Open-access research into drug discovery has arrived in South America, with a ground-breaking collaboration between leading scientists in North America, Europe and Brazil to provide completely free and open research results to the world.
British scientists from Oxford University are taking part in highly innovative research into new drugs being launched in the university city of Campinas close to São Paulo, as part of an international collaboration programme that will form a “super-network” of early stage drug discovery. This strategy offers Brazil a cheap way to lay the foundations of an advanced biotech industry in a continent where no such enterprise currently exists.
The University of Campinas (UNICAMP) in São Paulo state, on March 10th established Brazil’s first open-access research facility, the Protein Kinase Chemical Biology Centre. The new US$ 6.2 million laboratory is the third research base established by the Structural Genomics Consortium (SGC) alongside its birthplace at the University of Toronto, and in the UK at the University of Oxford.
The Centre, led by Professor Paulo Arruda of UNICAMP, will examine the protein kinases in the human genome that are key regulators of RNA biology and epigenetics and explore the application of the new discoveries to plant research. The new Centre will advance unrestricted discovery as a member of SGC — a public-private partnership that supports the discovery of new medicines through open access research.
Should there be any doubt about the real value of drugs built around new kinase discovery, pharma major AbbVie recently purchased a company called Pharmacyclics for $21 billion – all because of what experts say is one single asset – a kinase inhibitor.
Previously in 2008, Arruda had shown his credentials as a scientist-entrepreneur by leading the development, build-up and then disposal of two biotech companies to Monsanto for US$290 million. These ventures — CanaVialis S.A. and Alellyx S.A. — had been established with funding from Brazilian industrial group Votorantim. CanaVialis went on to become the world’s largest private sugarcane breeding company, developing and commercializing proprietary germplasm to increase commercial yields for ethanol producers.
“We are especially pleased that this partnership, led by Prof. Arruda and UNICAMP, boosts cooperation between internationally renowned research institutions and the private sector,” said Carlos Henrique de Brito Cruz, scientific director of FAPESP. “This paves the way for a vibrant and self-sustaining bioscience cluster that will bring benefits to the State of São Paulo and to Brazil.”
FAPESP (São Paulo Research Foundation) is providing a $4.3-million (USD) grant, which together with an in-kind contribution of US$ 1.9 million by UNICAMP totals US$ 6.2 million. This will fund Brazil’s first open-access research facility into kinase types.
Researchers in Campinas will work closely with colleagues at the University of Oxford and the University of Toronto to generate selective small molecule inhibitors — or chemical probes — that can be used to uncover new ideas for therapies. In addition to human biology, UNICAMP’s research into chemical probes will uncover new leads in plant and animal biology. So the research has implications for plant crop biology, for animal husbandry and biodiversity.
The human genome contains around 500 protein kinase types. These regulate the splicing of all human genetic material by RNA to create new healthy cells. Disregulation of these kinases is the trigger for most human cancers and complex diseases involving inflammation, infection or neurodegeneration.
After sufficient testing, these drug precursors will be made available to Brazilian and international scientists without restriction on use. The knowledge gained by SGC researchers is shared freely with the world, bound by no patents or proprietary agreements. So this ‘Creative Commons’ is coming to the business of target discovery for drug pipeline research, and Brazil has just leap-frogged its way onto the moving train.
Yet to date 90% of all the research work being done on kinases focuses on just 10% of these substances, which have in the past led to commercially viable drug pathways. With an eye to share prices, risk-averse research institutions have adopted a “sunk cost” view of going further into areas already explored to find new kinase inhibitors, rather than starting afresh in new areas. This explains why huge neurodegenerative disease areas such as Alzheimer’s and dementia remain largely unexplored by the leading drug companies.
“Despite their importance and suitability for drug discovery, only a small fraction of kinases have been studied,” said Arruda. “We will be targeting a list of 26 under-explored kinases that are linked to neurological diseases, angiogenesis, and cancer. They represent a rich source of new biology and are the focus of this proposal. By creating this open access chemistry platform at UNICAMP, we hope to establish UNICAMP as one of the world centers of kinase chemical biology.”
The limited nature of kinase research to date is confirmed by Dr Lee Wen Hwa, the SGC’s strategic alliances manager based at Oxford University. “Kinases are a very particular family of proteins. If you look at all drugs in the market that are trying to fight cancer, the vast majority of them will target a kinase. Yet of the 520 different types of kinases, almost 90% have not been worked on,” said Dr Lee. “We are targeting 26 kinases that regulate very important functions in cellular systems and we hope to tweak the function of these kinases to see what their role is and therefore identify their link to different diseases. This research could potentially impact on the search to cure cancer and inflammation among other diseases.”
