Future Directions of HTS Trends 2012

‘Selected Findings’

April 2012

www.htstec.com This document contains only ‘SELECTED FINDINGS’ from the above market report. It

is intended to provide the reader with a brief insight into recent market trends. The full report should be consulted to view the entire dataset, details of the breakdown

of the responses for each question, its segmentation and all the estimates for the future (3 years’ time). Please contact [email protected] for more information about HTStec reports.

HTStec Limited has exercised due care in compiling and preparing these ‘Selected Findings’ from its REPORT, which is based on information submitted by individuals in respondent companies. HTStec Limited has NOT verified the accuracy of this information, nor has it is established

respondent’s authority to disclose information to HTStec Limited. HTSTEC LIMITED EXPRESSLY DISCLAIMS ANY AND ALL WARRANTIES

CONCERNING THIS REPORT, INCLUDING ANY WARRANTIES OF MERCHANTABILITY AND/OR FITNESS FOR ANY PARTICULAR PURPOSE, AND

WARRANTIES OF PERFORMANCE, AND ANY WARRANTY THAT MIGHT OTHERWISE ARISE FROM COURSE OF DEALING OR USAGE OF TRADE. NO WARRANTY IS EITHER EXPRESSED OR IMPLIED WITH RESPECT TO THE USE OF THE REPORT. Under no circumstances shall HTStec Limited be

liable for incidental, special, indirect, direct or consequential damages or loss of profits, interruption of business, or related expenses that may arise from use of this REPORT, including but not limited to those resulting from inaccuracy of the data therein.

© HTStec 2012

Future Directions Of HTS Trends 2012

‘Selected Findings’ Page 1

Background Information & Survey Demographics: •

This document is limited to ‘SELECTED FINDINGS’ only from HTStec’s ‘Future Directions of HTS Trends

2012’ Market Report which was published in April 2012. •

The original report was based on the results of HTStec’s industry-wide global web-based benchmarking survey on the future directions of high throughput screening (HTS) carried out in March 2012.

•

The study was initiated in response to enquiries made by vendors and industry analysts asking the

question - Does HTS still have a future? The questionnaire was compiled by HTStec with the assistance of vendors and direct input from interested HTS directors. •

The main objectives were to establish the current status of HTS operations and record what screening groups think they might be doing in the future (3 years' time). It is intended that this full report

should be a reference source of metrics and opinion as to the possible future directions of HTS operations. •

This ‘SELECTED FINDINGS’ report focuses on the CURRENT status of HTS operations, with a bias

towards the cell-based aspects of the report. • •

The survey collected 57 validated responses, of these 45 (79%) provided comprehensive input.

Survey responses were geographically split: 49% North America, 44% Europe; 5% Japan; and 2% Asia (excluding Japan).

•

Respondents came from 23 Large Pharma; 12 Academic Screening Centers; 6 Medium-Small Pharma;

6 University/Research Institute/Government Lab/Not-for-Profit Facilities; 4 Others; 3 Biotechs; and 3 Biopharma.

•

Most survey respondents had a senior job role or position in HTS operations which was in descending

order: 14 HTS directors; 12 heads of screening group; 7 senior/principal scientists; 6 others; 4

principal investigators; 4 section/group leaders; 3 vice presidents; 1 department head; 1 professor/assistant professor; and 1 HTS lab manager.

© HTStec 2012

Future Directions Of HTS Trends 2012

‘Selected Findings’ Page 2

Selected Survey Findings:  HTStec 2012

Fig. 1. Respondent's Current View On HTS No longer believe entirely in HTS, actively pursuing alternatives 2%

Take a pragmatic viewpoint, it is only one of many approaches 40% Enthusiastic supporter, believe it still has a pivotal role in drug discovery 58%

Figure 1. Reports on survey respondents’ current view of HTS. This showed that the majority (58%) of survey respondents were enthusiastic supporters of HTS, who believe it still has a pivotal role to play in

drug discovery. Of the remainder 40% take a pragmatic viewpoint, HTS is only one of many approaches they use and only 2% no longer believe entirely in HTS, and are actively pursuing alternatives.  HTStec 2012

