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
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