June 2022
Volume 63, Issue 7
Open Access
ARVO Annual Meeting Abstract  |   June 2022
ROCK’Sters, a novel compound class combining Rho kinase inhibition with corticosteroid anti-inflammatory activity for the treatment of ocular inflammation
Author Affiliations & Notes
  • Jill M. Sturdivant
    Aerie Pharmaceuticals Inc, Durham, North Carolina, United States
  • Curtis Kelly
    Aerie Pharmaceuticals Inc, Durham, North Carolina, United States
  • Daphne Clancy
    Aerie Pharmaceuticals Inc, Durham, North Carolina, United States
  • Natalie Girouard
    Aerie Pharmaceuticals Inc, Durham, North Carolina, United States
  • Maria Ina
    Aerie Pharmaceuticals Inc, Durham, North Carolina, United States
  • Qing Wang
    Aerie Pharmaceuticals Inc, Durham, North Carolina, United States
  • D'Quan Cutno
    Aerie Pharmaceuticals Inc, Durham, North Carolina, United States
  • Stuart Williams
    Aerie Pharmaceuticals Inc, Durham, North Carolina, United States
  • Mitchell A. deLong
    Aerie Pharmaceuticals Inc, Durham, North Carolina, United States
    Duke University, Durham, North Carolina, United States
  • Casey Kopczynski
    Aerie Pharmaceuticals Inc, Durham, North Carolina, United States
  • David Hollander
    Aerie Pharmaceuticals Inc, Durham, North Carolina, United States
  • Jeffrey C. White
    Aerie Pharmaceuticals Inc, Durham, North Carolina, United States
  • Footnotes
    Commercial Relationships   Jill Sturdivant Aerie Pharmaceuticals, Code E (Employment); Curtis Kelly Aerie Pharmaceuticals, Code E (Employment); Daphne Clancy Aerie Pharmaceuticals, Code E (Employment); Natalie Girouard Aerie Pharmaceuticals, Code E (Employment); Maria Ina Aerie Pharmaceuticals, Code E (Employment); Qing Wang Aerie Pharmaceuticals, Code E (Employment); D'Quan Cutno Aerie Pharmaceuticals, Code E (Employment); Stuart Williams Aerie Pharmaceuticals, Code E (Employment); Mitchell deLong Aerie Pharmaceuticals, Code E (Employment); Casey Kopczynski Aerie Pharmaceuticals, Code E (Employment); David Hollander Aerie Pharmaceuticals, Code E (Employment); Jeffrey White Aerie Pharmaceuticals, Code E (Employment)
  • Footnotes
    Support  None
Investigative Ophthalmology & Visual Science June 2022, Vol.63, 2111 – F0127. doi:
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      Jill M. Sturdivant, Curtis Kelly, Daphne Clancy, Natalie Girouard, Maria Ina, Qing Wang, D'Quan Cutno, Stuart Williams, Mitchell A. deLong, Casey Kopczynski, David Hollander, Jeffrey C. White; ROCK’Sters, a novel compound class combining Rho kinase inhibition with corticosteroid anti-inflammatory activity for the treatment of ocular inflammation. Invest. Ophthalmol. Vis. Sci. 2022;63(7):2111 – F0127.

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

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Abstract

Purpose : Topical corticosteroids are commonly used to treat ocular surface and post-operative inflammation. Topical corticosteroid use is limited by its potential for ocular adverse events, such as elevated intraocular pressure. We have previously described a new class of compounds comprised of a corticosteroid covalently linked to a Rho-kinase inhibitor (ROCKi), termed “ROCK’Sters” that are designed to mitigate steroid-induced intraocular pressure (IOP) elevation. Herein, is described the synthesis, biochemical, and cellular activity of ROCK’Sters as well as a demonstration of their anti-inflammatory efficacy in a rabbit model of post-operative inflammation.

Methods : ROCK’Sters were evaluated for inhibition of ROCK enzyme isoforms in kinase biochemical assays. Steroidal activity of several ROCK’Sters was characterized by inhibition of the pro-inflammatory IL-23 pathway in mouse splenocytes. In vivo, anti-inflammatory efficacy of ROCK’sters was evaluated in a rabbit model of post-operative inflammation after cataract surgery. Post-surgery, ocular examinations evaluated surface morphology and anterior/posterior inflammation using a modified Hackett and McDonald ocular grading system. ROCK’Ster activity in the post-op model was compared to marketed steroids, Pred-Forte® and Durezol®.

Results : Several of the ROCK’Sters demonstrated potent inhibition of Rho kinase activity in enzymatic assays with IC50 < 10 nM. In a cellular context, these compounds strongly inhibited the pro-inflammatory IL-23 pathway in mouse splenocytes with IC50 values ranging from approximately 1 nM to 30 nM. In a rabbit post-operative inflammation model, ROCK’Sters displayed significant efficacy for resolution of inflammation that was noninferior to both Pred-Forte® and Durezol®.

Conclusions : ROCK’Sters represent a proprietary compound class with in vitro Rho kinase inhibitory activity, cellular steroidal activity, and anti-inflammatory efficacy in an animal model of post-operative inflammation. This class of compounds provides potent efficacy for the treatment of ocular surface and post-operative inflammation coupled with the potential for extended therapeutic use by providing a reduced risk of steroid-induced IOP elevation.

This abstract was presented at the 2022 ARVO Annual Meeting, held in Denver, CO, May 1-4, 2022, and virtually.

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