Opening up malaria drug discovery for good

A Kenyan women poses with her baby son Ethan, who was in the hospital for 2 weeks with malaria. Photo: PATH/Gabe BienczyckiGlobal efforts to tackle malaria have proved hugely successful over the last 16 years, with more than 6.8 million lives saved. Yet, these gains are at risk. As we are seeing across all microbial diseases, the development of drug resistance is a huge threat. There is an urgent need to discover new medicines with novel mechanisms of action able to treat resistant parasites to ensure malaria patients can continue to be cured and we can continue the drive to end malaria for good.

The traditional approach to drug discovery is clothed in secrecy, as scientists compete to find the next billion-dollar blockbuster. For "diseases of poverty" such as malaria, however, the low commercial value of the end product means that the need for confidentiality and competition is reduced, if not counterproductive. Scientists across the world are now starting to open up drug discovery research for these diseases with exciting results.

MMV’s approach for malaria

Medicines for Malaria Venture (MMV) is a nonprofit organization working with partners around the world to bring forward the next generation of antimalarials to tackle challenges like drug resistance. Our approach to drug discovery is “open innovation.” Over the years, we have built up a community that shares data and assays among a set (or subsets) of partners for a given project or projects. These open innovation projects are not transparent to the outside world, rather they operate within contractual “bubbles,” with a semi-permeable membrane securing confidentiality.

For example, from 2008 to 2014, MMV and partners conducted an extensive screening campaign to stir up new chemistry for drug discovery projects. More than six million compounds were screened against the parasite, generating tens of thousands of new chemical starting points. One series, known as the aminopyridines, were identified through a screen performed by scientists from Griffith University, Australia. The series was then selected and explored further by a team of scientists at the University of Cape Town, South Africa, working in collaboration with scientists at MMV. With parasitological support from the Swiss Tropical and Public Health Institute and drug metabolism expertise from Monash University, Australia, the South African team selected the most promising compounds from the series for optimization and re-testing. In 2014, it became the first new antimalarial medicine to enter phase 1 studies in Africa. Today, preparations are being made to begin a phase IIa trial on this promising compound as a single dose cure.

The advantage of this open innovation approach is that it allows MMV to tap into a wide range of expertise and existing research facilities—as well as share early proprietary knowledge among a select group of partners—together with risk, cost, and effort.

Opening up beyond malaria

With the success of the screening campaign and open innovation approach for malaria research, we were keen to apply the learnings and lessons to other neglected diseases. In 2010, following the screening campaign, GlaxoSmithKline, the Genomics Institute of the Novartis Research Foundation, and St Jude Children's Research Hospital in Memphis, Tennessee, released the details of 20,200 compounds active against malaria into the public domain. The research community responded largely with enthusiasm, yet many felt blocked without physical access to the compounds.

MMV responded in December 2011 by launching the open access Malaria Box, making 400 diverse compounds divulged by the screening campaign available for free. Since its launch, more than 250 copies of the Malaria Box have been delivered to researchers in 30 countries to catalyze malaria and neglected diseases drug research. All that was asked in return was that the researchers continue the virtuous cycle of sharing and collaboration by releasing their data into the public domain.

Researchers screening the Malaria Box found hits against 16 different protozoa, seven helminths, nine bacterial and mycobacterial species, as well as the dengue mosquito vector and human cancer, many of which are undergoing further research today. The big lesson here is that compounds active against one disease (malaria) can be repurposed for a range of other diseases. Based on this and the successful uptake of the Malaria Box, MMV launched the Pathogen Box in 2015, comprising 400 compounds with activity against malaria or one of a range of other neglected diseases. This box, alongside several Challenge Grants awarded to promising projects, are not only catalyzing neglected diseases drug discovery, but also helping to support researchers in disease-endemic countries and bringing forth future generations of scientists.

In this vein, our next initiative is the Pandemic Box, which will include antiviral and antibiotic compounds—again, at no cost to researchers. The goal is to provide chemical starting points for drug discovery for diseases like Zika and Ebola, as well as repurpose compounds for malaria and neglected diseases. This will be a joint project between MMV and Drugs for Neglected Diseases initiative.

Can we open up further?

Exploring the possibility of working completely in the open, in another project with Dr. Mat Todd of the University of Sydney, Australia, we have broken the membrane and created an Open Source Malaria drug discovery project. Essentially, everything related to the project is entirely in the public domain so that anyone, anywhere can follow and contribute. The idea is that it will work by “natural selection”—anyone can work on the shared data and, over time, the project will evolve. In this case, the best ideas will be prioritized and a new candidate drug for malaria will hopefully emerge.

So far, the project has taught us that there is a enormous willingness to contribute and share expertise, but money and resources are still rate limiting. If people don’t synthesize compounds in a reasonable timeframe, research comes to a halt. MMV believes in open source approaches, but realizes they need a sustainable supply of resources and more importantly, focus. With limited resources, it is important to prioritize the most promising ideas.

Working in partnership to end malaria for good

These different knowledge-sharing projects clearly demonstrate that through collaboration we can achieve so much more than if we go at it alone. Since 2010, MMV’s collaborations have delivered 17 candidate molecules for malaria. This has created a strong pipeline, but many more candidates are needed if we are to succeed in defeating malaria. We continue to enlarge our partnership network and explore new ways to open up drug discovery research for the global good.