Jean-René Kiechel, Senior Pharma Advisor & Product Manager, DNDi
The beginning of the current millennium saw a radical change in the way malaria was treated. In 2001, in response to rising chloroquine resistance, the WHO recommended replacing this monotherapy with artemisinin-based combination therapies, known as ACTs. The Drugs for Neglected Diseases Working Group of the MSF Access Campaign and WHO-TDR came together with other experts and stakeholders from both non-endemic and endemic countries to form the Fixed-Dose Combination Therapies (FACT) consortium in 2002, with projects subsequently transferred to DNDi when it was established in 2003.
The consortium aimed to develop fixed-dose combinations (FDCs) of two of the WHO-recommended ACTs, combining artesunate (AS) – the artemisinin-based component – with amodiaquine (AQ) or mefloquine (MQ). These malaria treatments were destined for use by patients in Africa, Asia, or Latin America, and were specifically developed with them in mind. They were to be affordable, with clear, self-explanatory packaging and formulations useful for all ages, including infants, and able to withstand tropical environments.
Led by DNDi, the FACT project team was composed of members who participated initially largely on a voluntary basis, from industry, universities, and research institutes worldwide, notably including experts from endemic countries. Advisors were brought in on an ad hoc basis to help address specific problems. Patients’ needs, particularly those of children, were kept at the centre throughout: African children under the age of five account for the majority of deaths from the disease. The characteristics of the treatments to be developed were discussed in consultation with experts and defined at the outset through Target Product Profiles, with progress regularly monitored throughout in twice yearly review meetings and specific local team meetings.
Despite cultural, expertise, and organizational differences, we overcame the challenge of building a team from members spread across different continents, having a common vision. The early pharmaceutical development steps were more time-consuming than may normally occur in an industrial setting, and working with limited resources, both in terms of personnel and finance, meant that the team needed to be flexible, but this led to innovative problem-solving. Clinical data was previously available on the individual drug components from their use in loose-combinations or blister-packs, but data was needed on the safety and effectiveness of these new fixed-dose combinations in a variety of patient populations, which was used to provide evidence for registration in endemic countries.
In Brazil, ASMQ FDC was developed with the public pharmaceutical company Farmanguinhos of Fiocruz. A large study carried in collaboration with the Ministry of Health in the Amazonian state of Acre, a hot-spot for falciparum malaria, attracted immense local interest, including at the highest political level in the State. Not only did it demonstrate the usefulness of ASMQ in tackling malaria, but it was found to strengthen the local malaria management system and showed that early diagnosis and treatment of patients living in remote communities was possible.
For ASAQ FDC, DNDi and Sanofi developed an extensive programme monitoring the treatment’s safety and efficacy, and providing data to support registration in endemic countries. Studies were carried out in adults and children, and ranged from small-scale (investigating repeated and long-term use of ASAQ in areas of high endemicity where patients have multiple malaria infections in a short period of time) to large-scale trials monitoring use in real-life situations. This Risk Management Plan was the first of its kind submitted to the WHO. Results of the largest of these trials, undertaken in the Côte d’Ivoire by Sanofi with MMV and involving 15,000 patients, are expected later this year.
But clinical development is not the end of the story, and enormous and ongoing efforts have been needed to ensure that patients are able to access these treatments, ranging from obtaining WHO prequalification and registration in endemic countries, to advocating for policy change and securing sufficient supplies. The non-exclusivity agreement with Sanofi to produce the ASAQ FDC allowed its production by other generic manufacturing companies, enlarging the market and increasing its distribution: it also facilitated the transfer of technology to Zenufa which will manufacture the treatment in Tanzania. Furthermore, Sanofi’s commitment to producing ASAQ FDC at cost-plus a small margin has led to a decrease in the price of other ACTs.
The successful development of ASAQ and ASMQ, two fixed-dose ACTs given as a single daily dose of 1 or 2 tablets over 3 days, has demonstrated that development model DNDi put into place works, with the two treatments registered for use in endemic countries across the globe. To date, more than 400 million treatments of ASAQ FDC have been distributed worldwide, including products developed by generic companies, and over 800,000 treatments of ASMQ FDC. These projects were officially handed over to the Access and Product Management team of the Medicines for Malaria Venture (MMV) in May of this year. MMV is a long-term partner of DNDi and has built the largest ever portfolio for malaria, and ensures the future availability of these treatments to patients in the years to come.
Senior Pharma Advisor & Product Manager, DNDi