MethylGene Presents Phase I Data For Its Novel Antifungal Agent, MGCD290, At The 49th Annual ICAAC Meeting

Main Category: Infectious Diseases / Bacteria / Viruses
Also Included In: Clinical Trials / Drug Trials
Article Date: 16 Sep 2009 - 23:00 PDT

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MethylGene Inc. (TSX:MYG) disclosed Phase I and preclinical data for MGCD290, an oral, small molecule, Hos2 fungal inhibitor. In preclinical studies, MGCD290 potentiates and broadens the spectrum of activity of azole antifungal agents against multiple human fungal pathogens including azole-resistant clinical isolates. MethylGene is currently evaluating MGCD290 in Phase I clinical trials in adult healthy volunteers as a single agent and in combination with fluconazole. The data were presented in a poster session and an oral presentation at the 49th Annual Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC) Annual Meeting in San Francisco, California.

Favorable Phase I data from three MGCD290 clinical studies were reported. All studies were performed in healthy adult volunteers and were double-blind, placebo-controlled and randomized. The objectives of the Phase I studies were to determine the tolerability and pharmacokinetics of MGCD290 when administered alone and in combination with fluconazole. All studies remain blinded.

The first two studies were sequential single ascending-dose (SAD) studies with MGCD290 administered alone (Trial 290-001) and in combination with fluconazole (Trial 290-002). Dose levels of MGCD290 for study 290-001 ranged from 100mg to 1000mg and for study 290-002, doses of MGCD290 were 300mg and 450mg in combination with 400mg of fluconazole. In study 290-001, 42 subjects received MGCD290 and no clinically significant adverse events were observed at any dose level evaluated. Maximal plasma concentrations were observed two hours after oral administration with a mean elimination half-life of eight hours. In study 290-002, no clinically significant adverse events were observed and MGCD290 with fluconazole was well-tolerated without apparent drug-drug interactions.

The third study (Trial 290-003) is an ongoing multiple ascending-dose (MAD) study evaluating the daily dosing of MGCD290 for two weeks at dose levels of 100mg, 180mg, 360mg and 540mg. Data for the first three cohorts in this study were reported. A fourth study (Trial 290-004), a MAD study evaluating daily dosing of MGCD290 for two weeks in combination with 400mg of fluconazole, is planned.

Oral Presentation Session M-1919: MGCD290, A Novel Small Molecule, Modulates Azole Antifungal Activity through Specific Inhibition of the Histone Deacetylase Hos2.

Fungi and fungal pathogens have multiple forms of the fungal histone deacetylase (HDAC) enzyme: Rpd3, Hos1, Hos2, Hda1 and Hos3. To determine the HDAC target of MGCD290, yeast knockouts of each homologue were performed and the sensitivity to azoles was determined. An HDAC knockout that was hypersensitive to azoles became a candidate target of MGCD290.

The deletion of the HOS2 gene, but not other fungal HDAC genes, decreased the minimal inhibitory concentration (MIC) of azoles (fluconazole, voriconazole and itraconazole) required to inhibit fungal growth. The synergy between MGCD290 and the azoles was abolished only in the HOS2 deletion mutant, and the deletion of this gene was sufficient to sensitize yeast to azoles. The deletion of the other homologues produced no change or only a very modest increase in azole susceptibility when compared to the deletion of Hos2. Hos2, therefore, appears to be the target of MGCD290.

Source
MethylGene