An Open-Label Phase II Study Assessing the Safety of Bilateral, Sequential Administration of Retinal Gene Therapy in Participants with Choroideremia: The GEMINI Study.

Choroideremia, an incurable, progressive retinal degeneration primarily affecting young men, leads to sight loss. GEMINI was a multicenter, open-label, prospective, two-period, interventional Phase II study assessing the safety of bilateral sequential administration of timrepigene emparvovec, a gene therapy, in adult males with genetically confirmed choroideremia (NCT03507686, ClinicalTrials.gov). Timrepigene emparvovec is an adeno-associated virus serotype 2 vector encoding the cDNA of Rab escort protein 1, augmented by a downstream woodchuck hepatitis virus post-transcriptional regulatory element. Up to 0.1 mL of timrepigene emparvovec, containing 1 × 1011 vector genomes, was administered by subretinal injection following vitrectomy and retinal detachment. The second eye was treated after an intrasurgery window of <6, 6-12, or >12 months. Each eye was followed at up to nine visits over 12 months. Overall, 66 participants received timrepigene emparvovec, and 53 completed the study. Visual acuity (VA) was generally maintained in both eyes, independent of intrasurgery window duration, even after bilateral retinal detachment and subretinal injection. Bilateral treatment was well tolerated, with predominantly mild or moderate treatment-emergent adverse events (TEAEs) and a low rate of serious surgical complications (7.6%). Retinal inflammation TEAEs were reported in 45.5% of participants, with similar rates in both eyes; post hoc analyses found that these were not associated with clinically significant vision loss at month 12 versus baseline. Two participants (3.0%) reported serious noninfective retinitis. Prior timrepigene emparvovec exposure did not increase the risk of serious TEAEs or serious ocular TEAEs upon injection of the second eye; furthermore, no systemic immune reaction or inoculation effect was observed. Presence of antivector neutralizing antibodies at baseline was potentially associated with a higher percentage of TEAEs related to ocular inflammation or reduced VA after injection of the first eye. The GEMINI study results may inform decisions regarding bilateral sequential administration of other gene therapies for retinal diseases.

A Prospective, Observational, Non-interventional Clinical Study of Participants With Choroideremia: The NIGHT Study.

PURPOSE: The NIGHT study aimed to assess the natural history of choroideremia (CHM), an X-linked inherited chorioretinal degenerative disease leading to blindness, and determine which outcomes would be the most sensitive for monitoring disease progression. DESIGN: A prospective, observational, multicenter cohort study. METHODS: Males aged ≥18 years with genetically confirmed CHM, visible active disease within the macular region, and best-corrected visual acuity (BCVA) ≥34 Early Treatment Diabetic Retinopathy Study (ETDRS) letters at baseline were assessed for 20 months. The primary outcome was the change in BCVA over time at Months 4, 8, 12, 16, and 20. A range of functional and anatomical secondary outcome measures were assessed up to Month 12, including retinal sensitivity, central ellipsoid zone (EZ) area, and total area of fundus autofluorescence (FAF). Additional ocular assessments for safety were performed. RESULTS: A total of 220 participants completed the study. The mean BCVA was stable over 20 months. Most participants (81.4% in the worse eye and 77.8% in the better eye) had change from baseline > -5 ETDRS letters at Month 20. Interocular symmetry was low overall. Reductions from baseline to Month 12 were observed (worse eye, better eye) for retinal sensitivity (functional outcome; -0.68 dB, -0.48 dB), central EZ area (anatomical outcome; -0.276 mm2, -0.290 mm2), and total area of FAF (anatomical outcome; -0.605 mm2, -0.533 mm2). No assessment-related serious adverse events occurred. CONCLUSIONS: Retinal sensitivity, central EZ area, and total area of FAF are more sensitive than BCVA in measuring the natural progression of CHM.

Assessment of Visual Function with Cotoretigene Toliparvovec in X-Linked Retinitis Pigmentosa in the Randomized XIRIUS Phase 2/3 Study.

