July 2018
Volume 59, Issue 9
Open Access
ARVO Annual Meeting Abstract  |   July 2018
Evaluation of Selective NaV1.7 Inhibitors for the Treatment of Ocular Pain
Author Affiliations & Notes
  • Anton Delwig
    SiteOne Therapeutics, South San Francisco, California, United States
  • Hassan Pajouhesh
    SiteOne Therapeutics, South San Francisco, California, United States
  • David Yeomans
    SiteOne Therapeutics, South San Francisco, California, United States
    Stanford University, Palo Alto, California, United States
  • Justin Du Bois
    SiteOne Therapeutics, South San Francisco, California, United States
    Stanford University, Palo Alto, California, United States
  • George Miljanich
    SiteOne Therapeutics, South San Francisco, California, United States
  • John Mulcahy
    SiteOne Therapeutics, South San Francisco, California, United States
  • Footnotes
    Commercial Relationships   Anton Delwig, SiteOne Therapeutics (E); Hassan Pajouhesh, SiteOne Therapeutics (E); David Yeomans, SiteOne Therapeutics (C); Justin Du Bois, SiteOne Therapeutics (C); George Miljanich, SiteOne Therapeutics (E); John Mulcahy, SiteOne Therapeutics (E)
  • Footnotes
    Support  NIH NEI 1R43EY025921-01
Investigative Ophthalmology & Visual Science July 2018, Vol.59, 2679. doi:
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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.

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      © ARVO (1962-2015); The Authors (2016-present)

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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.

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