Investigation of ocular events associated with taprenepag isopropyl, a topical EP2 agonist in development for treatment of glaucoma.
OBJECTIVE
Taprenepag isopropyl is an EP2 receptor agonist that is in development for the treatment of glaucoma. Iritis, photophobia, and increased corneal thickness observed in a Phase 2 clinical trial with taprenepag isopropyl were not previously observed in topical ocular toxicity studies in rabbits and dogs. In vivo studies using cynomolgus monkeys and in vitro models were used to elucidate the mechanisms underlying these ocular events.


METHODS
Monkeys were dosed daily for 28 days in 1 eye with taprenepag and in the other with vehicle control. Complete ophthalmic examinations were performed at baseline and weekly thereafter. Serial sections of eyes were examined histopathologically at the end of the study. Recovery after the discontinuation of taprenepag was assessed for 28 days in the monkeys in the high-dose group. In vitro studies evaluated cell viability, paracellular permeability, and cytokine induction with human corneal epithelial or endothelial cell cultures.


RESULTS
Monkeys demonstrated a dose-related incidence of iritis and increased corneal thickness that resolved within 28 days of discontinuing taprenepag. There was no evidence in vivo of taprenepag toxicity to the corneal endothelium or epithelium. Cell viability of stratified epithelial cells was primarily affected by excipients and was similar to Xalatan(®). The viability of HCEC-12 cells was not affected by taprenepag at concentrations up to 100 μM.


CONCLUSIONS
The lack of in vivo or in vitro endothelial cytotoxicity and the reversibility of the increase in corneal thickness and iritis in the monkey provide confidence to permit further clinical development of taprenepag.
1 Drug Safety Research & Development, Pfizer, Inc. , San Diego, California.
Gina M
GM
Yanochko
Timothy
T
Affolter
Johnnie J
JJ
Eighmy
Mark G
MG
Evans
Su
S
Khoh-Reiter
Dong
D
Lee
Paul E
PE
Miller
Michael H I
MH
Shiue
Dusko
D
Trajkovic
Bart A
BA
Jessen
D000085:Acetates / Q000008:administration & dosage*; D060433:Administration, Ophthalmic; D000287:Administration, Topical; D000818:Animals; D002417:Cattle; D002478:Cells, Cultured; D004285:Dogs; D055808:Drug Discovery / Q000379:methods / Q000639:trends*; D019573:Epithelium, Corneal / Q000187:drug effects* / Q000473:pathology*; D005901:Glaucoma / Q000188:drug therapy* / Q000473:pathology; D006801:Humans; D008252:Macaca fascicularis; D008297:Male; D058307:Receptors, Prostaglandin E, EP2 Subtype / Q000819:agonists*; D013449:Sulfonamides / Q000008:administration & dosage*; D016896:Treatment Outcome
D000085:Acetates; C568861:PF 04217329; D058307:Receptors, Prostaglandin E, EP2 Subtype; D013449:Sulfonamides