°®¶¹´«Ã½

May 26, 2011

Background

Transmitted by the bite of the assassin bug or vinchuca, Chagas Disease is a public health problem particularly in the poorer areas of Latin America and the Caribbean. °®¶¹´«Ã½ 8 million people are believed to carry the disease, and 100 million people are estimated to live in the endemic areas. The number of diagnosed cases has been increasing over recent years due to population mobility to areas classified as being nonendemic for Chagas Disease, such as Australia, Canada, Europe, Japan, and the United States of America.

Chagas Disease has acute, asymptomatic, and chronic phases; the chronic phase falls into a chronic asymptomatic phase and a chronic phase with organ dysfunction. The acute phase usually occurs unnoticed, but in cases of symptomatic acute Chagas Disease, non-specific symptoms such as fever, fatigue, and swollen lymph nodes develop, which resolve spontaneously within about 4-6 weeks. In the asymptomatic phase, no apparent symptoms are observed. It often takes several decades to progress to the chronic phase. In the chronic phase, the central nervous, gastrointestinal, and cardiovascular systems are affected in 10-30% of infected people, and peripheral neuropathy, cardiomyopathy, megacolon, or megaesophagus may be observed. If infected people are left untreated, about a third of them will develop serious heart or intestinal damage that could lead to death. An average of 14,000 people per year dies from Chagas Disease in Latin America. This figure is more than the number of deaths due to any other parasite-born disease, including malaria, in the region.

There are two existing treatments for Chagas Disease: nifurtimox (brand name: Lampitâ„¢, made by Bayer) and benzinidazol (brand name: Radanilâ„¢, made by Roche), both of which are older drugs approved in the 1960s and 1970s. They are effective in the acute phase of the disease, but their efficacy in the chronic phase is supposed to be limited, with poor tolerability profiles in adults ¹⁾. In this context, the development of a new treatment which could be effective against the chronic phase of the disease, particularly in adults, would be very significant.

In addition, since most people affected by Chagas Disease are poor and cannot afford to buy drugs, the market is limited. Therefore, currently pharmaceutical companies are not actively working toward the development of new therapeutic agents for Chagas Disease.

Technology development

Ravuconazole is an azole anti-fungal drug discovered and developed by Eisai, which inhibits fungal growth by interfering with the biosynthesis of ergosterol, the main component of the fungal cell membrane. The significant effectiveness of the compound was demonstrated in preclinical studies, where it was demonstrated to possess broad-spectrum antifungal activity against not only Candida, the main pathogen of deep fungal infection, but also against zygomycetes, for which other drugs are less effective ^2-8).

However, due to its poor solubility, the compound was not suitable for use as antifungal drugs in oral and injectable form, which was the original development goal. Eisai therefore licensed it to Bristol-Myers Squibb Company (BMS), which succeeded in the development of a prodrug with improved solubility ^{9, 10)}. BMS conducted Phase I and II studies of the prodrug and reached proof-of-concept stage, but they subsequently suspended the development. After the license was returned to Eisai, Phase I study of E1224, in which the salt form was changed, was conducted again. In this Phase I study, oral administration of E1224 demonstrated good ADME properties and safety, and a dosing regimen of E1224 to maintain the effective blood concentration of ravuconazole (the active form of E1224) for a prolonged period of time was established.

After Dr. Urbina in Venezuela presented in his paper that ravuconazole has potent activity both in vitro and in vivo against Chagas Disease caused by infection with Trypanosoma cruzi (protozoan) ^{11, 12)}, collaboration and licensing agreement of E1224 was proposed by the Drugs for Neglected Diseases initiative (DNDi), an independent non-profit foundation which has been working to develop a treatment for Chagas Disease.

In September 2009, Eisai and DNDi entered into a collaboration and license agreement for the clinical development of a promising new drug for the treatment of Chagas Disease. The development of E1224 started under which DNDi conducts the clinical development of E1224 as a treatment for Chagas Disease and assesses its efficacy and safety, while Eisai provides DNDi with its scientific expertise in clinical development as well as supplies the drug for the clinical studies.

Selected References

• 1)
  Nature Outlook 2010 June 24, S12-15
• 2)
  Hata, K. et al. Antimicrob Agents Chemother 1996;40:2237-42.
• 3)
  Hata, K. et al. Antimicrob Agents Chemother 1996;40:2243-7.
• 4)
  Fung-Tomc, JC. et al. Antimicrob Agents Chemother 1998;42:313-8.
• 5)
  Pfaller, MA. et al. Antimicrob Agents Chemother 2002;46:1032-7.
• 6)
  Pfaller, MA. et al. Antimicrob Agents Chemother 2002;46:1723-7.
• 7)
  Minassian, B. et al. Clin Microbiol Infect 2003;9:1250-2.
• 8)
  Gupta, AK. et al. J Eur Acad Dermatol Venereol 2005;19:437-43.
• 9)
  Ueda, Y. et al. Bioorg Med Chem Lett 2003;13:3669-72.
• 10)
  Petraitiene, R. et al. Antimicrob Agents Chemother 2004;48:1188-96.
• 11)
  Urbina, JA. et al. Int J Antimicrob Agents 2003;21:27-38.
• 12)
  Diniz, LD. et al. Antimicrob Agents Chemother 2010;54:2979-86.