PURPOSE: Cotoretigene toliparvovec (BIIB112/AAV8-RPGR) is an investigational vector-based gene therapy designed to provide a full-length, codon-optimized retinitis pigmentosa GTPase regulator (RPGR) protein to individuals with RPGR-associated X-linked retinitis pigmentosa (XLRP). We assessed efficacy and tolerability of cotoretigene toliparvovec subretinal gene therapy. DESIGN: Part 2 of the XIRIUS trial (ClinicalTrials.gov identifier, NCT03116113) was a phase 2/3, 12-month, randomized (1:1:1) dose-expansion study. PARTICIPANTS: Male patients ≥10 years of age with RPGR-associated XLRP were included. METHODS: Participants were randomized 1:1:1 to receive low-dose subretinal cotoretigene toliparvovec (5 × 1010 vector genomes/eye), high-dose cotoretigene toliparvovec (2.5 × 1011 vector genomes/eye) or to be an untreated control participant. MAIN OUTCOME MEASURES: The primary end point was the percentage of participants meeting microperimetry responder criteria (≥ 7-dB improvement at ≥ 5 of 16 central loci). Secondary end points included change from baseline in retinal sensitivity at the central 16 loci and the entire 68 loci at 12 months and change from baseline in low-luminance visual acuity (LLVA) at 12 months, as well as the proportion of eyes with a ≥ 15-Early Treatment Diabetic Retinopathy Study ETDRS letter LLVA and ≥ 10-ETDRS letter LLVA change from baseline at month 12. RESULTS: Because of the impact of the COVID-19 pandemic, enrollment ended before reaching the initial target, leaving the trial underpowered. Twenty-nine participants were included (low-dose group, n = 10; high-dose group, n = 10; control group, n = 9). At month 12, the percentage of participants meeting microperimetry responder criteria was not significantly different between either cotoretigene toliparvovec group (low dose, 37.5% [P = 0.3181]; high dose, 25.0% [P = 0.5177]) and the control group (22.2%). However, the mean change from baseline in microperimetry sensitivity improved significantly with the low-dose group versus the control group at month 12 (P = 0.0350). Significant improvement in LLVA occurred in the low-dose group versus the control group at month 12 (33.3% difference [80% confidence interval, 14.7%-55.2%]; P = 0.0498). Three ocular-related serious adverse events (SAEs) occurred in the low-dose group versus 7 SAEs in the high-dose group. CONCLUSIONS: The primary microperimetry end point was not met. Significant improvements in LLVA and mean microperimetry were observed compared with controls and fewer SAEs occured with low-dose compared with high dose cotoretigene toliparvovec. FINANCIAL DISCLOSURE(S): Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.

Subretinal timrepigene emparvovec in adult men with choroideremia: a randomized phase 3 trial.

Choroideremia is a rare, X-linked retinal degeneration resulting in progressive vision loss. A randomized, masked, phase 3 clinical trial evaluated the safety and efficacy over 12 months of follow-up in adult males with choroideremia randomized to receive a high-dose (1.0 × 1011 vector genomes (vg); n = 69) or low-dose (1.0 × 1010 vg; n = 34) subretinal injection of the AAV2-vector-based gene therapy timrepigene emparvovec versus non-treated control (n = 66). Most treatment-emergent adverse events were mild or moderate. The trial did not meet its primary endpoint of best-corrected visual acuity (BCVA) improvement. In the primary endpoint analysis, three of 65 participants (5%) in the high-dose group, one of 34 (3%) participants in the low-dose group and zero of 62 (0%) participants in the control group had ≥15-letter Early Treatment Diabetic Retinopathy Study (ETDRS) improvement from baseline BCVA at 12 months (high dose, P = 0.245 versus control; low dose, P = 0.354 versus control). As the primary endpoint was not met, key secondary endpoints were not tested for significance. In a key secondary endpoint, nine of 65 (14%), six of 35 (18%) and one of 62 (2%) participants in the high-dose, low-dose and control groups, respectively, experienced ≥10-letter ETDRS improvement from baseline BCVA at 12 months. Potential opportunities to enhance future gene therapy studies for choroideremia include optimization of entry criteria (more preserved retinal area), surgical techniques and clinical endpoints. EudraCT registration: 2015-003958-41 .

Changes in Retinal Sensitivity Associated With Cotoretigene Toliparvovec in X-Linked Retinitis Pigmentosa With RPGR Gene Variations.

Importance: X-linked retinitis pigmentosa (XLRP) is a severe cause of early-onset RP in male individuals, characterized by degeneration of photoreceptors, an extinguished electroretinogram, and vision loss. Objective: To assess the duration of improvements in retinal sensitivity associated with a single, subretinal injection of cotoretigene toliparvovec (BIIB112/AAV8-RPGR) gene therapy after vitrectomy surgery in the dosed eye over 12 months in part 1 of the Clinical Trial of Retinal Gene Therapy for X-linked Retinitis Pigmentosa Using BIIB112 (XIRIUS) study, compared with untreated fellow eyes and eyes from the untreated subgroup from the Natural History of the Progression of X-Linked Retinitis Pigmentosa (XOLARIS) study. Design, Setting, and Participants: This was a post hoc analysis of the XIRIUS and XOLARIS studies. Part 1 of the XIRIUS study was a phase 1, dose-escalation study of 18 male participants 18 years or older enrolled between March 8, 2017, and October 16, 2018, with genetically confirmed RPGR-variant XLRP with active disease and best-corrected visual acuity better than or equal to light perception (cohort 1), 34 to 73 letters (20/40 to 20/200 Snellen equivalent; cohorts 2-3), or greater than or equal to 34 letters (better than or equal to 20/200 Snellen equivalent; cohorts 4-6). Participants from the noninterventional, multicenter, global, prospective XOLARIS clinical study who met the inclusion and exclusion criteria of part 1 of XIRIUS were included as a comparator group (n = 103). Safety assessments included all XIRIUS participants; post hoc associations of retinal sensitivity assessments in XIRIUS only included the 12 participants receiving the 4 highest doses of cotoretigene toliparvovec. Data were analyzed on June 30, 2021. Main Outcomes and Measures: Incidence of dose-limiting toxicities (DLTs), treatment-emergent adverse events, changes from baseline in retinal sensitivity (as assessed by macular integrity assessment microperimetry), retinal sensitivity response (achievement of ≥7-dB improvement from baseline at ≥5 of 16 central loci), and low-luminance visual acuity were assessed over 24 months. Results: A total of 18 participants (mean [SD] age, 31.9 [9.4] years; male, 100%) were enrolled and completed the XIRIUS study. A subgroup of 103 participants (mean [SD] age, 30.8 [11.4] years; male, 100%) from the XOLARIS study was included. Administration of the 4 highest doses of cotoretigene toliparvovec (n = 12) among the 18 XIRIUS participants was associated with early improvements in retinal sensitivity. One of 103 untreated participants (1%) in the XOLARIS subgroup achieved improved retinal sensitivity at month 12. No DLTs were noted at any dose, and serious adverse events of reduced visual acuity (n = 2) and noninfective retinitis (n = 1) occurred. Conclusions and Relevance: Results suggest that early and sustained improvements in retinal sensitivity and low-luminance visual acuity in some participants through 12 months support consideration of additional clinical trials. Trial Registration: ClinicalTrials.gov Identifier: XIRIUS: NCT03116113; XOLARIS: NCT04926129.