SGC is a not-for-profit charity based on a principle that is easy to understand but hard to grasp. Research scientists working together and sharing knowledge in an “open innovation” regime unfettered by rules of intellectual property and commercial secrecy, will come up with solutions faster and cheaper than commercial companies driven by the short-term needs of investors and capital markets. By renouncing the need to work secretly towards valuable patents, the creativity of scientists is unlocked. In some respects it duplicates the popular rural Brazilian mutual support concept of the “Mutirão.”
What’s notable is that SGC is not planning to license or sell back to the drug companies the molecules its scentists develop. They will be given away free to those enterprises able to further their clinical development — in practise only those institutions clustered around the SGC labs in Canada, the UK — and now Brazil.
According to SGC’s Lee, the benefit of the open access model is that it “lets us look into big problems without the pressure of a return on investment that pharmaceutical companies face. These are problems that are too big to tackle alone and we hope that this research is a model for others to follow in the future.”
So far, SGC has demonstrated an astonishing success rate in discovering drug pathways at an accelerated pace, and with resources that are tiny in comparison with the major pharmaceutical companies. The Oxford arm of SGC, for instance, has just signed a UK£30 million (US$ 46 million) deal for a Drug Discovery Alliance with Alzheimer’s Research UK. The work at Oxford will be carried out at the SGC’s labs at the Old Road campus in Headingly.
“Through our international public-private partnership, we are able to support a robust, efficient and effective network that can identify new pharmaceutical treatments to address unmet medical needs in cancer, metabolism, inflammation and other diseases,” said Professor Aled Edwards, CEO of the SGC. “Capitalizing on the outstanding scholarship already present at UNICAMP, supported by FAPESP, a third SGC outpost can be established to further our commitment to open access research and discovery.”
This work is supported by partners in the pharmaceutical industry, including GSK, who contribute both technical expertise and funds to uncover new discoveries in one of the most successful target areas in drug discovery.
Perhaps the greatest tribute is that 11 of the world’s top drug companies are now supporting an initiative that at first glance might appear to compete with their own research activity. In addition to cash, these companies known collectively as ‘Big Pharma,’ have shared important research data on kinase proteins.
In January 2013, scientists from GlaxoSmithKline, Harvard, the Institute for Cancer Research in London, Novartis, Roche, Rutgers, Strathclyde and the Structural Genomics Consortium (SGC) wrote a white paper in Nature Chemical Biology, calling for a global effort to generate chemical probes for protein kinases within an open access public-private partnership.
For Big Pharma, the “sticker-price” of US$1 billion per FDA approved new drug, plus 10+ year timelines for development of new drugs, and a 90% failure rate in research, have all combined to generate a crisis of self-confidence – just at a time when the burden of health cost in developed societies is rising fastest. R&D budgets are falling as Big Pharma pulls out of research and hands this to third parties.
To give an idea of the scale of the “blind alley” that Big Pharma is stuck in, a new report by Jim O’Neill (he who invented the BRIC label) says that drug resistant infections will kill 10 million people a year by 2050, and that the cost to the world economy of antimicrobial resistance will be US$100 trillion. O’Neill believes new diseases that today’s drugs industry can’t find any answers for, will reduce world economic output by up to 3.5%.
So there is a huge pot of gold awaiting a new drugs industry able to restart the stalled innovation process. Yet it just can’t be done in the old way, and even Big Pharma is looking elsewhere for leadership as control of this global industry begins to fragment.
What’s happening is that scientists are proving their ability not only to unlock the primary secrets of how diseases work, but to take responsibility for secondary research activity that until now only took place behind the closed doors of huge pharmaceutical companies – at staggering cost. For a decade, the monolithic nature of drug research by commercial companies has been breaking down under pressures of rising cost, and the task is increasingly outsourced to smaller institutions called contract research organisations (CROs) with one foot in academia, and another in industry.
At a stroke, SGC’s approach eliminates the fatal negation of knowledge-sharing that Big Pharma had fallen into. Research academics live to publish: unless they publish, they can’t get new funding and won’t get more postings, tenure or personal advancement. They have to share knowledge and see their findings rigorously tested in public. Researchers in Big Pharma can’t share anything until it’s strongly patented. That explains why they are so often wrong: at Bayer, only 14 out of 67 drug discovery projects were reproducible. At Amgen, the figure was 6 out of 53. The timeline for development of a drug by Novartis like Glivec is six years.
