Drug and Market Development

D&MD's High-Throughput Screening

Overcoming the Innovation Deficit

Market Analysis Report

By Ken Rubenstein, Ph.D.

Report Extract
Table of Contents
How to Purchase this Report

1.0 Executive Summary

1.1 Introduction

The screening of chemical compounds for pharmacological activity has been ongoing in various forms for at least forty years. The screening paradigm says that when a compound interacts with a target in a productive way, that compound then passes the first milestone on the way to becoming a drug. Compounds that fail this initial screen go back into the library from whence they came, perhaps to be screened later against other targets.

The perceived needs of the pharmaceutical industry have changed with time and driven marked changes in the industry, both in terms of its business structures and its scientific approaches to drug discovery and development. In response, screening methodologies have also improved with time, both in terms of throughput and the amount of information to be derived from the screen. Advances in assay and instrument technologies have provided the means necessary to address these evolving needs.

Big pharma has relied to a large extent on blockbuster drugs to maintain growth. Many of the largest companies currently face pipeline gaps and must resort to heroic improvisations as mainstay products go off-patent. New technologies and perspectives, culminating in what has come to be called the industrialization of drug discovery, are helping to add predictability and manageability to the pharmaceutical enterprise. Major shifts in the market environment are prompting innovative responses from big pharma. A trend toward products with added information content may well drive companies toward greater disease specialization with franchises based on packages of goods and services.

Long-term industry responses to a changing environment leave a gap during which companies must find interim solutions to maintain profits at acceptable levels. Companies are pressured to increase rates of new product introductions, as managed care groups erode prices and volumes, and governments call for cost controls. These and other factors have led to substantial increases in R&D costs as a percentage of sales. Large expenditures in time and costs required for companies to introduce new drugs, together with a large project attrition rate, have led to the perception of an innovation deficit. Companies on average introduce less than one drug per year, while between two and three drugs are required to maintain profits at acceptable levels. Indications of progress against the deficit exist, but success is not yet assured. Mergers provide interim solutions, but scientific and technological advances promise more permanent results.

The report considers the elements of high-throughput screening technology by first placing the field in its pharmaceutical context, offers a definition of high-throughput screening, and discusses the origins and evolution of its contributory technologies. Turning next to a consideration of market factors, the report discusses current bioanalytical technologies, the changing nature of drug discovery, and the relevance of high-throughput screening in today’s pharmaceutical industry.

The current status of high-throughput screening technology is delineated, first considering classical approaches, next the assay downsizing movement, the status of robotics and automation, and finally the role of microfluidics. In viewing the status of high-throughput screening research, the report considers key publications in the field, funding sources for relevant research, and the organization of the high-throughput screening research community. A subsequent section views specific product offerings and their categorization.

In a section on business aspects, the report considers strategies of major players in the categories of pharmaceutical companies and technology platform companies. A discussion of collaborations and deals is followed by a market analysis in which current and projected sales for various product and service segments are considered. Following an extensive company profile section, the report concludes with a consideration of future trends in high-throughput screening.

Information for this report is derived from both primary and secondary sources. A thorough survey of company literature, trade journals, press releases, on-line articles, scientific journals, and the like generated a base of information, which was expanded through discussions and interviews with participants in the field, both pharmaceutical companies and equipment/reagent suppliers.

1.2 Elements of High-Throughput Screening Technology

High-throughput screening is a key link in the chain comprising the industrialized drug discovery paradigm. Today, many pharmaceutical companies are screening 100,000-300,000 or more compounds per screen to produce approximately 100-300 hits. On average, one or two of these become lead compound series. Larger screens of up to 1,000,000 compounds in several months may be required to generate something closer to five leads. Improvements in lead generation can also come from optimizing library diversity. Limited success has been achieved to date in this realm.

High-throughput screening is perhaps most accurately understood as one stage in an evolving process. Since the 1980s, improvements in screening technologies have resulted in throughputs that have increased from 10,000 assays per year to current levels, which can approach ultra-high-throughput screening levels of more than 100,000 assays per day. High-throughput screening is evolving not only as a discrete activity, but as a perspective that is expanding backward toward target identification and validation and forward to converting assay hits to qualified leads via information generated either within screens or through downstream, high-throughput ADME (absorption, distribution, metabolism, and excretion) and toxicity testing.

In terms of definition, high-throughput screening can be considered the process in which batches of compounds are tested for binding activity or biological activity against target molecules. Test compounds act as inhibitors of target enzymes, as competitors for binding of a natural ligand to its receptor, as agonists or antagonists for receptor-mediated intracellular processes, and so forth. High-throughput screening seeks to screen large numbers of compounds rapidly and in parallel. Yet in another sense, high-throughput screening is an evolving process that is today a discrete activity and may tomorrow become more highly integrated into a rapidly changing drug discovery paradigm.

Positive high-throughput screening results are usually called hits. Compounds resulting in hits are collected for further testing in which, for example, the potency of an enzyme inhibitor or the binding affinity of a ligand for a receptor may be determined. After this second level of triage, hits become lead compounds. Further synthesis may then be required to provide a variety of compounds structurally related to the lead. These sub-libraries must then be screened against targets in order to choose optimal structures. At this stage, some basic indicators of toxicity or bioavailability may be considered in an attempt to eliminate potential failures as early in the discovery process as possible.

