Pharmaceutical and biopharmaceutical firms need to reduce the cost and lead time of drug development. A range of recently
developed technologies makes that goal possible.
|by Peter Gwynne and Gary Heebner
DNA microarrays, based on the principles of semiconductor technology
Roche Applied Science
kits and systems for genomics and proteomics research
Takara Bio, Inc.
kits and reagents for molecular biology research
+81 77 543 7247
scientific instruments, vacuum technologies, and contract manufacturing solutions for the life sciences
|•||High throughput screening|
|•||Rational drug design|
Within the past few decades, the time and cost of drug development have soared. Today it typically takes about 15 years and costs up to $800 million to convert a promising new compound into a drug on the market. Those costs reflect the complexity of the process.
First, scientists must identify the molecule — a target — involved in a disease. That demands an understanding of the metabolic processes of a cell in both its normal and diseased states. The successful sequencing of the human genome has opened the way to genomics based methods for this component of drug discovery. The 30,000 or so human genes offer a vast number of possibilities for molecular researchers to consider in the search for new drugs. Understanding how the genes function and malfunction provides the key to choosing which genes to consider as targets for the discovery process.
Next, scientists have to search for another compound — a lead — that can alter the action of the target molecule. In times past, that task had the unfocused quality similar to seeking a needle in a haystack. "And in the past decade we've made the haystack a lot bigger," says George Purvis, vice president and founder of CAChe Software Group, part of Fujitsu America.
Even when they are identified, active leads often lack certain properties required to become a drug. So researchers must develop chemical analogs of those compounds, synthesize them, and test them until they find a drug candidate with the desired characteristics.
That represents only a start. A compound that looks highly promising at the discovery stage can fail at several points in drug development, as it undergoes tests for toxicology and efficacy, initially in animals and then in humans. "The largest cost in drug development comes when bad side effects occur at the toxicology point," says Steve Levine, senior director for strategic partnerships at Accelrys, a wholly owned subsidiary of Pharmacopeia.
Plainly, pharmaceutical and biopharmaceutical companies need to find ways to screen for potential problems with promising molecules at the earliest possible stage. They also need to streamline the entire process in such a way that compounds that pass the screening move quickly along the development pipeline. "In drug discovery, time is money," says Axel Jahns, director of product management at Eppendorf. "Convenience and reliability go together."
While they promise a cornucopia of new drugs, genomic methods alone will not reduce the cost and time of drug development. However, other new developments, many stemming from biotechnology, will help to improve the productivity of drug development. Such approaches as rational drug design, combinatorial chemistry, and in silico experimentation via computers have started to expedite the overall search for new drugs. New methods of data management complement those approaches. "It is often said that the next drug is buried in a pile of data," says Shawn Green, founder of LabBook and BSML.org. "So we need informatic solutions that can transform data into knowledge — the most important asset in a life science company."
The new tools and methods have already given researchers better understanding of the biochemical processes in cells and the ways in which they can synthesize compounds that will alter cellular behavior. "About 40 percent to 45 percent of all drugs in human clinical trials originated in biotechnology, up from 10 percent or less 10 years ago," says William Haseltine, chairman and CEO of Human Genome Sciences. "The next decade will bring a rising tide of functional data from study of the human and other genomes that will aid in drug discovery," adds Carl Feldbaum, president of the Biotechnology Industry Organization.
Increasing productivity means screening more samples in less time and with less labor. To accomplish this, manufacturers have developed high throughput screening (HTS) systems that range from semi automated work stations to fully automated robotic systems. "At the beginning of the 1990s only a few hundred proteins were well characterized," recalls CAChe's Purvis. "Now crystallographers are talking about high throughput crystallography — doing a structure in perhaps one day using robotics to work on crystallization conditions and the ability to express large quantities of proteins."
HTS has universal utility. "Drug discovery and development involves looking at undefined substances, screening synthetic compounds for their drug potential, taking off from PCR, and other standard methods," says Harald Andrulat, product manager of Eppendorf. "All ultimately have something to do with HTS."
HTS products start out with liquid handling systems for the research laboratory, such as multichannel pipetters, 96-well plate fillers, and washers produced by Rainin Instruments and other firms. Eppendorf, meanwhile, recently introduced epMotion 5070, a work station aimed at scientists who need flexibility in liquid handling. Beyond that, says Jahns, "We want to look into solutions rather than supplying single products or pieces of equipment. "We aim to provide consumables and reagents with each piece of instrumentation for high throughput."
At the other end of the HTS range suppliers provide work stations that fill, wash and rinse, and read fluorescence or other characteristics of a sample in addition to handling liquids. PerkinElmer is among the leaders in laboratory automation and HTS, while Applied Biosystems, Beckman Coulter, and Zymark offer sophisticated robotic systems that are even more versatile than work stations. Hamilton Company is developing high throughput proteomics work stations for applications such as MALDI TOF MS target spotting and protein crystallization. "We have been working with Data Centric Automation for a complete protein crystallization optimization work station," adds Gary Engelhart, Hamilton's national sales manager. Hamilton also offers flexible and sophisticated work stations, automating assays, and sample preparation during every phase of the drug discovery process.
