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Periodic Report Summary 3 - BERENICE (Benznidazol and Triazol REsearch group for Nanomedicine and Innovation on Chagas diseasE)

Project Context and Objectives:
Chagas disease is a chronic, systemic, parasitic infection caused by the protozoan Trypanosoma cruzi, which was discovered in 1909. Recognised by the World Health Organization (WHO) as one of the world’s 13 most neglected tropical diseases, is considered endemic in all countries of South America, Central America and the Southern United States, except those in Caribbean. Its prevalence is estimated between 8 and 10,000,000 people infected and approximately 14,000 deaths/year, representing the second highest burden of disease among Tropical Diseases in the Americas.
Although Chagas disease has been identified and described for more than 100 years, the therapeutic alternatives are limited: benznidazole and nifurtimox are the only 2 drugs available for treatment. Treatment is effective during the acute stage of the infection. Different studies show that approximately 60-85% of parasitological cure is achieved in treated patients. During chronic phase it is not so clear (Caryn Bern, 2011). Both benznidazole and nifurtimox have frequent side effects, especially in adults, requiring up to 30% of cases to discontinue the medication.
BERENICE (BEnznidazol and triazol REsearch group for Nanomedicine and Innovation on Chagas diseasE) is a solid and well balanced consortium which gathers highly qualified expertise in all the different scientific, technological and clinical areas critical for the success and future valorisation of the results of the project.
The expected positive results will be the Development of a new drug formulation. The encapsulation of benznidazole using nanotechnology will generate a new drug delivery system. This new approach will allow a release of medication directly into the intracellular space, therefore increasing tissue drug concentration and avoiding side effects. A better toxic profile will be obtained because of the reduced amount of benznidazole used.
CIBER BBN, will test two innovative formulations for Benznidazole via sublingual administration avoiding the first pass metabolization. Selection of the best technical-economic solution will be determined after performance of several comparative tests of the two raised formulations with the current ones:
- In vitro determination of drug release profile, biological activity and toxicity carried out by UB
- In vivo tests of release profile and biological activity of formulations performed by FIOCRUZ.
- Toxicity evaluation carried out at IHMT.
- Biodistribution tests of new formulations in order to compare them with the currently existing drugs (FIOCRUZ)
Afterwards, clinical trials will be carried out and led by ICS-HUVH, in cooperation with ANLIS in Argentina. They will take place in order to compare the new formulation with the original Benznidazole formulation and with new drugs PRAXIS will lead the “Exploitation and Dissemination” of results with collaboration of ELEA under the recommendations of WHO and the cooperation of Civil Society Associations.).
The main objectives of the project are the following:
Primary objective:
- Obtain a more effective, better tolerated and cheaper formulation of a drug with trypanocidal activity to cure Chagas disease.
Secondary objectives:
- Obtain the firsts results of pharmacokinetics of Benznidazol and its new formulation.
- Collect the fragmented and dispersed selected knowledge to serve as a basis for new developments.
- Achieve a safer and optimized drug delivery through nanotechnologies.
- Improve the toxic profile of the main current treatment, Benznidazole.
- Assess trypanocidal activity of new formulations in vitro and in animal model.
- Assess trypanocidal activity of new triazole in humans.
- Assess trypanocidal activity of combined therapy against Chagas disease for the first time.
- To involve partners, research and industry in EU and in endemic countries.
- To promote technology transfer and foster in-site solutions at a lower cost.
- To get the registration of final product.
- To concrete an exploitation plan to increase the access to treatment.

