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2020 OMIG Abstract

Filociclovir (MBX-400) Demonstrates Antiviral Activity against Adenovirus In Vitro and in the Ad5/NZW Rabbit Ocular Model

Eric G. Romanowski, MS1, Islam Hussein, DVM, MS, PhD2, Steven Cardinale, BS2, Michelle Butler, PhD2, Lucas Morin2, Robert M.Q. Shanks, PhD1, Regis P. Kowalski, MS, M(ASCP)1, and Terry L. Bowlin, PhD 2
1The Charles T. Campbell Ophthalmic Microbiology Laboratory, Department of Ophthalmology,
University of Pittsburgh School of Medicine, Pittsburgh, PA; 2Microbiotix, Inc., Worcester, MA

Purpose: Presently, there is no FDA approved antiviral therapy for the treatment of adenovirus (Ad) ocular infections, the most common ocular viral infection worldwide. The goals of the current study were to determine the in vitro antiviral activity of the novel broad-spectrum nucleoside analog, filociclovir (FCV; MBX-400) and the antiviral efficacy of topical FCV in against an ocular Ad infection in the Ad5/NZW rabbit ocular model.

Methods: : In vitro: the 50% inhibitory concentrations (IC50) of FCV and cidofovir (CDV) for the human Ad types Ad3, Ad4, Ad5, Ad7a, Ad8, Ad19/64 and Ad37 were determined using standard plaque-reduction assays on A549 cells. Briefly, cells infected with ~100 PFU of the Ad types were treated with final concentrations of FCV and CDV of 100, 10, 1.0, 0.1, 0.01 and 0.001 ÁM. After incubation, the numbers of plaques from each virus/drug concentration were counted and the mean IC50 from triplicate assays were determined by regression analysis. In vivo: 37 NZW rabbits were topically inoculated in both eyes, following corneal scarification, with 1.5 x 106 PFU/eye of Ad5. On day 1, the rabbits were divided into 4 topical treatment groups (n=9-10/group): 1) 0.5% FCV 4x daily x 10 days; 2) 0.1% FCV 4x daily x 10 days; 3) 0.5% CDV twice daily x 7 days (positive antiviral control); 4) Vehicle (negative antiviral control) 4x daily x 10 days. All eyes were cultured for virus on days 0, 1, 3, 4, 5, 7, 9, 11, and 14. Resulting viral titers from the eye cultures were determined using standard plaque assays.

Results: The mean in vitro IC50 for FCV ranged from 0.50 to 4.68 ÁM, whereas those for CDV ranged from 0.49 to 30.30 ÁM. FCV produced lower IC50 concentrations than CDV for 5 of 7 Ad types. In vivo, compared to Vehicle, 0.5% FCV, 0.1% FCV, and 0.5% CDV produced lower Ad5 eye titers on Days 5, 7, 9, and 11, fewer numbers of positive eye cultures per total on Days 4, 5, 7, 9, and 11, and shorter durations of eye infection (11 vs. 5, 7, 5 days respectively) (P<0.05, Kruskal-Wallis, Fisher Exact Test). In addition, 0.5% FCV produced lower eye titers on Days 3 and 4 and 0.1% FCV produced lower eye titers on Day 4 compared to the Vehicle (P<0.05). Furthermore, 0.5% FCV produced lower eye titers on Day 1 compared with 0.5% CDV and on Day 4 compared with 0.1% FCV as well as fewer positive eye cultures per total compared with 0.1% FCV on Days 4 and 7 (P<0.05).

Conclusion: FCV demonstrated effective anti-adenovirus activity in vitro. Topical FCV demonstrated dose-dependent antiviral efficacy better or equal to CDV in the Ad5/NZW rabbit ocular model. Further development of filociclovir to treat Ad ocular infections in a timely fashion is warranted.

Disclosure: S (Microbiotix, Inc.)



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