Drug trial for top parasitic killer of the Americas: Mixed results, new evidence to improve therapy

(Press-News.org) Contact information: Oliver Yun
oyun@dndi.org
646-266-5216
Drugs for Neglected Diseases Initiative
Drug trial for top parasitic killer of the Americas: Mixed results, new evidence to improve therapy First placebo-controlled study in adults with Chagas disease highlights urgent need to scale up treatment for millions of patients at risk [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. 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. (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. http://www.wellcome.ac.uk

Media contacts (on site at ASTMH):

(North America; English) Oliver Yun: e-mail: oyun@dndi.org / Mobile: +1-646-266-5216

(Latin America; Español/Português) Betina Moura: e-mail: bmoura@dndi.org / Mobile: +55 21 8122 2798