Many different influences have contributed to the decline in innovation and productivity in the pharmaceutical industry, delegates were told at IBC's "Drug Discovery Technology Europe 2005" conference in London.
There is, however, no shortage of new tools and solutions available to streamline the drug discovery and development process. The challenge for the industry now is to put these into practice and overcome the many nontechnical barriers slowing down the emergence of new medicines onto the market.
The FDA has been concerned about the lack of productivity in the pharmaceutical industry for some time, according to Murray Lumpkin, Ph.D., deputy commissioner for international and special programs, and has begun to look at its own role in this.
The problem does not stem from a lack of therapeutic areas or unmet medical needs, nor from a lack of effort in basic science and R&D investment. The number of NMEs continues to decrease relative to R&D spending, and the proportion of new drugs taking the FDA priority review path to approvalseen as a mark of innovationhas remained steady at 1520% over the last several years.
Four out of five products in Phase I do not make it onto the market, and 50% in Phase III go on to fail. The $800 million price tag on developing a drug (though such estimates vary widely) inevitably includes failure costs.
"We conclude that this failure of prediction in drug development systems is no longer acceptable," said Dr. Lumpkin. Regulators, he added, get to see the drug failures, which rarely get exposed in the public domain. This angle has helped drive the FDA's Critical Path Initiative (CPI), a venture that is calling for a new focus on the hitherto neglected science of development.
Tools such as biomarkers and manufacturing QC systems could help stop doomed products earlier. "Some companies have already developed such tools," added Dr. Lumpkin. "But they have tended not to share them with others."
The FDA has been consulting widely on the CPI and is soon to publish a Critical Path Opportunities List, which should help re-focus both FDA and external research in drug development and, it is hoped, attract Congressional funding.
Robert Ruffolo, Ph.D., president, R&D, Wyeth Pharmaceuticals and senior vp, Wyeth (www.wyeth. com), gave a perspective on the industry's poor image and perceived lack of innovation. "Patients and shareholders alike expect and need us to succeed," he said.
Part of the blame, he admitted, has to be placed at the door of the industry itself, but there were also many external factors. Healthcare costs are spiralling out of control in all countries. While drug costs still make up a minority of the total healthcare expenditure, they have been rising faster than other components, which has led to negative perceptions of the industry.
Development times are getting longer, for a variety of reasons. Mergers and acquisitions can have a devastating effectimpacting R&D productivity for more than three years after the event.
Meanwhile, the regulatory authorities have, in Dr. Ruffino's view, greatly contributed to the lack of innovation in the pharmaceutical industry. "We are the most over-regulated industry in the world," he commented.
Lack of progress on international harmonization is "the single greatest cause of our inefficiency." The balance between safety and benefit has shifted with an over-emphasis on safety, growing conservatism (following the Vioxx/Celebrex case), and an increasing emphasis on the precautionary principle. "We are never going to win the debate on safety," said Dr. Ruffolo. "Expectations have become unrealistic and unachievable."
The science of drug discovery and development has become more difficult too, with an increasing importance placed on molecular targets and molecular pathology. Added to that is the increasing perception of heterogeneity in both disease states and patient populations. The drug pipeline is, in fact, getting more innovative for this reason but, of course, it will take many more years for these medicines to emerge.
Meanwhile, Wyeth has been putting its own house in order since 2001 with a new R&D productivity model, which is already bearing fruit in terms of drugs coming to market.
"We wanted to become the first company to bring two drugs to market per year every year," explained Dr. Ruffolo. This goal is now seen as achievable with products due in mid-2005 and beyond.
In short, Wyeth has completely re-engineered its R&D at every stage of operations, making scientists more accountable, linking reward to performance, and focusing on putting innovative (rather than life-cycle management, LCM) and high-value products into the pipeline.
"We ripped the organization apart," said Dr. Ruffolo. Wyeth's performance at all stages of development is now above the industry average. In 2001, the company had one NME and eight LCM products in Phase III; today the balance has shifted to eleven NMEs and eight LCMs. "We intend to keep the FDA and EMA very busy over the next few years," concluded Dr. Ruffolo.
Tools to Improve Process
Many companies are dedicated to providing new tools to improve the drug discovery and development process. For instance, Tripos (www.tripos.com) provides a range of chemistry research software products and solutions. The company recently expanded its portfolio by the acquisition of Optive Research, a specialist in computer-aided molecular discovery, which gives Tripos 15 new products that are complementary to its existing range.
"Tripos is expanding beyond its core user base of computational chemists to also help the bench scientist and medicinal chemistry labs become more efficient," said Bryan Koontz, vp of marketing and corporate development and formerly CEO of Optive.
In recent years, Tripos has been building up its discovery research business (Tripos Discovery Research) in Bude, U.K., where it has benefited from input and direct feedback from the lab's scientists who use Tripos software.