Fig.2. Main Target Classes Screened In HTS

Protein-protein interactions

93%

Other enzymes

87%

Kinases

82%

Phenotypic screening

82%

Proteases

76%

GPCRs

73%

Other cytoplasmic receptors

73%

Other membrane receptors

71%

Epigenetic targets

69%

Ion channels

58%

Phosphatases

53%

Phosphodiesterases

49% 0%

10%

20%

30%

40%

50% 60% % Responding

70%

80%

90%

100%

Figure 2. Reports on the target classes survey respondents are actually screening in HTS today. The results

showed that the target class most screened in HTS today to be protein-protein interactions (93% screening). It was followed by other enzymes (87% screening); kinases and phenotypic screens (both 82%

screening). Least screened in HTS today were ion channels (58% screening); phosphatases (53% screening); and then phosphodiesterases (with only 49% screening).

© HTStec 2012

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‘Selected Findings’ Page 3

 HTStec 2012

Fig. 3. Assay Readouts Most Used In Primary Screening

Time Resolved FRET (TR-FRET or HTRF)

23%

Glow Luminescence

18%

Fluorescence Intensity (FI)

16%

AlphaScreen/AlphaLISA

7%

Fluorescence Polarisation (FP)

7%

Fluorescence Intensity - with injection (e.g. Flipr)

7%

HCA - cell imaging

5%

Absorbance

3%

Fluorescence Resonance Energy Transfer (FRET)

3%

Flash Luminescence (e.g. Aequorin)

2%

Radiometric

2%

HCS - laser scanning cytometry

2%

Label-Free (optical-biosensor plates)

1%

Label-Free (MassSpec)

1%

Electrochemiluminescence (e.g. Mesoscale)

1%

Fluorescence Lifetime (FLT)

1%

Time-Resolved Fluorescence (TRF)

1%

Label-Free (SPR)

0%

Label-Free (impedance-based)

0%

NMR-based screening

0%

Flow Cytometry

0% 0%

5%

10%

15% % Use In Screening

20%

25%

Figure 3. Reports on the assay readouts that are most used in primary screening today. This shows that

TR-FRET was the most popular readout (used in 23% of screens); followed by glow luminescence (18% of

screens) and then fluorescence intensity (16% of screens). Least used in primary screens were label-free

(optical biosensor plates); label-free (mass spec); electrochemiluminescence (Mesoscale); fluorescence lifetime (FLT); and time-resolved fluorescence (TRF) (all used in only 1% of screens). Several readouts were not reported to be used in any high throughput primary screens, these were label-free (SPR): label-free

(impedance-based); NMR-based screening; and flow cytometry.  HTStec 2012

Fig. 4. % Utilization Of Cell-Based Assay Approaches In HTS

35% 35% 30%

% Responding

25%

20%

15%

15%

10%

11% 7%

5% 4% 0%

2%

0%

4% 0%

4% 2%

2%

2%

2%

0%

2%

0%

4%

2%

0%

0%

0%

5% 10% 15% 20% 25% 30% 35% 40% 45% 50% 55% 60% 65% 70% 75% 80% 85% 90% 95% 100% % Cell Based

Figure 4. Reports on utilization of cell-based assay approaches in HTS today (Please Note: the remaining %

is assumed to be biochemical assays). The data shows quite a spread with a median of 50% utilization of

cell-based assay approaches in HTS today.

© HTStec 2012

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‘Selected Findings’ Page 4

 HTStec 2012

Fig. 5. Proportion Of Different Cell Types Used In Primary Cellular Screens Stem cells or iPS derived phenotypes 2%

Primary cells 6%

Transiently transfected cells 12%

Transformed or recombinant cell lines 44%

Tumor cell lines (e.g. Hela, U937 etc.) 17% Native immortalized cells (e.g. HEK293, CHO etc.) 19%

Figure 5. Reports on the proportion of different cell types used in respondent’s HTS cellular primary

screens today. The results showed that the most used cell type in primary cellular screens today was

transformed or recombinant cell lines (44% of screens). This was followed by native immortalized cells

(19% of screens); tumor cell lines (17% of screens); transiently transfected cells (12% of screens); primary cells (6% of screens); and then stem cells or iPS derived phenotypes (only 2% of screens).  HTStec 2012

Fig. 6. Main Target Classes Where Cell-Based Assays Are The Preferred HTS Format Phenotypic screening

