Safety and efficacy of twice daily administration of KPI-121 1% for ocular inflammation and pain following cataract surgery

Abstract

Purpose: KPI-121 is a nanoparticle suspension of loteprednol etabonate with improved ocular pharmacokinetics compared with marketed formulations. The efficacy and safety of KPI-121 1% ophthalmic suspension (INVELTYS™) dosed twice daily (BID) were evaluated in participants who had undergone cataract surgery.

Materials and methods: In two multicenter, randomized, double-masked, parallel-group, vehicle-controlled clinical trials, 386 participants with ≥ grade 2 anterior chamber cells (≥6 cells) on the day following routine cataract surgery were treated with KPI-121 1% and 325 participants were treated with placebo (vehicle); each group was dosed BID for 2 weeks. Primary efficacy endpoints were complete resolution of ocular inflammation by slit-lamp biomicroscopy and complete resolution of subject-rated ocular pain at Days 8 and 15 with no rescue medication before Day 15. Safety assessments included adverse events (AEs), visual acuity, intraocular pressure measurements, and evaluation of ocular AEs by slit-lamp biomicroscopy and dilated ophthalmoscopy.

Results: Both trials achieved statistical significance favoring KPI-121 1% BID for both primary efficacy endpoints. Combined data analysis showed that significantly more participants treated with KPI-121 vs vehicle achieved complete resolution of anterior chamber cells at Days 8 and 15 (P≤0.0001) and complete clearing of ocular pain at Days 4, 8, and 15 (P<0.0001). AEs were reported more frequently with vehicle than KPI-121.

Conclusion: KPI-121 1% ophthalmic suspension was effective in resolving postoperative ocular inflammation and pain when dosed BID for 2 weeks in patients following cataract surgery. KPI-121 was found to be safe and well tolerated in both trials.

Keywords: loteprednol etabonate; mucus penetrating particles; nanoparticle; pain; postoperative ocular inflammation.

Figure 1

Schematic of the study design. Notes: In both Trial 1 and Trial 2, subjects completed up to seven clinic visits (including the surgery day) over 18–33 days of total planned trial duration. Screening occurred prior to surgery, and subjects who met preoperative screening inclusion/exclusion criteria were enrolled in the trial. At Day 0 (surgery), subjects underwent routine, uncomplicated cataract surgery according to normal procedures. Randomization occurred on the day following surgery (Day 1). Subjects self-administered 1–2 drops in the study eye (defined as the surgery eye) for 14 days and returned to the clinic to be evaluated at Days 4, 8, and 15. The last dose of study treatment was administered on the morning of the Day 15 visit, upon completion of 14 days of dosing.

Figure 2

Proportions of subjects achieving and maintaining complete resolution of anterior chamber cells at Days 8 and 15 (pooled ITT population). Notes: Data for the KPI-121 1% BID and vehicle treatment groups were pooled for both trials. Subjects were considered responders at Day X (ie, 8 or 15) if they had complete resolution of anterior chamber cells (grade =0) starting at that visit and continuing through Day 15 with no rescue medication prior to Day 15. A subject was not considered to have been rescued if rescue medication started on the Day 15 visit date. Subjects with missing scores at Day 15 were counted as nonresponders for the Day 15 analysis. P-values are based on two-sided chi-squared tests, unadjusted, wherein the significance level was P=0.05. Abbreviations: BID, twice daily; ITT, intent to treat.

Figure 3

Proportions of subjects achieving and maintaining complete resolution of ocular pain at Days 4, 8, and 15 (pooled ITT population). Notes: Data for the KPI-121 1% BID and vehicle treatment groups were pooled for both trials. Subjects were considered responders at Day X (ie, 4, 8, or 15) if they had complete resolution of ocular pain (grade =0) starting at that visit and continuing through Day 15 with no rescue medication prior to Day 15. A subject was not considered to have been rescued if rescue medication started on the Day 15 visit date. Subjects with missing scores at Day 15 (five subjects in the KPI-121 1% group and seven subjects in the vehicle group) were counted as nonresponders for the Day 15 analysis. P-values are based on two-sided chi-squared tests, unadjusted, wherein the significance level was P=0.05. Abbreviations: BID, twice daily; ITT, intent to treat.