PYRAPREG-extended

The challenge

Because of hormonal and immunological changes, pregnant women are particularly vulnerable to malaria infections. As well as affecting maternal health, such infections can cause a range of adverse birth outcomes, including stillbirths and premature delivery. Around 30 million pregnant women are exposed to malaria infections in sub-Saharan Africa each year, leading to an estimated 10,000 maternal deaths and up to 200,000 infant deaths.

Several highly effective artemisinin-based combination therapies (ACT) have been developed to treat malaria. However, for safety reasons, pregnant women are typically excluded from key clinical trials, so there are limited data to support the use of some key ACTs in pregnancy. There is a need to increase the therapeutic options to treat malaria during the 2nd and 3rd trimester of pregnancy with one combination treatment, such as pyronaridine–artesunate (PA), also known as Pyramax®, which has been developed by the Medicines for Malaria Venture (MMV) and Shin Poong Pharm and is active against both Plasmodium falciparum and P. vivax malaria.

PA has an excellent safety profile, and pre-clinical studies suggest that it is unlikely to harm developing babies. However, robust clinical data on safety and efficacy are required before the treatment can be recommended for pregnant women.

The project

Funded through the EDCTP2 programme, the PYRAPREG project has organised a clinical trial comparing the treatment success and safety of PA and two other widely used ACTs, artemether–lumefantrine (AL) and dihydroartemisinin piperaquine (DP). The project aimed to recruit nearly 2,000 pregnant women diagnosed with malaria, who were randomly allocated to one of the three treatments. The trial is being conducted in Burkina Faso, the Democratic Republic of the Congo (DRC), the Gambia, Mali, and Mozambique, at sites with varying intensities of malaria transmission. 

Recruitment into the trial was disrupted by the COVID-19 pandemic. The additional funding from Global Health EDCTP3 will enable the project team to complete a one-year follow-up of newborns to confirm safety and to finalise trial data analysis. 

In addition, the project is carrying out pharmacokinetic (PK) studies to determine how pyronaridine is metabolised and distributed through various body tissues. By providing information on drug concentrations in different tissues, PK studies are important for establishing optimal dosing – achieving concentrations sufficient to kill parasites without raising safety concerns. Due to their differing physiology, pregnant women may require different dosages. Since malaria infection also affects drug metabolism, drug levels in pregnant women are being compared with those in non-pregnant women who are also being treated for malaria.

Impact

The PYRAPREG project will generate key data on the safety and efficacy of pyronaridine–artesunate (PA) in pregnant women. It will:

• Provide high-quality evidence on PA to inform national and global decision-making.
• Identify whether existing dose levels are appropriate for pregnant women.
• Potentially expand the range of treatment options available for malaria treatment in pregnant women.
• Enable ACTs to be used more selectively, for example, allowing some treatment options to be reserved for intermittent preventive treatment in pregnancy (IPTp). 

As pregnant women are typically excluded from pivotal clinical trials, they are generally among the last to benefit from new medical interventions. The PYRAPREG-extended project will ensure that they gain access to a highly effective new malaria treatment, which will help to reduce the impact of the disease on both them and their babies.