A Perspective on the Evolution of Collaborative Drug Discovery and Future Challenges
Melior Discovery, Waterford, CT, USA
In this chapter I would like to bring in a personal perspective illustrating how, in just a decade, collaborative drug discovery (CDD) went from an idea with little traction to one warranting an entire book. I consider drug repurposing and the discovery of treatments for rare and orphan diseases as major opportunity factors for CDD. CDD per se will not solve any of the myriad problems evident in mainline big pharma drug discovery but with respect to academic drug discovery does pose new challenges that are more organizational and cultural rather than technical and scientific.
Evolution of Collaborative Drug Discovery
In the year 2000, the Pfizer laboratories in Sandwich, UK, produced a white paper on drug repurposing (the Pfizer terminology for drug repurposing was “indications discovery”). Widely viewed within the Pfizer organization as scientifically sound and eminently reasonable, the proposal to engage in drug repurposing went nowhere. To implement the proposal, some sort of centralized screening group or facility would have to be set up to run in vitro and in vivo assays across the tremendous breadth of Pfizer research across multiple therapeutic areas. A specific small example gives an idea of the organizational hindrance to setting up this type of effort. In 2000, when a therapeutic area anywhere in the Pfizer world nominated a compound for clinical development, an information freeze went into effect on any information exchange that required testing of the compound. The nominated clinical candidate could not be obtained from the central Pfizer sample repository for testing anywhere within Pfizer without the explicit permission of a senior director or VP from the originating therapeutic area. In 2000, the Pfizer organizational structure and cultural mind-set in drug discovery was just not ready for the concept of discovering a new use for an existing drug.
In mid-2002 I retired from the Pfizer discovery organization, and over the next 4 years, the corporation kindly allowed me to continue my scientific activities in an office in the computational suite. While in my Pfizer office, I was contacted by Andrew Reaume, a then Pfizer employee working in the Pfizer technology zone who had very interesting ideas on using automated in vivo phenotypic rodent screening to find new uses for existing drugs. Andrew was struggling to set up drug repurposing within Pfizer using technology he had learned and developed within Pfizer. The upshot is that up to 2005, the internal attempt at drug repurposing within Pfizer failed. The positive aspect is that Pfizer legal saw no problem with Andrew leaving Pfizer with his technology since his automated in vivo rodent assays were all based on literature assays with high citation count that the biologists typically used to convince themselves that the activity was real. Andrew left Pfizer on good terms and cofounded Melior Discovery, an Exton PA drug repurposing start-up, with Mike Saporito in 2005. Before he left Pfizer, Andrew had recruited me for the Melior Discovery Scientific Advisory Board (SAB), and we had picked CP-26154 as our first drug to explore in drug repurposing. CP-26154 was a compound I had made at Pfizer in 1972 as an antiulcer drug and which had reached Phase 2 studies in a time era where compounds entered the clinic without knowing mechanism. As it turned out, CP-26154 (now renamed as MLR-1023) was found by Melior Discovery to have unexpected activity in four phenotypic models, suggesting utility in type II diabetes and later was found by Melior to be an allosteric Lyn kinase activator. Subsequent to the phenotypic discovery, the investigational new drug (IND) application for the diabetes indication was approved by the Food and Drug Administration (FDA). As of 2005, Pfizer, the largest pharmaceutical organization in the world, was not yet ready for internal drug discovery in drug repurposing.
In 2004, I was the cochair of the Society for Biomolecular Screening (SBS) national conference in Orlando, Florida. SBS was the big high-throughput screening (HTS) conference in the United States, and I remember that we had no more than 10% academic attendees. This was a big contrast to the SBS meeting in 2007 in Montreal with about 30% academic attendees. With Mel Reichman (LIMR Chemical Genomics Center, Wynnewood, PA) at this later conference, I participated in a Point-Counterpoint entitled “Is the NIH Roadmap a New Model for Drug Discovery: Pipelines or Pipedreams of Future Drugs.” Mel was the pipeline spokesman and I was the pipedreams proponent, and we both felt strongly about our respective positions.
On the lecture circuit I had been speaking on how I felt that intellectual property (IP) considerations were hindering information exchange. In the PowerPoint slides in my talks I had used the terminology of “anti-intellectual effects of intellectual property.” In 2005, I was approached by the editors of an edition of Current Opinion in Computational Biology (COCB) to write on the subject of “anti-intellectual effects of intellectual property.” I agreed to write an opinion piece, and over the next 9 months, every time I visited a university I asked to speak to the university intellectual property people. The “Anti-Intellectual Effects of Intellectual Property” was published in COCB in August of 2006 [1]. From the academic researchers’ viewpoint, IP was at best something they learned to live with and at worst was a royal pain in the neck. In their opinion, IP considerations, at that time period, did nothing to enhance their scientific productivity.