Prospective Evaluation of Outcomes in Patients Undergoing Treatment for Myopia Using the WaveLight Refractive Suite.

PURPOSE: To evaluate outcomes in patients with myopia up to -12.00 diopters (D), with or without astigmatism up to 6.00 D, who underwent LASIK with the WaveLight Refractive Suite (Alcon Laboratories, Inc., Fort Worth, TX). METHODS: This multicenter, prospective, single-arm study evaluated patients at baseline, on the day of surgery, and 1 day and 1, 3, and 6 months postoperatively. The primary outcome was comparison of 1-month postoperative binocular uncorrected distance visual acuity (UDVA) with preoperative binocular corrected distance visual acuity (CDVA). Noninferiority was defined as the upper bound of the 95% confidence interval less than 0.1 logMAR. Post-hoc analyses for superiority were conducted for monocular and binocular CDVA at 1, 3, and 6 months. Continuous variables were summarized using mean (95% confidence interval), median, quartiles, standard deviation, minimum and maximum, and categorical variables as counts and percentages. RESULTS: Of the 96 patients (54% female, mean age: 31 years), 5 underwent monocular and 91 binocular LASIK surgery (187 eyes). Preoperatively, mean binocular CDVA was -0.025 ± 0.126 logMAR, mean binocular UDVA was 1.148 ± 0.626 logMAR, and mean manifest spherical refraction equivalent was -3.67 ± 1.98 D. Postoperative binocular UDVA at 1 month (-0.088 ± 0.107 logMAR) was noninferior to preoperative binocular CDVA. Postoperative binocular UDVA at 1, 3 (-0.098 ± 0.107 logMAR), and 6 months (-0.105 ± 0.113 logMAR) were significantly superior to preoperative binocular CDVA (P < .0001 each). CONCLUSIONS: The primary study objective was exceeded; postoperative UDVA was significantly superior to preoperative CDVA in patients with myopia and myopia with astigmatism who underwent LASIK with the WaveLight Refractive Suite. [J Refract Surg. 2017;33(5):322-328.].

Bromfenac ophthalmic solution 0.07% dosed once daily for cataract surgery: results of 2 randomized controlled trials.

PURPOSE: To evaluate the efficacy and ocular safety of bromfenac ophthalmic solution 0.07% (Prolensa) dosed once daily for the treatment of ocular inflammation and pain in subjects who underwent cataract surgery with posterior chamber intraocular lens implantation. DESIGN: Two phase 3, randomized, double-masked, placebo-controlled, multicenter clinical trials. PARTICIPANTS: Four hundred forty subjects (440 study eyes: 222 in the bromfenac group and 218 in the placebo group). METHODS: Two phase 3, prospective, randomized, double-masked, placebo-controlled clinical trials were conducted at 39 ophthalmology clinics in the United States. Subjects 18 years of age or older were randomized to receive either bromfenac 0.07% or placebo dosed once daily beginning 1 day before cataract surgery, on the day of surgery, and continuing for 14 days after surgery (for a total of 16 days). Subjects were evaluated on days 1, 3, 8, 15, and 22 after surgery. The primary efficacy end point was cleared ocular inflammation, as measured by the summed ocular inflammation score of zero (anterior chamber cell count = 0 and absence of flare) by day 15. Secondary end points included cleared ocular inflammation at day 15 and the number of subjects who were pain free at day 1. The data from the 2 clinical trials were integrated for analyses. MAIN OUTCOME MEASURES: Summed ocular inflammation score and ocular pain. RESULTS: A significantly higher proportion of subjects treated with bromfenac 0.07% achieved complete clearance of ocular inflammation by day 15 and at day 15 compared with placebo (P < 0.0001). A statistically significantly higher proportion of subjects in the bromfenac 0.07% group were pain free at all study visits compared with those in the placebo group (P < 0.0001). Fewer subjects in the bromfenac group (3.2%) discontinued investigational product early because of a lack of efficacy than in the placebo group (23.9%; P < 0.0001). The incidence of adverse events was significantly lower in the bromfenac 0.07% group compared with the placebo group (P = 0.0041). CONCLUSIONS: Bromfenac ophthalmic solution 0.07% dosed once daily was clinically safe and effective compared with placebo for the treatment of ocular inflammation and pain in subjects who had undergone cataract surgery and may be a beneficial addition to the current standard of care, which commonly includes ophthalmic antibiotics and corticosteroids.

