Biomarkers – The Biotech/Pharma perspective R&D manager - Kim Holmstrøm Bioneer What are Biomarkers? § The modern definition was proposed at the US National Institutes of Health workshop in 1998: “A biomarker is a characteristic that is objectively measured and evaluated as an indicator of normal biological processes, pathogenic processes or pharmacological responses to a therapeutic intervention.” 2 What are Biomarkers? Classical Molecular markers • Body temperature § Proteins (e.g. antibodies, • Blood pressure membrane receptors) • Heart rate, etc. § Hormones (e.g. peptide hormones, steroid hormones) • Imaging (MR, PET) § Carbohydrates (e.g. glucose) § Nucleic acids (DNA, mRNA, ncRNA) § Epigenetic factors (methylation, histone modifications) § Lipids (e.g. cholesterol) § Metabolites Biomarkers in human disease and drug development § Diagnostic - Determines the type of disease § Predictive - Identification of subpopulations of patients most likely to respond to a given treatment § Prognostic - Provides information of the likely course of e.g. a cancer disease § Mechanistic - Provides infomation on e.g. specific cell signaling mechanisms that are affected by a drug § Safety - Indicates toxicity effects 4 Genome for science, for health, for individuals Your genome First human genome 1000 Genome 50 Danish families Personal genomes! sequencing Project 150 genomes in total for everyone 1990-2002 2009-2012 The Danish reference (2015-2025) genome The human ! Human genome Healthy lifestyle “building blocks” variation 2011-2015 Prevention of disease Role of individuals The basis for Personalized Medicine implementation Prof. Jonathan Knowles -Institute for Molecular Medicine Finland – ”Building a bridge from discovery to medicine” (Statement from October 2013 – Cancer Crosslinks Meeting, Lund) § Genetics do not reveal everything! § Improved characterization of disease should not exclusively rely og genetics but also include: - Transcription analysis - Protein expression - Epigenetic factors - Molecular interaction analyses - Localization – in situ detection 6 The challenges for the pharmaceutical industry in drug development 7 Critical issues for the Pharmaceutical Industry § Biomedical research spending continues to grow, while earnings and new drug approvals continue to decline § Only approximately 8-12% of drugs entering phase 1 clinical trials eventually gain regulatory approval 8 What is the problem with current pharmacotherapy? § ”Blockbuster philosophy” in the pharmaceutical industry has been predominant § Heterogeneous patient populations – big patient to patient variation § Over- and mistreatment § Little scientific insight - Pathophysiology - Mechanism of action of the drug 9 One size does not fit all Efficacy of pharmacotherapy 10 Today: faced with ”imprecision medicine” 11 Pharmaceutical industry and biomarkers § Biomarkers can be used as - potential new targets for drug discovery, - a mean to understand the mechanism of action of a drug § In the drug development phase biomarkers can - show early if a compound could lead to side effects that should terminate further research - reduce failure rate and minimizing risk § In clinical trials, biomarkers can help - to identify suitable subjects for initial human testing § Biomarkers can be used to - reduce treatment overheads by optimizing dosage and measuring a patient’s response more quickly and accurately (e.g. SNPs in Cytochrome P450 genes) 12 Introducing the term Personalized Medicine Published 1999 (SNP-consortium commentary) 13 Companion Diagnostics and Clinical co- development of Herceptin 14 The first Pharmacodiagnostic (pharmDx) Link 15 Example of the value of Companion Dx Herceptin would not have been so successful without a patient selection factor 16 Guidelines for developing companion Dx § Treatment costs are high § Overall efficacy (including marker-negative subgroup) is minimal § Segmented patient population has great clinical benefit § Consequence of treatment failure is high 17 Companion diagnostics (CDx) approved by FDA Jørgensen, Oncology 2013;85:59–68 18 Conclusions and Future Perspectives § Understanding of the pathophysiology and drug mechanism of action is a prerequisite for the development of a more individualized pharmacotherapy. § The drugs and diagnostics will be co-developed in the future to improve the success rate of new targeted drugs. § ”Old” drugs may see a usage upon optimized patient stratification - repositioning. § The use of CDx will pave the way for a more rational drug development process and the subesequent use of the drug in the clinic. § We are slowly moving towards stratified medicine and new drugs being developed for smaller groups of patients. § ”In 2020 most specialist therapies will include a companion diagnostic as a key component”. 19 The Age of Personalized Medicine is getting closer! Risk Assessment: Diagnosis: Genetic testing to reveal Accurate disease diagnosis predisposition to disease. enabling individualized treatment strategy. Prevention: Treatment: Behaviour/Lifestyle/ Improved outcomes Treatment intervention through targeted to prevent disease. treatments and reduced side effects. Detection: Management: Early detection of disease Active monitoring of at the molecular level. treatment response and disease progression. Biomarkers are paving the way 20 .