By contrast, SGC’s open model brought the BRD compound being researched for NUT midline carcinoma through to first study in man in less than three years. 25 companies are now working on BRD inhibition. Because knowledge accumulation in the open access model is free and exponential in growth, the time needed to reach the target validation stage (Phase II clinical trials) is much shorter than the closed model driven by patents.
Since it began in 2004, SGC has developed research teams of around 200. They have examined over 1,500 structures and are generating more than one article a week (total 776). Total funding at this point is an estimated US$150 million – a pinpick in industry terms.
SGC is also working actively with patient groups (sufferers from rare diseases such as progressive lymphoma with no available medication who are funding research) and with organisations focusing on single ailments such as Huntingdon’s disease.
“We are strong proponents of an open public-private partnership to address the untargeted kinome,” said Bill Zuercher, Senior Scientific Investigator, GSK Research and Development. “This Centre will allow us to work alongside other partners in a non-competitive way to share knowledge and access to privileged and valuable research tools that otherwise may have remained unutilized. We are excited and hopeful that this effort will improve our ability to select effective targets for new medicines – even a marginal improvement would significantly benefit patients.”
By exploiting this new alliance with a team of “disruptive” medical science innovators, FAPESP hopes to attract clusters of high-level researchers to São Paulo to reinforce teams already at the University of Campinas. They will join a global initiative to develop new drug pathways, and at the same time will build up what promises to become a pharma-type “silicon valley” around Campinas of contract researchers, drug startups and the financial system of private equity, M&A lending etc, to support them.
In terms of the “cluster effect” bringing industry closer to academic centres, the entrepreneurship ripple effect is already visible in Canada. Start-ups and spinouts based on SGC protocols and discoveries are already operating in Canada and the US. More are raising funds through private equity. And there is already progress towards patents. In the case of Bromodomains (in the epigenetics research cluster), there have been 80 patents filed since 2010, and there are already five Bromodomain inhibitors in clinical trials.
SGC was conceived a decade ago at the University of Toronto by Professor Aled Edwards. He received funding from the Canadian and Ontario state governments. The initiative was created as a not-for-profit institution to promote open access science, 100% in the public domain.
Oxford University followed suit, with support grants in various tranches from the Wellcome Foundation that are reported to total over £50 million. In both Toronto and Oxford the SGC Consortium laboratories have become the centre of academic and semi-commercial activity known as a “research cluster.” The Oxford labs are booming – hundreds work there and a new building is planned to accommodate the influx of commercial and semi-commercial companies needed to make the cluster work.
The step that led to Brazil joining the SGC was the hosting by Nature magazine of an “Open Access Chemical Biology” conference in Campinas in March 2014 (the first Nature Conference in South America). Also last year, Oxford Vice Chancellor Andrew Hamilton visited Brazil – and the result is that FAPESP has joined the consortium. “We are delighted that Campinas is joining Oxford and Toronto in what is rapidly evolving into a global research programme addressing a number of humanity’s leading health challenges,” said Hamilton. “We already enjoy a close and fruitful partnership with FAPESP, and Oxford is planning other research and higher education initiatives with our Brazilian partners.”
FAPESP’s initiative might look like a small one and the money makes it look that way too. But the “flywheel effect” of collaborative research makes this a highly significant investment that could kickstart a whole industry of precisely the type Brazil needs to build a knowledge society and escape from dependence on export of commodities for its economic future.
As research at SGC UNICAMP is transformed into commercial opportunity and industry in São Paulo state pays taxes, that in turn are partly transformed into further research funding, the “virtuous circle” is strengthened.
SGC’s decision to come to Brazil and to share its ethos of open innovation is a vote of confidence in the emerging “knowledge society” of São Paulo state and the region’s ability to provide the kind of infrastructure needed for the seeds of a state-of-the art pharmaceuticals industry to be nurtured toward fruition.
For FAPESP, this could turn out to the “best US$6.25 million ever spent,” if the pattern already proven at Oxford and Toronto is repeated in Campinas – as it will be.
So FAPESP has laid the foundation stone upon which a whole new industry can be built.
** SGC is funded by Abbvie, Bayer, Boehringer Ingelheim, Canada Foundation for Innovation, Eli Lilly Canada, Genome Canada, GlaxoSmithKline, Janssen, Merck, Novartis, Ontario Ministry of Research & Innovation, Pfizer, Takeda, and the Wellcome Trust. For more information about the Structural Genomics Consortium, please visit www.thesgc.org