N E W S & A N A LY S I S FROM THE ANALYST’S COUCH
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Stephen Frye, Marina Crosby, Teresa Edwards and Rudolph Juliano Research portfolios and capabilities. A broad range of therapeutic areas are included in the interests of the academic drug discovery (ADD) centres (FIG. 1a). Cancer and infectious diseases are the most common, with 86% and 71%, respectively, of centres reporting these areas in their project portfolios. In contrast to the historical direction of commercial drug research, diseases prevalent in less developed countries (30%) and orphan diseases (36%) are also a major focus. A diverse range of potential drug targets are being addressed (FIG. 1b). They include known ‘druggable’ targets, such as protein kinases and G protein-coupled receptors, but there is also considerable activity involving less traditional targets such as non-enzyme proteins (12%) and phenotypic assays lacking a defined target (20%). On average, 49% of targets being investigated are based on unique discoveries that had little validation in the literature; 27% of targets had significant preclinical validation in the literature but no clinical validation; and only 18% of targets were associated with clinical evidence of
Survey and analysis Seventy-eight units in the United States were identified as small-molecule drug discovery centres sited within universities or non-profit research organizations, and their response rate in our survey was 71%. a
Cancer
86
Diabetes, endocrine, metabolic
38
Pyschiatric/ neurodegenerative 32
29
Obstetrics/ gynaecology
5
Nuclear receptors
10
2
14
Diseases of LDCs
Phenotypic assays
30
Orphan diseases
20
Other
36
Other
d 12
Non-proteins
Opthalmological
Preclinical validation 27%
6
Other nonenzyme proteins
11
3
Undisclosed targets
9
Innovative 49%
Undisclosed 7% Clinical validation 18%
3
Non-kinase enzymes
5
Dermatological
11
Proteases 71
c
12
Ion channels
Infectious diseases Stroke, neuromuscular
Protein kinases GPCRs
45
Cardiovascular
b
validity (FIG. 1c). So, centres are clearly choosing to pursue long-term, higher risk strategies. The research capabilities within the centres are focused on early phases of drug discovery (Supplementary information S2 (figure), panel a). Most reported capabilities for in vitro or cell-based primary assay development (93%), for target identification (77%), and for cellular biology and secondary functional assay development (79%). With 72% of centres reporting capabilities for hit-to-lead medicinal chemistry, the integration of chemistry into ADD centres has also progressed considerably. By contrast, only 51% of the centres reported capabilities for in vivo efficacy testing and 42% for drug metabolism and pharmacokinetics studies. HTS accounted for 45% of the generation of tractable hits, with focused library screening (20%) and knowledge-based design (21%) being the other main contributors to hit generation (FIG. 1d). We sought to evaluate the ADD ‘pipeline’ by aggregating several questions in the survey concerning the number of biological targets that have progressed to various stages of drug ▶
16
Percentage of responses
There has been substantial investment in the past decade to provide academic institutions with the capabilities for early-stage drug discovery, such as high-throughput screening (HTS) of large compound libraries and medicinal chemistry for hit optimization. However, so far, analysis of the rationale for and impact of this investment has relied on expert opinions rather than on data. To address this lack of data, we conducted a survey (see Supplementary information S1 (box) for methods) of academic and non-profit drug discovery entities in the United States. We excluded work on large molecules, such as monoclonal antibodies, because our intent was to capture the emerging systematic focus on small-molecule drug discovery.
50
High-throughput screening Screening of focused compounds Fragment-based screening Knowledge-based design Did not answer
45
40 30 20
21
20
10
10 3
0
20
40
60
Percentage of responses
80
0
5
10
15
20
Percentage of responses
0
Figure 1 | Research focus of academic drug discovery centres. a | Therapeutic area. b | Target-class focus (the undisclosed targets result from the centres Nature | DrugFor Discovery providing no information). c | Degree of validation of target portfolios. d | Sources of tractable hits by discovery strategy (averaged over allReviews respondents). more information, see Supplementary information S1 (box), survey questions 14–16 and 19. GPCRs, G protein-coupled receptors; LDCs, less developed countries.
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N E W S & A N A LY S I S ACADEMIC DRUG DISCOVERY ▶ development (FIG. 2). Not surprisingly, given
the limited time most centres have been in operation (see below), many targets were still at the assay development or hit discovery stage. Questions regarding comparisons between academic and industrial drug discovery evoked intense and informative responses. Academia was perceived to be much stronger than industry in disease biology expertise and innovation, and was considered to be better aligned with societal goals (Supplementary information S2 (figure), panel b). By contrast, industry was perceived to be much stronger in assay development and screening, and particularly in medicinal chemistry.
