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Role of Academic Drug Discovery in the Quest for New CNS Therapeutics Brian H. Yokley,†,∥ Matthew Hartman,‡,∥ and Barbara S. Slusher*,§ †
GE Healthcare Life Sciences, Marlborough, Massachusetts 01752, United States Academic Drug Discovery Consortium, Baltimore, Maryland 21205, United States § Johns Hopkins Drug Discovery, Departments of Neurology, Neuroscience, Psychiatry, Medicine, and Oncology, Johns Hopkins School of Medicine, Baltimore, Maryland 21205, United States ‡
ABSTRACT: There was a greater than 50% decline in central nervous system (CNS) drug discovery and development programs by major pharmaceutical companies from 2009 to 2014. This decline was paralleled by a rise in the number of university led drug discovery centers, many in the CNS area, and a growth in the number of public−private drug discovery partnerships. Diverse operating models have emerged as the academic drug discovery centers adapt to this changing ecosystem. KEYWORDS: Academic drug discovery, public-private partnerships
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growing numbers of these centers (http://www.addconsortium. org/) and today has over 144 academic drug discovery (ADD) centers in its membership. Over 45% of these drug discovery centers were created since 2009 (ADDC membership data), and interestingly more than half have reported that they are engaged in CNS drug development. This dramatic growth has coincided with an increase in the number of translationally focused public−private partnerships, which have exhibited over a 500% increase in the past 10 years (Thompson Reuters Cortellis). Many companies have adopted a lower risk strategy for exploring CNS projects by using open innovation models in which multiple players (i.e., pharma, biotech and academia) work together to progress a drug discovery and development project.3 ADD centers have been adapting to this new network with tremendous variety in their approach. Funding appears to be the main hurdle and is the chief driver of the diversity in ADD center operating models. Centers are utilizing a variety of strategies to obtain funding and bridge the “valley of death”, including National Institutes of health (NIH) Blueprint grants, philanthropy, private capital, commercial partnerships, and venture funding. For example, Vanderbilt Center for Neuroscience Drug Discovery (VCNDD) has utilized the NIH Blueprint grant mechanism as well as philanthropic and disease foundation funding mechanisms to advance promising preclinical candidates through Investigational New Drug (IND) enabling studies and regulatory filing. Similarly, the Institute for Drug Discovery (IDD) at Purdue has relied heavily on government and foundation grants to advance its candidates through the drug discovery pipeline. However, instead of taking assets through IND with public funds, it has partnered with Boilermaker Health Innovations, a dedicated 501c3 at Purdue, to fund later stage development.
ajor pharmaceutical companies have downsized their central nervous system (CNS) research and development programs. In the 5-year period between 2009 and 2014, there was a 52% drop in the number of total CNS drug discovery and development programs pursued by large pharma, with almost all companies showing a decline1 (Figure 1). This
Figure 1. CNS program portfolios in large pharma: 2009 versus 2014. Data taken from ref 1. Total number and associated percent decrease of CNS drug development programs targeting neurological or psychiatric disorders.
decrease has been attributed in part to challenges in target identification and validation, predictive neurological animal models, relevant biomarkers, and heterogeneous clinical symptoms which contribute to greater risk in CNS therapy development when compared to that of other therapeutic indications.2 Concurrent with the decrease in Pharma CNS R&D, there has been an increase in the number of both universitysupported drug discovery centers and public-private drug discovery partnerships (Figure 2). In 2012, the Academic Drug Discovery Consortium (ADDC) was created to connect the © XXXX American Chemical Society
Received: January 26, 2017 Accepted: February 2, 2017
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DOI: 10.1021/acschemneuro.7b00040 ACS Chem. Neurosci. XXXX, XXX, XXX−XXX
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ACS Chemical Neuroscience
Figure 2. Total and CNS-focused academic drug discovery centers and partnerships: 2006−2015. Total number of academic drug discovery centers segmented by those targeting neurological and psychiatric indications and total number of public private partnerships. Data gathered from Academic Drug Discovery Consortium membership data and Thompson Reuters Cortellis.
