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Knowledge-based genotoxicity prediction tools used universally in pharmaceutical development

A long-running collaboration involving the Chemical Biology and Medicinal Chemistry Group and partners from the chemical and pharmaceutical industries led to the establishment of Lhasa Ltd and the creation of a knowledge-based system to predict the toxic hazard of organic chemicals. 

Summary of the impact
Lhasa Ltd. has made widely available toxicity prediction software, currently known as Derek Nexus (Derek) that exploits underpinning research undertaken at the University of Leeds.

The use of Derek by large pharmaceutical companies to support drug development is effectively universal. Toxicology prediction software has led to changes in guidelines issued by regulatory authorities and to industry-wide changes to the investigation of the toxicity of trace impurities. These changes have reduced the resources needed for experimental investigation of toxicity, and have increased revenues derived from launched drugs by extending their patent period of exclusivity. Lhasa Ltd. derives income in support of its charitable aims from Derek, and a related product Meteor Nexus (Meteor) also based on research undertaken in Leeds. 

Details of the impact 
The ability to predict potential significant toxicity of pharmaceutical impurities is of vital importance to the pharmaceutical industry because many drug candidates fail in development due to toxicity problems. Early toxicity testing can prevent the costs associated with unnecessary R&D and the late failure of drug candidates.

Universally accepted by regulators
In 2008 the US Food and Drug Administration (FDA) published guidance on “a variety of ways to characterize and reduce the potential lifetime cancer risk associated with patient exposure to genotoxic and carcinogenic impurities both during clinical development and after approval.” Derek is specifically cited as a recommended prediction tool to inform decision-making (A). Although a number of methods are mentioned alongside Derek for this initial toxicity evaluation, in practice, the use of Derek by large pharmaceutical companies is effectively universal. Changes to guidelines have been informed and the pharmaceutical sector has adopted Derek as a tool for toxicology prediction.

Faster to market to increase revenues
The universal application of the Derek system derives from its excellent success rate in identifying structures that represent a genotoxicity risk and providing supporting evidence for its assertions. Since the mid-2000’s the success of Derek has embedded the software in the workflow industry-wide as a means of reducing costly and time consuming experimental evaluation.

Reduced costs during development
The embedding of predictive toxicity tools has also had a significant bearing on cost and resource. Each year, on average, a major pharmaceutical company might perform 100 Derek screens on impurities to adhere to regulatory guidelines for genotoxic impurities. Of these, a significant proportion (>50%) will generate a clean signal and, as a result, development can proceed without further safety testing.