84%

GPCRs

76%

Other membrane receptors

62%

Ion channels

60%

Other cytoplasmic receptors

53%

Epigenetic targets

29%

Protein-protein interactions

22%

Kinases

13%

Other enzymes

13%

Proteases

11%

Phosphatases

9%

Phosphodiesterases

7% 0%

10%

20%

30%

40%

50%

60%

70%

80%

90%

% Responding

Figure 6. Presents data on the target classes where cell-based assays are the preferred HTS assay format

(i.e. >50% of screens for this target use it) today. The target classes where cell-based assays are the most

preferred HTS format by survey respondents today were phenotypic screens (84% preferring). This is

followed by GPCRs (76% preferring); then other membrane receptors (62% preferring); and ion channels (60% preferring). Least preferred were most enzyme targets, although even these are increasingly investigated by cell-based pathway analysis assays today.

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 HTStec 2012

Fig. 7. % Utilization Of Phenotypic-Based/Black Box Assay Approaches In HTS

40% 35% 33%

30%

% Responding

25% 20% 17%

15% 10%

9%

9% 5%

7% 4%

2%

0% 0%

2%

2%

0%

0%

2%

0%

0%

4%

0%

4%

0%

0%

0%

4%

5% 10% 15% 20% 25% 30% 35% 40% 45% 50% 55% 60% 65% 70% 75% 80% 85% 90% 95% 100% % Utilizing Approach

Figure 7. Reports on the utilization of phenotypic-based/black-box assay approaches in HTS today (Please Note: the remaining % is assumed to be target-based approaches). The data showed a median of 10% utilization of phenotypic assay approaches in HTS today.  HTStec 2012

Fig. 8. Actual Use In HTS Of New Technologies, Techniques Or Approaches Direct titration/dilution dose-response curve creation

3.77

Chemoinformatics

3.52

Acoustic dispensing

3.20

High content screening/imaging assays

3.16

Bioinformatics

3.02

Cryopreserved cell aliquots

3.00

Assay ready plate production

2.93

In silico screening

2.72

Label-free assays/biophysics

2.37

Screening against primary cells

2.00

Microfluidic technologies

1.81

Screening against stem cell-derived phenotypes

1.67

Libraries screened simultaneously against batteries of different assays (>25)

1.66

3D cell culture and use of microtissues in screening qPCR

1.52 1.35

1.00

1.50

2.00

2.50

3.00

3.50

4.00

4.50

5.00

RATING SCALE 1 to 5, where 1 = not using, 3 = moderate use, and 5 = full implementation.

Figure 8. In this graph survey respondents rated their actual level of use in HTS of various new technologies, techniques or approaches. Survey respondents rated that their implementation of new

technologies, techniques and approaches was highest for direct titration/dilution used in dose-response curve creation; followed closely by chemoinformatics and then acoustic dispensing and high content

screening/imaging assays. Rated least used was 3D cell culture and use of microtissues in screening and

qPCR.

© HTStec 2012

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‘Selected Findings’ Page 6

 HTStec 2012

Fig. 9. HCS Translation Efficiency Compared To Other Screen Types: 17%

Non-HCS Cell-Based Assays:

10%

19%

Biochemical Screens:

0%

10%

10% 20%

45%

19%

21% 30%

5% 5%

36%

40%

50%

60%

70%

5% 80%

10%

90%

100%

% Responding N/A - not investigated HCS screens

Major Improvement

Slight Improvement

Not observed any difference

Slight Deterioration

Major Deterioration

Figure 9. Reports on whether hits identified through high content screens translate more efficiently into

leads and nominated candidates compared to hits identified through non-HCS cell based assays and

biochemical screens. Survey respondents informed that the translation efficiency of HCS assays compared

to non-HCS cell-based assays was most ‘not observed any difference’ (44% reporting), this was followed

by 19% ‘slight improvemen’t and 10% ‘major improvement’. The translation efficiency of HCS assays

compared to biochemical screens was most ‘not observed any difference’’ (36% reporting), this was

followed by 21% ‘slight improvement’ and 10% ‘major improvement’.  HTStec 2012

Fig. 10. Average % Success Rate For HTS Operations (defined as the % of screens that produce hits that progress to active lead or probe optimization chemistry)

