Open Innovation Platforms to Boost Pharmaceutical Collaborations: Evaluating External Compounds for Desired Biological Activity

Keywords::

• collaboration
• drug discovery
• open innovation
• partnership
• pharma R&D

Open innovation (OI) has become a hot topic within industries relying on innovation. The use of OI to boost corporate innovation is fairly well established and other industries have adopted the concept of actively and decidedly seeking external input to internal innovation. OI is therefore complementary to traditional innovation where proprietary innovation is solely conduced in-house. The reason of why companies open up their innovation process is to stimulate growth and, to lesser extent, defensive motives such as a reducing cost. Also in the pharmaceutical industry, the concept of OI has received a fair amount of attention as a possible countermeasure to the general decline in R&D productivity [1]. Even though OI has been in use for more than a decade [2], it has not yet been broadly implemented by the pharmaceutical industry and many different variations of practical execution exists. In addition, the concept is not clearly defined, in particular, the degree of openness and associated legal and business constraints are not fully aligned in the industry. One specific aspect of OI involves sourcing of external compounds to provide alternative chemistry for screening campaigns or to more easily explore collaborations. This article aims to provide an overview of the current existing OI platforms that provide biological testing of external compounds. Furthermore, the intention is to provide an objective overview of such OI platforms and describe the purpose, setup, constraints and possible benefits for both the innovation seeker (in this case, the pharmaceutical company providing an OI platform with the means to test compounds for desired bioactivity) and provider (the external partner with chemistry assets in the form of compounds).

The fully integrated business model of many large pharmaceutical companies is being questioned and might no longer provide an optimal solution for discovering innovative drugs [3]. The traditional research business model can be considered to be ‘closed innovation’ with need for complete confidentiality and well-protected intellectual property (IP). With a fully integrated pharmaceutical business this has been the preferred and, in many cases, a very successful model. However, with increasing competition and technological advancement, it has become clear that it is no longer feasible to maintain a completely closed model, and external collaborations are more actively pursued. With growing determination, the pharmaceutical industry is reaching out to external partners in an effort to boost internal innovation by collaborations [4]. The realization that a company cannot only rely on internal expertise should be followed by the implementation of a process that is able to identify and capture external proficiencies. Furthermore, the speed of which new technologies are emerging is increasing and it is not feasible to adapt and implement all possibilities internally. Instead, an alternative option is to establish a platform capable of assessing such external technologies.

The discovery and development of new chemical entities is probably the most fundamental part of the traditional pharmaceutical industry and is focused on creating innovations based on medicinal chemistry. In order to further boost such innovations, pharmaceutical companies use both internal and external sources to identify and design compounds. The acquirement of external compounds for drug discovery can be accomplished in many different manners, for example, purchasing from compound and library vendors, in-licensing, partnerships and co-development collaborations. With the desire to increase compound sourcing, alternatives to traditional collaborations are emerging in the form of OI platforms for testing external partners’ compounds in a mutually beneficial setting.

Enabling new opportunities through open innovation

The OI approach allows external parties to, by their own initiative, provide compounds for testing by the pharmaceutical company. Ideally the OI platform does not only provide an entry point for compound submission, but also discloses some of the company's capabilities, desires or research focus. By providing a process for external partners, the OI platform extends an invitation to participate in the pharmaceutical company's research. If the invitation is attractive, the external partner can initiate the collaboration, through which they may gain access to opportunities that might otherwise be unavailable at their pharmaceutical company. In this specific case, the opportunity is the testing of, otherwise inaccessible and unknown, novel compounds for relevant biological effect. As the success of the OI platform relies on the external partner's initiative, it is important to provide a mutually beneficial model that respects both parties. Some of the major points that require mutual respect include; IP rights, use of generated data, confidentiality and cost. These are all important factors that are critical both for the OI platform provider as well as for the potential external partner.

The opportunity that the OI platforms provide is, for the pharmaceutical company, the chance of expanding the chemical space by exploring the biological effect of otherwise unknown compounds and identifying a new collaboration possibility. And, the opportunity for the external partner is the chance to expand the scope of the compounds, explore new areas of biology, increase asset value, create awareness and establish relationships, as well as gaining scientific data that often can be published.