Project Results:
The work performed during the first 54 months of the project can be summarized as follows:
WP1 Project Management: Set-up of the scientific coordination and management structure: organization and lead the meetings of the Steering Committee and General Assembly. The main purpose of these meetings have been to supervise the progress of BERENICE project, to monitor the results and to deal with the scientific and technical problems raised by the PIs of the consortium.
WP2 Treatment Map: Revision of all the current published and unpublished data about Chagas disease to determine the current best available technologies and practices, in order to select the possible new technological solutions for the development of new low cost medicines. The first pharmacokinetic curves in healthy volunteers have been obtained. We have also performed a complete study of biodistribution in animal models to find out the exact biodistribution behaviour of Benznidazol.
WP3 Innovative Galenic Development: None of the drug delivery systems (DDS) developed in the previous period (SLNs or SUVs) were suitable for the final formulation of the active. Thus, different approach based on the use of BNZ-Cyclodextrin
complexes was developed. In this reporting period, the work has been focused on the further development and optimization of such formulations for the generation of a potential final BNZ formulation.
Unlike the low encapsulation obtained with the SUVs, where the benznidazole concentrations were in the range of micrograms per milliliter of sample, it is remarkable to mention the tunable and high loaded nanoformulations obtained through the preparation of BNZ: CD complexes. For this type of drug delivery system, it was possible to produce nanostructured samples with different and high BNZ loadings (12-50% of BNZ per total mass of sample).
Due to the good results in the production of these BNZ:CD complexes, samples were sent to different partners in order to study the in vitro efficacy and citotoxicity , in vivo toxicity, the properties for tablet formation and in vivo bioavailability and efficacy.
WP4 Pre-clinical effectiveness: Efforts have been mainly focused on testing the different products generated by galenic partners and looking for some alternative molecules of bacterial origin to fight against the parasite.
The screening of the biological activity of nanoparticles received using the transfected CLB strain have been performed. In vitro cytotoxicity utilizing two mammalian cell lineages have been performed, the first one of murine origin: L929 (line also used for infecting cell to obtain trypomastigotes) and the second one of human origin with high metabolic activity: Hep G2.
WP5 Preclinical trials in murine model: To carry out complete preclinical trials to open a pathway for human clinical trials and medicament registry application: calculation of the Maximum Tolerated Dose (acute toxicity).To analyse parasitemia reduction in the acute phase. To analyze cure in the acute phase. To analyse Cure in the acute phase using resistant strains. To induct the murine Chronic Phase of Chagas disease.
WP6 Scaling up of technologies : Assessment of medicament properties at the lab scale and different designs and pilot testing for the GMP scale up of the production of lipid nanoparticles, nano vesicles, cyclo dextrin complexes and the final pharmaceutical form (tablets for sublingual administration), both for nanoformulations of BNZ and free BNZ but at a lower dose. Development of pilot medicament lots to be used for clinical trials, three for stability assays and one for the trials in humans.
WP7 Clinical trial: To evaluate BNZ toxicity and safety of decreased dose of BNZ.To determine pharmacokinetics of decreased dose of BNZ over infected patients.To determine the efficacy of decreased dose of BNZ.To determine the adequate dose of BNZ. To start the pre-clinical activities and set up the laboratory techniques. To select and procure contracts with CROs. To carry out the submission of the clinical trial to Ethics Committees and National Competent Authorities (NCA). To set up the laboratory techniques: molecular techniques (Implementation of the PCR technique and harmonization study) and serological techniques (serology and biomarkers) and Pharmacokinetics (Pk).
WP8 Exploitation and Dissemination activities: To present the project concepts and partial results to the potentially interested stakeholders: To increase the awareness of the BERENICE through numerous activities carried out by all partners.To organise the first main Workshop of the project held in Salvador de Bahía, Brasil connected to a big event related to parasitology and neglected diseases (XXIII Latin American Congress on Parasitology).

Potential Impact:
The expected result is that BERENICE project will develop a low-cost intervention with an important cost effective impact that can be implemented during the project period and thereby have an immediate effect on the control of Chagas diseases in endemic and non endemic countries. BERENICE is expected to have an impact at the following levels:
Scientific Community
Although benznidazole is a drug used for the treatment of Chagas disease over 40 years ago, its pharmacokinetics has been scarcely studied: data on how the medicine is absorbed, which concentrations reaches in the blood or at what speed is removed, are poorly known.
The first results on pharmacokinetics and pharmacodynamics of the major trypanocidal drug, benznidazole will generate new lines of research. Moreover, we plan to evaluate for the first time, an imidazole combined with benznidazol against Chagas disease.
The knowledge and products developed under the scope of BERENICE will yield new and cost-effective therapies for the treatment of CHAGAS disease with an impact on Nanomedicine development. More specifically, the use of nanostructuring techniques will allow to reformulate the actual benznidazole based CHAGAS treatment into novel nanotechnological drug delivery systems (NDDs) with exceptional pharmacological properties. NDDs will also mean, low medicine doses, making medicaments less toxic and safer, entailing an increase in the efficacy of the treatment a reduction of the expensive palliative treatments associated their toxicity.
Socio-economic impact
The infected population in Latin-America (LA) is estimated between 10 and 15,000,000 people (12,250.000 people average). In the EU, the increased presence of LA people due to immigration phenomena, infected in their original countries, represents a total population of about 90.000 people, most of them in Spain, France and Portugal. The new treatment will represent an important reduction of treatment cost and an important amount of money saved.
The cost of the final medicine developed could be acceptable for the affected markets after economical and effectiveness analysis. The price of new medicine could be less than the current one, the reduction of the adverse effects and a greater proportion of patients cured, avoiding future comorbidities, will represent a strong reduction of the cost of actual treatments.
Health Care Systems and Public Health
The reformulation of an old drug with the aim of obtaining a better toxicity and safety profile and possibly an increase in its efficacy, administered alone or in combination. It will mean an impact on the life of Chagas patients, increasing access to curative treatment for a greater number of people, a reduction on side effects, morbidity associated with the evolution of the disease and prevention of deaths attributed to cardiomyopathy.
The impact can be a great benefit both for the quality of life for the patients and for health systems which have to support them. The price of new medicine could be less than the current one, and the reduction of the adverse effects and, at the same time, and a greater proportion of patients cured, avoiding future comorbidities, will represent a strong reduction of the cost of existent treatments.
Additionally, a more effective and safer treatment would increase the number of patients treated and therefore a significant reduction or even definitive elimination of parasitaemia. This would reduce new acute cases acquired by vector-borne transmission (anthropozoonosis) and those transmitted from mother to child (vertical transmission).
Industry
The results obtained in BERENICE will enhance European competitiveness through the transformation of research into commercially successful products in the field of Neglected Diseases.

List of Websites:
www.berenice-project.eu

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INSTITUT CATALA DE LA SALUT
Spain
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