16%

No. Responding

14%

14%

12% 12% 10% 10%

10% 10% 10%

8% 6% 5%

4% 2% 0%

5%

2% 0% 0%

2%

2%

0%

5%

5%

2%

2% 0%

2%

0%

2% 0%

5% 10% 15% 20% 25% 30% 35% 40% 45% 50% 55% 60% 65% 70% 75% 80% 85% 90% 95% 100% N/A % Success Rate

Figure 10. Reports on the average success rates of survey respondents HTS operations today (Please Note:

we are defining success as the % of screens that produce hits that progress to active lead or probe

optimization chemistry). The data showed a median average success rate of their HTS operations today to

be 60%.

© HTStec 2012

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‘Selected Findings’ Page 7

 HTStec 2012

Fig .11. Main Obstacles/Limitations Respondents Are Facing In HTS Today Costs

3.63

Druggability of the target

3.48

Validation status of the target

3.44

Less or fixed resources

3.40

Biomedical relevance of assays

3.28

Aging instrumentation and maintaining operational capacity

3.19

Some technologies are not amenable to full deck screening

3.17

Reagent quality (e.g. good antibody available)

3.00

Compound or library quality

2.80

Instrument unreliability causing significant lost time

2.67

Sensitivity of the assay

2.52

Extending responsibilities into other areas

2.52

Bioinformatics

2.44

Keeping abreast of new technologies/approaches

2.30

Supporting a wide diversity of assay types

2.24

Maintaining staff enthusiasm

2.17

Recruiting experienced staff

2.12

Increased use of cell-based assays

2.05

Absorption of HTS activities from other sites

1.95

Staff turnover

1.83

1.00

1.50

2.50

2.00

3.00

3.50

4.00

4.50

5.00

RATING SCALE 1 to 5, where 1 = not limiting and 5 = major limitations.

Figure 11. Reports on the main obstacles/limitations that are facing HTS groups today. All Respondents rated costs as the greatest obstacle/major limitation they are facing in HTS today. This was closely

followed by druggability of the target; validation status of the target; and then less or fixed resources.

Rated least limiting was increased use of cell-based assays; absorption of HTS activities from other sites; and then staff turnover.  HTStec 2012

Fig. 12. Expected Future Source Of New Chemotypes In Respondent's Organization Full deck diversity HTS (primary screening)

6.13

In silico screening and focused libraries

4.41

In-licensing from 3rd parties

4.29

Fragment-based screening

3.72

Substrate/ligand-based drug design

3.56

Natural products

3.51

New chemical technologies that produce millions of compounds 1.00

2.55 2.00

3.00

4.00

5.00

6.00

7.00

MEAN RANKED ORDER, where 1 = least likely source and 7 = most likely source.

Figure 12. Feedback was collected on where respondents see the future source of new chemotypes

coming from in their organization. All Respondents ranked full deck diversity HTS (primary screening) as

the most likely source of future chemotypes. This was followed by in silico screening and focused

libraries; and then in-licensing from 3rd parties. Ranked as a moderately likely (possible) source were fragment-based screening; substrate/ligand-based drug design; and natural products. Ranked the least likely source of future chemotypes were new chemical technologies that produce millions of compounds.

© HTStec 2012

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‘Selected Findings’ Page 8

 HTStec 2012

Fig. 13. Key Industry Drivers For Continuing HTS Going Forward Proven success

3.98

Lack of known chemical starting points

3.63

More effective than alternative methods

3.43

Cost-effective process

3.14

Established infrastructure and process 1.00

2.95 1.50

2.00

2.50

3.00

3.50

4.00

4.50

5.00

MEAN RANKED ORDER, where 1 = least important and 5 = most important.

Figure 12. Reports on how survey respondents ranked the key industry drivers for continuing HTS going

forward. Survey respondents ranked ‘proven success’ as the most important industry driver for continuing

with HTS operations going forward. This was followed by ‘lack of known chemical starting points’ and

then ‘more effective than alternative methods’. Ranked least important was ‘established infrastructure and

process’.

Need More Information? Want to read the full report? Please contact HTStec by

emailing [email protected] to obtain details of the report pricing and claim a 10% discount by quoting code LT20121.

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Future Directions Of HTS Trends 2012

‘Selected Findings’ Page 9