Mean (SD)−0.45 (2.57)−0.76 (2.63)
       Median0.00−0.25
       Range−18.00 to 5.50−12.25 to 4.25
      Cylinder (D)
       Mean (SD)0.13 (1.05)0.25 (1.06)
       Median0.000.25
       Range−5.50 to 3.25−3.00 to 4.00
      D = diopters; IOP = intraocular pressure; LBN = latanoprostene bunod; SD = standard deviation.

       Efficacy

       Primary Efficacy Outcomes

      Mean IOP in the study eye was significantly lower in the LBN 0.024% group (range, 17.8–18.7 mmHg) than in the timolol 0.5% group (range, 19.1–19.8 mmHg) at all 9 efficacy time points assessed (8 am, 12 pm, and 4 pm at week 2, week 6, and month 3) (Fig 1). Noninferiority of LBN 0.024% to timolol 0.5% in the ITT population was demonstrated on the basis of ANCOVA for the comparison of mean IOP between treatment groups: The upper limit of the 95% CIs for the difference between treatments was ≤1.0 mmHg for all of the 9 efficacy time points (Table 3). Likewise, ANCOVA results demonstrated the superiority of LBN 0.024% to timolol 0.5% in the ITT population because the upper limit of the 95% CIs for the difference between treatments was ≤0 mmHg at all 9 time points (Table 3). The primary end point findings were supported by results of an ANCOVA analysis in the PP population and with WOCF in the ITT population (data not shown). Furthermore, primary end point findings were not affected by prior treatment status (subjects on treatment at enrollment vs. subjects not on treatment at enrollment), subject age (<65 vs. ≥65 years), or concurrent use of systemic β-blockers (data not shown).
      Figure thumbnail gr1
      Figure 1Mean intraocular pressure (IOP) (mmHg) in the study eye by visit, time point, and treatment group (intent-to-treat [ITT] population with last observation carried forward [LOCF]). Mean was the least squares mean of the mean IOP. LBN = latanoprostene bunod. *P ≤ 0.002 versus timolol at the same assessment point.
      Table 3Primary End Point: Mean Intraocular Pressure in the Study Eye (Intent-to-Treat Population, Analysis of Covariance with Last Observation Carried Forward)
      Week 2Week 6Month 3
      8 am12 pm4 pm8 am12 pm4 pm8 am12 pm4 pm
      LBN 0.024% (n = 284)
       N282282281283283284283283284
       Mean IOP, mmHg
      Mean was the least squares mean of the mean IOP for the corresponding time point and visit at time-matched overall average baseline under ANCOVA.
      18.618.018.118.617.817.818.717.917.8
      Timolol 0.5% (n = 133)
       N133131131133131131133131131
       Mean IOP, mmHg
      Mean was the least squares mean of the mean IOP for the corresponding time point and visit at time-matched overall average baseline under ANCOVA.
      19.819.419.219.619.119.119.719.219.2
      Treatment difference
      Treatment difference = LBN 0.024% − timolol 0.5%.
       Adjusted mean IOP
      Adjusted mean, 95% CIs, and P values were from an ANCOVA model with treatment as a classification variable and time-matched baseline mean IOP as a covariate.
      −1.2−1.4−1.1−1.0−1.3−1.3−1.0−1.3−1.3
       Upper 95% CI
      Adjusted mean, 95% CIs, and P values were from an ANCOVA model with treatment as a classification variable and time-matched baseline mean IOP as a covariate.
      −0.5−0.7−0.5−0.4−0.6−0.6−0.4−0.6−0.6
       Lower 95% CI
      Adjusted mean, 95% CIs, and P values were from an ANCOVA model with treatment as a classification variable and time-matched baseline mean IOP as a covariate.
      −1.9−2.1−1.8−1.7−1.9−2.0−1.7−1.9−2.0
      P value
      Adjusted mean, 95% CIs, and P values were from an ANCOVA model with treatment as a classification variable and time-matched baseline mean IOP as a covariate.
      <0.001<0.001<0.0010.002<0.001<0.0010.002<0.001<0.001
      CI = confidence interval; IOP = intraocular pressure; LBN = latanoprostene bunod.
      Mean was the least squares mean of the mean IOP for the corresponding time point and visit at time-matched overall average baseline under ANCOVA.
      Treatment difference = LBN 0.024% − timolol 0.5%.
      Adjusted mean, 95% CIs, and P values were from an ANCOVA model with treatment as a classification variable and time-matched baseline mean IOP as a covariate.

