Open drug discovery of anti-virals critical for Canada’s pandemic strategy

Open science can accelerate mission-oriented research. For example, the sequencing of the human genome constituted one of the greatest scientific achievements in history. In under 15 years, the project went from conception to completion. Its success is not solely due to technological advances, however. The Human Genome Project would never had succeeded as quickly, or provided its immense social and economic good, had the scientific community not carried out its science under open science principles. This transformational position allowed scientists, institutions and nations to set aside proprietary interests, which had been delaying progress, and instead focus on coordinated collective action, on reducing duplication of effort, and on providing freedom for innovators to use the information to advance both public and private-sector R&D. In sum, open science underpinned the project’s success. Other sequencing initiatives have followed suit, including sequencing efforts for other model organisms and pathogens. Researchers continue to add value to public genomics databases, such as GenBank, by contributing improved or new data, or by adding to new knowledge through the annotation of gene function. The rapid sharing of the SARS-CoV-2 genome by researchers in China initiated R&D of diagnostics, therapeutics and vaccines around the world.

Current open science initiatives for COVID-19 mirror longstanding, global initiatives to render research publications, reagents, and data more open and accessible. Access to knowledge, data and reagents facilitates transparency, provides opportunity for replication of results—an essential component of the scientific method—avoids duplication of effort, and leads to novel hypotheses and avenues for research. Without restrictions imposed by intellectual property rights, such as patents, follow-on research is unencumbered. In other words, follow-on-researchers are assured of their “freedom-to-operate”, i.e., to use, improve on knowledge, data and reagents, and potentially to commercialize resultant innovations.

In the context of COVID-19, publishers of scientific journals and research funders around the world have committed to making preprints of submitted but not yet peer-reviewed articles and peer-reviewed research articles freely available (OASPA 2020). The publishers have further committed to ensuring that COVID-19 submissions include a data availability statement, which conforms with the FAIR principles of the Research Data Alliance; these apply to data (or any digital object), metadata (data about the digital object), and infrastructure. FAIR data are Findable via metadata and identifiers in a registry or searchable resource; Accessible, including openly or via authentication or authorization; Interoperable with other data, applications or workflows; and Re-useable, meaning the metadata and data are well-enough described so that they can be replicated or combined in different settings (Wilkinson et al. 2016). Building on open research datasets, other initiatives are providing automated tools for analysis. Others have pledged to make their “intellectual property available free of charge for use in ending the COVID-19 pandemic and minimizing the impact of the disease” through licensing (Open COVID Pledge 2020). Similarly, in Canada and globally, genomics initiatives, such as CanCOGEN (genomecanada.ca/en/cancogen) engaged in COVID-19 related research deploy open science principles; however, a discussion of these initiatives is beyond the scope of this article.

Canada hosts world-leading open science initiatives in support of precompetitive biomedical R&D. For example, the Structural Genomics Consortium (SGC) is a global public–private open science partnership with a Toronto campus that carries out early-stage drug discovery research and makes all its output freely available. Its funding and drug discovery partners include national and provincial funding agencies, global Pharma and biotech companies, patient organizations, and disease foundations. Its work in ascertaining the three-dimensional structure of medically relevant proteins accounts for 15% of global output of new human protein structures (thesgc.org). Leaders of the SGC in 2011 noted that 75% of research on human proteins still focused on 10% of proteins, many of which were known prior to the mapping of the human genome in 2001 (Edwards et al. 2011). They noted, however, that the unrestricted availability of high-quality tools, in this case chemical probes for identified druggable targets on the proteins, led to diversification of research. In response to this observation, the SGC began to make available high-quality chemical probes to support drug discovery (Edwards et al. 2009). The chemical probes against novel protein targets are made available to the scientific community without IP restrictions, enabling scientists around the world to interrogate the biological function, disease relevance, and druggability of these proteins. The open accessibility of these SGC chemical probes (more than 25 000 samples have been distributed to scientists around the world) has spurred downstream innovation in clinical development against novel disease targets, including here in Canada (Arshad et al. 2016). The first chemical probe (inhibitor) against the WDR5 protein, part of a very important protein family mutated in cancer, developed through an open science collaboration between the SGC and the Ontario Institute for Cancer Research (OICR), formed the basis of a promising novel leukemia drug by Toronto-based start-up Propellon Therapeutics (Gold and Morgan 2019).