Efficacy of bepotastine besilate ophthalmic solution 1.5% for seasonal allergic conjunctivitis: a randomized, placebo-controlled, natural exposure, clinical trial.

Allergic conjunctivitis (AC) affects an estimated 20% of the population in the Western world, with a large fraction suffering due to seasonal or perennial allergen exposures. Bepotastine besilate ophthalmic solution (BBOS) 1.5%, a dual-acting histamine (H(1)) receptor antagonist and mast cell stabilizer, is indicated for itching associated with AC. This study was designed to evaluate the efficacy and safety of BBOS 1.5% for reducing ocular itching associated with AC in subjects enrolled in a natural exposure trial. Eligible subjects in a multicenter, double-masked, randomized, parallel-group, placebo-controlled, natural exposure clinical trial were randomly assigned to either BBOS 1.5% or placebo eyedrops on a 1:1 basis and instilled 1 drop of the test agent into both eyes twice daily for 2 weeks. The mean change from baseline in instantaneous and reflective ocular itching scores at the end of 2 weeks of treatment were evaluated based on subject-assessed severity of instantaneous and reflective itching. Subject-reported adverse events (AEs) were also recorded for safety. Treatment with BBOS 1.5% significantly reduced instantaneous and reflective ocular itching scores from baseline compared with placebo over the 2-week study period(p = 0.007 and p = 0.005, respectively). BBOS 1.5% was well tolerated, and AEs were generally transient and mild. This clinical study indicates BBOS 1.5% effectively and safely treated ocular itching in a natural exposure allergy study and is a useful treatment option for the management of ocular itching associated with AC. (ClinicalTrials.gov identifier number: NCT01174823.)

Integrated phase III trials of bepotastine besilate ophthalmic solution 1.5% for ocular itching associated with allergic conjunctivitis.

Allergic conjunctivitis is a clinical reaction to environmental allergens and is manifested by ocular itching caused by IgE-induced mast cell degranulation. Bepotastine besilate is a selective H(1)-antagonist with mast cell stabilizing properties. This report examines the reduction of ocular itching integrated from two conjunctival allergen challenge (CAC) clinical trials comparing bepotastine besilate ophthalmic solution (BBOS) 1.5% to placebo in subjects with a history of allergic conjunctivitis. Two phase III, double-masked, placebo-controlled, parallel-group, CAC clinical trials evaluated BBOS 1.5% versus placebo to reduce ocular itching. Eligible subjects were randomly assigned 1:1 to either BBOS 1.5% (n = 78) or placebo (n = 79). Ocular itching was graded by subjects using a standardized scale (0­4 U). Adverse events and ophthalmic clinical findings were recorded for safety. BBOS 1.5% was superior to placebo for reducing CAC-induced ocular itching (p < 0.0001) as early as 3 minutes post-CAC and for at least 8 hours after dosing. Post hoc analyses examining several populations also showed a significant improvement (p < 0.0001) for subjects with more severe itching response at screening and for the proportion of subjects with complete or nearly complete resolution of CAC-induced itching, both outcomes supporting the clinical benefit of BBOS 1.5%. Adverse events were generally transient and mild. BBOS 1.5% is safe and effective in the treatment of ocular itching associated with allergic conjunctivitis within 3 minutes of a CAC and with a sustained duration of action of at least 8 hours. (ClinicalTrials.gov numbers: NCT00424398 and NCT00586664).

Safety and efficacy of bromfenac ophthalmic solution (Bromday) dosed once daily for postoperative ocular inflammation and pain.