In summary, some of the reasons why the pharmaceutical industry is looking for new ways to innovate are the lack of R&D innovation and the realization that leading experts reside outside the company.

Open innovation versus traditional collaborations

The general intention of the OI platforms is to explore and access chemistry outside the usual internal borders. This is nothing new per se, as the pharmaceutical industry is already trying to increase the diversity of the internal screening libraries and access more or less advanced compounds via external collaborations. But the necessity for change in the traditional collaboration process comes from several aspects, such as the need to increase speed, lower the barrier, reduce the distance between partners and the science and include ‘nonobvious’ opportunities. By implementing OI, the company seeking compounds increases the chances to attract an external partner with novel chemistry. In turn, compound providers can increase their chances of finding a science or development partner, investor or buyer by participating in OI.

Increase speed

Traditional partnering processes can be lengthy and much effort is typically spent on business terms and legal contract details in the Material Transfer Agreement (MTA). The negotiation of the MTA is the single biggest hurdle and impeder of collaborative research [5], and much effort in OI is spent on establishing mutually respecting generic contracts that require minimal negation to sign. This is often achieved by keeping the contract very specific and with a clear ‘exit door' available for both the parties. However, the specific legal details of the different OI platforms vary greatly as they include several different aspects. First, it is in the OI platform provider's interest to minimize the possibilities of misuse of the platform, to avoid contamination of internal medicinal chemistry as well as ensuring the external ideas (i.e., compounds) actually can be used by the company.

In addition to these aspects, it is also critical to ensure the external partner's integrity is respected, as well as, secure the assets in form of novel compounds. In the interest of increasing the speed of which the agreement is signed, the legal description of the OI should take both parties’ interest into consideration. An external partner needs to recognize the security and trust the OI initiative in order to volunteer engagement. The OI contracts are often provided as generic documents with a lower level of legal details as the purpose is very specific and well defined. The intention is to provide an easy-to-accept contract that requires no or very little negotiation. With such a contract in place, a significant increase in speed can be obtained and the actual time spent on signing the MTA can be greatly reduced.

Lower the barrier

Exploring new possibilities with a potential external partner should ideally be of low complexity and focused on finding overlap in assets, that is, can your compound provide a desirable function? The OI platforms focus more on the science and exploration of opportunities, while letting the external partner decide to continue or not. The external partner usually remains in control throughout the process and can therefore commit more easily to the initiation of the compounds testing.

Ideally it should be easy to put your hypothesis to the test and readily evaluate if your asset, in form of a compound, can provide biological function that is attractive for the OI provider, the pharmaceutical company. A lower barrier will enable testing of unproven ideas and focus on science generation as part of the early exploration phase. Similar to the increase speed argument, the barrier is often related to contractual and legal issues, but can also be of a more practical nature. OI platforms often provide the partner with physical compound transfer solution in either prelabeled vials, tubes or microtiter plates in order to minimize the hurdle of entering the internal compound management process.

Reduce the distance between partners & the science

Traditional partnerships can be surrounded by a high level of confidentiality to protect both parties’ IP and know-how that can hinder the scientific discussion. This is often the case in order to protect IP, but a science-focused collaboration can more easily result in additional discoveries and spin out research projects [6]. The OI platforms often offer a more science-focused approach with the intention to create a dialogue between the internal and external scientists, both in order to learn, clarify and possibly provide guidance for next steps. The exact level and detail of disclosed background science varies between OI platforms. The results of the testing is usually shared and often provided for the external partner to publish, unless business collaboration is pursued. By providing information and/or access to specific biological assays, as well as sharing the results, the distance between the two parties can be reduced with the intention to increase the likelihood of new compounds with desired biological effect being discovered.

Inclusion of ‘nonobvious’ opportunities

This is an important difference to traditional collaborations, which usually rely on outsourcing of a predetermined solution concept while OI can potentially provide solutions that you didn’t know you could ask for. As an example, traditional one can identify a partner capable of designing a novel compound for a specific target, while an OI approach could provide a functional compound with a novel mode of action. However, it is essential that the OI platform provides the means for an external partner to understand the desired outcome in order to suggest a compound with a novel mode of action. In the specific case of testing compounds, this boils down to disclosing the exact platform that is being used to test the compounds, as well as providing a functional cell-based assay capable of responding to different pathways. Disease-relevant phenotypic assays can provide such functionality and are excellent in vitro tools to explore potential novel compounds, especially, if there is an established translational link from the phenotypic assay to more advanced models. OI platforms exist that provide both phenotypic and target-based assays. In the case of target-based assays, most of the innovation potential comes from the structural novelty of the compounds.

