Ocular iontophoresis of EGP-437 (dexamethasone phosphate) in dry eye patients: results of a randomized clinical trial

Michael A Patane¹, Amy Cohen¹, Stephen From¹, Gail Torkildsen², Donna Welch³, George W Ousler III³¹Eyegate Pharmaceuticals, Inc, Waltham, MA, USA; ²Andover Eye Associates, Andover, MA, USA; ³Ora, Inc, Andover, MA, USAPurpose: To assess safety and efficacy of EGP-437 (dexamethasone phosphate 40 mg/mL [DP]) in dry eye patients.Methods: The study employed a prospective, single-center, double-masked design utilizing a Controlled Adverse Environment (CAE). Patients (n = 103) with confirmed signs and symptoms of dry eye syndrome were randomized into 1 of 3 iontophoresis treatment groups: 7.5 mA-min at 2.5 mA (DP 7.5, n = 41); 10.5 mA-min at 3.5 mA (DP 10.5, n = 37); or 10.5 mA-min at 3.5 mA (placebo, n = 25). Three CAE visits and 4 follow-up visits occurred over 3 weeks. Patients meeting enrollment criteria received iontophoresis in both eyes after the second CAE exposure (visit 3) and before the third CAE exposure (visit 5). Primary efficacy endpoints were corneal staining and ocular discomfort. Secondary endpoints included tear film break-up time, ocular protection index (OPI), and symptomatology.Results: The DP 7.5 and DP 10.5 treatment groups showed statistically significant improvements in signs and symptoms of dry eye at various time points; however, the primary endpoints were not achieved. The DP 7.5 treatment group exhibited statistically significant improvements in corneal staining (when comparing the differences between study entry and exit, 3 weeks, P = 0.039), OPI (immediately following the second treatment, P = 0.048) and ocular discomfort at follow-up visits (a week after the first treatment, P = 0.032; 24 hours after the second treatment, P = 0.0032). Treatment-emergent adverse events (AEs) were experienced by 87% of patients and were consistent across all treatment groups. Most AEs were mild and no severe AEs were observed.Conclusion: Ocular iontophoresis of EGP-437 demonstrated statistically and clinically significant improvements in signs and symptoms of dry eye syndrome within a CAE model.Keywords: iontophoresis, dry eye, Controlled Adverse Environment (CAE), ocular protection index (OPI

Conjunctival tissue pharmacokinetic properties of topical azithromycin 1% and moxifloxacin 0.5% ophthalmic solutions: A single-dose, randomized, open-label, active-controlled trial in healthy adult volunteers

Background: Effective ocular tissue concentrations and prolonged residence times of antibacterial agents are important in treating both acute and chronic diseases. Conjunctival biopsy allows the determination of specific tissue concentration data for topical ophthalmic agents. Drug concentration analysis at various time points following instillation allows interpretation of the residence time and a rationale for dosing frequency. Objective: This study compared the pharmacokinetic parameters of 2 currently available topical ocular antibiotics—azithromycin ophthalmic solution 1% and moxifloxacin ophthalmic solution 0.5%—in the conjunctiva of healthy volunteers after a single topical administration. Methods: This single-dose, randomized, open-label, active-controlled clinical trial was conducted at ORA Clinical Research and Development, North Andover, Massachusetts. Subjects were randomly assigned to receive a single dose of azithromycin or moxifloxacin and to undergo biopsy sampling at 30 minutes or 2, 12, or 24 hours after administration. Concentrations of azithromycin and moxifloxacin were determined using liquid chromatography tandem mass spectrometry. Adverse events (AEs) were assessed at all visits using visual acuity measurements, slit-lamp biomicroscopy, and direct questioning. Results: Forty-eight subjects (mean age, 40.0 years; 48% female; 96% white, 2% black, and 2% Asian) underwent conjunctival biopsy. Mean (SD) concentrations of azithromycin in conjunctival tissue (lower limit of quantitation [LLOQ], 1 µg/g for 1-mg biopsy specimen) were 131 (89), 59 (19), 48 (24), and 32 (20) µg/g at 30 minutes and 2, 12, and 24 hours, respectively (median values, 117, 69, 46, and 30 µg/g). Mean concentrations concentrations of moxifloxacin in conjunctival tissue (LLOQ, 0.05 µg/g for 1-mg biopsy sample) were 1.92 (2.03), 3.77 (8.98), 0.02 (0.04), and 0.01 (0.02) µg/g at 30 minutes and 2, 12, and 24 hours, respectively (median values, 1.12, 0.12, <0.05, and <0.05 µg/g). Thirteen subjects (6 in the azithromycin group and 7 in the moxifloxacin group) experienced 20 AEs, 11 of which were considered possibly related to study treatment, and 15 of which were ocular (most commonly conjunctival hemorrhage). Conclusions: In this single-dose study of 2 currently available topical ocular antibiotics in healthy volunteers, therapeutic concentrations were achieved with both agents. Both treatments were well tolerated in the population studied. Clinical Trials Identification Number: NCT00564447