PURPOSE: To evaluate the efficacy and ocular safety of bromfenac ophthalmic solution (bromfenac) 0.09% dosed once daily for the treatment of ocular inflammation and pain after cataract surgery with posterior chamber intraocular lens implantation. DESIGN: Randomized, double-masked, vehicle-controlled or active-controlled, multicenter, clinical trials. PARTICIPANTS AND CONTROLS: A total of 872 subjects (872 study eyes: bromfenac in 584, placebo in 288). METHODS: Four randomized, double-masked, vehicle or active-controlled, clinical trials were conducted at 134 ophthalmology clinics in the United States. Subjects aged ≥ 18 years were randomized to receive either bromfenac 0.09% or placebo dosed once daily beginning 1 day before cataract surgery (day -1), continuing on the day of surgery (day 0), and continuing for an additional postoperative 14 days. Subjects were evaluated for efficacy and safety on days 1, 3, 8, 15, and 22. The primary efficacy end point was cleared ocular inflammation, measured by the summed ocular inflammation score (SOIS; anterior chamber cells and flare) by day 15. The secondary efficacy end point was the number of subjects who were pain-free at day 1. The data from the 4 trials were pooled for analyses. MAIN OUTCOME MEASURES: The SOIS and ocular pain. RESULTS: The proportion of subjects who had cleared ocular inflammation by day 15 was significantly higher in the bromfenac 0.09% group than in the placebo group (P < 0.0001). The mean SOIS in the bromfenac 0.09% group was significantly lower than in the placebo group at days 3, 8, 15, and 22 (P < 0.0001). The proportion of subjects who were pain-free at days 1, 3, 8, and 15 was significantly higher in the bromfenac 0.09% group than in the placebo group (P < 0.0001). The incidence of adverse events reported in the bromfenac 0.09% group was significantly lower than in the placebo group (P < 0.0001). On day 15, 84.0% of the bromfenac subjects had ≥ 1-line improvement in visual acuity compared with 66.1% of placebo subjects (P < 0.0001). CONCLUSIONS: Bromfenac 0.09% dosed once daily was clinically safe and effective for reducing and treating ocular inflammation and pain associated with cataract surgery. FINANCIAL DISCLOSURE(S): Proprietary or commercial disclosure may be found after the references.

Once daily dosing of bromfenac ophthalmic solution 0.09% for postoperative ocular inflammation and pain.

OBJECTIVE: To evaluate the efficacy and ocular safety of bromfenac ophthalmic solution 0.09% dosed once daily for the treatment of ocular inflammation and pain following cataract extraction with posterior chamber intraocular lens implantation. METHODS: A total of 455 subjects (455 study eyes: 230 bromfenac, 225 placebo) were enrolled in two randomized double-masked, placebo-controlled, clinical trials at 64 ophthalmology clinics in the United States. Subjects were randomized to receive either bromfenac 0.09% or placebo dosed once daily. Dosing began 1 day before cataract surgery (Day -1), continued on day of surgery (Day 0), and for 14 days following surgery. Evaluations were completed on Days 1, 3, 8, 15 and 22. The primary efficacy endpoint was cleared summed ocular inflammation score (SOIS) by Day 15. The secondary efficacy endpoint was the number of subjects who were pain-free at Day 1. RESULTS: The bromfenac 0.09% group was significantly higher compared to the placebo group in the primary endpoint of the proportion of subjects who had cleared ocular inflammation by Day 15 (P < 0.0001). The mean SOIS for the bromfenac 0.09% group was lower than the placebo group at Days 3, 8, 15, and 22 (P < 0.0001). More bromfenac 0.09% subjects were pain free at Days 1, 3, 8, and 15 (P < 0.0001). Fewer subjects in the bromfenac 0.09% group withdrew from the clinical trials due to lack of efficacy at Day 15 (P < 0.0001). Fewer adverse events were reported in the bromfenac 0.09% group than the placebo group. Limitations included advanced age, female predominance, and surgical nuances among cataract surgeons, making cross-trial comparisons difficult. CONCLUSIONS: Bromfenac ophthalmic solution 0.09% dosed once daily is clinically safe and effective for the treatment of ocular inflammation and the reduction of ocular pain associated with cataract surgery.

Prolonged effectiveness of bepotastine besilate ophthalmic solution for the treatment of ocular symptoms of allergic conjunctivitis.

PURPOSE: This clinical trial evaluated the safety and effectiveness of bepotastine besilate ophthalmic solutions 1.0% and 1.5% compared with placebo for the treatment of ocular itching and conjunctival hyperemia (redness) using the conjunctival allergen challenge (CAC) model of allergic conjunctivitis when dosed 16 h before a CAC test. METHODS: Subjects with a history of allergic conjunctivitis were assigned to receive placebo or bepotastine besilate ophthalmic solution 1.0% or 1.5% in a single-center, randomized, placebo-controlled clinical trial. Eligible subjects (n=107) aged 10 years and older with a history of allergic conjunctivitis who had a reproducible positive reaction to a CAC were enrolled and dosed with test agent. The primary trial objectives included assessment of ocular itching and conjunctival redness at 16 h after instillation of test agent. Reductions in several CAC-induced secondary symptoms and signs of allergic conjunctivitis were also evaluated for tearing, ciliary and episcleral redness, eyelid swelling, chemosis, and mucous discharge. RESULTS: Bepotastine besilate ophthalmic solution 1.5% demonstrated clinical effectiveness and statistical significance in comparison to placebo for the reduction in CAC-induced ocular itching 16 h after drug administration. Bepotastine besilate ophthalmic solution 1.0% also achieved statistical significance in comparison to placebo for reducing ocular itching at all time points 16 h after dosing. Statistically significant reduction (P≤0.05) was additionally seen in this CAC test for the secondary ocular efficacy variable of allergen-induced tearing for bepotastine besilate ophthalmic solution 1.5%. No clinical benefit was seen for reducing the coprimary efficacy variable of conjunctival redness with the CAC model of allergic conjunctivitis. CONCLUSIONS: Bepotastine besilate ophthalmic solution 1.5% produced predefined clinically meaningful reduction in CAC-induced ocular itching and tearing in a single-site trial and was more effective than bepotastine besilate ophthalmic solution 1.0% and placebo for reducing ocular itching in a CAC test 16 h after dosing.

