The Executive Roundtable

Kevin Hrusovsky of Caliper Life Sciences, Nick Hughes from PA Consulting Group, David Weber of Stratagene, and Whatman's Dr Jens Beator offer their views on pharma's beating heart: drug discovery.

Kevin Hrusovsky was appointed President and CEO of Caliper Life Sciences immediately following the acquisition of Zymark Corporation by Caliper in July 2003. Prior to the acquisition, Mr Hrusovsky served as President and CEO for Zymark. He successfully transformed Zymark from a custom robotics company into a formidable life sciences ‘tools’ company through acquisitions, R&D investment and recruitment of top industry talent.

Dr Jens Beator obtained his PhD in molecular biology in 1992. His expertise covers blotting and detection methods for proteins and nucleic acids, DNA purification methods, PCR applications, histology and cytology. He joined Schleicher & Schuell BioScience, now a Whatman company, in 2002. In his role as Project Manager, he focuses his activities on the development of protein microarray application and business opportunities.

David Weber currently serves as Stratagene’s Senior Vice President of Marketing. From 2001 until 2004, Mr Weber served as President, Americas, of GE Healthcare (formerly Amersham Biosciences), a business of GE Healthcare that provides medical diagnostics, drug discovery and protein separation systems. Prior to this, Mr Weber was Vice President at Chemdex Corporation, Amersham Pharmacia and Pharmacia Biotech.

NGP. In what ways are emerging tools enabling companies to best utilise the resources they have to validate targets and to develop drugs in a more cost-effective and accurate manner?

NH. There are many, many tools that are currently being deployed, which is both a good and a bad thing. It’s a good thing in that companies are seeking to be as productive as they can, but a bad thing in that they are going to have to build a lot of data using those technologies before they can appropriately exploit them.

For example, an often-quoted comment is that there has been a 100-fold increase in screening data in high throughput screening and ultra high throughput screening. But that has not yet led to a corresponding increase in productivity as measured by new chemical entities. Does that invalidate the approach? Possibly not, but it doesn’t necessarily confirm that it’s the right way to go. Intuitively it might be, but the question is then how do you manage that proliferation of data?

One of the threats that we perceive in the industry right now, given the highly siloed nature of discovery and development, is that a good objective will fail because people have not yet sufficiently thought through their future processes – and decision-making which may need to be changed in light of the use and introduction of these new technologies.

DW. The drug development process is a long and expensive process today. It more often results in failure than success. Pharmaceutical and biotechnology companies are more aggressively than ever looking for new technologies to help them reduce time to market, reduce failure rate, and, of course, reduce cost. Success in any of these areas impacts company image, profitability, and stock price. Meanwhile, each step of the drug discovery process is being scrutinised and streamlined. It has now moved past the ‘low hanging fruit’ stage and requires genuine innovation and creativity.

Emerging tools and technologies companies such as Stratagene give pharmaceutical and biotechnology companies more options to enhance their research and development protocols, thereby impacting their time to market and overall project cost. These innovative tools reduce procedural time, increase specificity, and generate results that are more accurate and efficient than alternative technologies. Any of these benefits alone can significantly impact the outcome of research and development timelines by either accelerating discovery or by more quickly identifying those drug candidates least likely to succeed.

For example, the ability to examine a multiplicity of signaling pathways in parallel allows earlier identification of drug candidates that may or may not be prone to toxicity. Pathway reporters, target enzymes, arrays, and informatics tools enable wide screening of these types of panels. Similar screens can then identify candidates that may be more specific to the target pathway. Then, clinical trials can be designed to only select enrollees that have a chance to benefit from treatment based on their pharmacogenomic profile.

No longer can a drug discovery company simply add robots to speed up the process. Innovative tools such as Stratagene’s Mx Quantitative PCR systems, reagents, and software coupled with efficient sample RNA preparation kits, such as Stratagene’s SideStep lysis and stabilisation buffer, and sophisticated enzyme design contribute to improving the efficiency of the drug development continuum.

KH. Business pressures require pharmaceutical companies to continuously look for ways to get drugs to market in the fastest, most cost-effective way. However, it is imperative to also guard against late-stage or post-market drug failures. Early-stage discovery tools are emerging that better predict a drug’s safety and efficacy in the clinic, without completely sacrificing speed and cost considerations.

Examples include the explosion of information enabled by microarray technology, and the increasingly popular microfluidics-based screening tools. The microfluidics-based systems, manufactured by Caliper Life Sciences, are more clinically relevant than traditional screening tools for a number of reasons. For example, these systems can enable high-throughput screens using primary human cells and facilitate more accessible, relevant safety profiling experiments.

JB. In addition to using advanced genomics knowledge, the R&D for biological markers and drug development is increasingly using proteomics technologies. This is because the majority of processes in living cells are performed by proteins including, obviously, drug-targetable steps. Thus, the presence, isoform, or absolute amount of a given protein is of paramount importance in addition to the gene or mRNA itself.