By providing information of what the OI platform is aiming to achieve, for example, in the form of open disclosure of assay details, there is a great potential to discover compounds with desired functionality, and with nonobvious mechanisms.

The general setup of OI platforms to evaluate compounds for biological activity

OI does not have to mean that everything will be disclosed to everyone. The provided OI platform is ‘open’ from the perspective that it is officially announced, described, shared and accessible to external partners. However, the contract defining the framework also describes a strictly protected process where the partner's involvement, compounds and results are secure and only directly discussed between the partner and the platform provider (or during some initial phases via a third party independent evaluator).

The intention is to list currently available OI platforms that provide means to test external compounds for biological activity. Most of the mentioned platforms are offered by large- or medium-sized pharmaceutical companies. Also, the intention is to present an overview of the process as well as critical differences. As an aside, in addition to provide biological testing of external compounds, many other OI and open science initiatives exist, both in pharmaceutical industry as well as in academic settings, challenging current drug discovery models [7].

In general, the OI platform providers are looking for novel and drug-like chemistry that can be readily incorporated into the existing internal screening libraries, or be tested more specifically in physiological or disease-like in vitro models. Engaging in an OI process usually includes:

• ;Signing of a generic contract (both parties);

• Submitting digital information of the compound;

• Acceptance by the pharmaceutical company to receive the compound physically;

• Testing of the compound in either disclosed or undisclosed biological assays;

• Communication of results to the external partner and possibly, with further intentions.

Existing OI platforms that provide opportunities to evaluate compounds for biological activity

At this point, five pharmaceutical companies provide OI platforms focusing on evaluating external partners’ compounds in order to identify either chemical novelty to add to the internal screening library, or biological functionality to pursue via further collaboration or in-licensing. Table 1 shows a brief overview of the currently available pharmaceutical OI platforms for evaluating external partner's compounds. The order of appearance is based on the year in which the OI platform was launched.

Eli Lilly (2009)

Lilly is the official pioneering pharmaceutical company with a long standing OI initiative, including the OI Drug Discovery (OIDD) platform, providing both phenotypic and target-based screening assays [8]. The OIDD initiative has provided Eli Lilly with chemistry from both academia and biotechnology companies since 2009 and has proven to be a source of biologically active molecules that significantly complements the internal Eli Lilly compound collection [9]. The platform offers testing of compounds in both disease-relevant phenotypic and target-based assays. The provided assays are proprietary and undisclosed but permission can be given to publish results as well as the assay methods. Focus diseases include tropical and neglected diseases, diabetes and oncology, as well as emerging internal projects.

The process is initiated by registration on the OIDD web portal followed by digital submission of compounds structure to firewalled third party for calculation of fingerprints and database similarity searches. Compounds are selected by Eli Lilly for biological screening based on in silico difference to known compounds, drugability as well as availability of internal screening resources. Eli Lilly choose to invite participants to submit compounds physically, which in case they ask for 3–5 mg of compound to submit in provided vials. Participants get access to generated data upon completion and are encouraged to contact Lilly in order to publish. In business terms, Eli Lilly has first right to negotiate during a 180 day period.

Merck Serono (2012)

Merck Serono's OI portal, and specifically the Open Compound Sourcing initiative, was established in 2012 with the purpose of inviting potential partners to submit compounds to be included in high-throughput screening libraries [10]. With the compound sourcing process, Merck Serono is specifically looking for novel organic chemical compounds for testing in screening campaigns to provide starting point for further optimization. There is public access to the OI portal front page [11], but any details about specific programs, such as Open Compound Sourcing requires registration and Merck Serono's approval.

