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Anton Delwig, Hassan Pajouhesh, David Yeomans, Justin Du Bois, George Miljanich, John Mulcahy; Evaluation of Selective NaV1.7 Inhibitors for the Treatment of Ocular Pain. Invest. Ophthalmol. Vis. Sci. 2018;59(9):2679. doi: https://doi.org/.
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© ARVO (1962-2015); The Authors (2016-present)
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.
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.
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.
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.
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