Antimalarial drug resistance
Throughout recent history, malaria medicines have repeatedly been compromised by antimicrobial resistance (AMR). Significant progress has been made over the last 20 years in bringing malaria under control through intensified use of a mix of control measures, including insecticide-treated bed nets, diagnostics and artemisinin-based medicines. However, the malaria parasite continues to evolve in ways that diminish the efficacy of current medicines, first to chloroquine, then sulfadoxine/pyrimethamine and more recently to artemisinin combination therapies, the most used compound to treat malaria.
- Progress in reducing malaria cases and deaths has stalled over recent years due to multiple factors including reductions in funding and diversion of resources due to the COVID pandemic.1
Partial resistance to artemisinin derivatives, the mainstays of malaria treatment, has been observed for two decades in South-East Asia, and more recently in Africa.2,3,4
If resistance continues to spread throughout Africa – where malaria morbidity and mortality are highest – and especially if partner drugs become less effective, the impact on both mortality and morbidity could be devastating.
To get back on track, multiple tools and approaches will be needed, including new antimalarial medicines to help manage the emergence and spread of resistant parasites.
In the near term, optimizing the use of existing drugs by diversifying their use through multiple first-line therapies has been shown in modelling studies to help delay the emergence and spread of resistance.
Meanwhile, a combination of artemether-lumefantrine plus amodiaquine is in late-stage development as the first fixed-dose TACT (triple artemisinin-based combination therapy), which has demonstrated high efficacy against resistant parasites in studies to date.
What is antimalarial drug resistance?
Micro-organisms like viruses, bacteria, fungi and parasites naturally undergo mutations which, under the right conditions, can allow them to evolve resistance to the medicines used to treat them. This phenomenon, known as antimicrobial resistance, threatens the public health response to many diseases, including malaria.
Over time, malaria parasites evolve to evade the effects of antimalarial treatments, making them less effective. When this happens, antimalarial drugs may take longer to clear the parasites – this is known as partial antimalarial resistance. If resistance to partner drugs such as lumefantrine also develops, the medicines may no longer work at all – this is known as full or complete resistance.
Although six artemisinin combination therapies (ACTs) are first-line treatments used in Africa, the continent is heavily reliant on artemether-lumefantrine to cure malaria infections. However, over reliance on one combination treatment may create undue drug pressure on both the artemisinin component and the non-artemisinin partner drug.
Combining forces: how to combat antimalarial drug resistance
Partial artemisinin resistance has been confirmed in a number of African countries, notably Rwanda, Uganda, Tanzania and Ethiopia.2,3,4
Fortunately, despite reduced efficacy of artemether-lumefantrine in some countries, to date ACTs remain largely effective in Africa and there have been no confirmed reports of partner drug failure.
Combining drugs with different mechanisms of action reduces the exposure to any single compound, making it more difficult for parasites to develop resistance and maximizing the useful therapeutic life of existing drugs.
WHO’s strategy to respond to antimalarial drug resistance
In November 2022, the World Health Organization (WHO) released its ‘Strategy to respond to antimalarial drug resistance in Africa’. This strategy is based on four pillars, each comprising a set of interventions to be adapted to specific contexts and implemented at local, regional and global levels:
Strengthening surveillance of antimalarial resistance.
Optimizing and better regulating the use of medicines and diagnostics to reduce selection for resistance.
Limiting the spread of drug-resistant parasites.
Stimulating research and innovation to develop new tools against resistance and to better leverage existing ones.
Multiple first-line therapies (MFT)
Before discussing the role of new medicines, the WHO Strategy highlights the need to optimize the use of existing ones.
MFT is defined as the use of two or more first-line ACTs simultaneously to make it harder for parasites to evolve resistance and can be achieved in different ways:
- A stratification approach, tested in Burkina Faso, in which different patient groups are given different drugs,
- A rotational approach, tested in Kenya, in which first line drugs are switched frequently on a regular basis (eg 9 months-1 year),
- A geographical approach where neighbouring districts or regions use different ACTs.
Introducing multiple first-line treatments (MFT) is a critical step to preserve the effectiveness of ACT – including the commonly used artemether-lumefantrine – for as long as possible.
