MGCD290, an Oral Fungal Hos2 Inhibitor, Enhances the Antifungal Properties of Fluconazole following Multiple or Single Oral Dose Administration in Pre- and Post-Infection Settings

Ref ID: 18735

Author:

J. Besterman, PhD – Executive Vice President, Research & Development and Chief Scientific Officer, D. T. Nguyen, PhD – Senior Research Biologist, H. Ste-Croix, BSc – Senior Research Biologist;

Author address:

MethylGene Inc, Montreal, Canada.

Full conference title:

52nd Annual ICAAC

Date: 9 September 2014

Abstract:

Background: MGCD290 (290) is an oral small molecule in clinical development, which targets the Hos2 fungal enzyme. We previously demonstrated that this inhibitor increases the fungal sensitivity to azoles both in vitro and in vivo and broadens the spectrum of azole antifungal activity. Five Phase I trials are now completed. As first clinical proof of concept, a randomized Phase II study in vulvo-vaginal candidiasis is ongoing. We evaluated a variety of dosing schedules in a murine model of systemic candidiasis to demonstrate that fluconazole (Flu) + 290 would be superior to Flu alone under a variety of dosing schedules since Flu is used clinically in both single and multiple dosing settings. Methods: Three oral treatment schedules were evaluated by inoculating immunocompromised CD-1 mice i.v. with either Flu-resistant (MIC50=128μg/mL) or sensitive (MIC50=1.6μg/mL) strains of C. albicans. Kidneys were resected 24-36 hr post-infection and mean kidney fungal load was determined. The doses of 290 used were previously evaluated in this model. 1) A dose of Flu with or without 290 was given 1 hour prior to and 4 hr post infection. 2) A dose of Flu with or without 290 was given 1 hour prior to inoculation and a second dose of 290 given to the Flu + 290 group 4 hr post-infection. 3) A single dose of Flu with or without 290 was given 16 hr post-inoculation. Results: Significant decreases in kidney fungal load were observed in animals receiving Flu + 290 when compared with animals receiving Flu alone on all schedules tested. Prophylactic dosing followed by a second dose of either the combination of 290 + Flu or 290 alone significantly lowered the kidney fungal burden. Even a single dose of the combination significantly decreased the kidney fungal load, weight and size when administered 16 hr post-inoculation. Conclusions: Our studies demonstrate that co-administration of 290 with Flu decreased the fungal burden when compared to Flu alone on all schedules tested in a mouse model of disseminated candidiasis. These results suggest that the combination of Flu + 290 may be superior to Flu alone even in a single dose setting.

Abstract Number: M-1711

Conference Year: 2012

Link to conference website: NULL

New link: NULL

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