Discussion
PL9643, inflammation, pain, inferior corneal fluorescein, dilated fundoscopy).A
INFLAMMATION, SECONDARY, INTRAOCULAR PRESSURE
This study investigated the effect of an ophthalmic solution of the melanocortin MCR pan-agonist PL9643 on patients with DED over a 12-week period. The study explored a range of signs and symptoms of DED using commonly used measures, including the use of the CAE model. The prospective hypothesis that, in the ITT population of patients with mild to severe DED, PL9643 treatment would show statistically superior efficacy to placebo (pre-CAE to post-CAE) in inferior corneal fluorescein staining and ocular discomfort at week 12 was not supported. The ITT PL9643 group also did not demonstrate a significant difference from the placebo group for the secondary endpoints.In the Responses to the Ora Calibra Drop Comfort Scale in the overall ITT population were comparable for the PL9643 group compared with the placebo group, and PL9643-treated patients experienced no AEs of pain on instillation, in contrast to the 3.1% observed in the placebo group. PL9643 was well tolerated, with a safety profile trending toward superiority over placebo in the ITT population. No treatment-emergent serious AEs were considered related to the study drug, and no patients in the PL9643 group withdrew from the study due to AEs. PL9643 also showed no effects on other aspects of vision (visual acuity, slit-lamp biomicroscopy, intraocular pressure, or dilated fundoscopy).A major limitation of this study is that the results of the secondary endpoints have not been adjusted for multiplicity, so that changes in these endpoints are hypothesis generating only. Further studies with larger sample sizes will be able to address the statistical significance of these changes. The absence of significant improvements in the mild subpopulation may be a consequence of the small sample size. In the future, tests evaluating ocular surface inflammation such as matrix metalloproteinase 9 concentration (or other pro-inflammatory markers) in the tear film offer the potential to aid the evaluation of efficacy.The purpose of our initial clinical investigation was to identify patients that had the greatest response to PL9643. Although we did not see statistical significance for the overall ITT population, we were able to identify a responsive subpopulation which could be valuable for future clinical studies. In the subpopulation of moderate to severe patients (