Protein microarrays offer a new technology for the screening and multiplex analysis of many (tens to thousands of) proteins in one assay. It has been shown that protein microarrays of human or yeast proteome parts can be used successfully to identify novel kinase targets. Biomarker expression in response to drug treatments can be quantified with zeptomole sensitivity of detection in minute sample amounts such as laser capture microdissected cells.

Platforms for protein microarrays can be integrated with well-established instrumentation developed for genome research. Furthermore, systems are available which enable liquid handling of protein microarrays in a microplate-like format. Thus protein microarrays can enhance novel target identification, can give quantifiable results, and can be adapted to existing automated processes. We expect to see savings in costs due to the benefits of reduced time requirements.

NGP. How do you believe these technologies are impacting attrition rates and the development cycle for pharmaceutical companies, both short and long term?

DW. It’s all about throughput. By reducing the time any given step takes, one can then cycle through additional iterations more rapidly or get a desired response more quickly. Any new technologies that help alleviate barriers in the process will allow companies to look at more drug targets in less time. In the short term, these may help decrease the development and manufacturing phases. While, in the long term, companies will be able to focus on better targets since they will have been able to screen more candidates early on.

NH. There are some intuitively obvious places to go and try to impact on attrition or try to improve R&D productivity. One has to be in the areas of predictive ADME toxicology. If you could find better tools in silica or biological systems-based, that are going to give you confident prediction in ADME and toxicity, you should see much higher throughput in the drug discovery process. Better predictive tools don’t have to be 100% corroborated to ‘wet tests’, we have shown our clients how to improve efficiency by using imperfect data to shape future (or subsequent) experimental design.

KH. Using Caliper’s LabChip 3000 microfluidics-based screening system as an example, the most immediate way in which the system impacts attrition rates during the development cycle is by virtually eliminating false positives and false negatives during the primary screening phase of drug development. Eliminating compounds (false positives) that will fall out later anyway is clearly a direct benefit to reducing attrition.

In addition, our customers tell us that after some time, they grow very confident in their primary screening data, and can ‘skip’ confirmatory screens, which leads to faster development cycles in the short term.

Lastly, because of the accuracy and reproducibility of the data generated, our customers have reported that they can gather additional information (e.g. structure-activity relationships) from primary screening data, again saving time and positively impacting the drug discovery cycle.

Longer-term impact is more difficult to ascertain with microfluidics-based screening tools since the technology is only 4 years old – relatively new in the scope of a traditional drug discovery cycle. We believe, however, that the growing adoption reflects scientists’ conviction that propagation of superior data quality throughout their discovery process and throughout the enterprise will impact the pharmaceutical industry’s long-term ability to more quickly develop safer, more efficacious drugs.

NGP. Have any particular advances been especially important in opening up the pathways to discovery?

KH. Microarray technology has certainly been key. Affymetrix is developing new high-throughput microarray technologies to enable scientists to rapidly understand the role of genetics in human disease. This technology, particularly the higher-throughput platforms, will continue to be critical to the industry, especially as personalised medicine becomes more mainstream. This whole area is one of the reasons we are so pleased to be partnering with them to provide the automated target preparation system (GCAS) that they just launched. It is an exciting area for life sciences researchers.

JB. It is well known that protein structures and molecular recognition activities are well preserved in a three-dimensional, porous nitrocellulose membrane matrix. This property is crucial (e.g. for commercially available immunodiagnostic Western Blot test strips or lateral flow immunoassay tests). We have used our expertise to develop a nitrocellulose surface chemistry in a standard microarray slide format we have named FAST Slides. This new protein microarray platform technology combined with the availability of proteome-scale protein expression libraries has enabled the screening of proteome parts for novel protein-protein interactions. A number of case studies in peer-reviewed publications has proven that the combination of these two advancements offers novel approaches in the discovery of new targets.

NGP. How has technology brought things forward and what advantages does your company offer in the field? Is your expertise broadly or narrowly applied in the drug discovery and development continuum?

JB. Protein microarray technology offers the clear advantage of multiplex analysis on protein microarray slides. The development of FAST Slides with multiple but identical protein microarrays on a single slide increases the parallel analysis of several samples simultaneously even further. Four of theses slides can be mounted into a slide holder, which has a microtiter plate format, thus enabling microplate-type liquid handling and processing. FAST slides with their proprietary three-dimensional nitrocellulose matrix are considered to be the world standard for protein microarrays due to their high sensitivity of detection, reproducible manufacturing and long term stability of arrayed proteins.

In the past years we have invested heavily in the development of the protein microarray technology, optimised the procedures and accumulated a lot of expertise in this rapidly growing field. One result is our development of a novel test system for autoimmune diseases. The test system will be CE-certified for in-vitro diagnostic use and become available in the beginning of 2006. We are using our expertise not only for our own product development, but also offer assay development and arraying service to other companies use the benefits of this new technology. Currently, we are still early in the adoption phase of the emerging protein microarray technology but we see an increasing acceptance and use by both pharma and biotech companies.

DW. Stratagene’s technology offerings are focused primarily in the early phases of drug development – in target discovery, early stage development, and screening. Our goal is to help those in the drug development area work more efficiently, thereby increasing throughput, reducing experimental time, enhancing convenience, and being more cost effective.