a for-profit company called Bridge Medicines to commercialize identified assets. All projects that “graduate” from Tri-I TDI are eligible to be licensed to Bridge Medicines including projects selected by Takeda. In keeping with the educational mission of the universities, these cooperative models also create unique environments for drug discovery education. Many ADD centers regularly meet with interested university faculty to provide expertise and advice on the translation of their specific projects. Several ADD centers also run graduate level drug discovery courses at their university and aide in the mentoring and education of students interested in careers in drug discovery and translational medicine. As an extension of this, multiple ADD centers have collaborated in directing a week-long, NIH-sponsored Training in Neurotherapeutics Development course (https://www.aspet. org/Neurotherapeutics_course) designed to teach academic investigators about the step by step processes involved in CNS drug discovery and development. While ADD centers are certainly taking a more prominent role in the new drug discovery ecosystem, how they will most effectively operate within this network remains to be seen. An equally important objective that adds an additional level of complexity is educating tomorrow’s drug discoverers and balancing drug development activities with mentoring, training, and teaching. Trainees in drug discovery centers are pressured to attain timely publications, which can compromise optimal patent strategies. Further, the academic advancement criteria of “scientific independence” and the focus on “hypothesis-driven research” can be in contrast with the team-orientation of drug discovery and the focus on product discovery and development. While conducting drug discovery in academia has challenges, there are also advantages. Drug discovery centers working within universities are uniquely positioned to collaborate with colleagues who have incredible depth of knowledge and expertise, as faculty often spend a lifetime of research on single disease areas and/or therapeutic targets. This is in contrast to drug discovery efforts in industry where scientists are often forced to reinvent themselves as corporate strategy and directions change. In addition, academic researchers are free to tackle complex and long-term projects that may not optimally address the shareholder expectations that often
The Warren Family Research Center for Drug Discovery & Development at the University of Notre Dame has leveraged private foundation funding and an industry partnership along with internal support for the development of a treatment for a rare disease by copartnering with the biotechnology company Retrophin and the Grace Science Foundation. This three-way collaborative relationship enables each partner to provide their unique expertise and capabilities resulting in mutual benefit for all parties. Johns Hopkins Drug Discovery (JHDD) and their partner Eisai Inc. have utilized hybrid industry/academic development teams. In this collaboration, Eisai screens their internal proprietary compound library using targets identified and assays developed by JHDD. Development of the resulting hits can occur with integrated projects teams consisting of chemistry, assay screening, pharmacology, and drug metabolism/pharmacokinetics studies being performed by both sides. Success in identifying lead candidate molecules can then trigger Eisai in-licensing. JHDD has also created a strategic academic partnership to enhance its medicinal chemistry capabilities by forming a teaming agreement and postdoctoral exchange program with the Institute of Organic Chemistry and Biochemistry (IOCB) in Prague, who employs over 600 chemists and biochemists. The IOCB chemistry expertise is then paired with the biology, pharmacokinetic, and clinical expertise at Johns Hopkins to efficiently move drug discovery projects toward clinical candidate selection. The Tri-Institutional Therapeutics Discovery Institute (Tri-I TDI) employs another unique model. Tri-I TDI was created to translate discoveries from the Memorial Sloan Kettering Cancer Center, Rockefeller University, and Weill Cornell Medicine by partnering with a drug discovery team from Takeda. Takeda has right to first offer of developed assets. Robust partnerships between these four main stakeholders and additional partners, such as Charles River, WuXi, Schrodinger, and Ablexis, create an environment that supports its pipeline of candidates. They aggressively outsource commoditized parts of the development chain to their most efficient partners. A unique benefit of this model is that it enables the development of projects without being slowed by the traditional grant process. Recently, Tri-I TDI and Takeda partnered with venture capital groups to form B
DOI: 10.1021/acschemneuro.7b00040 ACS Chem. Neurosci. XXXX, XXX, XXX−XXX
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ACS Chemical Neuroscience drive corporate agendas. ADD centers also have access to cutting-edge scientific advancements, new disease models, and patient samples that may not be commercially available. The downsizing of CNS projects by large pharma illustrates the daunting task of drug discovery and development in this area. It is unknown whether the current trends of enhanced drug discovery efforts in academia and increased public−private partnerships will have a positive effect on overall R&D efficiency and productivity.4 Although ADD centers are not at the mercy of nonscientific commercial drivers they still battle with their own unique challenges. While the future remains to be seen, the overall sentiment is optimistic that the new drug discovery ecosystem and the increased role of academia will be beneficial.
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AUTHOR INFORMATION
Corresponding Author
*Mailing address: Johns Hopkins Drug Discovery, 855 North Wolfe Street, Baltimore, MD 21205, USA. Phone: 410-6140662. Fax: 410-614-0659. E-mail:
[email protected]. ORCID
Barbara S. Slusher: 0000-0001-9814-4157 Author Contributions ∥
B.H.Y. and M.H. contributed equally to this work.
Funding
R01 CA161056, P30 MH075673, R25 NS077582, and R01 CA193895 (to B.S.S.). Notes
The authors declare no competing financial interest.
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REFERENCES
(1) Choi, D. W. (2014) Medicines for the Mind: Policy-Based ‘‘Pull’’ Incentives for Creating Breakthrough CNS Drugs. Neuron 84, 554−63. (2) Thomas, D. W. et al. (2016) Clinical Development Success Rates 2006−2015. Retrieved from http://www.bio.org. (3) Kaitin, K. I. (2010) Deconstructing the Drug Development Process: The New Face of Innovation. Clin. Pharmacol. Ther. 87, 356− 61. (4) Scannell, J. W., Blanckley, A., Boldon, H., and Warrington, B. (2012) Diagnosing the decline in pharmaceutical R&D efficiency. Nat. Rev. Drug Discovery 11, 191−200.
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DOI: 10.1021/acschemneuro.7b00040 ACS Chem. Neurosci. XXXX, XXX, XXX−XXX