1.3 Market and Technology Factors Underlying High-Throughput Screening

High-throughput screening was formed from a confluence of market-driven needs within the pharmaceutical industry and technological strategies originated within the in vitro diagnostics industry. This section examines the pharmaceutical industry market environment that has given rise to the need for the industrialization of research and the technology legacy that is finding a potential outlet for its creative energies.

A convergence of several trends is promising to yield a highly effective new paradigm for drug discovery. While the exact nature of the new paradigm is not yet clear, its outlines are starting to emerge from the mist. Trends include: the influence of genomics on increasing both the quantity and quality of new drug targets; advances in combinatorial organic synthesis to increase both the quantity and quality of compound libraries; the influence of high-throughput screening in providing an increased supply of new lead compounds; and the enhanced use of bioinformatics for process integration.

High-throughput screening borrows heavily from methods and equipment designed originally for biomedical research applications and later for in vitro diagnostic assays. Ligand-receptor assays originated with the Nobel-prize winning invention of radioimmunoassay during the 1960s. The early 1970s also saw the introduction of homogeneous technologies in which no physical separation of components was necessary in order to read a result. Homogeneous enzyme immunoassay and fluorescence polarization were used during the 1970s and 1980s to commercialize certain in vitro diagnostic assays. FRET (fluorescent resonance energy transfer) and time-resolved fluorescence assays were also developed in a clinical context.

Microfluidic technologies, as practiced by development-stage companies such as ACLARA and Caliper, were originally intended for diagnostic application, particularly in the area of immunodiagnostics. However, shifts in the diagnostic market, due to forces similar to those imposing needs for research cost reductions and efficiency increases in the pharmaceutical industry, have led to decreased emphasis on the application of new technologies to diagnostics and increases in their application to drug discovery.

The pharmaceutical industry currently has a pressing need for improvement in high-throughput screening technology. Although the industry has a seemingly insatiable appetite for new lead compounds, it is also under continuing pressure to reduce the costs of discovery and development. Historically, the industry has shown its enormous potential both for the improvement of human health and the realization of significant profits in that process. Over the past three decades, this potential has propelled rapid advancement both in the valuation of large pharmaceutical companies and in the basic sciences that provide them with their technical foundation.

In the last half of the current decade, high-throughput screening instruments, assays, and services have emerged as a significant growth market. From the field’s origins with home-brew tests and generic research instrumentation, high-throughput screening has become an increasingly sophisticated and important element in the armamentarium of the drug discoverer. The discovery process is currently on a steep growth curve both with respect to the number of targets and compounds to be screened and the complexity of the assays required. Increased numbers of targets and compounds call for greater parallelism and/or increased throughput in screens. Furthermore, the expense and scarcity of targets and compounds have driven a trend toward smaller assay volumes through miniaturization.

Manufacturers have risen to the occasion with a plethora of new offerings, including new assays, new formats, new technologies, and new instruments. Microfluidics technologies, for example, are being applied to the development of systems that consume sub-nanoliter quantities of reagents. New alternative technologies and systems come at a cost, and manufacturers are continually faced with assessing their true cost-benefit ratios.

Purchasing this Report

For complete information on how to purchase this report, contact D&MD Publications at +1-508-616-5566, +1-508-616-5544 (fax). One Research Drive, P.O. Box 5194, Westborough, MA 01581-5194, USA, www.drugandmarket.com/1993, lwood@drugandmarket.com.

