Issue Date: July 11, 2011
In an environment where pharmaceutical companies are under intense pressure to spend their R&D dollars judiciously, the industry is in a quandary: how to manage risk and become more productive without sacrificing innovation.
The sentiment echoed throughout the halls of the Biotechnology Industry Organization’s (BIO) annual convention, held late last month in Washington, D.C. And in meetings with C&EN, R&D executives from GlaxoSmithKline, AstraZeneca, and Eli Lilly & Co. explained how they are tackling the problem. The tactics vary, but the executives have a common goal of reducing the uncertainty inherent in drug discovery and development.
GSK has taken on the innovation challenge by narrowing its focus to fields in which the firm thinks the basic science can best guide drug discovery and development—and by stepping away from those areas in which the risks are simply too great.
Several years ago, GSK’s best scientists teamed up with leaders in various biomedical fields to spend a year reviewing their areas of expertise. The goal was to understand where the basic science was and where breakthrough biology was emerging. “We were very cautious not to be smitten by fashion, because unfortunately that exists a lot in science,” said Moncef Slaoui, GSK’s chairman for R&D.
In all, 17 therapeutic areas were reviewed. At the end, the company identified a handful of them that were “ripe with new science,” Slaoui said. For example, inflammation research appeared to be at an inflection point at which the intricacies of immune signaling were beginning to be understood.
GSK then shifted its resources to the areas where a critical mass of biological information was accumulating and away from ones where too many questions remained, making it tough to invent innovative drugs. In hypertension, for example, “there is no new biology that is compelling,” Slaoui said, thus no direction for improving on existing medicines. Likewise, GSK moved most of its resources out of neurology, where the lack of new biology combined with poorly characterized clinical end points made drug development daunting.
“This is the most dangerous area, where you don’t understand the biology and you have no means to clinically test the biology in a scientifically robust way,” Slaoui explained. “The only way to do that is a very large Phase III study.”
In addition to focusing on the most promising therapeutic areas, GSK has embraced several broad drug discovery technologies that it believes are, scientifically, at an inflection point. Epigenetics, pattern recognition receptors, and cancer cell metabolism are a few areas that Slaoui said are risky but worth taking a chance on.
GSK plans to conduct the same kind of review of the scientific landscape every five years or so to adjust its strategy and ensure that its portfolio maintains the right balance between risk and opportunity.
AstraZeneca has also taken a hard look at its research approach and revamped how it chooses projects and conducts R&D. The company recently assessed its efforts in drug discovery and early development over the past five years to understand what had been driving decision-making, said Mene Pangalos, executive vice president for innovative medicines. The review of more than 150 projects raised questions about scientists’ confidence in the targets and pathways they were working on and made clear that the firm’s focus had been on quantity rather than quality.
“As a company, we were probably the most productive organization in delivering volume, if you measure drug candidates and [Investigational New Drug Applications] filed,” Pangalos said. But when it came to getting a drug candidate through proof-of-concept trials and onto the market, “we were not so good.” The organization has since moved away “from what historically has been a volume-driven culture to one focused on quality and value,” he argued.
Last year, AstraZeneca revamped its R&D structure to give its therapeutic units more accountability for what is coming out of their labs. Scientists now have more power over their development programs, enabling them to tailor studies to best fit the disease and target. “That’s actually a tough culture change,” Pangalos said. In the past, early-stage development programs were all designed to fit a “playbook for drug discovery,” he says, an approach that didn’t always allow scientists to ask the right questions.
AstraZeneca is also keeping closer tabs on the progress of its projects and the science supporting them. Every two months, a research board meets to assess the drug development pipeline and review the science to ensure that resources are being put toward the right programs. “It means we’ve had transparency across the whole portfolio,” Pangalos said, allowing the company to make clear decisions in an environment where funding is more restrained.
The therapeutic units are also trying to inject more certainty into the earlier stages of drug development by teaming with AstraZeneca’s personalized-medicine and biomarker team. Historically, biomarkers and companion diagnostics have been developed after a compound has reached clinical trials, but the new goal is to identify the right patients much earlier to enable more informative, less expensive studies. A year ago, just 15 to 20% of AstraZeneca’s programs used a patient stratification or personalized-medicine strategy; today, that number is close to 50%, Pangalos said.
While some companies are focused on cultural changes to their R&D organizations, Lilly is hoping new technology will bring the right balance between the risk of drug development and the need for innovation. At the BIO conference, Lilly announced that it is investing in the research and development of “multispecific therapeutics,” or single-protein-based drugs that are engineered to modulate two distinct targets.
Most treatments, even if initially effective, become subject to resistance, noted Jan M. Lundberg, executive vice president for science and technology and president of Lilly Research Laboratories. Because the treatment paradigm for diseases such as cancer, diabetes, and inflammatory disorders is shifting to combinations of drugs, Lilly believes its “two in one” technology will make discovery and clinical development of combination treatment much more efficient.
The two targets being modulated could both be well established, providing “an opportunity to improve upon past innovation,” said Thomas F. Bumol, Lilly’s vice president of biotechnology discovery research. Other options include combining a novel target with a known target or building a drug that hits two novel targets. The first multispecific therapeutic, a coagonist peptide for diabetes, is expected to begin clinical trials later this year.
“Since we’ve now established this technology, it can help us to do R&D quicker and cheaper,” Lundberg said. “When refined, it could be a step change in how we do R&D.”
The technology can also revive projects that may have failed in the past because of potency or other problems, Bumol added. “We have decades of research in novel agents, some of which have never seen the light of day,” he observed. Yet those molecules might prove effective in combination with other mechanisms, “allowing us to look back historically at what we’ve tried through a new lens.”
The technology was developed in-house, with expertise gained through Lilly’s acquisitions of ImClone Systems and Applied Molecular Evolution. Lilly will double the number of scientists working on the project in coming months by adding 20 researchers each at its Indianapolis and San Diego sites.
Lilly has not specified how much money it is devoting to the new technology, but executives said they are confident it will become a critical component of R&D. “I don’t give an exact number today because I think it’d be too low,” Lundberg said. “We will expand [this effort] in time, and it may encompass a major proportion of our portfolio.”
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