Antimicrobial resistance, malaria and next-generation medicines
Exposing microbes to drugs leads to selection for mutants that can survive, which is a natural process known as ‘antimicrobial resistance’. This process is a fact of life in infectious disease research and, to minimize the spread of resistance, malaria is treated with combination therapies such as ACT.
Partial resistance to artemisinin derivatives has been present for two decades in South East Asia and has now been reported in several sites in Africa.1 To date, resistance to key partner drugs, such as lumefantrine and pyronaridine, has not been reported. MMV is piloting ways of slowing the spread of artemisinin partial resistance in Africa using multiple first-line therapies.
However, what is urgently needed are new classes of medicines that are fully active against all clinical strains of malaria and have a low propensity for malaria parasites to generate resistance. This is a key goal for MMV and, through its PDP model, MMV works with partners to fast-track innovation in antimalarial drug discovery and development.
Dr Timothy Wells discusses MMV’s research and development strategy in 2020 in the context of global health security and antimicrobial resistance.
1. How did COVID-19 affect the discovery and development of new antimalarials?
COVID-19 slowed our operations slightly, but MMV has adapted to the challenges and found new ways of working. MMV has a world-class compound logistics system, which operated continuously during 2020, transferring compounds from their manufacturing sites to testing sites. Although some of our partners had to shut down activities in the short term in response to the pandemic, we were still able to maintain delivery and produce results. At the clinical development stage, we have benefitted from teams working tirelessly to keep sites open through collaborations with our partners. We also developed new ways of ensuring clinical trial quality, despite travel restrictions.
2. What lessons can we learn from COVID-19 about how to do things better in the treatment of malaria?
The rapid development of COVID-19 vaccines was only achievable through the significant upfront work that developed a solid foundation for innovation in new areas, such as messenger RNA (mRNA) vaccines and adenovirus vaccines. Funding was made available rapidly, governments took funding decisions quickly, and the pathway to approval by regulators and the WHO was streamlined extensively. For malaria, we can see how communicating a pathway to policy change is critical. We must communicate that malaria is not only a disease that kills around 400,000 people per year,2 but also has massive economic consequences in countries that can least afford such challenges.
3. What is your take on the emergence of partial artemisinin drug resistance in Africa?
The challenge is to contain emerging resistance geographically, preserve the lifespan of our current medicines and prevent the emergence of more resistant strains. There is a need for new classes of medicines and our most advanced are already in Phase II clinical studies. All the new medicines in our portfolio are active against existing resistance mutations in the field and we also check to see whether resistance can be generated in laboratory conditions. We prioritize those that can eliminate parasites with a low risk of resistance mutations developing. It’s important to highlight that two of our ACTs have partners that have had no resistance mutations detected (lumefantrine and pyronaridine), even after decades of clinical use in the case of lumefantrine.
4. What are the key priorities in malaria drug research and development?
There are currently three priority areas: developing new medicines for uncomplicated malaria, developing new medicines for severe malaria, and finding new ways to protect people from getting malaria (prophylaxis). For uncomplicated malaria, the challenge is to have medicines that do not produce resistant parasites and also offer the chance of a simplified, shortened regimen. The single-dose cure will be difficult to achieve but would be transformative for malaria treatment. Since more than two drugs are likely to be needed, new molecules must be more and more potent.
Regarding severe malaria, MMV is in partnership with the European and Developing Countries Clinical Trials Partnership and Novartis on the development of cipargamin, which is ready to be tested in patients. Prophylaxis is a key emerging area and we co-sponsored a workshop with the WHO on the ideal prophylactic medicines in December 2020. Last year, 30 million children were protected with drugs as part of SMC. In future, this may be done with an antibody therapy given once per season.
Additionally, we need new therapies that are known to be safe in women at all stages of pregnancy. There is excitement regarding monoclonal antibody therapy for malaria in pregnant women as it is very specific (i.e. lower chances of off-target effects), has minimal transfer to the developing foetus and may be safe even in the early stages of pregnancy.3
1. Uwimana A, et al., “Emergence and clonal expansion of in vitro artemisinin-resistant Plasmodium falciparum kelch13 R561H mutant parasites in Rwanda”. Nat Med. 26(10): 1602–1608 (2020).
2. WHO World Malaria Report 2020: https://www.who.int/publications/i/item/9789240015791
3. Macintyre F et al., "Injectable anti-malarials revisited: discovery and development of new agents to protect against malaria" Malaria J. 2018 Nov 1; 17(1):402.