WANECAM 3

The challenge

Artemisinin-based combination therapies (ACTs) have been the mainstay of malaria treatment for decades. However, strains of the malaria parasite less susceptible to the artemisinin component of ACTs have been detected in various sub-Saharan African countries, raising fears that such treatments could be rendered ineffective and highlighting the need for new drugs with different mechanisms of action.

In addition, the current standard of care for malaria uses three-day treatment regimens. It is estimated that up to half of patients do not complete the recommended course, increasing the risk of resistance.

The project

Building on an existing EDCTP-funded clinical trial network in West Africa, the WANECAM 3 project is utilising a clinical trial platform established by Novartis to test new antimalarial compounds. The project brings together African and European researchers, Novartis, and the Medicines for Malaria Venture (MMV), a public–private partnership focused on new antimalarial development.

The key aim of the new WANECAM 3 project is to develop a new antimalarial combination that does not include artemisinin-related components and is sufficient to cure infections when given as a single dose.

The project focuses on three investigational compounds that show highly promising action against malaria parasites and have raised no safety flags in clinical studies to date:

• Cipargamin (KAE609): A potent and fast-acting antimalarial which is active against multiple species of Plasmodium, has a novel mechanism of action, and also shows activity against gametocytes – the stage in the Plasmodium life cycle that is taken up by mosquitoes, suggesting it will also have transmission-blocking activity.
• INE963: A highly active and long-lasting antimalarial with an unknown mechanism of action and a high barrier to resistance.
• MMV533: A fast-killing and long-lasting antimalarial, also with an unknown mechanism of action.

Notably, in studies to date, there has been no evidence that malaria parasites develop resistance to these compounds when used in combination. 

To advance a new treatment, the phase II PLATINUM platform will be used to test the efficacy and safety of a combination of cipargamin and INE963 against uncomplicated malaria in children aged 2–12 years. In an additional study arm, the efficacy of different doses of MMV monotherapy will be assessed in adults.

Depending on the results of the phase II study arms, a large phase III trial will then be run comparing the chosen dual or triple combination antimalarial when given as a single-dose treatment to a 3-day regimen of standard of care. The clinical program will generate sufficient robust data to support a marketing authorisation application. The clinical studies will include WANECAM 3 partners in Burkina Faso, Gabon, Kenya, Mali and Uganda, with a site in Ethiopia also intended to join phase III following capacity building. 

In addition, the project is generating data on gametocyte clearance to reduce onward malaria transmission and on drug resistance by screening all participants for known resistance genes.

Impact

The WANECAM project could lead to a radical shift in the treatment of malaria. It will:

• Reveal whether promising antimalarial compounds can be as effective and safe as 3-day artemisinin-based combination therapies (ACTs) when given as a single-dose malaria treatment.
• Generate the data required to support marketing authorisation applications.
• Demonstrate whether the new combination could also reduce community disease burdens through transmission-blocking effects.
• Generate extensive new data on patterns of drug resistance at multiple sites across sub-Saharan Africa.

A single-dose treatment for malaria would be easier for health systems to deliver and for patients to take, ensuring rapid cure while reducing the risk that treatment effectiveness is undermined by poor compliance and adherence.