The lab was recently awarded a $850,000 grant from the NIH to create a full-scale library design system for use by medicinal chemists, which can search a million times more structures than previously possible.
Now that the lab is well-established, Tripos is turning its attention back to the scientific software and informatics side, according to Trevor Heritage, Ph.D., senior vp of discovery informatics.
"We are seeing scientists becoming more open-minded about new ways of doing things. We want to provide them with software that will help them toward better research decision making."
One way of doing this is to help the medicinal chemist get more from molecular models of targets with Lithium, Tripos' new, user-friendly desktop system for 3-D chemical visualization and decision support.
Lithium uses the same file formats as molecular modeling packages, but its molecular editor is modeled on the 2-D sketchers that are more familiar to medicinal chemists, allowing the addition of viewpoints, annotation, and hyperlinkable captions for the exploration of new candidate molecules in their biological context.
Experience so far with Lithium is showing promise in the industry as it provides an infrastructure that promotes valuable collaboration between computational and medicinal chemistry teams to improve laboratory productivity.
Real-Time Parallel Analysis
Also at the meeting was Chip-Man Technologies (www.chipmantech.com), a technology company launching Cell-IQ, a long-awaited tool for drug discovery and other applications that allows real time parallel analysis of all morphological and physiological changes down to the individual cell level in continuous cell culture.
In Cell-IQ, All-in-Focus optics, incubation, environmental conditions, detection, and analysis are all controlled by an integrated artificial intelligence system; this allows monitoring and measurement of all changes, such as size, shape, migration, dendritic outgrowth, apoptosis, or proliferation, without resorting to tags or labels.
Multiple events can be monitored in parallel from each microplate well and the information generated outputted in a simple graphical form. Stored image files can be repeatedly interrogated to retrieve new data, thus eliminating the need to repeat experimentation.
Cell-IQ is optimized for measuring cell lines, co-cultures, primary cells, and stem cells. "Cell-IQ is a wet lab in a complete package," explained Jula Korpinen, CEO of Chip-Man.
"Cell-IQ contains the incubator, detector, in silico expert analysts, and technicians." The company, which was founded in 2002 from the University of Tampere, the Technical Research Center of Finland, and other Finnish academic institutions, has just raised first-round private funding of x1.2 million to further develop the Cell-IQ system.
The product will help meet the growing need for automated cell-based assays for drug discovery and development, entering a market currently estimated at $500 million and growing at 30% per annum.
Case histories presented at the conference showed how strategies and technologies are put into practice. Pfizer (www.pfizer.com) has been developing CCR5 antagonists against HIV/AIDS, an area where there is an ongoing need for effective agents.
A lesion in the CCR5 gene has been linked to lack of progression of the disease in high-risk groups, highlighting this as a new target. Tony Wood, Ph.D., head of discovery chemistry at Pfizer, described the evolution of a compound now in Phase III and the work that had been done on moderating lipophilicity, potency, and toxicity of the compound.
"We set high targets in terms of delivering selectivity against ion channels linked with cardiac toxicity," he said. The lead compound has already been shown to reduce viral load with its antiviral effect lasting beyond the last day of dosing. It may have some limitations but has been shown to be first in class, according to Dr. Wood.
Alison Holt, M.D., senior medical advisor at AstraZeneca (www.astrazeneca.com), described the development of fulvestrant, a drug for advanced breast cancer. Fulvestrant is an antiestrogen based on estrodiol, which is meant to lack the adverse effects on the endometrium of tamoxifen.
The drug has been shown to be similar in efficacy to tamoxifen but so far has not demonstrated superiority over the more traditional drug, despite promising preclinical data. "We need to do more work to understand patient populations," said Dr. Holt.
Professor Ulf Eriksson, Ph.D., principal scientist at AstraZeneca R&D in Sweden, described the development of ximelagtran, an oral anticoagulant.
Standard treatment of clotting disorders with warfarin is fraught with difficulties, and there is a clear need for new approaches. Ximelagtran is an inhibitor of thrombin, a key component of the clotting cascade.
"If there is a good understanding of the biology and the target it helps toward the goal," said Dr. Eriksson. Ximelagatran is actually a pro-drug of the compound that was first discovered, melagratran, which has good pharmacodynamics but not good pharmacokinetics. Ximelagatran has better properties and also has a low potential for drug-drug interactions.
Finally, a new feature at the conference was a showcase of London-based start-ups organized by the London Biotechnology Network to demonstrate the breadth of expertise in the capital itself.
Alan Palmer, Ph.D., CEO of CNS delivery specialists Pharmidex (www.pharmidex. com), talked about blood-brain delivery challenges. Anne Brunveils, Ph.D., CEO of Curidium, spoke about the Homomatrix approach, which explores the role of known targets in common diseases, and Rajani Kanth Vangala Ph.D., CEO of Helix Genomics (www.helixgenomics. com), discussed their biological intelligence-based informatics platform.