TABLE OF CONTENTS

1.0 Executive Summary

1.1 Introduction

1.2 Elements of High-Throughput Screening Technology

1.3 Market and Technology Factors Underlying High-Throughput Screening

1.4 Current Approaches to High-Throughput Screening

1.5 High-Throughput Screening Products and Services

1.6 The Business of High-Throughput Screening

1.7 The Future of High-Throughput Screening

2.0 Introduction

2.1 The Rapidly Changing Pharmaceutical Industry Context

2.2 Format of the Report

2.3 Sources of Information

3.0 Elements of High-Throughput Screening Technology

3.1 High-Throughput Screening in Context

3.2 The Nature and Definition of High-Throughput Screening

4.0 Market and Technology Factors Underlying High-Throughput Screening

4.1 The Drug Discovery Revolution

4.2 Origins of High-Throughput Screening

4.3 The Role of High-Throughput Screening in the New Drug Discovery Paradigm 4-7

5.0 Current Approaches to High-Throughput Screening

5.1 Current High-Throughput Screening Technologies

5.1.1 Current high-throughput screening assays

5.1.2 Current high-throughput screening assay technologies

5.1.3 Current high-throughput screening consumables

5.1.4 Current high-throughput screening instrumentation

5.2 Emerging High-Throughput Screening Technologies

5.2.1 In vitro assay technology

5.2.2 Cell-based assays

5.3 Downsizing of High-Throughput Screening

5.4 Automation of High-Throughput Screening

5.5 Microfluidics and High-Throughput Screening

5.6 The Role of Informatics in High-Throughput Screening

6.0 Basic and Applied Research Activities

6.1 Selected High-Throughput Screening Literature References

6.2 Funding for High-Throughput Screening Research

6.3 The High-Throughput Screening Research Community

7.0 High-Throughput Screening Products and Service

7.1 Instruments

7.1.1 Comprehensive systems

7.1.2 Modular automated systems

7.1.3 Assay workstations

7.1.4 Imaging systems

7.2. Assay Kits and Receptors

7.3 Assay Development and Screening Services

8.0 The Business of High-Throughput Screening

8.1 Strategic Considerations

8.1.1 High-throughput screening strategies of pharmaceutical companies

8.1.2 High-throughput screening strategies of platform companies

8.2 Strategic Alliances in High-Throughput Screening

8.3 High-Throughput Screening Market Analysis

9.0 Company Profiles

9.1 3-Dimensional Pharmaceuticals, Inc

9.2 ACLARA BioSciences

9.3 Alexion Pharmaceuticals, Inc

9.4 Amersham Pharmacia Biotech AB

9.5 Aurora BioSciences Corporation

9.6 The Automation Partnership Ltd

9.7 Axiom Biotechnologies

9.8 Biometric Imaging, Inc

9.9 Cadus Pharmaceutical Corporation

9.10 Caliper Technologies Corporation

9.11 Cellomics, Inc

9.12 Cerep, Inc

9.13 EG&G Wallac

9.14 Evotec BioSystems AG

9.15 IGEN International, Inc

9.16 LJL BioSystems

9.17 MDL Information Systems, Inc

9.18 Molecular Devices Corporation

9.19 Packard Instrument Company

9.20 PE Biosystems

9.21 Zymark Corporation

10.0 The Future of High-Throughput Screening

LIST OF EXHIBITS

2.1.1 Ratios of research and development expenditures to sales, 1970-1999

5.2.1.1 Packard BioSignal’s AlphaScreen™ principle

5.5.1 Layout for a Caliper Technologies chip

5.5.2 A Caliper Technologies Sipper Chip for high-throughput screening

5.5.3 A development-stage prototype of the 96-channel ACLARA LabCard™

7.1.1 Categories of high-throughput screening instrumentation

7.1.1.1 Complete high-throughput screening systems

7.1.1.2 The Aurora UHTSS™ System

7.1.1.3 The Zymark Allegro™ Combo System

7.1.2.1 Modules for high-throughput screening systems

7.1.2.2 The Packard MiniTrak™

7.1.2.3 The CCS PlateTrak™ automated microplate processing system

7.1.3.1 Assay workstations for high-throughput screening

7.1.3.2 The Cellomics ArrayScan™ analyzer

7.1.3.3 The VICTOR²™ multi-mode plate reader

7.1.3.4 The LJL BioSystems ACQUEST™

7.1.3.5 The LJL BioSystems ScreenStation™

7.1.3.6 The Molecular Devices FLIPR™, shown with plate stacker

7.1.3.7 The Torcon Prospector™ Luminometer system

7.1.3.8 The Tropix NorthStar™ workstation

7.1.4.1 Selected imaging systems for high-throughput screening

7.2.1 Assay kit and key reagent offerings from selected companies

7.3.1 Selected companies offering high-throughput screening services

8.2.1 Selected strategic alliances in high-throughput screening

8.3.1 Estimates of current and projected U.S. revenues for high-throughput

screening instruments, consumables, and services, 1998-2003

8.3.2 Estimates of current and projected worldwide revenues for high-throughput screening instruments, consumables, and services, 1998-2003

8.3.3 Estimates of current and projected U.S. revenues for high-throughput screening, instruments, 1998-2003

8.3.4 Estimates of current and projected worldwide revenues for high-throughput screening, instruments, 1998-2003

8.3.5 Estimates of current and projected U.S. revenues for high-throughput screening, workstation instruments, 1998-2003

8.3.6 Estimates of current and projected worldwide revenues for high-throughput>screening, workstation instruments, 1998-2003

8.3.7 Estimates of current and projected U.S. revenues for high-throughput screening, modular instruments, 1998-2003

8.3.8 Estimates of current and projected worldwide revenues for high-throughput screening, modular instruments, 1998-2003

8.3.9 Estimates of current and projected U.S. revenues for high-throughput screening, consumables, 1998-2003

8.3.10 Estimates of current and projected worldwide revenues for high-throughput screening, consumables, 1998-2003

8.3.11 Estimates of current and projected U.S. revenues for high-throughput screening, reagent consumables, 1998-2003

8.3.12 Estimates of current and projected worldwide revenues for high-throughput screening, reagent consumables, 1998-2003

8.3.13 Estimates of current and projected U.S. revenues for high-throughput screening, plasticware consumables, 1998-2003

8.3.14 Estimates of current and projected worldwide revenues for high-throughput screening, plasticware consumables, 1998-2003

8.3.15 Estimates of current and projected U.S. revenues for high-throughput screening services, 1998-2003

8.3.16 Estimates of current and projected worldwide revenues for high-throughput screening services, 1998-2003

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