Safety and Biodistribution of Topical Laquinimod, an Immunomodulator Targeting Aryl Hydrocarbon Receptor: The LION Study.

PURPOSE: To evaluate the safety, tolerability, and distribution of laquinimod (LAQ) eye drops as a potential steroid-sparing anti-inflammatory therapy.

DESIGN

Phase I clinical trial conducted at the Byers Eye Institute, Stanford University. NCT06161415.

PARTICIPANTS

Patients scheduled for elective pars plana vitrectomy for various noninfectious indications.

METHODS

Enrolled subjects were instructed on proper LAQ storage and administration and received the drops for 14 days prior to surgery. Patients were sequentially assigned into 3 groups receiving daily LAQ doses of 0.6, 1.2, and 1.8 mg, with dose escalation permitted only in the absence of safety concerns in the preceding cohort. A preoperative visit was performed following 7 days of LAQ administration. On the day of surgery, aqueous, vitreous, and plasma samples were collected for LAQ quantification. Two postoperative follow-up visits were conducted.

MAIN OUTCOME MEASURES: Tolerability; safety of the LAQ eye drop, assessed via ophthalmic examination, multimodal imaging, laboratory tests, and electrocardiogram; and LAQ concentrations in aqueous, vitreous, and plasma.

RESULTS

Ten participants completed the 14-day topical LAQ and all study visits, except one where pars plana vitrectomy was canceled; however, subject completed LAQ course and safety follow-up. The mean age was 59.9 ± 15 years, with a female predominance (70%). Given there were no dose-limiting toxicities, participants sequentially received daily doses of 0.6 mg (n = 4), 1.2 mg (n = 3), and 1.8 mg (n = 3). Following the exclusion of insufficient samples, LAQ levels were analyzed in 8 vitreous and 7 aqueous specimens. Laquinimod was well tolerated at all doses, with 3 adverse events unrelated to the study drug. Laquinimod was detected in aqueous, vitreous, and plasma with dose-dependent levels across all doses. Mean total LAQ level was significantly higher in aqueous rising from 508.5 to 3640.0 ng/mL, exceeding vitreous levels that rose from 6.89 to 38.50 ng/mL. Notably, unbound LAQ levels remained significant. Plasma concentrations remain within established safety ranges, with mean LAQ levels increasing from 153.4 to 563.5 ng/mL.

CONCLUSIONS

Topical LAQ was safe and well tolerated at daily doses of 0.6, 1.2, and 1.8 mg, with measurable penetration into the posterior segment. Dose-dependent drug levels were detected in vitreous, aqueous, and plasma. These findings support investigation of LAQ's therapeutic potential for inflammatory eye diseases.

FINANCIAL DISCLOSURES: Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.