RAMP

The challenge

Artemisinin combination therapies (ACTs) have proven highly effective in treating malaria, saving millions of lives. However, there are growing concerns that parasites in Africa are becoming less susceptible to artemisinin derivatives, particularly in East Africa. While this has not yet had a major impact on clinical outcomes, if parasites also develop resistance to an ACT partner drug, this could seriously undermine the effectiveness of ACTs.

Various strategies are being advanced to address this challenge. One is the use of ‘triple ACTs’, which contain a third antimalarial drug. A malaria parasite would need to develop resistance to three distinct drugs with different modes of action to survive such treatments. In addition, WHO recommends using drugs with transmission-blocking activity, such as primaquine, alongside ACTs. These drugs target a late stage in parasite development, so they do not prevent disease directly but reduce the risk that parasites will be transmitted to others, delivering community-wide benefits.

The project

The RAMP project is advancing development of an existing antiviral drug, ravidasvir, which is not only an effective antimalarial but also has transmission-blocking activity. It has the potential to be added to an existing ACT – not only protecting the ACT against the development of resistance but also reducing community transmission of malaria parasites.

Ravidasvir, developed as a treatment for hepatitis C virus (HCV) by DNDi and Pharco Pharmaceuticals, has completed phase III trials with minimal safety concerns and is now approved in Malaysia for HCV treatment in combination with sofosbuvir. In a screen of a chemical library, it was found to have activity against malaria parasites: it reduces the flexibility of parasite-infected red blood cells, causing them to be removed by the spleen. It can be taken orally and is relatively inexpensive. It has not been tested in children, but other drugs with the same biochemical target have been found to be safe for use in children.

Given this promising backdrop, the RAMP project is assessing the safety, efficacy and transmission-blocking activity of ravidasvir in combination with an existing ACT, dihydroartemisinin–piperaquine (DP). DP has no effect on parasite transmission, so any transmission-blocking activity observed following treatment with the new combination will be due to ravidasvir.

First, a study in Gabon (CERMEL) will assess the ability of ravidasvir to clear asymptomatic infections in adult carriers. Increasing doses of ravidasvir will be assessed to identify the optimal dose for future studies.

Next, a trial in Mali (USTTB) will assess efficacy and transmission-blocking activity in adults with malaria. This study will compare the effects of DP alone, DP plus ravidasvir, and DP plus primaquine, so the transmission-blocking activity of ravidasvir can be compared with that of primaquine. This activity will be assessed using a membrane feeding assay, in which laboratory-grown mosquitoes are given the opportunity to feed on participants’ blood samples through an artificial membrane; the number of mosquitoes that become infected provides a measure of transmission-blocking activity.

Finally, a multi-centre trial will be run in Gabon, Ghana (KNUST/KCCR), Mali and Uganda (EPICENTRE), comparing the efficacy of the new triple therapy with an existing ACT. The trial will start with older children, enrolling earlier age groups once the combination has been shown to be safe.

The project is also conducting consultations with caregivers about their perceptions of malaria and the use of transmission-blocking drugs to assess their likely acceptability and any potential barriers to their use.

In addition, it assesses the activity of the drug combination on parasites carrying mutations known to affect sensitivity to artemisinin derivatives. It is also screening for such mutations in malaria cases detected in the trial and sequencing parasites to identify potential new genetic variants associated with drug resistance.

Impact

The RAMP project will advance a highly promising new antimalarial that has already been licensed for human use. It will:

• Confirm the antimalarial activity of ravidasvir alone and when combined with an existing ACT.
• Quantify its transmission-blocking activity in comparison to primaquine.
• Demonstrate its safety and efficacy in the key target group, young children.
• Generate additional data on the presence of resistance genes across trial sites.

With ravidasvir already licensed for human use, these studies could lead to its rapid adoption as part of a triple ACT, helping to protect the other drug components against resistance while also reducing the community burden of malaria through its transmission-blocking effects.