ASAQ-PAC

The challenge

Malaria remains one of the biggest killers of young children across much of sub-Saharan Africa, responsible for ~450,000 deaths. For many years, artemisinin combination therapies (ACTs) have been the mainstay of antimalarial drug treatments. Recently, however, genetic mutations have been detected in malaria parasites that reduce their sensitivity to the artemisinin-derived component of such treatments; this is referred to as artemisinin partial resistance. While ACTs remain effective, the spread of less-sensitive strains could be devastating if parasites also develop resistance to the second component of an ACT.

Six different ACTs are available to treat malaria. Most countries currently use artemether–lumefantrine (AL) as their first-line ACT. However, to reduce drug pressure that drives resistance, the WHO now recommends that countries adopt a mix of ACTs, known as multiple first-line treatments. Modelling suggests that the concurrent use of multiple therapies better protects drugs against resistance than periodic switching between drugs.

Artesunate–amodiaquine (ASAQ) is another effective ACT but is less commonly used. One key barrier is the lack of an age-appropriate, fixed-dose combination of ASAQ suitable for young children. Currently, tablets have to be broken up and dissolved in water, which can lead to inaccurate dosing and poor adherence because AQ has a very bitter taste.

The project

The ASAQ-PAC project is evaluating a new ASAQ formulation that overcomes these challenges, paving the way for its wider use among young children in Africa.

Formulating AS and AQ together has been a challenge: they need to be kept separate because AS is unstable and prone to degradation when in direct contact with AQ. Existing fixed-dose combination tablets compress the drugs in separate layers. However, the ASAQ-PAC project team has developed an alternative approach in which the individual drugs are encapsulated in micropellets, coated with a material that prevents the two compounds from coming into contact. 

In addition, the innovative ‘MicroCoat’ technology masks the bitter taste of AQ and prevents the micropellets from clumping together during manufacturing. The micropellets can be made separately for AS and AQ, then combined in a ‘stick pack’ – a disposable pouch that allows the micropellets to be placed directly on a child’s tongue or dispersed in water.

This process is compatible with standard manufacturing processes and is easy to scale up at a relatively low cost. It is a technology that could be readily transferred to manufacturing sites in low- and middle- income countries, including those in sub-Saharan Africa. In addition, all the other materials used in manufacture have already been shown to be safe for children, and ASAQ micropellets have been shown to be palatable in studies with adults in the UK. The ASAQ-PAC project is now conducting studies in sub-Saharan Africa to generate the evidence needed to support its adoption by African countries.

The main clinical evaluation will be a trial in Malawi comparing 28-day cure rates in children with uncomplicated malaria given either standard ASAQ tablets or the new micropellets. Although ASAQ is known to have good antimalarial activity, a key challenge is to demonstrate that the new formulation delivers sufficient levels of the drugs in the blood to be effective. This requires detailed pharmacokinetic studies, whereby multiple blood samples are taken and blood concentrations measured. Repeated blood draws are not feasible for young children. Therefore, as an alternative, the project will assess day 7 levels of desethylAQ, the main active AQ metabolite, which provides a good proxy for drug exposure. We will compare the day 7 desethylAQ concentrations between standard ASAQ tablets and the micropellets in the two clinical studies of the project. 

In addition, the project is taking advantage of this trial to generate additional data on a child-friendly version of primaquine, developed by the EDCTP-funded Developing Paediatric Primaquine (DPP) project that has developed tropical fruit-flavoured tablet formulations to mask the bitter taste of primaquine. The WHO recommends that single low-dose primaquine be used alongside ACTs, as it has activity against late-stage, sexual malaria parasites, called gametocytes, which are taken up by mosquitoes and seed new infections. Blocking transmission, therefore, reduces the community disease burden. 

This second study will compare the effect of adding primaquine to the micropellet formulation of ASAQ on transmission-blocking. The transmission-blocking activity will be assessed using a membrane-feeding assay, in which laboratory-grown mosquitoes feed through an artificial membrane on blood samples from trial participants. The number of mosquitoes that become infected with malaria parasites following feeding provides an indication of transmission-blocking activity.

Impact

The ASAQ-PAC project could have a significant impact on malaria treatment in Africa. It will:

• Demonstrate whether a child-friendly formulation of artesunate–amodiaquine (ASAQ) is as potent as standard ASAQ.
• Enable ASAQ to be used more widely among children as part of multi-therapy strategies to delay the development of resistance to artemisinin combination therapies (ACTs).
• Generate additional data on the potential of a child-friendly version of primaquine to reduce the community burden of malaria.
• Create commercial opportunities to manufacture the micropellet formulation of ASAQ in Africa. 

ASAQ is currently the only ACT without an age-appropriate formulation. The ASAQ-PAC project will correct this anomaly without significantly increasing the cost of the final product, paving the way for greater use in countries to extend the lifespan of these key lifesaving treatments.