Pharmaceutical companies have long tried to replace serendipity with logic in the effort to develop new drugs. In years past, rational drug design required medicinal chemists working at a lab bench to synthesize a relatively small number of compounds with the desired properties of a potential new drug. The step-by-step approach took many months or even years to complete.
The effort has produced results. "Our Tamiflu oral anti-influenza treatment was created through rational design by chemists at our partner Gilead," says Lee Babiss, vice president of preclinical R&D at Roche. "But so far those results have tended to be one-off." That situation is changing, however. "In the next five years," Babiss predicts, "you'll see a large number of compounds coming onto the market as a result of rational drug design."
Current methods of rational drug design accelerate discovery by removing some of the randomness from the process. The methods involve the design and optimization of small organic molecules based on either information derived from a protein structure or a small collection of hits from high throughput screening. "You need two things: databases to hold all the information that comes out of your high throughput screening and various proprietary algorithms that allow you to dock compounds into the active sites you're targeting," explains Babiss.
Roche scientists use rational drug design to examine what happens at the molecular level when a drug binds with a receptor, thereby obtaining a three-dimensional picture of a binding site. They aim to develop drugs that bind optimally to a given receptor with greater selectivity, thus improving efficacy. "We are starting a program in metabolic diseases that involves lipid metabolism," says Babiss. "It's an example of our ability to do the in silico screening based on having a very deep database from screening data against the targets."
Information companies also have a role in the process. "One of our real competencies has been rational drug design," says Levine of Accelrys. "It's important to get the information to the desktop without the need for written reports. Enabling people to access the science is almost as important as the science itself."
Another approach to generating many compounds that may interact with a target is combinatorial chemistry, a method that creates every possible variant of a parent compound. Combinatorial chemistry plays a major role in constructing chemical libraries, a service offered by Cambridge Drug Discovery and PPD, among other companies. "We have a number of products that allow you to do virtual screening and database building," says Levine of Accelrys. "Uniquely, we allow that information to be shared across products by chemists and biologists who don't have to communicate individually. That helps companies to reengineer their culture to make work more efficient, getting everyone on the same page."
Effective as they are individually, rational drug design and combinatorial chemistry work even better in partnership to shorten the drug discovery process. Companies such as Accelrys and Tripos have developed computer programs to help the design of synthetic molecules likely to have the desired biological properties, while minimizing the risks of such adverse effects as toxicity. "ADMET [absorption, distribution, metabolism, and excretion plus toxicity] is important," says Purvis of CAChe. "We provide a number of tools to help the chemist predict those processes using simple rules such as Lipinsky's rule of five, as well as allowing them to build their own custom systems. The software is universal, so that medicinal chemists can customize their models."
Finding the right compounds once meant spending long hours searching the literature and making calls to colleagues in hopes of locating several compounds with specific characteristics. To reduce this time and increase the efficiency of locating possible drug candidates, companies have developed large databases and powerful search engines that allow researchers to enter the characteristics of a compound of interest and search for natural or synthetic compounds with similar properties. Accelrys, ChemNavigator, and Sigma-Aldrich provide scientists with the searchable chemical databases and also provide sources for the hits from these searches.
Databases have one disadvantage: an excess of information. "Chemical departments in drug discovery face an overload," says Hans Johansson, CEO of Swedish company Personal Chemistry. "A lot of new hits have come into lead optimization through the use of high throughput screening. The overload, combined with methodology issues in which chemistry has not really been adapted to HTS and an almost global shortage of chemists, has made this a bottleneck, particularly for biotechnology companies that are moving into drug development."
In response, "We're looking at a new way to create, store, and share chemical knowledge," Johansson continues. "We're applying focused microwave energy to speed up chemical reactions, to increase yield, and to enable chemistries that would be difficult to get to go." The technology, coherent synthesis, delivers highly reproducible results that are automatically stored and made available to any chemist in the organization. Personal Chemistry recently launched Emrys Knowledge Builder and Emrys Pathfinder. "We're looking at a chemistry book of five thousand to 10 thousand pages in terms of proprietary knowledge," says Johansson. "Applied throughout a large pharma's chemistry department, it will rapidly exceed even that size and become a tremendously valuable asset for the whole organization. Scientists have already talked at conferences about up to 400 percent increases in productivity in terms of the lead optimization phase."
Even laboratory notebooks are going the way of automation. "We are seeing a convergence of informatics and wet lab experimentation in the drug discovery process," says Shawn Green of LabBook. Thus companies such as LabBook and ChemSW offer specialized versions of electronic laboratory notebooks to help scientists organize their information and experimental data.
"From a researcher's perspective, paper based lab books remain the places to capture and share all key activities and assets within the drug discovery enterprise," explains Green. "Electronic lab books need to overcome the hurdles established by paper records such as ease of use, portability, and legal and regulatory compliance — and in addition provide affordable functionality in information management." That's beginning to happen. Thus LabBook provides an electronic notebook — eLabBook — that integrates local data and documents with web based capabilities.
