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Awarded Amount$3,840,892DiseaseNTD (Chagas disease)InterventionDrugDevelopment StageClinical Phase2Collaboration PartnersEisai Co., Ltd. , Drugs for Neglected Diseases initiative
Introduction and Background of the Project
Chagas disease is a global public health problem, particularly in the poorer areas of Latin America and the Caribbean. About 8 million people are believed to be infected, and about a third of these - if left untreated - will develop serious heart or intestinal damage that could lead to death. Two currently used drugs, discovered decades ago, have variable efficacy in treatment of the chronic phase of the disease and an unsatisfactory tolerability profile in adults. In this context, the development of a new treatment effective for the chronic phase of the disease with similar or improved efficacy but a better tolerability profile, particularly in adults, would represent a breakthrough.
DNDi and Eisai joined efforts to conduct a Phase 2, proof-of-concept study of the combination of E1224, a new generation triazole compound with potent inhibitory activity against ergosterol biosynthesis, and the reference drug, Benznidazole, in standard and reduced dosing regimens, to provide a new treatment strategy for Chagas Disease. In preparation for future registration, all required chemistry, manufacturing, and controls activities and nonclinical tests will be conducted.
How can your partnership (project) address global health challenges?
Chagas disease is one of the world’s most neglected diseases. There is global consensus that new treatment alternatives are needed. Chagas disease is recognized by the World Health Organization (WHO) among the “tool-deficient” neglected tropical diseases, a so-called Type III disease.
DNDi and Eisai aim to develop a new effective treatment for Chagas disease that is oral, easy to use, safe, and affordable to address the population’s needs. The challenges of access in Chagas disease cannot be over-emphasized. Today, a very small fraction of patients with Chagas disease receive treatment. Access issues are considered from the start of this joint development in order to maximize the regimen’s availability and future adoption.
Broad registration of the new treatment regimen is planned upon conclusion of Phase 3 studies, with an initial focus on the countries with the highest burden of disease, but also to include stringent regulatory authorities. In addition, early submission for inclusion of the combination in the WHO Essential Medicines List would be targeted.
What sort of innovation are you bringing in your project?
This project targets the development of an innovative new effective treatment regimen for Chagas disease that is oral, easy to use, safe, and affordable.
E1224, developed by Eisai Co., is the water-soluble monolysine salt of a phosphonoxymethyl ether of ravuconazole (RAV) and is rapidly converted to RAV in mammalian species. Benznidazole is the current first line treatment for Chagas disease in most countries. Current treatment regimens and dosing intervals have been derived from decades-old patient studies and with very limited direct comparisons. Treatment recommendations vary significantly from country to country and the comparative evidence-base with the current treatment regimens is limited.
Leveraging data obtained from the recently completed Phase Ⅱ, randomized, blind, comparative trial of three regimens of E1224 and one of BZN versus placebo, the current project will evaluate different treatment regimens of E1224 and Benznidazole for the treatment of adults of chronic indeterminate Chagas disease.
Combination therapy is a well-recognized treatment modality in many disease settings, including cancer, cardiovascular disease, and infectious diseases. Infectious diseases such as tuberculosis, malaria, leprosy, and HIV only came under control and were effectively treated only after introduction of combinations of drugs that utilize different mechanisms of action.
Role and Responsibility of Each Partner
Eisai will provide the chemistry, manufacturing, and control of the drug product and substance. Eisai will also provide supplies of the drug for the clinical studies. As collaborating partner, the principal investigators will lend their scientific expertise in clinical development and lead and perform specific clinical and preclinical studies such as a human mass balance study.
DNDi as principal investigator will be responsible for the clinical development of E1224, a pro-drug of ravuconazole, use in patients with Chagas disease (CD) in endemic countries. Specifically, DNDi will conduct a drug-drug interaction study, will initiate the Phase II Proof-of-Concept study, with its partners, and recruit patients for the trial. For implementation of clinical trials, DNDi will work with Eisai and the Chagas Disease Clinical Trial Platform, a network of CD clinicians and researchers from endemic countries established in 2009, who strengthens clinical research capacity and facilitates assessments of new and promising interventions.
1. Project objective
Chagas disease (CD) is a neglected tropical disease endemic in 21 countries in Latin America, but present also in North America, Europe, Japan, and Australia. Benznidazole, the most commonly used for CD, has proven effective, but the side effects and treatment duration of its standard regimen are among the main barriers to treating patients.
This project aimed to provide a new treatment strategy for CD. A Phase 2, proof-of-concept was conducted to evaluate benznidazole/E1224 (a compound discovered by Eisai) combination regimens and benznidazole monotherapy in standard and reduced dosing regimens for the treatment of adult patients with chronic indeterminate CD.
2. Project design
A double-blind, Phase 2, randomized, placebo-controlled study was carried out in 3 sites of Bolivia. It tested, against a placebo, six benznidazole treatments of differing lengths and dosages, both as a benznidazole monotherapy and in combination with E1224 to determine the efficacy and safety.
In preparation for future registration, all required chemistry, manufacturing, and controls activities and nonclinical tests have also been conducted, which include:
- Drug Substance (DS) and Drug Product (DP) formal stability testing and process validation
- Pre-clinical Distribution, Metabolism, Pharmacokinetics (DMPK) studies
- Toxicology studies
3. Results, lessons learned
A total of 518 adult patients were screened, of whom 210 adult patients with chronic indeterminate CD participated in the study, randomized to one of the six treatment regimens or matching placebos. The total duration of patient participation in the study was approximately 22 months, including 10 months of recruitment, up to 40 days for screening, 8 weeks of treatment, and follow-up visits up to 12 months after treatment initiation. The majority of patients completed the study (202 patients). The efficacy was measured by testing for the absence of parasite DNA in the blood using PCR. Patients with no signs of the parasite in any blood tests up to 12 months after the initiation of the treatment were considered to have been successfully treated.
The study showed that, in patients with chronic indeterminate CD, treatment with benznidazole effectively induced parasitological response and was well tolerated, regardless of benznidazole treatment duration, dose, or when used in combination with E1224. The new regimens had also very good safety profiles. The rate of treatment discontinuation due to side effects was as expected and is consistent with other studies using standard regimens.
In conclusion, shorter treatment with benznidazole (2 weeks treatment with a daily dose of 300mg/day) is particularly promising as it is significantly shorter than the standard treatment (8 weeks treatment with a daily dose of 300mg/day (fixed dose correspondent to 5mg/kg/day for 60 days)). Changing the treatment protocol to reduce treatment duration could help remove one of the main barriers to expanding access to Chagas treatment. The shorter treatment would remove some common concerns of both caregivers and patients, and thus improve treatment adoption. It would also reduce treatment costs for national programmes. DNDi will now work with the Pan-American Health Organization/WHO, national programmes, health ministries, and other partners to propose a policy change and registration of this new indication.
Finally, we acknowledge the significant value of in-kind and effort provided by Eisai team to the project, that was invaluable to the advancement in treatment for people with CD.