The SGC shares all of its data and materials without restrictive intellectual property (IP). Within weeks of the release of the SARS-CoV-2 viral sequence, the SGC had purified half of the ∼25 different SARS-CoV-2 proteins and had begun to distribute them to Canadian scientists in all sectors. These proteins are key reagents to develop medicines, serve as potential vaccine candidates, and facilitate the development of serology diagnostics. Similarly, the Toronto-based Centre for Phenogenomics (TCP) is part of an international network of data and biorepositories for rodent models for biomedical R&D. Biorepositories, such as TCP and its US equivalent, the Jackson Laboratory (JAX). This networks simplifies the exchange of rodent reagents (e.g., sperm, embryos, mice, rats) and associated data as freely as possible via simplified conditions of use, which reduce transaction costs otherwise associated with more complicated material and data transfer agreements (MTAs and DTAs) (Bubela et al. 2017). TCP is in the final stages of validating its COVID-19 mouse model, essential for pre-clinical research, for distribution to the Canadian research community.

Drug discovery norms dictate that ideas from academia should be tested in clinical trials by the private sector, thereby shifting along the drug discovery continuum from precompetitive to competitive research, protected by patents and other forms of intellectual property. Indeed, many of the downstream efforts following on from SGC’s open science projects have followed this path. The OICR and its commercialization arm, FACIT, recently sold the Propellon Therapeutics leukemia program to Celgene in the largest deal for a preclinical drug in Canadian history (OICR NEWS 2019). This traditional approach has the advantage of attracting venture financing for further development of the drug, but in the absence of alternative models, the quid pro quo is that any knowledge gained remains proprietary, and private sector pressures influence the research agenda and potentially the accessibility and affordability of any drugs that receive market authorizations. The development of the Ebola vaccine out of the Public Health Agency of Canada’s Winnipeg laboratories and the subsequent public sector trialing of the vaccine following the 2014 Ebola outbreak, demonstrates the feasibility of a public sector-led drug development (Herder et al. 2020).

Given that the “first-in-man” test of an innovative idea or target is at its core a fundamental research exercise and a public good, open science is particularly apt, in the context of a pandemic, to carry out target and drug development through to end of Phase 1. Spreading risk across sectors and placing data in the public domain not only decrease duplication and increase coordination, but also ensures that another actor can accelerate its own development or pick up a project dropped by another. The SGC is pushing the boundaries of open science along the drug discovery continuum through the incorporation of a series of not-for-profit drug discovery companies (Edwards et al. 2017; Morgan et al. 2018). For example, the SGC spinoff, M4K Pharma Inc., is starting Investigational New Drug (IND)—enabling studies for a rare childhood brain cancer, diffuse intrinsic pontine glioma. M4K Pharma’s mission is to deliver safe, efficacious, and most importantly, affordable medicines that enable access to the patients that need them. M4K Pharma R&D is supported by multiple public, private and philanthropy funding sources, including the Ontario Institute for Cancer Research (OICR).

M4K Pharma follows the SGC model in rapidly sharing knowledge, results, data, and materials without patent restrictions (Morgan et al. 2018). These practices are inconsistent with a patent position that rewards inventions that are not already in the public domain. The patent bargain exchanges a 20-year right to exclude others from practicing the invention in exchange for the public disclosure of the invention in the patent document. Patents are published 18 months after the initial filing date of the patent, which should contain enough information that a skilled person could practice the invention. In reality, 18 months is not only too late during a pandemic but the information is rarely readily usable without the tacit know-how only shared through person–person collaboration or through licensing agreements. Costs for prosecuting the set of patents that would cover all aspects of drug discovery (e.g., the active ingredients, the formulation, the methods for manufacture, new uses, dosage forms) in multiple jurisdictions are in tens to hundreds of thousands of dollars and then enforcing those property rights against infringement, for example through litigation against would-be generic competitors, can run in the many millions of dollars.

