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[e-drug] Mixed Results for Parasitic Killer - New Evidence for Improved Therapy

E-DRUG: Mixed Results for Parasitic Killer - New Evidence for Improved Therapy
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Drug Trial for Leading Parasitic Killer of the Americas Shows Mixed Results but 
Provides New Evidence for Improved Therapy

First placebo-controlled study in adults with Chagas disease highlights urgent 
need to scale up treatment for millions of patients at risk
Spanish and Portuguese version here:
http://www.dndi.org/media-centre/press-releases/354-media-centre/press-releases/1700-e1224.html

[Washington, DC - November 14, 2013] - According to results of the first-ever 
Phase 2 clinical trial in Bolivia, conducted by the Drugs for Neglected 
Diseases initiative (DNDi), the experimental drug candidate E1224 showed good 
safety and was effective at clearing the parasite that causes Chagas disease, 
but had little to no sustained efficacy one year after treatment as a single 
medication. On the other hand, standard therapy for Chagas, benznidazole, was 
shown to be effective in the long term but continued to be associated with side 
effects. The results, presented today at the Annual Meeting of the American 
Society of Tropical Medicine and Hygiene (ASTMH), highlight the need to 
investigate alternative dosing regimens and possible combination therapies to 
improve patient care.

Less than 1% of patients living with Chagas disease currently receive 
treatment. The new findings fill a long-standing knowledge gap, providing 
evidence that will help to inform public health policies and help to increase 
access to treatment now, as well as shaping the direction of future research 
for new Chagas therapies.

E1224 is a new antifungal compound discovered and manufactured by the Japanese 
pharmaceutical company Eisai that is being developed as a treatment for Chagas 
disease with support from the Wellcome Trust. The Phase 2 double-blind, 
randomized, controlled trial evaluated the safety and efficacy of E1224 at 
three different dose regimens and was the first study to collect comprehensive 
clinical data on the current approach to treatment, benznidazole. Both 
treatments were compared to a placebo control.

A total of 231 adult patients with chronic indeterminate (showing no symptoms) 
Chagas disease were treated for a maximum of 60 days and evaluated at treatment 
completion and at several different time points up to a 12-month follow-up 
assessment. The study took place at two sites (Cochabamba and Tarija) in 
Bolivia, which have the world's highest incidence of Chagas disease.

At end of treatment, E1224 was found to be safe and efficacious in clearing the 
Chagas parasite in patients when compared to placebo and to benznidazole. Few 
patients receiving the highest dose stopped treatment with E1224 due to side 
effects, less than in the benznidazole group. However, at 12 months after 
treatment, less than one third of patients treated with E1224 continued to 
maintain parasite clearance compared with over 80% of patients treated with 
benznidazole, demonstrating relatively low sustained eradication rates with 
E1224 in this study.

"In this prospective placebo-controlled study, these mixed results actually 
have provided very important scientific evidence on new drug development for 
Chagas disease, which has long been ignored," said Dr Isabela Ribeiro, Head of 
the Chagas Clinical Programme at DNDi, and the E1224 Project Leader. "We now 
have clear safety and efficacy data on two compounds that will be very useful 
in guiding future Chagas disease drug research efforts."

Although E1224 was found to be ineffective as a single-treatment agent 
(monotherapy), it holds promise for use in combination with existing drugs, 
since it showed strong positive activity during treatment, with a third of 
patients having a sustained treatment response at the higher dose. E1224 will 
no longer be tested as monotherapy for Chagas disease, but DNDi and Eisai are 
exploring the possibility of testing E1224 in combination therapy with 
benznidazole
"Eisai remains committed towards the elimination of neglected tropical diseases 
and hopes to continue collaboration with DNDi in future studies that could 
determine the role that E1224 may play in the treatment of chronic 
indeterminate Chagas disease and provide newer and better treatment options for 
patients suffering from this disease," stated Dr Frederick P. Duncanson, Senior 
Director of Chief Innovation Officer Group at Eisai Inc., and the E1224 Project 
Leader at Eisai.

