An approach to pharmaceutical research inspired by open source software development could help find a treatment for mycetoma, a fungal infection that in a significant number of cases can require amputation.
Mycetoma, which can be fatal if left untreated, is endemic in tropical and subtropical regions, according to the Geneva-based Drugs for Neglected Diseases Initiative (DNDi), which is backing the Mycetoma Open Source project along with Erasmus MC and the University of Sydney.
Supporters have already released a manuscript for review, “Addressing the Most Neglected Diseases through an Open Research Model: the Discovery of Fenarimols as Novel Drug Candidates for Eumycetoma”, which will help provide a starting point for the project.
“While MycetOS was developed by participants from the University of Sydney, Erasmus MC and DNDi, it is not ‘owned’ by any of us,” said Wendy van de Sande, associate professor, Erasmus MC.
“This early work merely starts a process of discovering potential new chemical entities for eumycetoma, and we invite anyone interested to identify how they might contribute and participate as an equal partner in this search for a new treatment for this most neglected of tropical diseases.”
“The DNDi is funding the first clinical trial of one molecule, and they need a backup to discover more possible compounds — and we’re the backup,” said University of Sydney Associate Professor Matthew Todd.
Todd last month told the Linux.conf.au conference in Sydney that the project will build on the Open Source Malaria initiative: An effort spearheaded by Todd to use an open source approach in the development of new antimalarials.
OSM is supported by the University of Sydney’s School of Chemistry and the Medicines for Malaria Venture.
In turn, OSM has built on Todd’s experience of a WHO-backed effort to improve praziquantel, which can be used to treat parasitic worm infections, in order to eliminate its side effects.
As part of that project Todd and his collaborators built an online community — The Synaptic Leap — to “connect and enable open source biomedical research” and produced a public online lab notebook. (The approach developed to improving praziquantel during the project has drawn interest from the Pediatric Praziquantel Consortium and from pharmaceutical giant Cipla, Todd said.)
The Sydney Uni researcher told the conference that although there have been a lot of discussions about “open innovation” when it comes to biomedical research, that approach has “nothing to do with open source at all”.
Open innovation has meant putting a problem in the public domain – not the radical experiment, so to speak, in open problem solving being undertaken by the OSM project, he explained.
OSM is currently in investigating its fourth series of molecules that could potentially lead to new antimalarial treatments, Todd told the conference. Although the other three series have stalled, the data is still readily available for further research.
“The current molecules we’re working on – they are very promising,” Todd said. “They’re at the point where you would normally patent the series,” though he said more work needs to be done to understand the mechanism that makes the particular molecule effective at combating malaria.
At the heart of OSM is the concept of an online electronic lab notebook — everything participants do goes online immediately, every day. The project also employs GitHub’s wiki and issue tracking features to help organise tasks, Google Sheets to share data on molecules, and a lightweight website to act as a central hub.
The OSM is underpinned by “six laws of open science,” Todd said:
• All data are open and all ideas are shared.
• Anyone can take part at any level of the project.
• There will be no patents.
• Suggestions are the best form of criticism.
• Public discussion is much more valuable than private email.
• The project is bigger than, and is not owned by, any given lab.
OSM believes that its open source approach can potentially deliver breakthroughs in situations where conventional research approaches won’t.
“The ability of the pharmaceutical industry to provide new medicines cost-effectively is diminishing,” argues a 2016 paper produced by OSM participants including Todd.
“The industry acknowledges that lack of innovation is a problem,” states the paper.
“Pharma is responsible for the creation of most marketed drugs, yet many of these are arguably not innovative; in contrast academia and the biotech industry generate more innovative leads, but many are orphan drugs. Such challenges disproportionately affect research into new medicines for tropical diseases, which would inevitably generate a slim profit margin unlikely to recoup the necessary expenses of research and development.”
A key next step for the project will be attempting to get the fourth series of molecules into clinical trials, Todd said. Doing so would be a world first for a “public domain molecule, where everything is known and nothing is owned,” he said.
More research still needs to be done, and the tools used by OSM also need to be improved, he said.
When it comes to major open source software projects, businesses have made significant contributions, Todd said. However, there has been no equivalent shift within the pharmaceutical industry, he said, though OSM has received valuable contributions from individual experts.
“Openness accelerates research – no one can doubt that,” Todd said. “If you want to collaborate, the best way to do that is to not have secrets; that works fine. But in pharma, who’s going to pay for all this stuff? How is that going to work?”
Open source delivers the “greatest possible community involvement” in developing solutions, but “the transparency brings economic uncertainty in how to exploit the solutions” notes a 2017 PLOS paper of which Todd is a co-author.
“The underlying financial and legal structures of the pharmaceutical industry are designed for use by profit-making entities in ways that rely on monopolies, usually through patents,” the paper sates.
“Under the current model, it is assumed that without exclusive ownership, there can be no guarantee of profit to shareholders—a disincentive for private sector investment in certain areas of health R&D, despite significant public investments.”
However, when it comes to potentially producing an open source developed drug, “the problem is not the finance — the problem is a lack of precedent,” Todd told the conference.
There are already significant funds from philanthropic organisations and governments being put towards drug discovery, he noted.
Patents are not a precondition for the development and production of drugs, he added, citing the examples of penicillin and the polio vaccine.
“Hopefully we can get that precedent we need to show you don’t need to be so protective,” he said.
How it will play out in practice is still an open question, but Todd said he believes that test data exclusivity could be an alternative to patents.
The idea is essentially that if an entity pays for the clinical trials necessary to prove a new drug is safe and effective, it gets the exclusive right to sell that drug in a market for a certain period (for example in the US, New Chemical Exclusivity lasts for five years).
“It’s very attractive because the clock only starts when the drug hits the market, whereas with a patent it depends,” Todd said.
“There’s no law that says you can’t put all that data in the public domain. So there’s a chance you could develop a drug completely [openly] and then be granted some exclusivity — enough to put the price of the molecule at a level which in six years ... whoever wants their money back can get their money back and at the point it goes generic. That could be a way of solving this need for a big investment...”