While pharmaceutical organizations are developing new drugs, the suppliers of instrumentation and reagents are busy supporting this industry with tools that are faster, more powerful, and more automated. To be effective, these new products must be designed with the end-user's needs in mind. Working together, these industries offer the promise of more targeted and more effective drugs that will benefit all humankind.
The View from BIO
What challenges does the biotechnology industry face in its participation in drug discovery? How successful has the industry been in improving the efficiency of drug development? And what key technologies coming down the pike will improve the efficiency of drug development? We put those questions and others to representatives of the Biotechnology Industry Organization (BIO). A selection of their comments follows.
"Drug discovery is a very expensive proposition. One of our toughest challenges today, when there are literally thousands of biotech companies worldwide pursuing promising ideas, is maintaining an extensive network of financial support," says BIO president Carl Feldbaum. "Financing has been difficult for young public companies over the last few months, leading dozens of companies to trim their scientific ambitions and staffs."
William Haseltine, chairman and CEO of Human Genome Sciences and a board member of BIO, echoes that point. "Biotechnology firms generally don't have the experience and capital that large companies have," he explains. "So there are always capital and expertise constraints. The boom of 1999-2000 allowed many biotechnology companies to become well capitalized; that has stood them well in the present period. But should market conditions prevail it will be very difficult for many biotechnology firms, particularly with early stage products only, to continue to raise funds. They'll either merge or go out of existence."
Biotechnology companies have achieved their present prominence in drug development "with a combined R&D budget in aggregate somewhat less than that of any one of the top 10 large pharmaceutical companies," says Haseltine. "That tells you that productivity is about tenfold greater in the discovery and development process in the biotechnology industry than in the large pharma."
On the political front, adds Feldbaum, the Prescription Drug User Fee Act, which Congress passed in 1992 and renewed in 1997 and 2002, with encouragement from the biotechnology industry, includes several provisions significant for the industry. It allows companies to request that independent consultants participate in discussion on the design of pivotal phase 3 trials. It earmarks funds for targeted initiatives to improve the drug review process. It expands and improves electronic submission capability. And it launches pilot programs to strengthen communications between the U.S. Food and Drug Administration and developers of fast-track products for life-threatening diseases. "We hope these measures and additional financial resources from a user fee hike will drive down development and review times and make the process more predictable," says Feldbaum.
NEW TECHNOLOGIES AND INITIATIVES
"Right now," says Feldbaum, "the industry is still assimilating the late 1990s wave of drug discovery technologies that are bringing about a powerful convergence of molecular biology, miniaturization, and materials and information technologies. Computer and chip technologies have given thousands of scientists the human genome as a bench tool, an opportunity unthinkable just 10 years ago. Scientists already have a publicly available catalog of 1.8 million single nucleotide polymorphisms to work with, and geometric expansion of proteomics research and technologies will create multiples of the existing data volume. The convergence of information technology and biology may well be the biggest story in biotechnology over the next decade. As we learn more about the cascades of reactions essential to disease and health, in silico modeling and testing will become more refined, perhaps alleviating some of the bottlenecks characteristic of wet biology."
In terms of policy, Feldbaum adds, "BIO is continuing its efforts to bolster the industry's economic foundations through investor outreach initiatives, new investor and partnering conferences, and expansion of our existing conferences. We also plan to revive our push for new tax incentives, including a credit for net operating losses at development stage biotechs, with the new congress. We believe the tax code should be revised to better reflect the high risk, long development time frames, and social benefits of investment in innovative biomedical products."
THE VALUE OF MEETINGS
"Because so many BIO members are young, entrepreneurial companies in need of partnerships and investment to advance their research, BIO has assumed the role of matchmaker by hosting meetings throughout the year," says Cynthia Beckman, BIO's chief operating officer for conventions and conferences. Highlights include February's CEO & Investor Conference in New York City, April's Mid-American Venture Forum Conference in Chicago and BIO-Windhover Partnering Conference in Washington, DC, and the Annual Convention in the same city from June 22 to June 25 this year.
The Annual Convention, the largest gathering of biotechnology leaders in the world, touches on every aspect of biotechnology, including business development, bioethics, and science and public policy. It has emerged as the single most important forum for bringing together the players who will determine the nature of molecular biotechnology's impact on the planet over the coming decades.
"Thinking Beyond Tomorrow," the theme of the next Annual Convention, "really captures the outstanding progress of the biotechnology industry, and the promise of what is to come," Beckman adds. "Although biotechnology has led to more than 140 new medicines and dozens of new crops, we've really just scratched the surface. More than 370 additional medicines and vaccines are in clinical trials now, and there remains much basic research territory to explore. For BIO, thinking beyond tomorrow means laying the political groundwork for the breakthroughs to come, in stem cell research, genetics, and more conventional medicine."
Peter Gwynne is a freelance science writer based on Cape Cod, Massachusetts, U.S.A. Gary Heebner is a marketing consultant serving the scientific industry, based in Foristell, Missouri, U.S.A.
This article was published
as a special advertising supplement
in the 7 February issue of Science