Upon digital submission of structural information, chemical and physical properties, an in silico evaluation determines if the compounds are to be accepted and incorporated in the screening libraries. If the submitted compound (in the form of 20 mg in crystalline powder) passes an additional quality check, the external partner will receive a reward of €200 for an exclusive compound and €100 for a nonexclusive compound. If the compound is identified during screening, a subsequent collaboration and patent application including five analogs could result in a total financial reward of €20000. Biological data from screening campaigns will not be shared to the external partner. The legal contract ‘Participation and Material Supply Agreement (P&MSA)’ covers legal, IP and commercial aspects of transferring novel small organic compounds to Merck Serono, who claims perpetual rights to use obtained data.

Bayer Healthcare (2013)

The Grants4Leads [12] platform was established in 2013 and offers cash rewards for accepted compounds and the setup resembles a funding application process with an initial reward of €5000. The intention of Grants4Leads is to investigate novel chemistry that the external partner already has identified as leads compounds with promising biological activity in their own assays and models. This platform differs in the way that it does not necessarily generate new biological data initially, but depends on the external partner's data for the first evaluation, which if successful, could lead to further biological assessments.

The therapeutic focus is oncology, cardiology, hematology and gynecology, but the actually used biological assays are not disclosed. The online digital submission, including external participant's own biological data is evaluated based on molecular descriptors, documented biological activity and the patent situation that could warrant a reward if found to be interesting. The decision to offer a grant or enter collaboration is made at the sole discretion of Bayer. The submitted information is nonconfidential, but structural information is not required during the initial steps.

AstraZeneca (2014)

The OI platform, New Molecule Profiling, for testing compounds was launched in early 2014 [13] and AstraZeneca will test compounds in their screening campaigns against disease-relevant targets. The initial phase of the process includes signing a contract with AstraZeneca's third party service provider to explore the properties and therapeutic innovation potential by using advanced in silico cheminformatic analysis. The external partner is invited to sign another contract after the digital evaluation is successfully completed and compounds are accepted by AstraZeneca for screening.

The New molecule profiling initiative offers testing of compound libraries, up to 1000 as part of standard process and 1000+ after agreement. The partner is provided with the results, which it may publish. The primary focus is AstraZeneca's key therapeutic areas such as cardiovascular and metabolic diseases, oncology and respiratory, inflammation and autoimmunity. There are no obligations and the external partner is always in complete control of the decision to move to the next step, if such opportunity is presented. From a business contract perspective, AstraZeneca retains the rights of first negotiation, should it become relevant.

LEO Pharma (2015)

LEO Pharma OI [14] was launched in March 2015 in order to meet an increasing need to explore potential collaborations by allowing external partners access to disease-relevant in vitro assays. The offered in vitro assays are fully disclosed with a focus on inflammatory skin disorders and include the use of primary human keratinocytes stimulated to express disease-like phenotypes. The disclosure of assay details makes it possible for external partners to suggest compounds with novel mode of action, which provides insights both from a compound and a target perspective. Cytotoxicity is also measured and evaluated in parallel in order to strengthen the confidence in the primary disease-relevant readouts.

To engage with LEO Pharma OI a simplified contract is signed and compounds are digitally submitted without disclosing the structures. Vials are shipped to the external partner and returned with compounds to LEO Pharma. All data generated is returned to the external partner and, if relevant, further collaboration discussed. In general LEO Pharma is looking for small molecules that could be relevant for business collaboration, science and disease exploration, or provide a starting point for a collaborative project. There are no limiting business terms attached to the contract and the external partner always retains IP rights as well as the decision to continue the collaboration or not.

Opportunities for medicinal chemistry providers and the pharmaceutical industry

With the emergence of OI platforms and access to biological testing platforms, there are increasing opportunities to explore biological functionality, industrial interest and to widen the possible implication of ones compounds. OI will in the end improve the possibilities of finding a scientific match between novel chemistry and disease biology, optimally work to develop new and innovative medicines in favor of the patients.

As pharmaceutical companies are focusing more and more on the patients, the industrial drug discovery process, as we know it today, could be left with a technological gap. In combination with an increasing number of biotech companies and academic drug discovery units, there are numerous compound designers and providers who can be used to feed the drug discovery process more efficiently. OI capable of evaluating external compounds for relevant biological effect will become a powerful tool to engage with the growing number of compound opportunities to complement internal chemistry efforts. These platforms will reduce the hurdles to test hypothesizes and increase the chances of matching assets in the form of compounds and drug discovery platforms. Also, drugs sourced via OI tend to have a higher success rate and increased probability of success in late-phase clinical studies [15]. A few pharmaceutical companies have established OI platforms that vary in science scope, openness, reward structure and business terms. But they all send the same signal – the pharmaceutical industry is getting ready to interact hands-on with external compound providers in order to explore science and business opportunities from a mutual beneficial perspective.