MMV's approach to tackling antimalarial drug resistance
MMV is actively working in several ways:
Firstly, by advocating use of MFT within a population: MMV supported pilot implementation studies in Burkina Faso with the Institut de Recherche en Sciences de la Santé and Strathmore University in Kenya that demonstrated the practical feasibility and stakeholder acceptance of MFT.5
Secondly, we are developing combination medicines that work against existing resistant parasite strain. For example we are partnering with the Fosun Pharma, Mahidol-Oxford Research Unit (MORU) and Marubeni Corporation to develop triple-drug artemisinin combination therapies as fixed-dose combinations.
Finally, we are working to prevent the spread of resistant parasites by developing medicines with less frequent dosing regimens to improve compliance and reduce the likelihood of resistance developing due to failure to complete the course of treatment. For example, WHO’s antimalarial drug resistance strategy for Africa recognized the value of Pyramax® (pyronaridine-artesunate) with a ‘Strong’ recommendation and inclusion in its guidelines for malaria in November 2022. It is a fixed-dose artemisinin-based combination therapy that treats the two dominant species of the malaria parasite, Plasmodium vivax and Plasmodium falciparum, available for adults (tablets) and children (granules to ensure correct dosage).
Developing a robust pipeline of antimalarials
The best way to prepare for the inevitability of antimalarial resistance is a robust pipeline of medicines to have available as and when existing treatments become less effective. To date, MMV’s partnerships have resulted in 15 approved medicines, all of which are active against current resistant malaria strains.
MMV's strategy to contain antimalarial resistance includes four pillars:
Developing patient-friendly medicines, including children’s formulations and medicines with simpler dosing regimens (ideally, single-dose cures) which improve adherence to treatment and reduce the chances of resistance emerging.
Developing and delivering only high-quality, WHO-prequalified medicines.
Establishing discovery networks and assay platforms to accelerate the identification of molecules with activity against all known malaria parasite strains, as well as those resistant to currently available treatments. We also check to see how easily resistance can be generated in laboratory conditions and prioritize compounds that can eliminate parasites with a low risk of resistance developing.
Supporting national malaria control programmes and other partners to deliver the right medicine to the right patient at the right time.
How is MMV developing the next generation of antimalarials?
MMV prioritizes molecules that are highly active against existing resistant strains, with low potential to generate future resistance – particularly compounds for which no resistant strains can be developed in the laboratory or isolated clinically.
In November 2022, MMV and Novartis announced the decision to move a novel combination for adults and children to a Phase III study. This represents a major milestone in the effort to bring forward new medicines to combat antimalarial drug resistance. Ganaplacide/lumefantrine is a novel non-artemisinin combination therapy for both adults and children that will offer a once-daily alternative to current ACT treatments should resistance become widespread.
Because incomplete cure also contributes to the development of resistance, we and our partners seek to improve treatment adherence by developing patient-friendly medicines with shorter and simpler treatment regimens, ideally requiring only a single dose.
Responding to antimalarial drug resistance
Latest Science: Antimalarial drug discovery: progress and approaches, Nature, June 2023.
Abstract from a recent review co-authored by Jeremy Burrows, Head of Discovery at MMV:
Recent antimalarial drug discovery has been a race to produce new medicines that overcome emerging drug resistance, whilst considering safety and improving dosing convenience. Discovery efforts have yielded a variety of new molecules, many with novel modes of action, and the most advanced are in late-stage clinical development. These discoveries have led to a deeper understanding of how antimalarial drugs act, the identification of a new generation of drug targets, and multiple structure-based chemistry initiatives. The limited pool of funding means it is vital to prioritize new drug candidates. They should exhibit high potency, a low propensity for resistance, a pharmacokinetic profile that favours infrequent dosing, low cost, preclinical results that demonstrate safety and tolerability in women and infants, and preferably the ability to block Plasmodium transmission to Anopheles mosquito vectors. We describe the approaches that have been successful, progress in preclinical and clinical development, and existing challenges. We illustrate how antimalarial drug discovery can serve as a model for drug discovery in diseases of poverty.