A phase 1 trial treating autoimmune uveitis with a novel intraocular small molecule - further data analysis

Abstract

Purpose : After extensive and successful preclinical investigations of effects and side effects of the small molecule inhibitor of pyrimidine synthesis that targets DHODH (KIO-100/PP-001) and thus efficiently suppressed T and B cells and uveitis in rats we have performed a clinical phase 1 trial for patients suffering from posterior uveitis. Aim of this ethically approved study was the intraocular and systemic safety of the molecule, and in addition its effect on intraocular inflammation was assessed.

Methods : 12 patients (8f, 4m, mean age 52 years) with longstanding, bilateral, chronic, noninfectious posterior uveitis were injected once intravitreally in their worse eye with one of 3 doses (0.3, 0.6, 1.2 µg) of KIO-100/PP-001. Plasma drug levels were determined 4h and 2 days post injection. Systemic (vital signs, blood chemistry) and ophthalmic parameters (VA, IOP, visual field (30°), AC cells, vitreous haze (according to SUN grading), central retinal thickness and CME (OCT) were determined weekly until day 28 (end of study), while fluorescein angiography, VECP and ERG and corneal endothelial cells were investigated at study onset and day 28.

Results : No toxic or other adverse events were observed. VA increased in a dose dependent manner and in the 1.2 µg group on average by -0.3 log[MAR]. Combined inflammation score of AC cells and vitreal haze decreased by 53% until week 2 and remained low until week 4 (end of study). There was a strong correlation between VA and combined inflammation score of 0.83 correlation coefficient. CME resolved in 3 of 5 patients receiving 0.6 or 1.2 µg KIO-100. There was no correlation with central retinal thickness and VA. IOP, visual fields and ERG remained stable in all groups throughout the study period. Systemic levels of the study drug levels (plasma) were below the assay quantification limit of 10 ng/ml in all patients at the respective test points. Two patients seen after study completion remained stable.

Conclusions : In this clinical phase 1 trial the DHODH-inhibitor KIO-100/PP-001 did not only demonstrate safety for intravitreal use but also presented the potential for a new intraocular therapy of autoimmune uveitis and CME.

This abstract was presented at the 2023 ARVO Annual Meeting, held in New Orleans, LA, April 23-27, 2023.