       Secondary Efficacy Outcomes

      A higher percentage of subjects in the LBN 0.024% group (22.9%) compared with the timolol 0.5% group (11.3%) had an IOP ≤18 mmHg consistently at all 9 efficacy time points measured (Fig 2) (difference, 11.6%; 95% CI, 4.3–18.9; P = 0.005). Likewise, a higher percentage of subjects in the LBN 0.024% group (34.9%) compared with the timolol 0.5% group (19.5%) had an IOP reduction ≥25% consistently at all 9 time points measured (Fig 2) (difference, 15.3%; 95% CI, 6.6–24.0; P = 0.001). Similar results were observed in the PP population.
      Figure thumbnail gr2
      Figure 2Response rates for key secondary efficacy end points after 3 months of treatment with latanoprostene bunod (LBN) 0.024% or timolol 05% (intent-to-treat [ITT] population with last observation carried forward [LOCF]). CFB = change from baseline; IOP = intraocular pressure. *P ≤ 0.005 versus timolol.
      Further ANCOVA analysis showed that the mean CFB in mean IOP was greater in the LBN 0.024% group (range, −7.7 to −9.1 mmHg) than in the timolol 0.5% group (range, −6.6 to −8.0 mmHg) at all 9 efficacy time points (Fig 3). The difference in the CFB in mean IOP between treatment groups was statistically significant at all 9 efficacy time points (P ≤ 0.002). As was the case for the individual time points, mean diurnal IOP (average of IOP at 8 am, 12 pm, and 4 pm) was significantly lower in the LBN 0.024% group compared with the timolol 0.5% group at each visit (18.2 vs. 19.5 mmHg at week 2, 18.1 vs. 19.3 mmHg at week 6, and 18.2 vs. 19.4 mmHg at month 3; P < 0.001 for all). Similar to the CFB at individual time points, at each study visit, there was a statistically significantly (P < 0.001) greater CFB in mean diurnal IOP in the LBN 0.024% group (range, −8.4 to −8.6 mmHg) than in the timolol 0.5% group (range, −7.1 to −7.3 mmHg).
      Figure thumbnail gr3
      Figure 3Change from baseline in mean intraocular pressure (IOP) (mmHg) in the study eye by visit, time point, and treatment group (intent-to-treat [ITT] population with with last observation carried forward [LOCF]). Mean was the least squares mean of the mean IOP change. LBN = latanoprostene bunod. *P ≤ 0.002 versus timolol at the same assessment point.

       Safety

       Exposure

      Mean ± SD days of exposure to study drug in the safety population was similar in the LBN 0.024% group (89.7±14.4 days) and the timolol 0.5% group (89.4±18.4 days) during the 3-month efficacy phase.

       Ocular Adverse Events

      The percentage of study or fellow treated eyes experiencing at least 1 ocular TEAE was comparable in the LBN 0.024% and timolol 0.5% groups (Table 4). Ocular TEAEs reported in ≥1% of eyes in both treatment groups included eye irritation, conjunctival hyperemia, eye pain, dry eye, and instillation site pain. Most ocular TEAEs were considered related to the study drug and mild or moderate in severity with a few exceptions. In the LBN 0.024% group, 2 subjects experienced a severe TEAE in treated fellow eyes, scleritis and foreign body requiring surgery, both considered unrelated to treatment. One subject in the timolol 0.5% group had severe eye pain (study and fellow treated eye) and instillation site pain (study eye) considered possibly related to treatment, and 1 subject experienced a severe IOP increase considered unrelated study treatment.
      Table 4Ocular Treatment-Emergent Adverse Events Occurring in ≥1% of Study and Treated Fellow Eyes in Either Treatment Group (Safety Population)
      LBN 0.024%Timolol 0.5%
      Study Eye N = 283Fellow Treated Eye N = 276Study Eye N = 135Fellow Treated Eye N = 134
      n (%)n (%)n (%)n (%)
      ≥1 ocular TEAE38 (13.4)40 (14.5)16 (11.9)17 (12.7)
      ≥1 treatment-related ocular TEAE31 (11.0)31 (11.2)12 (8.9)12 (9.0)
       Eye irritation11 (3.9)10 (3.6)3 (2.2)3 (2.2)
       Conjunctival hyperemia8 (2.8)10 (3.6)2 (1.5)3 (2.2)
       Eye pain4 (1.4)7 (2.5)3 (2.2)1 (0.7)
       Dry eye3 (1.1)2 (0.7)1 (0.7)1 (0.7)
       Foreign body sensation in eyes3 (1.1)5 (1.8)0 (0.0)0 (0.0)
       Instillation site pain3 (1.1)2 (0.7)2 (1.5)3 (2.2)
      LBN = latanoprostene bunod; TEAE = treatment-emergent adverse event.
      Two subjects in the LBN treatment group discontinued because of ocular adverse events; 1 subject had mild conjunctival edema and mild conjunctival irritation, considered probably treatment related, in both eyes, and the other had severe scleritis in the treated fellow eye considered unrelated to study treatment. In the timolol group, 5 subjects discontinued because of an ocular adverse event. These included eyelid edema (mild, probably related), eye irritation (moderate, definitely related), eye allergy (moderate, unlikely related), and allergic conjunctivitis (moderate, unrelated) in both eyes of 4 subjects; and elevated IOP (severe, unrelated) in the treated fellow eye of 1 subject.

