An MMV-authored paper, “Risks of Plasmodium falciparum Resistance to Select Next-Generation Antimalarials” has been published in the leading review journal Trends in Parasitology. With the rise and spread of Plasmodium falciparum resistance to existing therapies, researchers are urgently seeking to progress new compounds with new mechanisms of action and a high barrier to resistance. The paper details a cost-effective selection approach in drug discovery and a risk quantification in development, which can help identify the candidate drugs with the strongest merit to advance further from a resistance perspective. 

The challenge of resistance in compound selection

Malaria is an infectious disease and due to the high parasite numbers in patients, antimalarial drug resistance is ultimately, over time, an inevitability. It is hoped to mitigate this risk by identifying compounds with the lowest potential for generating resistance and combining compounds into new treatment regimens in a manner that further reduces the risk of resistance. To achieve this, a full and early assessment of candidate drug susceptibility to select for drug resistance in malaria parasites is an imperative.

If genetic markers for resistance (genotypic analysis) are identified in the drug discovery phase, then it is important to understand whether this could translate into clinical failure when used in malaria infected patients. To do so, parasites from patients in a clinical trial can be taken before the antimalarial is administered, and also after dosing of the drug in the event of parasite recrudescence.  Analysis of the parasite genome and drug sensitivity (the phenotypic analysis) immediately gives comprehensive information as to whether resistance is limiting efficacy, and this can then be factored into the clinical plan. 

MMV’s new strategy to identify potential resistance risks

MMV has developed a new strategy of resistance identification focusing on the drug discovery phase, which will allow for early decisions to stop or deprioritize a compound/series if a significant risk of drug resistance is identified. This new strategy also includes a tool to assess the comprehensive resistance risk for a candidate drug early in the preclinical phase even before it progresses into clinical trials. The aim is for this risk assessment to inform investment decisions and, for early-stage testing, to improve the quality of compounds over time from a resistance perspective. 

The “triangle of resistance” acts as a guide

Dr Didier Leroy, Senior Director Drug Discovery MMV says: “Our guiding principle was to develop an assessment tool that can integrate data from across different platforms and studies to help predict the risk of resistance, and most importantly, its potential impact on clinical efficacy.”

“The tool applies a triangular assessment of resistance, with the clinical outcome being one apex of the triangle and the genotypic and phenotypic analyses the other two. This allows a comprehensive interpretation of clinical failure in the light of potential resistance. The paper communicates the necessity to verify this triangle before concluding that a clinical trial failure is due to resistance.”

The advantage of a predictive tool

An early understanding of how candidate compounds lose efficacy as parasites evolve resistance will help the prioritisation of candidate drugs, inform the necessary combination strategy, improve resistance detection in the field, as well as potentially help future drug design. It also presents a major advantage in terms of optimizing resources and accelerating research, with a focus on prioritising the development of those compounds that demonstrate ideally a low risk of potential resistance.

The “triangle of resistance” approach could also be of interest beyond the field of malaria, as a welcome and cost-effective aid in the development of drugs for other infectious diseases.