Late stage failure of candidate compounds in drug development programmes is very expensive to the pharmaceutical industry. Whilst commercial considerations and liver toxicity account for the halting of many programmes, most large pharmaceutical companies will suffer occasional stops or more likely delays in phase 1 or phase 2 trials as a consequence of genotoxicity data. The incidence of serious late stage genotoxicity concern is around 12%. At the very least, these problems lead to costly delays in clinical trials whilst mechanistic studies are carried out as part of a risk assessment exercise. For a potential blockbuster there is the even greater cost of delays in bringing a compound to market. The abandonment of a compound at this stage is currently estimated to cost between 5 and 30 million dollars.
An effective screening strategy would identify genotoxic liability during lead optimization. If there is still a broad choice of chemistry, the at-risk members might be abandoned and efforts concentrated on other choices. If there is less choice, then chemical development strategies should focus on separating useful pharmacology from damaging genotoxicity. Given the very high rate of attrition for compounds in drug discovery (from tens of thousands to just 2 or 3 candidates), a screening programme should be able to substantially reduce the number of genuine genotoxins reaching the later stages of development. The GreenScreen HC assay identifies at least 80% of genotoxic carcinogens. Its use in early screening should therefore reduce the late failure rate from 12% to about 2.4%.
The current regulatory protocols were not conceived for screening. In practical terms they are too time-consuming and compound hungry. In performance terms they mostly lack specificity. The GreenScreen assays have high specificity and were developed specifically for screening. They used by over 65 companies world wide, saving millions of dollars in late stage failure.
The cost of this saving is not high. The battery of regulatory tests costs about 60 thousand US dollars per compound. That is an expensive way to find problems in late preclinical development. The GreenScreen assay costs about 400 US dollars per compound – for low numbers. It costs considerably less when used in screening, and you still have time to address any problems that are identified.