       Nonocular Adverse Events

      The proportion of subjects experiencing ≥1 nonocular TEAE was comparable in the LBN 0.024% and timolol 0.5% groups (12.7% and 14.1%, respectively). Treatment-related nonocular TEAEs were reported by 5 subjects (1.8%) in the LBN 0.024% group (headache in 2 subjects; fatigue in 1 subject; sinus congestion in 1 subject; hair color changes and hair disorder in 1 subject) and 3 subjects (2.2%) in the timolol 0.5% group (bradycardia, procedural headache, and rhinorrhea, each in 1 subject). Severe/serious nonocular TEAEs were experienced by 5 subjects in the LBN 0.024% group (femoral neck fracture, surgery for osteoarthritis, dizziness, chest pain, each in 1 subject; peripheral edema and pain in extremity in 1 subject) and by 2 subjects in the timolol 0.5% group (torn rotator cuff, arthropod bite). All severe/serious TEAEs were considered to be unrelated or unlikely related to the study drug; all other TEAEs were mild or moderate in severity. No deaths occurred during the 3-month treatment period.
      Two subjects in the LBN treatment group discontinued because of a nonocular adverse event: severe dizziness considered unlikely to be related to treatment in 1 subject and moderate fatigue considered possibly related to treatment in the other.

       Other Safety Measures

      Mean vital sign measures (systolic blood pressure, diastolic blood pressure, and pulse rate) were similar between treatment groups, and no treatment-related trends were observed. In addition, mean logMAR BCVA values did not vary notably during the study. Mean (SD) logMAR BCVA in the study eye in the LBN and timolol treatment groups was 0.09 (0.137) and 0.07 (0.124) at baseline and 0.08 (0.134) and 0.07 (0.139) at 3 months, respectively.
      Approximately 40% of subjects were observed by the investigator to have conjunctival hyperemia, mostly mild, at baseline before treatment, in their prospective evaluation of hyperemia using photographic standards. The percentage of subjects with conjunctival hyperemia was similar between posttreatment study visits and between the 2 treatment groups for both the study eyes and the treated fellow eyes with small variations from baseline in the overall incidence of conjunctival hyperemia through 3 months. However, the percentage of subjects with moderate or severe hyperemia was numerically higher in the LBN 0.024% group compared with the timolol 0.5% group in both study eyes and treated fellow eyes at week 2 (study eye: 9.6% and 0.7%, respectively; treated fellow eye: 10.2% and 1.5%, respectively), week 6 (study eye: 11.8% and 3.8%, respectively; treated fellow eye: 10.7% and 5.4%, respectively), and month 3 (study eye: 8.5% and 2.4%, respectively; treated fellow eye: 9.8% and 1.6%, respectively).

