Priming the pipeline
The drugs that a company has in development are known as its pipeline. Ideally, a company wants to have a good flow of drugs through its pipeline, launching new products as old ones lose their patent protection. During the 1990s, this flow became a trickle across the industry. Many new approaches are being adopted to replenish the pipeline and get more drugs to market more rapidly. Three areas have been a major focus: genomics, high-throughput screening and combinatorial chemistry.
There were hopes that the sequencing of the human genome would speed the development of new drugs. Although this has not come to pass, genomics is now critical in drug development. For example, it has opened up the possibility of looking at the role of all human genes in disease processes. The functions of hundreds or thousands of genes can be studied simultaneously. Sequence comparisons and analysis can be done on computers (bioinformatics), and structures of many proteins can also be studied on a desktop. These types of approach make it easier to identify and characterise new therapeutic targets.
As for the agents that might act on these targets, high-throughput screening can accelerate the search for chemical entities with a possible biological effect. Automated techniques can now rapidly assess thousands of compounds, the most promising being selected for more specific analysis.
It is also possible to gather more data from each screen, by looking for changes in the activities of thousands of genes (transcriptomics), proteins (proteomics) or metabolites (metabolomics). A new approach, high-content screening, uses automated high-throughput microscopy to record the effects of compounds on living cells. As well as robotic handling of samples, image analysis is also automated.
For high-throughput screening, researchers need a large number of compounds. While in the past these might have been painstakingly collected from natural products, combinatorial chemistry has created immense new libraries for industry to work with. The approach is like building Lego structures using randomly chosen bricks - even with only a few different colours to choose from, a huge number of combinations can be built.
Speeding up
While these techniques have greatly increased the numbers of targets and potential drug compounds, all the other time-consuming stages of drug development have to be gone through with candidate drugs.
At all stages, drugs will fall by the wayside. But a lot of work will have gone into characterising a compound, and it would be better to rescue a partly developed drug than start again from scratch.
One approach is to take drugs that have not worked well in one disease and screen them for effects in another. Several drugs, including the anti-HIV drug AZT and Viagra, were developed for one use but were repurposed.
Innovative screens have been set up. One company looks for the ability of compounds to correct deficiencies in zebrafish.
Pharmacogenetics may also give a drug a new lease of life. In theory, if the genetic factors linked to a harmful reaction were known, a drug could be given to everyone except the susceptible. At the moment, even if only a tiny proportion react badly to a drug, it is unlikely to be used. In the shorter term, pharmacogenetics is allowing companies to screen for potential ill-effects and to carry out clinical trials with smaller, more targeted groups.