1619. SAD and MAD Studies in Healthy Subjects Demonstrate Safety and Pharmacokinetics of MGCD290, an Oral Fungal Hos2 Inhibitor Fluconazol
Session: Poster Abstract Session: Novel Antimicrobial Agents
Saturday, October 20, 2012
Room: SDCC Poster Hall F-H
Background: MGCD290 is an oral Hos2 enzyme inhibitor in Phase 2 clinical trials that potentiates and broadens the spectrum of activity of azole antifungal agents against multiple human fungal pathogens, including azole-resistant clinical isolates. The tolerability and PK of MGCD290 ± fluconazole in healthy volunteer studies are described.

Methods: Four Phase I, double-blind, placebo-controlled, randomized, single and multiple ascending dose, first in human studies evaluating the safety and tolerability of MGCD290 alone (Trials 290-001 and 290-003) and MGCD290 + 400 mg fluconazole (Trials 290-002 and 290-004) following oral administration for up to 14 days have been completed. Dose levels ranged from 100 - 1000 mg daily. The PK profile of oral MGCD290 was determined under fasting conditions in cohorts of 8 subjects (6 active, 2 placebo) per dose level.

Results: For all four studies, no clinically significant drug-related adverse events were observed at any dose level evaluated in either the SAD or MAD setting. No dose-limiting toxicity was identified. Maximal plasma concentrations were observed 1.5-2.5 hours after oral drug intake with a mean elimination half-life of approximately 10 - 11 hours. AUC values were approximately proportional to dose. PK parameters, including the apparent volume of distribution, suggest excellent tissue distribution. No significant drug accumulation occurred with dosing for 14 days.  Safety and PK data suggest that MGCD290 + fluconazole was well tolerated without drug-drug interactions up to 540 mg MGCD290 + 400 mg fluconazole.

Conclusion: Oral administration of MGCD290 for up to 14 days was well-tolerated and showed favorable PK following multiple doses of MGCD290 ± fluconazole.  PK data suggest that target plasma concentrations of MGCD290 based on preclinical models are achievable and safe when given alone or with 400 mg fluconazole for up to 14 days.  A Phase 2 study in vulvovaginal candidiasis is underway comparing a single dose of 150 mg fluconazole to a single dose of 150 mg fluconazole plus 540 mg MGCD290.

Gregory Reid, MSc, Michel Drouin, MD and Jeffrey Besterman, PhD, MethylGene Inc., Montreal, QC, Canada

Disclosures:

G. Reid, MethylGene Inc.: Employee, Salary

M. Drouin, MethylGene Inc.: Consultant, Salary

J. Besterman, MethylGene Inc.: Employee, Salary

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