Predictive toxicology tools and safety strategies put in place earlier in the drug-development process will begin to deliver in the future, according to Stephane Dhalluin, Ph.D., director of investigative nonclinical safety at UCB Pharma, who spoke at Mondial Research Group’s “Predictive Human Toxicity and ADME/Tox Studies” conference held recently in Brussels.
As an example, he referenced data gathered between 1991 to 2000 and between 2001 to 2007 that shows a decrease in attrition for toxicology and safety reasons in the latter period. The formation of data-sharing consortia between big pharma companies and academia like eTOX, a program of the EU’s Innovative Medicines Initiative (IMI), has already helped, and is expected to help drive this improvement.
Among the representatives from big pharma sharing their approaches to predictive ADME/Tox at the meeting was Jonathan Moggs, Ph.D., head of molecular toxicology, translational sciences, at the Novartis Institutes for BioMedical Research. He discussed the growing importance of epigenomics in the assessment of drug safety.
“Most drugs have an epigenetic effect, and it is important to assess this in terms of toxicity,” he said. Novartis is looking at epigenetic mechanisms and biomarkers for drug-induced toxicity, particularly in the context of chronic administration. The value is that such epigenetic effects may be the earliest effects in nongenotoxic carcinogenesis.
It is easy to assess DNA methylation, one of the two main epigenetic changes, and researchers at Novartis have already determined a number of tissue-specific DNA methylomes. It is more challenging to determine histone acetylation, the other main epigenetic change, but Dr. Moggs believes the technology will become available in the next year or so.
Novartis is currently integrating its epigenetic profiling with transcript (mRNA and miRNA) profiling in a mouse liver tumor model—an approach that Dr. Moggs said poses some bioinformatic challenges but promises to lead to an understanding of the underlying mechanisms of drug-induced epigenetic perturbations. He concluded that future challenges in epigenomics in drug toxicity include trying to understand interindividual and inter-species differences, dynamics of healthy versus disease epigenomics, and the specificity, sensitivity, and validation of epigenetic biomarkers.
Dr. Moggs also talked about the work of the IMI’s newly launched MARCAR (Biomarkers and Molecular Tumor Classification for Nongenotoxic Carcinogens) consortium that brings together Novartis, UCB Pharma, Bayer Schering Pharma, Lundbeck, Boehringer Ingelheim, and CXR Biosciences, as well as a number of academic partners. The aims of MARCAR are improved drug safety, more efficient drug development, and advancement of alternative preclinical testing methods.
CXR Biosciences will perform miRNA analysis of samples to help identify possible candidate biomarkers that could be used as indicators of nongenotoxic carcinogenesis. With Taconic Artemis, CXR is making its transADMET humanized mouse models available to MARCAR partners.
Tom Shepherd, Ph.D., CEO of CXR Biosciences, explained that tumor findings are common endpoints in preclinical testing, but such in vivo carcinogenesis is rarely genotoxic in origin because directly genotoxic compounds would be excluded at an earlier stage. At present, there are no sufficiently accurate and well-validated short-term assays for identifying the nongenotoxic carcinogens, thus necessitating an expensive two-year rodent bioassay for assessing the carcinogenic risk of such compounds to human.
The MARCAR project also seeks to provide new mechanistic insights and early biomarkers that should enhance the design of more predictive tests for nongenotoxic carcinogenesis.