index
EDCTP portfolio: Malaria
Advancing a portfolio of malaria drugs
The PAMAFRICA project is advancing the development of a suite of drugs to address unmet needs in malaria treatment.
The challenge
Between 2000 and 2015, malaria deaths were more than halved, mainly through use of artemisinin-based combination therapies (ACTs). However, progress has slowed markedly, and may even have gone into reverse. The rise of resistance to ACTs in South-East Asia is also greatly concerning. To achieve ambitious malaria control and elimination goals, new tools are urgently required to close treatment gaps and to provide new impetus.
The project
Since its launch in 1999, the Medicines for Malaria Venture (MMV) and its partners have developed the most extensive portfolio of candidate malaria drugs ever seen. As many drugs do not make it through the development pipeline, a portfolio approach is essential. In addition, a portfolio approach is required so that treatments can be tailored to the needs of specific groups, including vulnerable populations such as young infants.
The PAMAFRICA project will draw on MMV resources – drug candidates and reformulations of licensed medicines – to address significant unmet needs in malaria treatment. One priority is a single-dose cure for malaria. The project is likely to focus on two promising compounds: M5717, which is active against all stages of the parasite life cycle; and SAR121, a potent and long-lasting agent that the malaria parasite is unable to develop resistance to. However, with additional clinical data due to be released shortly, other compounds in the MMV portfolio could be considered. A final decision will be made on the basis of all available clinical data.
PAMAFRICA will also undertake a specific study to develop and test a new formulation of artemether–lumefantrine for children less than 5 kg in weight. Drug metabolism changes significantly in the first two years of life, so current formulations may not be appropriate for newborns and young infants. Previous studies have identified a suitable dose combination, which will be tested in a phase II trial.
A further strand of work will advance a new injectable formulation of cipargamin, a highly potent antimalarial being developed as a back-up treatment for severe malaria caused by ACT-resistant parasites. A phase I study is planned to determine a suitable dose of the new formulation for a phase II trial in patients.
MMV has previously partnered with EDCTP-funded consortia such as WANECAM on highly successful projects and will again work with African and international partners, helping to build African research capacity.
Impact
The PAMAFRICA project will continue the successful relationship between EDCTP and MMV, which has already led to the licensing of new antimalarial treatments. It will be a joint funding venture, with MMV providing 50% of funding. The project will generate key data that will feed into licensing applications for treatments focused on some of the most urgent needs in malaria treatment – simple and effective treatments for deadly severe malaria and a treatment for the youngest and most vulnerable patients.
EDCTP portfolio: HIV & HIV-associated infections
The CHAPAS trials have ensured that many more children with HIV have benefited
from life-saving antiretrovirals.
Bringing antiretroviral drugs to children
“
crucial in
widening African
children’s access
to antiretrovirals
”
Between 2000 and 2015, malaria deaths were more than halved, mainly through use of artemisinin-based combination therapies (ACTs). However, progress has slowed markedly, and may even have gone into reverse. The rise of resistance to ACTs in South-East Asia is also greatly concerning. To achieve ambitious malaria control and elimination goals, new tools are urgently required to close treatment gaps and to provide new impetus.
The challenge
The later CHAPAS-3 trial compared the efficacy and safety of three fixed-dose combinations including two without stavudine (found to have some long-term side effects in adults, leading to a recommendation that its use be discontinued in children). The trial the first of its kind in Africa studied nearly 500 children at four sites in two African countries.
The project
Since its launch in 1999, the Medicines for Malaria Venture (MMV) and its partners have developed the most extensive portfolio of candidate malaria drugs ever seen. As many drugs do not make it through the development pipeline, a portfolio approach is essential. In addition, a portfolio approach is required so that treatments can be tailored to the needs of specific groups, including vulnerable populations such as young infants.
The PAMAFRICA project will draw on MMV resources – drug candidates and reformulations of licensed medicines – to address significant unmet needs in malaria treatment. One priority is a single-dose cure for malaria. The project is likely to focus on two promising compounds: M5717, which is active against all stages of the parasite life cycle; and SAR121, a potent and long-lasting agent that the malaria parasite is unable to develop resistance to. However, with additional clinical data due to be released shortly, other compounds in the MMV portfolio could be considered. A final decision will be made on the basis of all available clinical data.
PAMAFRICA will also undertake a specific study to develop and test a new formulation of artemether–lumefantrine for children less than 5 kg in weight. Drug metabolism changes significantly in the first two years of life, so current formulations may not be appropriate for newborns and young infants. Previous studies have identified a suitable dose combination, which will be tested in a phase II trial.
A further strand of work will advance a new injectable formulation of cipargamin, a highly potent antimalarial being developed as a back-up treatment for severe malaria caused by ACT-resistant parasites. A phase I study is planned to determine a suitable dose of the new formulation for a phase II trial in patients.
MMV has previously partnered with EDCTP-funded consortia such as WANECAM on highly successful projects and will again work with African and international partners, helping to build African research capacity.
Projects: Children with HIV in Africa Pharmacokinetics and Adherence of Simple Antiretroviral Regimens (CHAPAS): CHAPAS-1 and -3
Project lead: Professor Chifumbe Chintu, University Teaching Hospital, Zambia (CHAPAS-1); Dr Veronica Mulenga, University Teaching Hospital, Zambia (CHAPAS-3)
Target population(s): Children with HIV
Sample size: 71 (CHAPAS-1); 480 (CHAPAS-3)
Countries involved: Ireland, the Netherlands, the UK, the USA, Zambia (CHAPAS-1); Uganda, Zambia (CHAPAS-3)
Project duration: 2005–2009 (CHAPAS-1); 2010 –2011 (CHAPAS-3)
EDCTP funding: €1.2M (CHAPAS-1); €4.6M (CHAPAS-3)
Total project funding: €1.2M (CHAPAS-1); €5.0M
L’homme RF et al. Nevirapine, stavudine and lamivudine pharmacokinetics in African children on paediatric fixed-dose combination tablets. AIDS. 2008;22(5):557–65.
Mulenga V et al. Abacavir, zidovudine, or stavudine as paediatric tablets for African HIVinfected children (CHAPAS-3): an open-label, parallel-group, randomised controlled trial. Lancet Infect Dis. 2016;16(2):169–79.
WHO. Guidelines on the use of antiretroviral drugs for treating and preventing HIV infection: recommendations for a public health approach. 2010.
WHO. Consolidated guidelines on the use of antiretroviral drugs
for treating and preventing
HIV infection: Recommendations for a public health approach
(second edition). 2016
Impact
ratios forfixed-dose combinations and on appropriatedosage according to weight.
The CHAPAS-3 trial confirmed the effectiveness of fixed-dose combinations, providing further impetus to the rollout of antiretrovirals to children. Its evidence on abacavir informed the WHO recommendation of abacavir-containing combinations for first-line therapy in children. Trial data have also been used to support applications for regulatory approval for new scored efavirenz tablets.
The PAMAFRICA project will continue the successful relationship between EDCTP and MMV, which has already led to the licensing of new antimalarial treatments. It will be a joint funding venture, with MMV providing 50% of funding. The project will generate key data that will feed into licensing applications for treatments focused on some of the most urgent needs in malaria treatment – simple and effective treatments for deadly severe malaria and a treatment for the youngest and most vulnerable patients.