In addition to evaluating E1224, the study was the first to compare the 
clearance of Chagas parasites (Trypanosoma cruzi) with benznidazole treatment 
versus placebo in adults with chronic indeterminate Chagas disease. 
Benznidazole had a rapid and sustained effect, with significant drop in 
parasite counts after just one week of treatment. Some patients experienced 
adverse events, mostly nausea, skin reactions, and muscle and nerve pain. Since 
benznidazole treatment is typically 60 days long and undesirable side effects 
are common, shorter courses of the drug may be safer yet still effective. Based 
on these study findings, DNDi will investigate shorter-course treatments with 
benznidazole.

The study was the first Phase 2 clinical trial conducted in Bolivia, 
exemplifying the strengthening and sustaining of research capacity in a 
resource-limited, developing-country setting. A total of 97% of the enrolled 
patients completed follow-up at 12 months post-treatment, with only 7 of the 
231 patients being lost to follow-up. Important Chagas patient data were 
collected on pharmacokinetics and pharmacodynamics, characterization of the 
parasite population before and after treatment, and candidate biological 
markers for evaluation of treatment response.

"The completion of this drug trial was a success story for Chagas patients, 
doctors, and researchers in Bolivia, demonstrating that excellent clinical 
testing can be carried out in endemic countries," said Dr Faustino Torrico of 
Universidad Mayor de San Simon in Cochabamba, Bolivia, and one of the lead 
investigators. "The data generated were of high quality, and our clinical sites 
and research teams gained valuable experience and are ready to perform future 
studies."

"Chagas disease is one of world's most neglected illnesses, and millions of 
patients continue to be ignored and many needlessly die from the lack of 
treatment access and options," said Dr Bernard Pécoul, Executive Director of 
DNDi. "We have to take advantage of these important study results to scale up 
treatment access now, while we maintain momentum in developing safer, more 
effective, life-saving new treatments for Chagas patients around the world."

****
Key findings
§  At treatment completion, PCR-determined eradication rates of the Chagas 
parasite were 79-91% for E1224; 91% for benznidazole; 26% for placebo.
§  12 months after treatment, 8-31% of patients treated with E1224 maintained 
parasite clearance compared with 81% with benznidazole and 8.5% placebo.

Study partners and donors
Many institutions collaborated on this study, including: DNDi; Eisai Co. Ltd, 
Japan; Platform of Integral Care for Patients with Chagas Disease, 
Spain/Bolivia; Universidad Mayor de San Simon, Bolivia; Universidad Autónoma 
Juan Misael Saracho, Bolivia; Collective of Applied Studies and Social 
Development (CEADES), Bolivia; NUDFAC - Nucleus of Pharmaceutical and Cosmetics 
Development, Brazil; Centre de Recerca en Salut Internacional de Barcelona 
(CRESIB), Spain; and the National Council of Scientific and Technological 
Research (INGEBI-CONICET), Argentina.

Lead funding was provided by the Wellcome Trust, UK. Additional funding was 
provided by: Department for International Development (DFID), UK; Spanish 
Agency for International Development Cooperation (AECID), Spain; Dutch Ministry 
of Foreign Affairs (DGIS), The Netherlands; Médecins Sans Frontières/Doctors 
without Borders (MSF); and other foundations.

Release of study results
The clinical trial results were released during the oral presentation 
"E1224-results of proof-of-concept clinical trial in patients with chronic 
indeterminate Chagas disease", by Dr Faustino Torrico of Universidad Mayor de 
San Simon, Cochabamba, Bolivia, at an ASTMH symposium organized by DNDi, 
entitled "Chagas Disease: Recent Advances in Research and Development" (Session 
#53, November 14, 2013, 4:00-5:45 PM).  Other study findings presented at the 
symposium were: "Population-pharmacokinetics of benznidazole in children and 
adults with Chagas disease", Jaime Altcheh, Hospital de Niños Ricardo 
Gutierrez, Buenos Aires, Argentina; "TRAENA - placebo-controlled evaluation of 
impact of benznidazole treatment on long term disease progression in adults 
with chronic Chagas disease", Adelina Riarte, Instituto Nacional de 
Parasitología "Dr. Mario Fatala Chaben", Buenos Aires, Argentina; and "Advances 
in biological markers of therapeutic response in Chagas disease", Maria Jesus 
Pinazo, CRESIB - Barcelona Centre for International Health Research, Barcelona, 
Spain; and Alejandro Schijman, CONICET-INGEBI, Buenos Aires, Argentina.