Future perspective

Today's challenge with pharmaceutical OI is to actually incorporate the new innovation platforms and show that they create value in the traditional pharmaceutical R&D process. The next few years will be spent on tweaking and optimizing these OI platforms to make sure this actually happens. Parameters such as degree of openness, restricting legal and business terms, as well as the collaborative business model will be challenged back and forth in order to provide a mutually beneficial and productive OI frame work. After a few years of experimentation with different OI platforms the pharmaceutical industry will come to realize that it is essential to establish an operational interface between the internal core business-focused innovation challenges and external technology innovators. The extrapolation and evolution of the pharmaceutical OI platforms will be in the direction of increased openness in order reach the full potential of collaborative science. One such direction is open source, or open science, where underlying assay protocols will be shared openly and biological models developed cooperatively online, much like the software and electronics industry today. Furthermore an increasing amount of data will be generated publically by the OI platforms and provided as open access for researchers to further explore new scientific rationales, which is particularly relevant for, for example, phenotypic and physiological relevant assay with multiplexed readouts requiring a Big Data analysis approach. Molecules, and small molecules in particular, has been and will still remain one of the pharmaceutical industry's strong focus points for the OI platforms to explore. However, the above mentioned evolution towards open source and open access will facilitate the exploration of alternative disease-modifying agents such as natural and synthetic versions of peptides, antibodies and RNA-interference as well as more novel approaches such as cell therapy, gene editing and nanotechnology-based therapeutics. By opening up part of the R&D process to massive online cooperative science as well as specific engagement by highly specialized small and medium sized enterprises, and academic drug discovery units, the pharmaceutical industry will be able to boost innovation tremendously. But only if the pharmaceutical companies can clearly communicate the right innovation need as well as successfully establish an operational interface to identify and take advantage of external opportunities in a truly mutually beneficial manner. The current OI platforms represent an early experimental initiative that holds the potential to unlock pharmaceutical innovation by connecting patient needs with exponentially increasing external technologies.

Table 1.  Available open innovation platforms with the purpose of evaluating external partners’ compounds.

Company	Launch^† official year	Name of open innovation platform compound evaluation	Focus-targeted disease areas	Biological assays offered	Conditions selected specific details	Ref.
Eli Lilly	2009	Open Innovation Drug Discovery	Neglected and tropical diseases, diabetes and oncology	Proprietary phenotypic and target-based assays	Submit structure to third party, generated data shared	[8]
Merck Serono	2012	Open Compound Sourcing	Oncology, neurodegenerative diseases and rheumatology	Undisclosed	Structure is required, generated data not shared	[11]
Bayer	2013	Grants4Leads	Oncology, cardiology, hematology and gynecology	Undisclosed	Submission is non-confidential, structure is not required and no generated data	[12]
AstraZeneca	2014	New Molecule Profiling	Cardiovascular, respiratory and metabolic diseases, oncology, inflammation and autoimmunity	Undisclosed target-based assays	Submit structure to third party, generated data shared	[13]
LEO Pharma	2015	LEO Pharma Open Innovation	Dermatology and skin inflammation	Phenotypic, skin inflammation and general immunology	Structure is not required, generated data returned to partner and no business terms	[14]

^†Year refers to the launch of the open innovation platform for evaluating external compounds specifically.

Financial & competing interests disclosure

The authors are responsible for designing and implementing the LEO Pharma open innovation platform and can therefore be considered biased. The intention is to objectively and concisely summarize the existing open innovation platforms that provide evaluation of external partners’ compounds. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

No writing assistance was utilized in the production of this manuscript.

Additional information

Funding

The authors are responsible for designing and implementing the LEO Pharma open innovation platform and can therefore be considered biased. The intention is to objectively and concisely summarize the existing open innovation platforms that provide evaluation of external partners’ compounds. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.