RESUMO
Objective: Dry eye disease (DED) is a worldwide source of ocular discomfort. This first-in-human phase 2 clinical study determined the efficacy of treating signs and symptoms of DED using an ophthalmic solution of synthesized mimetic of human collagen (ST-100). Design: This double-masked, randomized, study compared high (60 µg/mL) and low (22 µg/mL) dose ST-100 to vehicle utilizing the Ora, Inc. Controlled Adverse Environment (CAE) during a 28-day period. Participants: Participants included males and females ≥ 18 years of age with signs and symptoms of DED for ≥ 6 months that worsened during CAE exposure who were not taking any topical prescription therapeutic. Intervention: Participants applied ST-100 or vehicle placebo topically to both corneas (1 drop) twice daily via a blow-fill-sealed preservative-free container. Main Outcome Measures: The prespecified primary efficacy sign end point was mean change from baseline (CFB) in total corneal fluorescein staining, and the primary symptom end point was mean CFB in ocular discomfort. A secondary prespecified efficacy end point was CFB in unanesthetized Schirmer's test for tear film production. Results: Of 160 subjects in the intent-to-treat population (112 female, 48 male, median age 64), 146 completed the study. Total corneal fluorescein staining CFB improved for high-dose ST-100, with superiority over vehicle when both eyes were considered together (2-sample t test: P = 0.0394). High-dose ST-100 was superior to vehicle in Schirmer's CFB for the study eye (least squares mean difference [confidence interval] = 2.3 [0.6, 4.0], P = 0.0094). For study eyes, the proportion of Schirmer's test responders (CFB ≥ 10 mm, Schirmer's responder rate) was 12.2% for high-dose ST-100 versus 0.0% for vehicle (P = 0.0266). The CFB for ocular discomfort score improved in study eyes for high- and low-dose ST-100 (paired t test, P = 0.0133, P = 0.0151, respectively) but without superiority over vehicle (ANCOVA: P = 0.5696, P = 0.8968, respectively). ST-100 Schirmer's responders also demonstrated total elimination of worsening of corneal fluorescein stain during the stress of CAE sessions. Conclusions: ST-100 significantly improved tear production and related outcomes in DED and was well-tolerated in reducing symptoms. Financial Disclosures: Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.
RESUMO
Dry eye disease (DED) is a major cause of ocular discomfort, inflammation and dysfunction worldwide. Tear film instability in DED both causes and is exacerbated by disruption of the corneal epithelium. This tandem leads to a cycle of inflammation at the corneal surface involving immune cell dysregulation and increased chemokines and cytokines, which activate mitogen-activated protein kinases in the epithelium and elevates matrix metalloproteinases (MMPs). We review evidence suggesting that corneal collagen might be highly susceptible in DED to MMP-induced disruption, digestion, and thinning. We also summarize that collagen is far from inert and contains binding sites that serve as ligands for multiple inflammatory and immune regulators. Fragmented collagen not only challenges these receptor-ligand binding relationships, but also can promote recruitment and motility of pro-inflammatory immune cells. Current physician-directed therapies for DED focus on reducing inflammation, but do not directly ameliorate the underlying corneal damage that could exacerbate surface inflammation. We argue that an important gap in practice is lack of a direct therapeutic reparative for damaged corneal collagen, which is slow to heal, and likely amplifies sight-threatening inflammation. Healing fragmented collagen in the cornea may represent a more effective means to interrupt the "vicious cycle" of inflammation in DED and other conditions that damages, sometimes irreversibly, the ocular surface.