About Chagas disease
The leading parasitic killer in the Americas, Chagas disease (American 
trypanosomiasis) infects an estimated 8 million people, mostly in Latin 
America, where it is endemic in 21 countries and kills some 12,000 people each 
year. The most affected people are very poor, live in inadequate housing 
conditions, and often have little access to healthcare. Cases of Chagas disease 
are increasingly recognized in North America, Europe, Japan, and Australia. 
Caused by the parasite Trypanosoma cruzi, Chagas disease starts with an early, 
acute stage lasting a variable period, and is followed by a late, chronic stage 
lasting a lifetime, in which up to 30% of patients develop life-threatening 
heart damage and up to 10% may have severe damage to their digestive system. 
The Chagas parasite is primarily transmitted via the bite of the blood-sucking 
triatome bug, sometimes called the "kissing bug". Chagas is also transmitted by 
blood transfusion, organ transplantation, oral ingestion, or during pregnancy 
from mother to newborn, in which an estimated 14,000 new cases occur annually. 
Current treatments are still difficult to implement due to the duration of 
treatment and side effects associated with their use. DNDi is working to 
develop a new, safe, effective, and affordable drug specifically to treat 
Chagas disease.

About DNDi
The Drugs for Neglected Diseases initiative (DNDi) is a not-for-profit research 
and development (R&D) organization working to deliver new treatments for the 
most neglected diseases, in particular sleeping sickness (human African 
trypanosomiasis), Chagas disease, leishmaniasis, filaria, and paediatric 
HIV/AIDS. Since its inception in 2003, DNDi has delivered six new treatments: 
two fixed-dose antimalarials (ASAQ and ASMQ); nifurtimox-eflornithine 
combination therapy (NECT) for late-stage sleeping sickness; sodium 
stibogluconate and paromomycin (SSG&PM) combination therapy for visceral 
leishmaniasis in Africa; a set of combination therapies for visceral 
leishmaniasis in Asia; and a paediatric dosage form of benznidazole for Chagas 
disease. DNDi was founded by Médecins Sans Frontières/Doctors without Borders 
(MSF), Indian Council of Medical Research, Kenya Medical Research Institute, 
Brazil's Oswaldo Cruz Foundation, Ministry of Health of Malaysia, and Institut 
Pasteur in France, with the UNICEF/UNDP/World Bank/WHO Special Programme for 
Research and Training in Tropical Diseases (TDR) as a permanent observer.
www.dndi.org<http://www.dndi.org/>

About Eisai
Eisai Co., Ltd. is a research-based human health care company that discovers, 
develops, and markets products throughout the world. 
(www.eisai.com<http://www.eisai.com/>). Eisai is committed to contributing to 
the improvement of public healthcare for peoples in emerging countries and the 
developing world and the expansion of economic development, the middle class, 
and other factors that may benefit those regions. The company considers this 
commitment as a long-term investment in its future in an increasingly 
globalized era and as such consistently engages in initiatives focused on 
overcoming issues related to access to medicines in order to effectively combat 
infectious diseases, including neglected tropical diseases (NTDs). Eisai is 
also a signatory to the London Declaration, which is the largest global 
public-private partnership to date and aims to eliminate ten NTDs by 2020.

About the Wellcome Trust
The Wellcome Trust is a global charitable foundation dedicated to achieving 
extraordinary improvements in human and animal health. It supports the 
brightest minds in biomedical research and the medical humanities. The Trust's 
breadth of support includes public engagement, education and the application of 
research to improve health. It is independent of both political and commercial 
interests.
www.wellcome.ac.uk<http://www.wellcome.ac.uk>

Gabrielle Landry Chappuis
Head of Communication and Advocacy
Drugs for Neglected Diseases initiative - DNDi
15 Chemin Louis-Dunant, 1202 Geneva, Switzerland
glandry@dndi.org

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