Non-clinical pharmacology, pharmacokinetics, and safety findings for the antihistamine bepotastine besilate.

SCOPE: The purpose of this review is to examine published non-clinical literature on the antihistamine bepotastine besilate, including pharmacokinetic and pharmacologic properties. METHODS: Standard literature searches using diverse databases were used to find articles on bepotastine besilate published between 1997 and 2009. Articles primarily described non-clinical data utilized for the development of an oral formulation of bepotastine besilate and were published in Japanese. No publications of non-clinical data for an ophthalmic formulation were found in the database searches. FINDINGS: Bepotastine besilate is a second-generation antihistamine drug possessing selective histamine H(1) receptor antagonist activity. Bepotastine has negligible affinity for receptors associated with undesirable adverse effects, including histamine H(3), α(1)-, α(2)-, and ß-adrenergic, serotonin (5-HT(2)), muscarinic, and benzodiazepine receptors. Bepotastine possesses additional anti-allergic activity including stabilization of mast cell function, inhibition of eosinophilic infiltration, inhibition of IL-5 production, and inhibition of LTB(4) and LTD(4) activity. Bepotastine in vivo dose-dependently inhibited the acceleration of histamine-induced vascular permeability and inhibited homologous passive cutaneous anaphylaxis in guinea pig studies. In mouse models of itching, oral bepotastine inhibited the frequency and duration of scratching behavior. Multiple in vivo animal toxicology studies have demonstrated bepotastine to be safe with no significant effects on respiratory, circulatory, central nervous, digestive, or urinary systems. The concentration of bepotastine after intravenous administration of bepotastine besilate (3 mg/kg) in rats was lower in the brain than in plasma, predicting reduced sedation effects compared to older antihistamines. CONCLUSION: Non-clinical in vitro and in vivo studies have demonstrated bepotastine is a histamine H(1) receptor antagonist with favorable pharmacokinetic, pharmacologic, safety, and antihistamine properties as well as operating on other pathways leading to allergic inflammation beyond those directly involving the histamine H(1) receptor.

Bepotastine besilate ophthalmic solution for the relief of nonocular symptoms provoked by conjunctival allergen challenge.

BACKGROUND: Bepotastine besilate is a selective histamine1-receptor antagonist and mast cell stabilizer with inhibitory effects on eosinophilic activity. OBJECTIVE: To evaluate the safety and efficacy of 1.5% bepotastine besilate ophthalmic solution in alleviating nonocular symptoms induced by a conjunctival allergen challenge (CAC), a clinical model of allergic conjunctivitis. METHODS: This was a single-center, double-masked, randomized, placebo-controlled clinical trial performed from March 1 to April 4, 2007. Patients 10 years or older with a history of allergic conjunctivitis and a reproducible, positive, clinical response to a CAC were eligible. Patients received either placebo or 1.5% bepotastine besilate, 1 drop in each eye. After 15 minutes, 8 hours, or 16 hours after dosing, a CAC was performed and patients evaluated nonocular symptoms using standardized grading scales. RESULTS: Seventy-one patients were enrolled in the study, and 66 comprised the per protocol population. A clinically meaningful reduction (> or = 1.0 unit) compared to placebo was achieved for rhinorrhea and nasal congestion at most time points after 1.5% bepotastine besilate instillation at 8 hours before a CAC test. Significant reductions (P < or = .05) in mean values were seen with 1.5% bepotastine besilate at 15 minutes and 8 hours after dosing for CAC-induced nasal congestion, rhinorrhea, ear or palate pruritus, nasal pruritus, and summed nonocular composite symptom (NOCS) scores and also at 16 hours after dosing for nasal congestion and rhinorrhea. CONCLUSIONS: The 1.5% bepotastine besilate formulation produced statistically significant reductions after a CAC in individual nonocular symptoms and NOCS scores at onset of allergic response and for at least 8 hours after instillation, with the greatest reduction seen for nasal congestion and rhinorrhea.

Multicenter clinical evaluation of bepotastine besilate ophthalmic solutions 1.0% and 1.5% to treat allergic conjunctivitis.

