Simulations Plus

DILIsym has been utilized by our clients for help with their liver safety goals within a number of high profile drug development programs.  Important DILIsym application examples include:

• Comparison across 5 CGRP receptor antagonists molecules for migraine treatment, which supported approval of rimegepant for both acute and preventive treatment of migraine
• Comparison of ubrogepant with prior in-class molecules for DILI potential, which was included in an FDA review of the ubrogepant safety data

• Comparison of lixivaptan’s liver safety profile with tolvaptan, which was submitted to the FDA as part of the new IND application for lixivaptan.   Note that lixivaptan clinical development has subsequently been halted based on a liver safety event in the ALERT clinical trial.  This trial only enrolled patients who had terminated treatment with tolvaptan due to liver toxicity.  Apparently, all but this patient was able to be safely converted to tolvaptan.  The DILIsym prediction that the liver safety of  lixivaptan is much greater than tolvaptan has not been disproven and is actually supported by the ALERT trial.   For additional discussion see Dr. Watkins’ blog post.

• Mechanistic analysis of acetaminophen’s carcinogenic potential, which was submitted to the California Office of Environmental Health Hazard Assessment regarding Proposition 65 as part of the weight of evidence suggesting no cancer risk; FDA agreed
• Mechanistic analyses of the liver safety of remdesivir, tolvaptan, pexidartinib, and TAK-875
• Comparison of the liver safety mechanisms of several macrolide antibiotics as part of the solithromycin new drug application advisory committee meeting
• Liver safety biomarker analyses for entolimod and GGF2
• Dose optimization for a novel antibiotic, BAL30072

Given the high social and economic costs associated with late stage drug failures, the U.S. FDA has been assessing the added value of computer modeling in regulatory decision making as a way of predicting drug safety and efficacy during drug development. A major effort in the Center for Drug Evaluation and Research is the development and use of computer simulations to predict drug toxicity and to understand the mechanisms responsible for unexpected adverse events. Liver and kidney toxicity remain areas in which safety concerns continue to lead to drug failures across all phases of drug development. The FDA was involved in a Cooperative Research and Development Agreement (CRADA) that led to the formation of the DILI-sim Initiative and the ultimate development of the DILIsym software platform. Recently, the FDA renewed their DILIsym licenses package.  A commentary published by employees of the FDA on the DILIsym software praised early examples of DILIsym use and commented on the prospect of future predictions.  Another review paper including an FDA author provided an overview of DILIsym. Finally, a published book edited by an FDA employee included a complete chapter on DILIsym. Many application examples of DILIsym have also been submitted to the FDA, as noted above.  Submissions to the EMA and PMDA have also occurred for some of the same development programs and others.