The safe exchange of information about compounds without actually revealing drug structure can be an important component to collaborative drug discovery. Tudor Oprea at the University of New Mexico and I jointly organized a session cosponsored by the CINF and COMP sections at the spring 2005 ACS national meeting in San Diego. A wide range of opinions on computational feasibility were presented, and although the session received reasonable publicity [2, 3], to my knowledge, there was no direct outcome from this session that enhanced collaborative drug discovery. In this time period, organizations facilitating information exchange began to appear, for example, in 2004 Collaborative Drug Discovery (CDD) (vide supra) was spun out of Lilly, and the formation of the Clinical and Translational Science Award Pharmaceutical Assets Portal (CTSA portal) was completed in 2008. The history of Collaborative Drug Discovery is described in this book in Chapter 19. The very interesting history of the evolution of the CTSA consortium launched by the NIH in 2006 into the CTSA portal has been recently described by Kate Marusina and colleagues in academia and industry in a special edition of DDT Therapeutic Strategies dedicated to drug repurposing [4], and in a chapter later in this book. As the editor of this special issue, I read the fascinating details of the very divergent views to data sharing and drug repurposing that were encountered among major pharmaceutical organizations. Of particular note is that Pfizer became a major sponsor of the CTSA portal. Taking Pfizer, as an example, there was a marked change between 2005 and 2008 in viewpoint toward collaborative drug discovery from caution in 2005 to advocacy in 2008.
In the summer of 2005, I spoke at a conference in central London organized by the Wellcome Trust, and over the 2005 Christmas break, I was one of the reviewers for a new innovative Wellcome Trust plan to sponsor academic drug research. This was the beginning of the successful grant program that was called “seeding drug discovery,” key elements of which have been summarized in Nature Reviews Drug Discovery (NRDD) [5].
From 2000 through 2006, I had been on the SAB of the Global Alliance for TB Drug Development (GATB), and in my first 2 years before the GATB recruited a resesarch director, I had sat in on SAB meetings where effectively the research policy was set by academic committee. With respect to any of the usual industry metrics regarding project planning, stage gates, and so on, this was a dysfunctional group. The situation radically changed for the better when the GATB hired an experienced research director with industrial experience. As a scientist at Pfizer, I had been somewhat dismissive of the management project planning process, but the early GATB SAB experience converted me into a believer to a sensible form of project planning. So it was with keen interest that I noted that the Wellcome Trust “seeding drug discovery” grants provided for external project planning through the Wellcome Trust. In light of my early GATB experience, I interpreted this as “We (the Wellcome Trust) know that academics are inexperienced in project discipline and because we know this is so important we will provide this ourselves.” In more recent times, it is really gratifying to me that this lesson has been learned by the better academic drug discovery groups. I would single out the Center for Drug Discovery at the KU Leuven in Belgium which has an outstanding IP licensing and development organization with initiatives relating to collaborations among the CD3 researchers, the academic biologists, and the little spin-out companies that I have not seen duplicated in the United States. As a member of the SAB of the KU Leuven CD3, I personally have seen the importance of “ring fencing” the medicinal chemistry so that the medicinal chemistry focus is directed entirely to drug discovery and not to the generation of peer-reviewed publications (more on this later).
The Wellcome Trust had a major role in opening up previously proprietary databases to the public. In 2008, the Trust awarded a 5-year, UK£4.7 million grant to transfer well-structured chemogenomics data from the publicly listed company Galapagos to the European Molecular Biology Laboratory’s European Bioinformatics Institute (EMBL-EBI) [6]. The databases in question were those developed by the former Inpharmatica, which was then owned by Galapagos. The Trust, in a senior management key strategic decision, decided to make the Inpharmatica data available to everyone whether in academia or industry. The Inpharmatica data and servers were moved from central London to the EBI Genome campus in Hinxton, UK, a few miles outside of Cambridge, and have now been accessed by hundreds of research groups worldwide.
In 2006, I had exchanged e-mails and had conversations with Barry Bunin (then at Libraria) who was to become the President and Founder of Collaborative Drug Discovery, and in 2007, I gave a keynote lecture at the March Collaborative Drug Discovery community meeting at the University of California, San Francisco, Mission Bay campus that was entitled “Academic Drug Discovery: The Chemistry Challenges of Target Choice and Screening Library Selection.” As the title suggests, I was beginning to come around to the notion that academic screening might have value, although I was still skeptical that the academics could get the medicinal chemistry part to work well. I still retain some of this skepticism and think that the biology–medicinal chemistry interface is among the most difficult parts of academic drug discovery and one in which fortunately there is notable recent progress. However, what is also very true is that there is a wide range in the skills sets in academic drug discovery. Some groups are very competent in true drug discovery and some are more at the other extreme.
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