PURPOSE: To evaluate the effectiveness of bepotastine besilate ophthalmic solutions 1.0% and 1.5% compared with placebo at reducing ocular itching and conjunctival hyperemia in the conjunctival allergen challenge (CAC) model of allergic conjunctivitis. DESIGN: Prospective, double-masked, randomized, placebo-controlled, phase 3 CAC clinical trial. METHODS: This multicenter trial enrolled 130 subjects with a clinical history of allergic conjunctivitis who were randomized to bepotastine besilate ophthalmic solution 1.0%, 1.5%, or 0.0% (placebo). One drop of test agent was instilled bilaterally before a CAC test evaluating responses at 15 minutes, 8 hours, or 16 hours after test agent instillation. Primary efficacy outcomes were unit improvements relative to placebo in mean scores for ocular itching and conjunctival hyperemia, each graded on 0- to 4-unit scales. RESULTS: Reductions of 1.2 units or more in mean ocular itching scores at all time points for both bepotastine besilate ophthalmic solutions 1.0% and 1.5% were observed at onset of action and 8-hour duration-of-action CAC tests (P < .0001). Statistically significant reductions in conjunctival hyperemia (P < or = .0125) were observed for bepotastine besilate ophthalmic formulations only at the onset of action CAC test. CONCLUSIONS: Bepotastine besilate ophthalmic solutions 1.0% and 1.5% both substantially decreased CAC-induced ocular itching for at least 8 hours after dosing. Reductions in conjunctival hyperemia after a CAC, although statistically significant for bepotastine besilate ophthalmic solutions 1.0% and 1.5% compared with placebo when assessed at 15 minutes after dosing, were modest.

Time to onset and duration of action of the antihistamine bepotastine besilate ophthalmic solutions 1.0% and 1.5% in allergic conjunctivitis: a phase III, single-center, prospective, randomized, double-masked, placebo-controlled, conjunctival allergen challenge assessment in adults and children.

BACKGROUND: Bepotastine besilate is a highly selective histamine H(1)-receptor antagonist with antihistaminic, mast cell stabilizing, and anti-inflammatory activity. Based on a history of clinical effectiveness and tolerability of oral bepotastine besilate in the treatment of allergic symptoms, bepotastine besilate is being tested as a potential ophthalmic medication for allergic conjunctivitis. OBJECTIVE: The aim of this study was to assess the effects of bepotastine besilate ophthalmic solution 1.0% and 1.5% for the treatment of ocular itching and conjunctival hyperemia in a conjunctival allergen challenge (CAC) model in adults and children. METHODS: This Phase III, single-center, prospective, randomized, double-masked, placebo-controlled, CAC clinical trial enrolled patients >or=10 years of age with a history of allergic conjunctivitis, skin-test reaction, and CAC response. Patients received bepotastine besilate ophthalmic solution 1.0%, bepotastine besilate ophthalmic solution 1.5%, or placebo, 1 drop on each eye on days 14 +/- 3 and 28 +/- 3. The primary efficacy end points, patient-assessed ocular itching (at 3, 5, and 7 minutes) and investigator-assessed conjunctival hyperemia (at 7, 15, and 20 minutes), were determined after CAC according to standardized 5-point scales (0 = none to 4 = severe). Clinical significance was defined in the protocol as >or=1.0-U between-group difference in mean ocular itching scores at the majority of time points at a study visit and also a >or=0.5-U difference at all time points. Tolerability of the test agent was assessed by visual acuity, slit-lamp biomicroscopy, intraocular pressure, dilated funduscopy, and adverse events. RESULTS: A total of 107 patients (male, 54%; age range, 11-73 years; white race/ethnicity, 93%) received investigational product and comprised the intent-to-treat (ITT) population (bepotastine besilate ophthalmic solution 1.0%, 36 patients; bepotastine besilate ophthalmic solution 1.5%, 35; and placebo, 36). All 107 patients received investigational product at visit 3A (day 0) and were included in the ITT population. Of the 107 patients who were enrolled, 103 completed the study without a protocol deviation or violation. The 1.0% and 1.5% solutions were associated with clinically and statistically significant reductions in mean ocular itching scores compared with placebo on the 15-minute onset-of-action and 8-hour duration-of-action CAC tests (reductions, 1.3-1.5 U and 1.0-1.7 U respectively; all, P < 0.001). Statistically significant reductions in conjunctival hyperemia were achieved with both bepotastine besilate concentrations. Overall, 13 patients experienced a treatment-emergent adverse event considered related to the study drug (bepotastine besilate ophthalmic solution 1.0%, 6 patients; bepotastine besilate ophthalmic solution 1.5%, 4; and placebo, 3). CONCLUSIONS: In this CAC model of allergic conjunctivitis in adults and children, bepotastine besilate ophthalmic solutions 1.0% and 1.5% were associated with clinically and statistically significant reductions in ocular itching, but not conjunctival hyperemia, within 15 minutes that were maintained for at least 8 hours after administration. Both solutions were well tolerated. ClinicalTrials.gov identifier: NCT00424398.

Ocular pharmacokinetics of a single dose of bromfenac sodium ophthalmic solution 0.1% in human aqueous humor.

