The productivity/innovation gap identified in a now-famous equation developed in 1996 by Juergen Drews, MD, that sent shock waves through the pharmaceutical industry is showing few signs of abating despite the addition of thousands of potential new genomic-based targets. Drews, managing partner of Bear Stearns Health Innoventures LP, provided an update February 3, 2004 at the LabAutomation 2004 conference in San Jose, Calif.
"There is some discrepancy between what the companies could expect and what they could deliver," said Drews.
In 1996, the equation, which combines expertise and cost of drug development with the success rates of moving from discovery to development to market and other factors, showed that the top 20 pharmaceutical companies faced a shortage of new compounds from those that could be expected, at a rate of about 1.3 per company. A recent update by the consulting firm Bain & Co used the same equation to show that the gap has increased to 2.3 compounds per company. The industry is in serious trouble, says Drews.
Drews spoke about two major bottlenecks: target validation and the fact that diversity-oriented chemistry needs to be replaced by target-oriented chemistry. With respect to target validation, "the progress of true drug discovery is really low because of it," Drews said. Early discovery can identify a multitude of targets, but until they are truly validated, they are no good to the industry.
More importantly, diversity-oriented chemistry has led to an unreasonable expectation of the number of possible compounds that might be effective in disease therapy. One estimate by a group associated with Novartis estimated that there are a possible 10 to the 62nd or 10 to the 63rd power drug-like molecules compared to a maximum of about 10,000 targets. "Why worry about this tremendous universe of chemical compounds?" said Drews.
The genomics revolution has led to a paradigm shift in drug development from chemistry-based programs toward information-based programs. The emphasis has slowly but surely shifted toward the targets themselves. "Many companies have now put the target at the center of the process," said Drews.
Drews then offered a few lifelines for the industry, including "privileged structures," a concept that he says was developed as early as 1988 and is now being revisited from a target perspective. A privileged structure refers to the idea that one type of structure might be responsible for a multitude of biological effects. "It somehow corresponds to the idea that there is some evolutionary convergence of structures," Drews said. "Nature finds structures that are useful in one context and evolves to use them in other contexts." This "master key" approach could hold the secret to an entirely new way of developing drugs.
But the companies themselves might have to change first.
Most of the pharmaceutical companies have marketing-oriented management, Drews said, which is why they are organized by disease area. Of course, these organizations have nothing to do with how the science rolls out, says Drews. "Science-chemistry, biology-do not function according to these restraints."
A better system, Drews said, would be to organize management according to the type of targets (e.g., GPCRs or kinases), because an understanding of a particular target plus a chemistry oriented to master keys provides access to a multitude of therapeutic areas. Drews says this type of attitude may even lead to a revival in the fortunes of the most dynamic pharmaceutical companies.
Drews also pointed to the acceleration of the development of protein drugs. "That approach plus the evolution of molecular immunology has led to a striking role of protein drugs that is already a reality in medicine," he said. In fact, five drugs based on this concept have already achieved blockbuster status, and biotechnology company new molecular entities (NMEs) are already approaching roughly one-third of the total NMEs that appear every year. Eventually, the stagnation of small-molecule drug development will become even more evident, Drews said, adding another complication to the necessity for radical changes in pharmaceutical development.