Abstract
Purpose :
Ocular discomfort is the single most common reason for a visit to an ophthalmologist. Existing ocular analgesics suffer from a short duration of action, poor efficacy, or toxicity to the corneal epithelium. There is a significant unmet medical need for an effective, safe, and long lasting topical ophthalmic analgesic suitable for patient self-administration. SiteOne Therapeutics has developed a series of highly-selective small molecule inhibitors of an important target in pain signaling, the NaV 1.7 voltage-gated sodium channel. The objective of this study was to determine whether compounds from SiteOne’s portfolio of selective NaV1.7 inhibitors are suitable for development as ocular analgesics.
Methods :
We assessed the efficacy, duration of action, pharmacokinetics, ocular tolerability and toxicity of NaV1.7-selective and non-selective sodium channel inhibitors in a mouse model of corneal mechanical sensitivity (Cochet-Bonnet esthesiometry), and in an single dose ocular PK study and a 4-day repeat dose ocular tolerability study in rabbits.
Results :
Topical ocular administration of non-selective NaV blockers in mice produced dose-dependent corneal anesthesia and iris paralysis, which is considered an unacceptable side effect. Topical ocular administration of a NaV1.7-selective blocker in rabbits resulted in therapeutically meaningful concentratino in the cornea based on our understanding of pharmacokinetic-pharmacodynamic relationship in a monkey model of somatic thermal analgesia. A 4-day ocular tolerability and toxicity study in rabbits did not reveal any systemic or ocular adverse effects.
Conclusions :
Compelling corneal exposure and ocular tolerability results support development of a compound from SiteOne’s portfolio of selective NaV1.7 inhibitors as a safe and effective topical ophthalmic analgesic. Such a compound would find use in the treatment of acute and chronic ocular pain and discomfort associated with dry eye syndrome, corneal injuries, corneal infections, and post-operative pain following ocular surgical procedures.
This is an abstract that was submitted for the 2018 ARVO Annual Meeting, held in Honolulu, Hawaii, April 29 - May 3, 2018.