      Discussion

      This randomized, multicenter, double-masked parallel-group study demonstrated that LBN 0.024% instilled qpm resulted in significantly greater IOP lowering compared with timolol 0.5% instilled BID throughout the day over 3 months of treatment. The mean IOP in the study eye was statistically significantly lower in the LBN group than in the timolol group consistently at all 9 measured time points, whether analyzed for the ITT population using the LOCF or WOCF, supporting the robustness of the findings. Of note, the difference between the LBN and timolol groups in mean IOP exceeded 1 mmHg at all time points. The clinical significance of this difference is underscored by results of the Early Manifest Glaucoma Trial, which found that in patients with OAG, each millimeter of mercury of IOP reduction from baseline at the first follow-up visit (3 months) was associated with an approximately 10% reduction in progression of visual field loss.
      • Leske M.C.
      • Heijl A.
      • Hussein M.
      • et al.
      Factors for glaucoma progression and the effect of treatment: the early manifest glaucoma trial.
      More recently, Heijl
      • Heijl A.
      Glaucoma treatment: by the highest level of evidence.
      suggested a 19% reduction in the risk of visual field progression for every 1 mmHg IOP reduction on the basis of a review of data from the UK Glaucoma Treatment Study evaluating the effect of latanoprost 0.005% compared with vehicle in patients with OAG.
      • Garway-Heath D.F.
      • Crabb D.P.
      • Bunce C.
      • et al.
      Latanoprost for open-angle glaucoma (UKGTS): a randomized, multicentre, placebo-controlled trial.
      • Heijl A.
      Glaucoma treatment: by the highest level of evidence.
      Results of secondary efficacy end points were consistent with the primary outcome measures. Significantly more subjects treated with LBN 0.024% than timolol 0.5% achieved predetermined criterions of an absolute IOP ≤18 mmHg or IOP reduction ≥25% at each of the 9 measured time points, and the CFB in mean IOP and mean diurnal IOP were consistently significantly greater in the LBN group throughout the study. Several landmark trials support the clinical practice of setting a target diurnal IOP in the treatment of patients with OAG or OHT and have demonstrated that IOP reduction to such targets slows the rate of development or progression of visual loss and structural damage caused by glaucoma.
      • Kass M.A.
      • Heuer D.K.
      • Higginbotham E.J.
      • et al.
      The ocular hypertension treatment study: a randomized trial determines that topical hypotensive medication delays or prevents the onset of primary open angle glaucoma.
      • Heijl A.
      • Leske M.C.
      • Bengtsson B.
      • et al.
      Reduction of intraocular pressure and glaucoma progression: results from the Early Manifest Glaucoma Trial.
      AGIS Investigators
      The Advanced Glaucoma Intervention Study (AGIS): 7. The relationship between control of intraocular pressure and visual field deterioration.
      • Leske M.C.
      • Heijl A.
      • Hussein M.
      • et al.
      Factors for glaucoma progression and the effect of treatment: the early manifest glaucoma trial.
      The Advanced Glaucoma Intervention Study demonstrated that patients with glaucoma reaching and maintaining a target IOP of ≤18 mmHg through surgical intervention supplemented with medical treatment had a significantly reduced progression of visual field loss compared with eyes that failed to meet this target.
      AGIS Investigators
      The Advanced Glaucoma Intervention Study (AGIS): 7. The relationship between control of intraocular pressure and visual field deterioration.
      Likewise, in the Ocular Hypertension Treatment Study, in which treatment with IOP-lowering medication resulted in a 23% reduction in IOP, only 36 of 817 patients developed glaucoma by 60 months versus 89 of 819 patients in the observation group.
      • Kass M.A.
      • Heuer D.K.
      • Higginbotham E.J.
      • et al.
      The ocular hypertension treatment study: a randomized trial determines that topical hypotensive medication delays or prevents the onset of primary open angle glaucoma.
      The Early Manifest Glaucoma Trial, in which treated patients had an average IOP lowering of 25%, demonstrated that IOP-lowering treatment halved the risk of disease progression in patients with OAG (hazard ratio, 0.50; 95% CI, 0.35–0.71).
      • Heijl A.
      • Leske M.C.
      • Bengtsson B.
