The results of the first clinical trial to test E1224, a candidate drug to treat adults with chronic Chagas disease, have just been published in Lancet Infectious Diseases. The results show that E1224 is well-tolerated but its parasite suppressive effect is transient, compared to the sustained efficacy of benznidazole. The study, supported by Drugs for Neglected Diseases Initiative (DNDi) and led by researchers from Universidad Mayor de San Simón in Cochabamba,Bolivia, and ISGlobal - an institution supported by the la Caixa Foundaton- provide a roadmap for exploring alternative treatments combining E1224 and benznidazole.
Few drugs to treat Chagas disease
Despite the disease having been described over 100 years ago, there are currently only two medicines available for treating Chagas —benznidazole and nifurtimox. Little data exists concerning the efficacy and safety of these drugs in adults with chronic indeterminate disease, but prolonged treatment is associated with safety concerns. Thus, the development of alternative treatments is urgently needed to improve morbidity in these patients. The E1224 drug (a pro-drug of ravuconazole) has been proposed as alternative treatment for Chagas disease, given its ability to inhibit the parasite’s growth and its pharmacokinetic properties, but no trials had been done in patients with Chagas disease.
First phase 2 trial with E1224
This study presents the results of a phase 2 study assessing three oral E1224 doses as compared to benznidazole or placebo. The study was done with 231 adults with confirmed Chagas disease, from two outpatient centres in Bolivia (Cochabamba and Tarija). Parasite clearance was determined by molecular amplification of parasite DNA at the end of treatment, as well as at 4, 6 and 12 months of follow-up, and levels of parasite-specific antibodies were also evaluated. Results show that although E1224 was better tolerated, its parasite suppressive effect was transient, whereas benznidazole showed early and sustained efficacy until 12 months follow-up (at 12 months, 82% of patients treated with benznidazole had undetectable parasite levels, as compared to 28% in the E1224 high-dose group).
“The results obtained with E1224 are certainly disappointing,” explains Joaquim Gascon, director of the Chagas Initiative and co-director of the study. “However, this trial has generated key data concerning benznidazole safety and efficacy in adult patients with chronic disease, and provides support to the scaling up of diagnosis and access to standard regimens of benznidazole”, he adds.
The authors conclude that, while E1224 will not be further investigated as monotherapy, this study opens the possibility of combining E1224 with shorter treatments of benznidazole for the treatment of adults with chronic Chagas disease.
Torrico F, Gascon J, Ortiz L et al. Treatment of adult chronic indeterminate Chagas disease with benznidazole and three E1224 dosing regimens: a proof-of-concept, randomized, placebo-controlled trial. Lancet Infect Dis 2018. Jan 15. doi: 10.1016/S1473-3099(17)30538-8.