Percentage of responses
Mission, staffing and funding. Other questions, reported in full in Supplementary information S2 (figure), investigated the goals, staffing, placement within the university and funding of ADD centres. Many ADD centres are new entities: 32 out of the 56 centres completing a response about their founding were established between 2003 and 2008. Self-description of centre missions indicated that traditional academic goals ranked highly, such as publication (ranked first out of eight goals), but the generation of intellectual property was also highly ranked (ranked third out of eight). In terms of perception of success, 53% of respondents indicated that their centres had exceeded initial institutional expectations. Centre leadership was equally divided between individuals with a non-industrial background (49%) and individuals with a substantial background in industry (51%), but 53% of centres had 25% or less staff with industrial experience. Interestingly, 37% of the centres reported a large number (7 or more) of tenure-track staff whose main research focus is drug discovery, which might reflect a major change in orientation for tenure-track faculty. 15
By far the largest source of financial support reported for ADD centres was federal grants or contracts, accounting on average for 41% of total funding. Only 14% of centres reported a long-term relationship with a for-profit organization, but there were exceptions to these patterns with some centres deriving 100% support from user/client fees and some obtaining up to 50% support from commercial organizations. There was tremendous variation in the total operating expenses reported by the centres: the lowest being US$25,000 and several centres reporting >$10 million. The distribution was skewed towards moderate levels of total funding, with 57% of respondents reporting $2 million or less. Discussion As this is the first systematic survey of the ADD sector that we are aware of, there is limited objective research with which to compare our results. However, some clear themes emerged from the data that broadly fit with the expectations highlighted by previous commentaries (for example, REFS 1–3). Thus, while creation of intellectual property is acknowledged as an important part of their mission, most centres are also focused on fulfilling the academic objectives of their institutions while creating new medicines. The innovative outlook of the centres is demonstrated by the relative lack of clinical validation data on the targets being pursued, a major focus on neglected and orphan diseases, and the fact that ~30% of the portfolios are based on novel protein targets and phenotypic assays. As discussed in recent analyses4,5, ADD efforts have contributed substantially to the discovery of the most innovative new drugs that have been introduced in the past decade or so, especially in the area of biologics. With the expansion of academic interests in small-molecule drug discovery, perhaps the
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Figure 2 | Aggregated depiction of the pipeline by stage for all centres. The mean number of instances in each drug discovery stage was calculated, with the mid-points of the ranges reported. For more information see Supplementary information S1 (box), survey questions 18–21. FDA, US Nature Reviews | Drug Discovery Food and Drug Administration; IND, investigational new drug.
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coming decade will see a similar impact on innovation in this domain as well. However, there are also major obstacles to maximizing the impact of these centres on health care. Of the respondents who answered our open-ended question about obstacles (Supplementary information S2 (figure), panel k), 68% identified some aspect of funding (such as amount and stability) as an obstacle. A lack of expertise in medicinal chemistry, a lack of understanding of drug discovery in academia or a poor fit between the more individually oriented conventional academic career paths and the team efforts required for drug discovery were also identified as obstacles by 25% of respondents. Although concerns over funding are not surprising, the expense of lead optimization and preclinical studies needed for filing of investigational new drug applications are daunting in the face of flat government funding and extreme competition for grants. Unless public and private funders create mechanisms to progress projects through this phase, much of the value may be lost. Unfortunately, the venture capital investments that drove the past decade of innovation4 have largely retreated from preclinical opportunities. Creative models for public–private partnerships to share the costs, risks and rewards are needed to sustain the current efforts in these centres, combine complementary skills, and address the key challenge of translation from a lead compound to a potential drug in clinical studies3. Stephen Frye and Rudolph Juliano are at the Eshelman School of Pharmacy,University of North Carolina at Chapel Hill, North Carolina 27599, USA. Marina Crosby and Teresa Edwards are at the Odum Institute for Research in Social Science, University of North Carolina at Chapel Hill, North Carolina 27599, USA. Correspondence to S.F. or R.J. e-mails:
[email protected];
[email protected] 1. Wyatt, P. G. The emerging academic drug-discovery sector. Future Med. Chem. 1, 1013–1017 (2009). 2. Tralau-Stewart, C. J. et al. Drug discovery: new models for industry–academic partnerships. Drug Discov. Today 14, 95–101 (2009). 3. Edwards, A. M. et al. Open access chemical and clinical probes to support drug discovery. Nature Chem. Biol. 5, 436–440 (2009). 4. Kneller, R. The importance of new companies for drug discovery: origins of a decade of new drugs. Nature Rev. Drug Discov. 9, 867– 882 (2010). 5. Stevens, A. J. et al. The role of public-sector research in the discovery of drugs and vaccines. N. Engl. J. Med. 364, 535–541 (2011).
Competing interests statement
The authors declare no competing financial interests.
SUPPLEMENTARY INFORMATION See online article: S1 (box) | S2 (figure)
www.nature.com/reviews/drugdisc © 2011 Macmillan Publishers Limited. All rights reserved