Concentrations of besifloxacin, gatifloxacin, and moxifloxacin in human conjunctiva after topical ocular administration

Gail Torkildsen1, Joel W Proksch2, Aron Shapiro3, Stephanie K Lynch3, Timothy L Comstock21Andover Eye Associates, Andover, Massachusetts, USA; 2Bausch and Lomb, Inc., Rochester, New York, USA; 3Ora, Inc., Andover, Massachusetts, USAPurpose: To evaluate the pharmacokinetic properties of besifloxacin, gatifloxacin, and moxifloxacin in the conjunctival tissue of healthy volunteers after topical application.Methods: One-hundred eight (108) subjects were randomly assigned to receive one drop of besifloxacin (0.6% suspension), gatifloxacin (0.3% solution), or moxifloxacin (0.5% solution) ophthalmic formulations in one eye prior to conjunctival biopsy. Conjunctival samples were taken from subjects at either 15 minutes, 30 minutes, 2 hours, 6 hours, 12 hours, or 24 hours after dosing.Results: All three fluoroquinolones reached a peak mean concentration 15 minutes after dosing. The mean concentrations of besifloxacin, gatifloxacin, and moxifloxacin at 15 minutes were 2.30 &amp;plusmn; 1.42 &amp;mu;g/g, 4.03 &amp;plusmn; 3.84 &amp;mu;g/g, and 10.7 &amp;plusmn; 5.89 &amp;mu;g/g, respectively. Concentrations decreased with each subsequent time point. At 24 hours after dosing, concentrations of besifloxacin were measurable in 4 of 6 subjects, compared with 3 of 6 subjects for gatifloxacin and 2 of 6 subjects for moxifloxacin. Besifloxacin had the greatest mean residence time (4.7 hours) in the conjunctival tissue. With regard to methicillin-resistant strains of Staphylococcus aureus and Staphylococcus epidermidis, besifloxacin had the greatest area-under-the-curve (AUC) to MIC90 ratio. Nine percent (9%) of study subjects (N = 7) experienced a transient reduction in visual acuity.Conclusion: All three fluoroquinolones were well tolerated and reached levels in the conjunctiva above the MIC90s of methicillin-sensitive S. aureus and S. epidermidis for at least 2 hours.Keywords: besifloxacin, fluoroquinolone, conjunctivitis, pharmacokinetics, minimum inhibitory concentratio

A Clinical Phase II Study to Assess Efficacy, Safety, and Tolerability of Waterfree Cyclosporine Formulation for Treatment of Dry Eye Disease

Purpose: To compare the efficacy, safety, and tolerability of waterfree cyclosporine formulation (CyclASol) at 2 concentrations (0.1 % and 0.05% of cyclosporine [CsA]) to vehicle when applied twice daily for 16 weeks in patients with dry eye disease (DED). An open-label Restasis (Allergan, Irvine, CA) arm was included to allow a direct comparison with an approved therapy. Design: An exploratory phase II, multicenter, randomized, vehicle-controlled clinical trial, double-masked between CyclASol and vehicle with an open-label comparator. Participants: Two hundred and seven eligible patients with a history of dry eye disease were randomized 1:1:1:1 to 1 of 4 treatment arms (CyclASol 0.05%, n = 51; CyclASol 0.1 %, n = 51; vehicle, n = 52, and Restasis, n = 53). Methods: After a 2-week run-in period with twice-daily dosing of Systane Balance (Alcon, Fort Worth, TX), patients were randomized to the respective treatment arm and dosed twice daily for 16 weeks. Main Outcome Measures: The study was set up to explore efficacy on a number of sign and symptom end points including total and subregion corneal fluorescein staining, conjunctival staining, visual analog scale (VAS) for dry eye symptoms VAS severity, and Ocular Surface Disease Index (OSDI) questionnaire. Results: CyclASol showed a consistent reduction in corneal and conjunctival staining compared with both vehicle and Restasis over the 16-week treatment period, with an early onset of effect (at day 14). A mixed-effects model-based approach demonstrated that the CyclASol drug effect was statistically significant over vehicle (total corneal staining P < 0.1, central corneal staining P < 0.001, conjunctival staining P < 0.01). This model-based analysis suggests a significant CyclASol effect for OSDI as symptom parameter (P < 0.01). The numbers of ocular adverse events were low in all treatment groups. Conclusions: CyclASol showed efficacy, safety, and tolerability at 2 concentrations in moderate-to-severe DED. In a direct head-to-head against open-label Restasis, CyclASol was found to have an earlier onset of action, as early as after 2 weeks of treatment, in relieving the signs of DED, as measured by corneal and conjunctival staining. The central region of the cornea, an important area for visual function in dry eye sufferers, was shown to have the most benefit from treatment. Excellent safety, tolerability, and comfort profile supports this new CsA formulation as having a positive benefit-to-risk ratio. (C) 2018 by the American Academy of Ophthalmology