How then, might an initiative or entity, such as M4K Pharma, retain control over its innovations to ensure it can deliver on its mission of affordable and accessible medicines? Patents are generally considered to be the most powerful tool to control an invention. Their purpose in drug discovery is to prevent generic or other competition, extending the patent term for as long as possible to command a monopoly price.

Instead of patents, we recommend using regulatory data protection and market exclusivities as mechanisms of control (Morgan et al. 2018). These regulatory mechanisms, described in detail in Morgan et al. (2018), arise automatically upon registration of a new compound as a drug, without additional cost, offering powerful protection, irrespective of patent protection or remaining length of the patent term. Data exclusivity is granted by drug regulatory agencies, such as the FDA, Health Canada, and the European Medicines Agency, over the information package on preclinical and clinical studies that support the case for market authorization for the intervention in question. Their effect is to prevent other companies from relying on these data for set periods of time (5–12 years), and often extend beyond the expiration of the 20-year patent period, most of which is lost during the 10–14 years it takes to bring a drug to market (Hay et al. 2014). Prior to expiry of data protection, to obtain marketing authorization, a would-be competitor would need to complete an entire preclinical and clinical development program sufficient to support its own independent product dossier, which in practice acts as a potent barrier to entry. Regulatory exclusivities provided to orphan disease products and novel antimicrobials offer even broader market protections (e.g., the 2012 US Generating Antibiotic Incentives Now (GAIN) Act) (Darrow and Kesselheim 2020).

Generic companies are able to produce off-patent drugs more cheaply because they can reference the information held by the regulators about safety and efficacy, without the added cost of repeating the studies. Regulatory product dossiers protected by data exclusivity provisions can therefore be licensed to enable manufacturing, impose price caps and to ensure global access. The benefit of relying on data exclusivity is that, unlike patents, it is not invalidated by prior public disclosure, making it possible to share scientific progress openly and quickly (Morgan et al. 2018). It also eliminates the additional costs of seeking patent protection and enforcing patents. Further, it does not preclude or require lengthy negotiations for follow-on innovation, as independent invention is not precluded by it.

An anti-viral drug discovery program requires coordination of multiple, parallel, projects to feed a drug discovery pipeline and overcome failures in collective action. One model for such an approach is DNDi, the governance structure of which reduces roadblocks to collaboration while promoting follow-on R&D, manufacturing, and equitable and affordable access to its products (DNDi.org). Its Intellectual Property Policy specifies that wherever possible, the results of its work are placed in the public domain; patenting is the exception, and the need for any form of intellectual property is judged on a case by case basis (DNDi 2018). Patents are not utilized to seek rents or pose barriers to follow-on research but may be used to negotiate contracts that result in the greatest benefit for the neglected patients. DNDi may also acquire rights to technologies to enable further research and access to patients. To date, DNDi has developed a new all-oral curative drug, Fexinidazole, for sleeping sickness, caused by the parasite T.b. gambiense (DNDi: Drugs for Neglected Diseases Initiative 2020b), pediatric treatment for Chagas disease, a strawberry-flavoured pediatric treatment for HIV, and cheaper treatments for hepatitis C, and it has active drug discovery programs for visceral and cutaneous leishmaniasis, Chagas disease, filaria (river blindness), and clinical trials for mycetoma (DNDi: Drugs for Neglected Diseases Initiative 2020c).

Bringing together the coordinated governance structure of DNDi and the open science approach of the SGC and M4K Pharma, Canada and the global community have the opportunity to undertake international pandemic preparedness anti-viral drug discovery initiatives. Two such initiatives have been launched in the US (READDI.org) and Canada (VIMIpen.org). Working in concert, these initiatives will coordinate and evaluate anti-viral candidates from academic or other centres that agree to abide by its open science principles in the context of pandemic preparedness. Their coordinated activities cover target discovery, with a focus on novel targets on human proteins (not viral proteins), such as those that help the virus evade the host immune system or enable the virus to infect human cells; identification of promising compounds that hit those targets, development of early lead compounds; lead optimization and candidate selection; preclinical enabling studies of promising candidates; and Phase 1 studies for safety and dosing in health volunteers. Validated compounds are poised to deploy in Phase 2 and 3 studies if and when a new virus emerges. With guaranteed State and philanthropy funding for clinical trials, manufacture, and use, Pharma and generic firms will be ready to participate to stave off a pandemic and its economic and social consequences. These private-sector participants would be guaranteed a reasonable return on any late-stage investments, but price caps would acknowledge the upfront and risky State and philanthropy contributions to R&D.

