New collaborative model at work

DNDi’s FACT (Fixed-dose Artesunate Combination Therapy) project aims to develop two new artesunate-based formulations to treat chloroquine-resistant falciparum malaria, register these new drug combinations, and have distributed them in developing countries at an affordable price. These combinations are artesunate amodiaquine (AS/AQ) and artesunate mefloquine (AS/MQ).

From formulation to registration:
the different steps of the pharmaceutical development process
In the work up to registration of the two drug combinations, pre-clinical and clinical studies have to be performed.

Pre-clinical studies investigate the effect of drugs on animals by studying the following:
• Pharmacology (the properties potential of a drug especially with relation to their therapeutic value)
• Toxicology (the toxic effects caused by the drug)
• ADME (the absorption, distribution, metabolism and excretion of a drug in the organism and its kinetics).

Clinical studies of DNDi’s artesunate combinations include the following phases:
• Phase I: the study of drug kinetics and tolerability is being conducted on 24 human normal volunteers
• Phase III: the comparative study with free combinations of drugs to confirm that the new drug combination is safe and effective, is being conducted on 500 patients.

After the phase III, the registration file will be submitted in parallel to a Medicines Control Agency in a European country as well as in African countries to obtain the Marketing Authorization (MMA).

DNDi is working with eight international partners (public and private institutions) from the North and South to develop these two new drug combinations. Each organization brings its individual expertise to FACT.

TropiVal, Bordeaux, France (AS/AQ association) and Far Manguinhos, Rio de Janeiro, Brazil (AS/MQ association) are working on the pharmaceutical development of the new formulation; Universiti Sains Malaysia on analytical studies, bioanalytics and phase I clinical studies; "Centre National de Recherche et de Formation sur le Paludisme" (CNRFP), Burkina Faso, Africa (AS/AQ) and Mahidol University, Thailand (AS/MQ) on Phase I and III clinical
trials. WHO/TDR provides scientific advice and financial support, and helps coordinate clinical trials. Foundation Médecins Sans Frontières (MSF) provided initial management of the project and financial support. And EU’s INCODEV Programme provided financial support.

How to develop a new formulation
The synthesis of a chemical drug is stringently regulated by good manufacturing practice (GMP) to ensure consistent, reliable, and accurate chemical composition.
In a fixed-dose co-formulation two (or more) active principles (molecules that are pharmacologically active) are combined in a single tablet. Many parameters have to be considered to create a new formulation, based on the physical and chemical properties of the drug substances. In addition, a new drug needs to be formulated in a manner appropriate to its route of administration. Finally, stability and compatibility in solution and excipient mixtures have to be studied. [Excipient: a usually inert substance required for the formulation, e.g., starch.].

AS/AQ PARTNERS WHO HELPED ALONG THE WAY
The AS/AQ formulation was born in Bordeaux through collaboration with several teams whose effort and flexibility proved them to be more than simple subcontractors.

TropiVal, a coordination centre for pharmaceutical projects focused on developing drugs for tropical and neglected diseases, was one of the principal FACT contractors of the EU program. TropiVal helped to bring several public institutions and private companies together and contributed to the coordination of their work to insure completion of the various pharmaceutical steps of the project.

The partners directly contracted by TropiVal were the Galenical and Biopharmacy Department of the University of Bordeaux 2 that performed the first pre-formulation studies, and Ellipse Pharmaceuticals, Pessac, France that performed pre-formulation optimization, improved the new formulation and manufactured the tablets on laboratory scale.

These two teams confronted many obstacles that emerged due to the incompatibilities of AS and AQ and the requirements for the physical and chemical characteristics of both drugs.

After the first formulation trials, additional studies were requested to improve both the stability of the formulation and the manufacture of the tablets. Changes in the excipient mixture and in some steps of the formulation development resulted in a new stable formulation and an optimized manufacturing process.

Tablets for both clinical and ICH stability batches of the AS/AQ fixed-dose combination were manufactured by Rottendorf Pharma, Germany, that scaled up the process to manufacturing scale.

First clinical trial batches were manufactured July 2004 and are being used in clinical trials in Burkina Faso and Malaysia. An additional 6 batches were manufactured in December 2004 and January 2005 to evaluate the ICH stability for registration.

The first 6-month results are promising and the formulation shows good stability. These studies will continue for 3 years in accordance with ICH stability guidelines.

MSF logistics department in Bordeaux sent the comparators for the clinical trials to the sites (Burkina Faso and Malaysia), so that the trials could start during the transmission season.

Both clinical and ICH batches were analyzed, released, and packaged by Créapharm, Le Haillan, France.

Finally Cardinal Health provided critical support to all the teams involved in the project on regulatory matters, so that the Registration dossier to the Regulatory Agencies would be ready for submission by the end of 2005.

AS/AQ today
• Clinical trials in Burkina Faso and Malaysia, and stability studies for Registration have started.
• More than 400 patients have been enrolled for the trials and recruitment is ongoing.
• First clinical results will be available by the end of 2005.
• After 2005, a broader clinical investigation will be needed to collect useful information regarding health policies of the various countries.
• The goal is to obtain Marketing Authorization in Europe as well as Africa and provide affordable and accessible drugs to developing countries by 2006.
• DNDi has signed an agreement with Sanofi Aventis to complete the development of the AS/AQ formulation.

EU funding for FACT

In 2002, the European Union committed €1.2m over three years to the development of the two FACT drugs. The EU (EC) Directorate General for Research funds projects through its International Cooperation Programme (INCO), a part of the EU Framework Programme for Research and Technological Development, a 5-year plan outlining the EC’s priorities and budget for research activities. The FACT project was approved under the FP5 (1997-2001) under the INCO DEV programme set up to encourage international cooperation in research with developing countries. DNDi is extremely grateful for this support and seeks to gain significant EU support for other projects in the future.