De-risking an asset
Central to the necessity to “de-risk” pharmaceutical assets is the significant attrition rate which drives drug costs; over ninety percent of clinical drug development failed between 2010 and 2017 (1). If molecules in the pre-clinical stage are included, the rate of attrition from Discovery to Commercialization rates as high as 99%. Causes for failure include lack of efficacy (40%), toxicity (30%), poor-drug-like properties (10%) and lack of strategic planning (10%) (2).
To a patent lawyer, de-risking an asset consists of ensuring the intellectual property can be protected. To the business development team, it means confirming the available market space for the drug to be sold. To the scientist, it consists of eliminating the aforementioned causes of failure: lack of efficacy, toxicity, poor pharmacokinetics, etc.
Building translational assessments of efficacy early in Discovery contributes to de-risking; choosing clinically-representative models can be aided with proteomics analysis to validate the existence of specific targets and pathways across species. Checking functional efficacy across multiple species is often performed in early Discovery as another means of de-risking an asset for translatability (3).
Incorporating early toxicity signals in the readouts of efficacy studies can be done efficiently, keeping an eye on critical off-target organ function (lungs, liver, kidneys, brain, heart). While the induced disease can complicate the interpretation of the “safety/toxicity” signals, experienced scientists with ample experience with a given pre-clinical model of human disease will identify unusual side effects early in molecule development; efficacy and toxicity will then drive molecule optimization.
Big Pharma uses the strategy routinely and has coined the phrase “Fail Early, Fail Fast”.
Applying the above de-risking strategy will decrease the chance that a pre-clinical drug candidate will fail in more expensive GLP-compliant, preclinical safety or toxicology studies. Once these are completed, the new dataset will further support the de-risking strategy, this time vs. clinical failure.
De-risking pre-clinical drug candidates for scientists has been the focus of IPS Therapeutique (IPST) for 24 years; every in vivo model has been developed with this dual purpose in mind: confirm and define the conditions for efficacy, and identify early indicators of toxicity.
From proteomics to GLP-compliant safety pharmacology studies, IPST’s scientists understand the impact of attrition on drug discovery and use early detection of failure signals to lower the cost of pre-clinical development.
1. Sun D., Gao W., Hu H., Zhou S. Why 90% of clinical drug development fails and how to improve it? Acta Pharmaceutica Sinica B, Volume 12, Issue 7, 2022, Pages 3049-3062.
2. Dowden H., Munro J. Trends in clinical success rates and therapeutic focus. Nat Rev Drug Disc., Volume 18, 2019, Pages 495-496.
3. Hughes J.P., Rees S., Kalindjian S.B., Philpott K.L. Principles of early drug discovery. Br J Pharmacol, Volume 162, 2011, Pages 1239-1249.
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