AG-920 (Articaine) Ophthalmic Solution: A Masked, Active-Controlled Evaluation of Its Local Anesthetic Efficacy and Safety in Pediatric Patients.

Purpose: The safety and efficacy of a novel topical ocular anesthetic (AG-920 sterile ophthalmic solution, 8%) was previously evaluated in adults. For both clinical and regulatory purposes, this new agent was evaluated in children. Methods: This was a Phase 3, randomized, active-controlled, single-masked, parallel-group design study in healthy pediatric subjects performed at a private practice retina clinic in the United States. The safety and anesthetic efficacy of AG-920 was compared with proparacaine hydrochloride ophthalmic solution 0.5% in 60 children undergoing ophthalmic examinations. The primary efficacy endpoint was whether the investigator was able to perform the eye examination. Results: In all subjects in each treatment group, the investigator was able to perform the eye examination without additional local anesthetic. There were no adverse events reported in this study. In both the study eye and fellow eye, there were no notable changes after dosing, and both treatment groups were similar. All external eye exams in all subjects in both treatment groups were normal. Conclusions: In this pediatric population aged 7 months to >11 years, AG-920 was therapeutically equivalent to marketed proparacaine with respect to having an ophthalmic examination performed without needing additional local anesthetic. Further, AG-920 was well tolerated, and there were no clinically significant safety findings.

Two Randomized, Double-masked, Placebo-controlled Studies of the Local Anesthetic Effect of Articaine Ophthalmic Solution.

Background: We wanted to develop a new topical ocular anesthetic with good bioavailability in anterior segment tissues. Given concerns about contamination and sterility in multi-dose products, we selected a unit-dose, nonpreserved presentation of AG-920 (articaine ophthalmic solution) in blow-fill-seal containers (similar to currently marketed pharmacological therapies for dry eye disease). Methods: Consistent with US Food and Drug Administration guidance, two pivotal, Phase 3, randomized, placebo-controlled, double-masked, parallel design studies conducted at two US private practices in 240 healthy subjects. A single dose of AG-920 or identical looking placebo into one (study) eye (2 drops 30 s apart). Subjects underwent a conjunctival pinch procedure and assessment of the pain associated with the pinch. The main outcome measure was the proportion of subjects with rating of "No pain at 5 minutes". Results: AG-920 provided a rapid onset of local anesthesia (less than one minute) with clinically and statistically significantly greater effect in AG-920 (68% and 83%) than placebo (3% and 18% for Study 1 and Study 2, respectively, P<0.0001). The most frequent adverse event was instillation site pain (27% vs 3%) followed by conjunctival hyperemia (probably related to the pinch, 9% vs 10%) in the AG-920 and placebo groups, respectively. Conclusion: AG-920 was found to be have a rapid onset and useful duration of local anesthesia with no major safety issues, and may be useful for the eye-care professional. Registered with clinicaltrials.gov as NCT04513652 and NCT04829344.

Early Nonclinical and Clinical Development of AG-920, a Repurposed Topical Ocular Anesthetic.

Purpose: To evaluate the preclinical effects, and preclinical and clinical ocular and systemic pharmacokinetics of a new topical, non-preserved ocular anesthetic, AG-920 (articaine ophthalmic solution). Methods: Five studies: one in vitro melanin binding study; three studies in rabbits receiving an ocular dose of AG-920 evaluating corneal sensitivity, ocular tolerability, and systemic exposure to articaine and its inactive metabolite, articainic acid; and one clinical study in 14 healthy adult volunteers receiving an ocular dose of AG-920, with blood samples over 24 h. A liquid chromatography with tandem mass spectrometry (LC-MS-MS) method was used to detect both parent and metabolite with a lower limit of quantitation (LLOQ) of 0.1 and 0.2 ng/mL, respectively. Results: Melanin binding of articaine was up to 7.4%. A decrease in corneal sensitivity was noted for 20 min post-treatment in all active groups, and returned to baseline by 60 min post-dose. No dose-response relationship was observed. Concentrations of articaine in ocular matrices generally peaked early and then decreased over time. Both parent and metabolite were observed in blood at early time points. There were no ocular safety issues with AG-920. Conclusions: These early stage development studies showed that AG-920 was well tolerated in the standard preclinical models and did not cause any toxicity. AG-920 ophthalmic solution elicited a rapid onset and potentially clinically useful duration of corneal anesthesia. The studies supported the clinical evaluation of the 8% strength. Registered with clinicaltrials.gov as NCT04759339.