Our company has products that can aid researchers in the areas of sample preparation for nucleic acid isolation, manipulation, and detection; functional biology studies of proteins and their contribution to health and disease; gene expression, microarray, and pathway analysis; and intellectual property available for licensing.

NH. None of our clients want to hire us because we’re better scientists than them. That wouldn’t be a very smart selling point from our perspective either, so where we can add the most value is to bring the process of management into the arena of science. That sounds very corny, but scientists are good at discovery but not necessarily good at assessing commercial risk. Scientists are great at trying to exploit technology but they don’t necessarily do it in a systematic way that relates to a broader set of strategic objectives. Scientists are great at sticking with something through hell and high water when, perhaps, the data says it would be wiser to abandon it. So, where I think we can bring the most value is in the management of science as opposed to the competition to be the better scientist.

I don’t think there is a consultancy firm around that can compare with PA in respect of its ability to innovate drug delivery devices or technologies that impinge on drug discovery processes.

NGP. Is there a growing trend in the industry for companies to seek out development partners? What should the considerations be when choosing the right partner? How do you stand out from the competition?

KH. Absolutely. We think that more and more companies are seeking to expand their capabilities, balance resources, and reduce their financial risk by leveraging the expertise of other companies. A key reason we purchased NovaScreen Biosciences in October was that our customers were coming to us wanting more than just an instrument. They wanted assay development help, safety profiling help…

We decided it was an advantage for us to add drug discovery services to our product offering. Now we can act as a central resource, providing pharmaceutical companies with outsource capabilities or an in-house setup. And since NovaScreen does safety profiling on our LabChip 3000 instruments, a LabChip 3000 customer could easily do the work in-house or at NovaScreen, and maintain the ability to transfer data and protocols back and forth as necessary.

JB. Numerous companies have developed specific know-how, databases, sample material or intellectual property in highly specific areas. A lot of these innovative techniques require expensive equipment and solid expertise to utilise the benefits. Pharma companies are under constant pressure to shorten development times with limiting resources and cannot invest in all potential new emerging technologies. Therefore, there is a noticeable trend towards partnering for developments requiring a specific know-how in special areas of interest. Due to the inherent complexity of developing and manufacturing protein microarray assays this field is definitively an area where partnering is highly advisable.

Whatman has a solid technology base and long-lasting experience with three-dimensional matrices and their use in various immunoassays. Since the first academic publications we are actively involved in protein microarray assay development. Together with partners as well as for own product portfolio we have successfully developed both quantitative and qualitative multiplex protein microarray assays including in-vitro diagnostic assays. We are offering our expertise and services to pharmaceutical companies to speed up their developmental work and support their activities in the field of specific protein screening.

DW. Many companies, from large pharmaceutical to small biotechnology firms, are seeking out partners with specific areas of expertise to assist in the drug development or clinical trials process. This outsourcing trend has been increasing over the last 5 years and will most likely continue as pressure mounts on those firms to reduce time to market and increase profits. Outsourcing enables companies to focus on their core competency, while leveraging specialised competencies of the partner.

The primary partnership models are the provision of contract services and surrogate R&D departments. Few companies can do everything themselves these days, and those that can develop effective alliances will be the most successful. Choosing the right partner is vital. Considerations in making this choice are similar to any other relationship into which a company may enter. How much risk for how much reward? You can reduce risk by analysing the proposed partner’s track record, financial security and independence, ability to hit timelines, technology symbiosis, and a general ability to get a cost effective, win:win deal done in a timely manner.

NH. There is definitely a growing trend for companies to seek out development partners. Whether they will actually succeed is very interesting. We have supported an R&D productivity conference in the United States for the last couple of years and one of the very interesting comments made to us was that, if a small biotech thought that they had a drug in phase two that looked promising, there is no way on earth they would seek to partner with a large pharmaceutical company unless absolutely pressed. They would want to retain as much business advantage for themselves as they could.

Although the advantage of going with a big pharma company means they have the size and scale to manufacture, distribute and promote that drug. How you affect an appropriate trade-off between getting a reward for the intellectual property that you have developed and paying an appropriate price for its commercial exploitation is something that these various partnerships have yet to resolve in a way that makes sense to everybody.

An increasing number of deals fall, generally, into four different categories: where you are looking to acquire a technology platform; where you are looking for alliances to access IP or a product; where you are looking to buy a pipeline to feed future R&D investments through commercially exploitable drugs that are on the market or approaching the market right now; and where you are looking to adjust your portfolio, normally divestment.

The nature of these deals is very different and the thing that we tend to observe, which will probably upset some of the people we consult, is that some of these deals are often treated as serendipitous events rather that processes that need to be managed in a structured way. There is often a lack of a clearly defined strategy for the collaboration. The intent is there, but the execution or the consistency of the process by which the alliance is managed is found wanting.

However, we see an acceleration in the number of collaborations each year. It is rapidly expanding and will continue to do so, and management is becoming a significant and increasingly difficult aspect of the way forward for these companies. Get it wrong and you potentially lose all the value of the partnership because you have not thought about how to husband it and exploit it.