PURPOSE: The aim of this study was to evaluate the ocular pharmacokinetics of a single dose of bromfenac sodium ophthalmic solution 0.1% in subjects undergoing routine cataract surgery with intraocular lens implantation. METHODS: An open-label, phase II confirmatory study of 54 subjects undergoing cataract surgery with intraocular lens implantation. A single drop of bromfenac sodium ophthalmic solution 0.1% was administered at 30, 60, 90, 120, 180, or 240 min prior to the initiation of cataract surgery. Samples of aqueous humor were aspirated through a paracentesis and analyzed by using high-performance liquid chromatography. Based upon these data, predicted concentrations of bromfenac in the aqueous humor over 24 h were generated by using computer simulation and compared with the IC(50) for bromfenac as a measure of anti-inflammatory efficacy. RESULTS: Peak aqueous-humor concentrations of bromfenac occurred between 150 and 180 min following ophthalmic dosing, with a mean concentration of 78.7 ng/mL. The level of bromfenac decreased in a log-linear fashion with an elimination-rate constant of 1.4. Bromfenac remained above the IC(50) value of cyclo-oxygenase-2 (COX-2) during the evaluated time points and over the 12-h dosing interval, using a computer model of extrapolated time points and assuming first-order elimination. CONCLUSIONS: Pharmacokinetic modeling, based upon samples collected over 240 min after a single dose of bromfenac sodium ophthalmic solution 0.1% suggests that aqueous-humor concentrations remain at clinically effective levels (above its IC(50) value for COX-2) for over 12 h. Based upon this rationale, these results supported clinical trials that demonstrated the efficacy of twice-daily dosing of bromfenac sodium ophthalmic solution 0.1% to manage patients with postoperative ocular pain and inflammation.

24-hour evaluation of the ocular distribution of (14)C-labeled bromfenac following topical instillation into the eyes of New Zealand White rabbits.

PURPOSE: The aim of this study was to determine the distribution and concentrations of bromfenac ophthalmic solution in ocular tissues following topical instillation in New Zealand White (NZW) rabbits. DESIGN: Two animal studies were conducted. METHODS: A single 50-muL (14)C-bromfenac ophthalmic solution (20-25 muCi or 0.09%) was administered into the right eyes of 14-18 randomly assigned NZW rabbits. At various time points, ocular tissues were collected and analyzed for (14)C-bromfenac contents. Ocular tissues were combusted and the amount of radioactivity was determined by liquid scintillation counting (LSC). Aqueous-humor samples were directly transferred to LSC vials. RESULTS: Peak concentrations of (14)C-bromfenac were observed in the aqueous humor and most ocular tissues at or before 2-hours. The highest concentrations were in the cornea, conjunctiva, and sclera. Similar amounts were detected in the aqueous humor, iris-ciliary body, choroid, and, to a slightly lesser degree, in the retina. Measurable amounts of bromfenac were detected in all samples at the 24-hours time point (> or =0.001 mug equivalent/g). CONCLUSIONS: Significant penetration and measurable amounts of (14)C-bromfenac were detected in all ocular tissues over 24 h, including the sclera, choroid, and retina. These results strongly suggest the utility of bromfenac ophthalmic solution 0.09% in treating inflammation of both the anterior and posterior ocular segments.

Predicting response of vitreous hemorrhage after intravitreous injection of highly purified ovine hyaluronidase (Vitrase) in patients with diabetes.

PURPOSE: To develop a predictive model for patients with diabetes who are most likely to have vitreous hemorrhage clearing by 3 months after a single, intravitreous injection of highly purified, preservative-free, ovine hyaluronidase (Vitrase; ISTA Pharmaceuticals, Inc., Irvine, CA). METHODS: Post hoc data analysis was performed on two randomized, double-masked, placebo-controlled, phase 3 clinical trials of a single intravitreous injection of Vitrase for severe vitreous hemorrhage. Vitreous hemorrhage density was scored using a 0 to 4 vitreous hemorrhage grading scale in 12 radial segments of the fundus ("clock hours"). Reduction in total hemorrhage point score (DeltaTHPS) between baseline and 1 month after injection was analyzed as a predictor of vitreous hemorrhage outcome at 3 months. RESULTS: A strong predictive model was demonstrated by receiver operating characteristic (ROC) curve analysis; area under the curve (AUC) = 0.845 (P < 0.0001). The DeltaTHPS was higher in hyaluronidase-treated subjects than in saline-treated control subjects. Median DeltaTHPS was 8.0 and 6.0 in subjects treated with 55 IU (68 USP) and 75 IU (93 USP) of hyaluronidase respectively, versus 2.0 in saline control subjects (P < 0.0001). discussion. The DeltaTHPS at 1 month provides quantitative guidance for predicting the outcome of a single intravitreous ovine hyaluronidase injection in patients with diabetes and severe vitreous hemorrhage (ClinicalTrials.gov numbers, NCT00198510 and NCT00198497).