About MGCD290.

MGCD290 is a first-in-class orally available small molecule inhibitor of the fungal enzyme Hos2. Hos2 is a fungal histone deacetylase (HDAC) enzyme HOS2 which regulates fungal genes.

Current antifungal therapies exhibit several limitations including toxicity, drug-drug interactions and lack of coverage of resistant pathogens. MGCD290 addresses these issues. MGCD290 is initially being developed for use in combination with fluconazole, the most widely prescribed antifungal drug, for the treatment of fungal infections. To date, MGCD290 has shown an excellent safety profile and there were no drug-drug interactions with fluconazole.

Clinical Status.

MethylGene has completed five Phase I studies in over 100 healthy adult volunteers with MGCD290. A multicenter, randomized, double-blind, placebo-controlled, Phase II trial (trial 290-005) to assess MGCD290 in patients suffering from moderate to severe acute vulvovaginal candidiasis (VVC) was recently completed. This trial was designed to assess the effectiveness of MGCD290 in combination with fluconazole, as compared to fluconazole alone. This study showed no statistically significant benefit of MGCD290 plus fluconazole compared to fluconazole alone. MethylGene is reviewing the data and evaluating plans for the MGCD290 program.

About Vulvovaginal Candidiasis.

Acute vulvovaginal candidiasis (VVC) is a yeast infection that affects an estimated 75% of healthy women at least once, and 40-45% will have two or more episodes within their lifetime1. Predisposing factors include uncontrolled diabetes and immunosuppression. A single dose of fluconazole is labeled for acute VVC, and is considered effective in the mild population2. However, in women with moderate to severe infections, fluconazole has only a 30-50% success rate.

VVC is most commonly caused by the type of fungus known as Candida albicans, although Candida glabrata is thought to be the cause of 10-15% of infections and non-albicans strains which are azole-resistant are more prevalent in growing sectors of the population such as diabetics3. Despite the medical need, few agents are currently in development.

Recurrent VVC, a more complicated form of VVC, is defined as four or more episodes of VVC in one year4. In the U.S. 6 to 8 million women are affected and over one million women are affected in Canada5. Treatment for RVVC is typically with the antifungal drug fluconazole; however, treatment is often long-term (at least six months) and upon completion of treatment, there is a high relapse rate. There is no FDA-approved therapy for the RVVC indication, and few agents in development.

About Invasive Fungal Infections.

Incidence of invasive fungal infections have risen rapidly over the past 20 years6. Hospital-acquired infections of Candida species are associated with a 40% mortality rate and the contribution of drug-resistant species is rising7. Aspergillosis is another form of invasive fungal infection with a mortality rate as high as 85%8. Incidence of drug-resistant aspergillis isolates from hospital patients are rising and may reach over 30%9. The fastest growing populations at risk of invasive fungal infections include transplant patients, surgery patients, cancer patients, those on immunosuppressive therapy, cancer patients, premature babies and the elderly.

1. Seidman & Skokos, (2005) Infectious Diseases in Obstetrics and Gynecology 13:197
2. Infectious Diseases Society of America Guidelines, (2009)
3. de Leon et al., (2002) BMC Infectious Diseases 2:1
4. Centres for Disease Control, (2011)
5. Sobel, (2006) Current Infectious Disease Reports 8: 481
6. Pfaller & Diekema, (2007) Clinical Microbiology Reviews 20:133
7. Snydman, (2003) CHEST 123:500S
8. Pfaller & Diekema, (2006) CID 43:S3
9. Bueid et al., (2010) Journal of Antimicrobial Chemotherapy 65:2116