"Drug resistance is fascinating because it demonstrates the idea that evolution always wins”

2021
Dr Maëlle Duffey

Characterizing resistance

Given the urgent need to develop new antimalarial treatments, it is important to have a defined and consistent way of characterizing the risk of resistance emergence to a specific compound and ranking them compared to one another. We can then make fully informed decisions regarding the choice of compounds to take forward.

Dr Maëlle Duffey discusses her work to characterize resistance as part of MMV’s Drug Discovery team.

1. Can you describe your work and how it will help MMV identify drugs that combat resistance?

My work focuses on the identification of new drugs with blood-stage efficacy and manageable or no resistance. I oversee various parasitology and pharmacology platforms supporting the discovery of new antimalarial compounds.

Based on clinical observations, various partner testing platforms and expert input, we have developed a new strategy that allows us to detect and characterize the risk of resistance at each step of the pipeline. We use known modes of action and mechanisms of resistance, genetic testing, detailed in vitro analysis and in vivo experiments. This allows us to identify and deprioritize early- and late-lead series exhibiting a very high risk of resistance, and have a comprehensive assessment of the resistance risk at the level of candidate selection.

2. What drew you to work on malaria drug resistance, and why is this work important?

Drug resistance is fascinating because it demonstrates the idea that “evolution always wins”. A number of years ago, partial resistance to artemisinin derivatives emerged in South East Asia, with worrying signs also recently detected in Africa. Fortunately, when artemisinin is used in combination with other drugs, such as lumefantrine or pyronaridine, efficacy is maintained. Having a well-characterised picture of the risk of resistance of an antimalarial compound early in its development helps us make better-informed decisions across the whole MMV pipeline.

3. How does this work fit in with MMV’s research and development strategy and the resistance work being conducted by David Fidock and his team who were awarded MMV Project of the Year 2020?

With its unparalleled expertise in molecular parasitology, the Fidock Lab has profiled over 180 compounds and discovered 18 new modes of action and mechanisms of resistance. David and his team have been a central pillar in our resistance work. In addition to being key contributors to the in vitro experiments that support our strategy, their research has interrogated drug resistance in the malaria parasite, increasing our understanding of malaria parasite biology. This understanding has informed our new resistance strategy that investigates resistance risk throughout the drug development process.

4. What has been the impact of your project on MMV’s portfolio?

Once the strategy has been validated using clinical data on the advanced compounds in our profile, the impact is likely to be an increase in the down prioritization of projects presenting an unacceptable resistance risk, freeing up resources to focus on more promising projects. We are expected to deliver preclinical candidates with a comprehensive resistance risk assessment, ultimately leading to fully informed decisions regarding compound prioritization and partner drug selection.