      • et al.
      Reduction of intraocular pressure and glaucoma progression: results from the Early Manifest Glaucoma Trial.
      • Leske M.C.
      • Heijl A.
      • Hussein M.
      • et al.
      Factors for glaucoma progression and the effect of treatment: the early manifest glaucoma trial.
      Intraocular pressure is the only modifiable risk factor in patients with OAG, with numerous studies demonstrating a relationship between IOP lowering and slowed progression or prevention of OAG, regardless of the interventional method.
      • Kass M.A.
      • Heuer D.K.
      • Higginbotham E.J.
      • et al.
      The ocular hypertension treatment study: a randomized trial determines that topical hypotensive medication delays or prevents the onset of primary open angle glaucoma.
      • Heijl A.
      • Leske M.C.
      • Bengtsson B.
      • et al.
      Reduction of intraocular pressure and glaucoma progression: results from the Early Manifest Glaucoma Trial.
      AGIS Investigators
      The Advanced Glaucoma Intervention Study (AGIS): 7. The relationship between control of intraocular pressure and visual field deterioration.
      • Lichter P.R.
      • Musch D.C.
      • Gillespie B.W.
      • et al.
      Interim clinical outcomes in the Collaborative Initial Glaucoma Treatment Study comparing initial treatment randomized to medications or surgery.
      • Leske M.C.
      • Heijl A.
      • Hussein M.
      • et al.
      Factors for glaucoma progression and the effect of treatment: the early manifest glaucoma trial.
      Collaborative Normal-Tension Glaucoma Study Group
      Comparison of glaucomatous progression between untreated patients with normal-tension glaucoma and patients with therapeutically reduced intraocular pressures.
      • Garway-Heath D.F.
      • Crabb D.P.
      • Bunce C.
      • et al.
      Latanoprost for open-angle glaucoma (UKGTS): a randomized, multicentre, placebo-controlled trial.
      Glaucoma Laser Trial Research Group
      The Glaucoma Laser Trial (GLT) and Glaucoma Laser Trial Follow-up Study: 7. Results.
      • Migdal C.
      • Gregory W.
      • Hitchings R.
      Long-term functional outcome after early surgery compared with laser and medicine in open-angle glaucoma.
      • Mao L.K.
      • Stewart W.C.
      • Shields M.B.
      Correlation between intraocular pressure control and progressive glaucomatous damage in primary open-angle glaucoma.
      • Kidd M.N.
      • O’Connor M.
      Progression of field loss after trabeculectomy: a five-year follow-up.
      • Chauhan B.C.
      • Mikelberg F.D.
      • Balaszi G.
      • et al.
      Canadian Glaucoma Study: 2. Risk Factors for the Progression of Open-Angle Glaucoma.
      Treatment options include pharmacotherapy, laser therapy, and surgery, and the choice of therapy should be individualized in consideration of patient factors and preferences. Pharmacologic treatment with prostaglandin analogs or β-blockers commonly is used as initial intervention for IOP lowering in patients with OAG.
      • American Academy of Ophthalmology
      Features such as IOP-lowering potential, safety, and dosing convenience are important considerations.
      Latanoprostene bunod is a novel monotherapy with the pharmacologic activity of both a prostaglandin F2α analog (latanoprost acid) and, via the NO donating moiety, the physiologic signaling mediator NO. Both active moieties of LBN independently have been shown to lower IOP via 2 distinct mechanisms: latanoprost acid via the uveosceleral (nonconventional) aqueous outflow pathway and NO via the trabecular meshwork/Schlemm's canal (conventional) outflow pathway.
      • Lindsey J.D.
      • Kashiwagi K.
      • Kashiwagi F.
      • Weinreb R.N.
      Prostaglandins alter extracellular matrix adjacent to human ciliary muscle cells in vitro.
      • Schachtschabel U.
      • Lindsey J.D.
      • Weinreb R.N.
      The mechanism of action of prostaglandins in uveoscleral outflow.
      • Gaton D.D.
      • Sagara T.
      • Lindsey J.D.
      • et al.
      Increased matrix metalloproteinases 1, 2, and 3 in the monkey uveoscleral outflow pathway after topical prostaglandin F(2 alpha)-isopropyl ester treatment.
      • Richter M.
      • Krauss A.H.
      • Woodward D.F.
      • Lutjen-Drecoll E.
      Morphological changes in the anterior eye segment after long-term treatment with different receptor selective prostaglandin agonists and a prostamide.
      • Nathanson J.A.
      Nitrovasodilators as a new class of ocular hypotensive agents.