Rapid placing of methods, reagents, data, and analyses into the public domain creates prior art that prevents others from patenting around the initiative’s products and methods. The initiatives retain rights over data packages submitted to regulators on preclinical and Phase 1 clinical studies as a powerful form of intellectual property that can be used to exert control. A consolidated governance structure enables the use of standard form agreements that support socially responsible licensing strategies for data and reagents (Roskams-Edris and Gold 2019). As evidenced by the DNDi and SGC, such initiatives attract partners in all sectors to work with leading researchers and institutions, enabling access to knowledge and research infrastructure. These partnerships especially benefit researchers in small and medium-sized enterprises (SMEs) who might otherwise not have access to cutting edge know-how and equipment. For example, partner artificial intelligence drug discovery SMEs would have the opportunity to develop, test, and improve their proprietary computational algorithms and models through access to the initiative’s experimental data (Gold et al. 2019).

Alternative models to overcome the challenges of drug discovery for neglected and pandemic diseases include patent pools and patent clearinghouses. A patent pool is an agreement between two or more patent owners to license their patents to one another or to third parties. Patent pools are often associated with complex technologies, with inter-depending technological requirements (Aoki and Schiff 2008). Examples in drug discovery include the United Nations supported Medicines Patent Pool, which has signed agreements with 10 patent holders for thirteen HIV antiretrovirals, one HIV technology platform, three hepatitis C direct-acting antivirals, and a tuberculosis treatment to enable generic manufacture of low-cost doses of drugs for use in low-resource settings (Medicines Patent Pool 2020). Two forms of clearinghouse exist: those that provide information about intellectual property, or those that facilitate the licensing of intellectual property. These are most prevalent in industries requiring firms to clear copyrights, for example in the music industry (Aoki and Schiff 2008).

Patent pools and clearinghouses have limited value during a pandemic. Both are ex ante solutions to the problem of restricting freedom to operate in follow-on R&D. They are analogous to closing the barn door after the horse has bolted, or in this case, after the delays caused in patenting and negotiations have been expended. While some firms have agreed to an Open COVID Pledge to render all COVID-related intellectual property accessible during the COVID-19 crisis (Open COVID Pledge 2020), this has engendered resistance from the pharmaceutical industry, thus causing further delays (Silverman 2020). Similarly, government mechanisms to force access to drugs, such as compulsory licensing, or to gain access to therapies developed using public research dollars, such as the U.S. National Institutes of Health march-in rights, have rarely been used and are again post-hoc remedial actions for the excesses of the patent-based system (Bubela and Cook-Deegan 2015; de Beer and Gold 2020).

Despite the benefits of open science, its implementation further along the drug discovery continuum faces critical barriers to success. These barriers include: (1) strongly held norms, especially by government decision/policy-makers, academic institutions, and some prominent researchers, that early-stage patenting is necessary to support or finance drug discovery and delivery; (2) incentive structures for promotion and tenure, and public research grants that favour and often mandate patent holding; (3) a lack of knowledge about the ways in which open science reduces transaction costs and accelerates research across the research and drug discovery continuum; (4) the absence of funding models to support open academic and commercial research; (5) a peer-review and financing system that favours low-risk research; and (6) too few successful examples to build confidence among governments and industry in the benefits of open science. Most significantly, substantial and long-term funding by governments and philanthropies is required to even get these partnerships off the ground. Governments need to recognize the return on investment that derives from reductions in future health system costs, which are promised by open drug discovery initiatives.