MethylGene Inc. has announced preliminary preclinical results for its histone deacetylase (HDAC) clinical candidate MGCD290 at the 107th General Meeting of the American Society for Microbiology (ASM).
MethylGene has previously reported MGCD290's ability to potentiate the antifungal activity of azoles against Candida and Aspergillus fungal species. The company disclosed in two poster presentations at the ASM, MGCD290's ability to extend this property to non-azole antifungal agents, specifically those that inhibit the ergosterol synthesis pathway at points that differ from those of azoles.
In a poster entitled "MGCD290, A Selective Histone Deacetylase (HDAC) Inhibitor, Potentiates the Anticandidal Activity of Ergosterol Synthesis Inhibitors, but not of Compounds with Other Mechanisms of Action," the Company demonstrated MGCD290's synergy when administered with the antifungal agents itraconazole, voriconazole, terbinafine and fenpropimorph in various Candida species. Results showed that in addition to synergizing with azoles, MGCD290 also synergized with terbinafine and fenpropimorph; both of which, like azoles, inhibit the ergosterol synthesis pathway. Therefore, MGCD290 may enhance antifungal activity widely with ergosterol synthesis inhibitors.
In a second poster entitled "MGCD290, A Selective Histone Deacetylase (HDAC) Inhibitor, Increases the Post-Antifungal Effect and Cidal Potential of Azoles in Candida Species and Decreases the Frequency of Azole Resistance in C. glabrata," the Company disclosed the post-antifungal properties of MGCD290. Data demonstrated that when the combinations of MGCD290 and itraconazole or voriconazole are used against C. glabrata, the post-antifungal effects and fungal cidal (killing) activity are increased when compared to the administration of each drug alone. In addition, the frequency of resistant mutants of C. glabrata decreased up to 25 fold when azoles were used in combination with MGCD290 compared to the administration of azoles alone.
"We continue to document compelling preclinical data for MGCD290 and its benefits when combined with commonly used anti-fungal agents, reflecting the broad potential of our HDAC technology in treating fungal infections," said Donald Corcoran, president and CEO of MethylGene. "We look forward to progressing this program toward clinical trials in 2008."
About Clinical Candidate MGCD290: an oral, small molecule fungal HDAC inhibitor
MGCD290 is an oral, small molecule histone deacetylase (HDAC) inhibitor that appears to target fungal HDACs preferentially to human HDACs. MGCD290 potentiates and broadens the spectrum of azole activity against human fungal pathogens, including azole-resistant isolates. Treatment with azoles, a commonly used class of drugs for fungal infections, often results in the emergence of resistant fungal strains, thereby rendering the azole treatment ineffective over time.