      • Schuman J.S.
      • Erickson K.
      • Nathanson J.A.
      Nitrovasodilator effects on intraocular pressure and outflow facility in monkeys.
      • Wiederholt M.
      • Sturm A.
      • Lepple-Wienhues A.
      Relaxation of trabecular meshwork and ciliary muscle by release of nitric oxide.
      • Schneemann A.
      • Dijkstra B.G.
      • van den Berg T.J.
      • et al.
      Nitric oxide/guanylate cyclase pathways and flow in anterior segment perfusion.
      • Kotikoski H.
      • Vapaatalo H.
      • Oksala O.
      Nitric oxide and cyclic GMP enhance aqueous humor outflow facility in rabbits.
      • Heyne G.W.
      • Kiland J.A.
      • Kaufman P.L.
      • Gabelt B.T.
      Effect of nitric oxide on anterior segment physiology in monkeys.
      • Cavet M.E.
      • Vittitow J.L.
      • Impagnatiello F.
      • et al.
      Nitric oxide (NO): an emerging target for the treatment of glaucoma.
      • Chang J.Y.
      • Stamer W.D.
      • Bertrand J.
      • et al.
      Role of nitric oxide in murine conventional outflow physiology.
      • Lei Y.
      • Zhang X.
      • Song M.
      • et al.
      Aqueous humor outflow physiology in NOS3 knockout mice.
      The intent in the development of this new monotherapy was to provide enhanced IOP-lowering potential over currently available glaucoma therapies without an increased risk of adverse events.
      The additional IOP lowering by LBN over latanoprost 0.005% (Xalatan, Pfizer, New York, NY) has been demonstrated in both nonclinical animal models of OHT and a phase 2 clinical study.
      • Krauss A.H.
      • Impagnatiello F.
      • Toris C.B.
      • et al.
      Ocular hypotensive activity of BOL-303259-X, a nitric oxide donating prostaglandin F2α agonist, in preclinical models.
      • Weinreb R.N.
      • Ong T.
      • Scassellati Sforzolini B.
      • et al.
      A randomised, controlled comparison of latanoprostene bunod and latanoprost 0.005% in the treatment of ocular hypertension and open angle glaucoma: the VOYAGER study.
      The phase 2 study compared LBN with latanoprost in 396 patients with OAG and OHT (the VOYAGER study).
      • Weinreb R.N.
      • Ong T.
      • Scassellati Sforzolini B.
      • et al.
      A randomised, controlled comparison of latanoprostene bunod and latanoprost 0.005% in the treatment of ocular hypertension and open angle glaucoma: the VOYAGER study.
      After 28 days of once-daily treatment in the evening, the reduction in mean diurnal IOP from baseline was significantly greater with LBN 0.024% than with latanoprost 0.005% (−9.0 vs. −7.8 mmHg, P = 0.005). These findings are suggestive of an additive benefit of the NO-donating component of LBN. Although the current study did not include a latanoprost comparator arm, an additional IOP lowering of >1 mmHg over timolol was apparent at all evaluation time points over 3 months.
      In addition to IOP-lowering effectiveness, it is important that LBN not be associated with clinically limiting safety or tolerability issues. In the current study, the adverse event profiles of LBN and timolol were similar over the 3 months of treatment. In fact, TEAEs were fairly uncommon in both groups, and reports of eye pain and irritation were low. Visual acuity findings and vital signs measurements were unremarkable. Although the overall proportions of subjects with ocular hyperemia as assessed by investigators were similar between treatment groups both before and after treatment at each visit, a greater proportion of subjects in the LBN group were rated as having moderate to severe hyperemia compared with subjects in the timolol group. These findings are consistent with reported rates of hyperemia in patients treated with latanoprost.
      • Zhang W.Y.
      • Po A.L.
      • Dua H.S.
      • Azuara-Blanco A.
      Meta-analysis of randomised controlled trials comparing latanoprost with timolol in the treatment of patients with open angle glaucoma or ocular hypertension.
      In conclusion, LBN 0.024%, a once-daily NO-donating prostaglandin monotherapy with a dual mechanism of action, was safe and significantly more effective than timolol 0.5% BID in reducing mean IOP in patients with OAG and OHT. The ability to more consistently lower IOP to ≤18 mmHg may provide a significant advantage over topical β-blockers.

      Acknowledgments

      Editorial assistance was provided by Churchill Communications (Maplewood, NJ) and funded by Bausch & Lomb, Inc.

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