Abstract
Purpose :
IVW-1001 Ophthalmic Eyelid Wipe (OEW; 0.2%), a novel transient receptor potential melastatin 8 (TRPM8) agonist that provides a cooling sensation upon activation of TRPM8 receptors in eyelids and cornea, is in development for treatment of signs and symptoms of dry eye disease (DED). IVW-1001 OEW was evaluated in pharmacology, ocular pharmacokinetic (PK) and toxicology studies to support a Phase 1/2a clinical trial with ≤ 0.2% IVW-1001 OEW applied to the upper eyelid twice daily (BID) in patients with DED.
Methods :
IVW-1001 was evaluated in a TRPM8 ion channel cellular assay. A single dose of 0.2% IVW-1001 Ophthalmic Solution (OS) was applied to the eyelid margin of rabbits and ocular tissues were analyzed for PK. In Good Laboratory Practice 1-month toxicity studies, ≤ 1.0% IVW-1001 OEW applied 3 times daily (TID) to upper eyelids in minipigs and ≤ 0.1% IVW-1001 OS applied TID to the ocular surface by eyedrop in minipigs and rabbits was evaluated for eyelid, ocular and systemic safety, and toxicokinetics.
Results :
IVW-1001 was a potent TRPM8 agonist with an EC50 of 0.96 µM in the cellular assay. Increased tear secretion by a single topical eyelid application of 0.2% IVW-1001 was previously reported in a DED mouse model.
In the ocular PK study in rabbits, ocular tissue concentrations were detectable up to the last time point at 8 hours and overall T1/2 was 3.5 hours and the mean residence time was 2.4 hours, suggesting IVW-1001 could be administered BID in humans without accumulation. Drug concentrations in tears, conjunctiva, eyelid skin, and cornea were 16- to 130-times higher than in vitro EC50.
In GLP 1-month toxicity studies in minipigs and rabbits, there were no ocular effects by ophthalmology, tonometry, and electroretinography, no eyelid dermal effects and no systemic effects or adverse eyelid, ocular and systemic microscopic findings and systemic exposure was negligible. The no-observed-adverse-effect-levels were the highest doses tested in both species with ocular/dermal safety margins of up to 16X in minipigs and 4.4X in rabbis compared to the starting dose in the Phase 1/2a clinical trial.
Conclusions :
Efficacy, ocular PK and toxicity studies of IVW-1001 OEW and OS demonstrated effective and safe ocular target concentrations when applied to the eyelid and/or ocular surface in rabbits and/or minipigs, which supported the Phase 1/2a clinical trial of ≤ 0.2% IVW-1001 OEW BID in DED patients.
This abstract was presented at the 2024 ARVO Annual Meeting, held in Seattle, WA, May 5-9, 2024.