Abstract
Purpose :
A critical role for TGF-β2 in the pathophysiology of several ocular diseases such as glaucoma, age-related macular degeneration or diabetic macular degeneration has been demonstrated, making this cytokine a relevant therapeutic target. To support clinical development in these indications, the ocular biodistribution and pharmacodynamics profile of ISTH0036, a 14-mer phosphorothiate locked nucleic acid-modified antisense oligodeoxynucleotide gapmer, was evaluated in Cynomolgus monkeys following intravitreal administration.
Methods :
To assess the time-dependency of ocular tissue drug biodistribution and pharmacodynamics effects, ISTH0036 was administered on Day 1 and Day 57 at a dose of 100 µg/eye to Cynomolgus monkey eyes. Furthermore, single administrations of the compound at increasing doses of 30, 100 and 300 µg/eye were performed to assess the dose-dependency on Day 29. An anion-exchange-HPLC method with fluorescence detection was used to analyze tissue concentrations. Target downregulation was determined using a branched DNA assay, protein concentration in humors with a multiplex ELISA assay.
Results :
Long-lasting and time-dependent biodistribution of ISTH0036 to the posterior eye tissues was observed. Similar high ISTH0036 concentrations were measured in the retina, choroid and ciliary body after 300 µg/eye administration (on Day 29: 5-6 µg/g). High median drug concentrations in posterior eye tissues were still observed on the last day of measurement (Day 113). ISTH0036 induced in vivo long-lasting and dose-dependent TGF-β2 mRNA downregulation in retina and lens. TGF-β2 protein concentration decreased in the vitreous humor after intravitreal injection of ISTH0036 and this effect was long-lasting, up to Day 113. These results confirm previous findings in the rabbit eye.
Conclusions :
ISTH0036 demonstrated potent target TGF-β2 mRNA downregulation in relevant tissues of the Cynomolgus monkey eye. Long-lasting posterior eye tissue distribution was consistent with the observed target engagement. Demonstrated biodistribution and target engagement supports further clinical development and provides rationales for Q2M or Q3M administration schedules of ISTH0036 in the ophthalmic setting.
This is an abstract that was submitted for the 2018 ARVO Annual Meeting, held in Honolulu, Hawaii, April 29 - May 3, 2018.