Molecular therapy
Personalized healthcare
Principle of personalized medicine
- The right therapy for right patient at right intensity at right time
- Molecular biomarkers as key drivers of patient selection
- = personalized healthcare, precision medicine
B-RAF and personalized medicine in melanoma
- B-RAFV600E cells always grow and become cancer cells → mutation in kinase domain that
binds ATP → mutation makes it always active
- RAF inhibitors will block pathway, block cell growth and inhibit cancers (in mice) that have B-
RAFV600E mutation
- 60% of melanoma patients have B-RAFV600E mutation
- Basis of a personalized medicine
Biomarkers
- A characteristic that is objectively measured and evaluated as an indicator of normal
biological processes, pathogenic processes, or pharmacologic responses to a therapeutic
intervention
- Or ‘whatever works in adding value’
- Molecular biomarkers provide a molecular impression of a biological system (cell, animal,
human)
- Biomarkers can be various sorts of data, or combinations thereof
Biomarker data-based translational medicine in pharma
- Exposure – Does the compound get to the site of action?
- Mechanism – Does the compound cause its intended pharmacological/functional effects?
- Efficacy – Does the compound have beneficial effects on disease or clinical pathophysiology?
- Safety – What is the therapeutic window (how safe is the drug)?
- Responders – How do sources of variability in drug response in target population affect
efficacy and safety?
Pharma strategy based on personalized medicine
- Right target
- Right tissue
- Right safety
- Right patients
- Right commercial potential
1
,Role of molecular (omics) biomarker data in personalized healthcare
The power of omics in diagnostics
- Increase diagnostic yield
- Put biomarker change in context
Personalized healthcare in rare metabolic disorders
- Technology innovation is driving impact in personalized healthcare
- Crucial to combine different molecular views to understand human health and disease (X-
omics)
- Fast translational of biomarker research to implementation needed
- On personalized diagnosis
o Metabolic screening adds strongly to genetic screening in identifying mechanisms of
disease
- On personalized medicine
o Impressive effects of uridine therapy
o Increase quality of life for patient and family
o Frequent issues regarding expensive medication versus cheap supplements
- Advantages in using holistic omics methods in clinical diagnostics
Moving to personalized health(care)
- People are more than linear pathways
- Different genetic make-up and lifestyles
- Different environments
- Different risk factors
- Different preferences
3 key aspects of personalized health(care)
- What to measure?
- How much can it change?
- What should be the follow-up for me?
3 translational innovation gaps
- Research to research
- Research to diagnostics
- Research to society
2
,Translation is key in personalized healthcare
Personalized health(care) model
Afterthought: there is no single one reflection of health
- Funhouse mirror effect
- Multiple sources of your data
o Multiple omics
o Clinical chemistry
o Electronic patient dossier
o Wearables
o Digital biomarkers
o Commercial health tests
o Social media
o Surrounding
- Each are a skewed image of you
- How to deal with all of this for your personal health(care)?
Pharmacology and drug disposition
Pharmacology
- The science that is concerned with the use, effects, and modes of action of chemicals on the
function of living system
Pharmacotherapy
- What does the patient with the drug? → pharmacokinetics
3
, - What does the drug with the patient? → pharmacodynamics
Rational vs. evidence-based pharmacotherapy
- Rational pharmacotherapy → mechanism-based pharmacotherapy
- Evidence-based pharmacotherapy → it does not matter how it works, as long as it works
Pharmacological phases in pharmacotherapy
- Exposition phase → behavior of a substance in the environment, changes in the application
form, available for uptake
- Toxicokinetic phase → absorption, distribution, metabolism (toxification, detoxification),
excretion (ADME)
- Toxicodynamic phase → interactions with receptors or other (macro) molecules at the site
of the operation
Classification of pharmacological effects
Classical drug-receptor-interactions
4
Personalized healthcare
Principle of personalized medicine
- The right therapy for right patient at right intensity at right time
- Molecular biomarkers as key drivers of patient selection
- = personalized healthcare, precision medicine
B-RAF and personalized medicine in melanoma
- B-RAFV600E cells always grow and become cancer cells → mutation in kinase domain that
binds ATP → mutation makes it always active
- RAF inhibitors will block pathway, block cell growth and inhibit cancers (in mice) that have B-
RAFV600E mutation
- 60% of melanoma patients have B-RAFV600E mutation
- Basis of a personalized medicine
Biomarkers
- A characteristic that is objectively measured and evaluated as an indicator of normal
biological processes, pathogenic processes, or pharmacologic responses to a therapeutic
intervention
- Or ‘whatever works in adding value’
- Molecular biomarkers provide a molecular impression of a biological system (cell, animal,
human)
- Biomarkers can be various sorts of data, or combinations thereof
Biomarker data-based translational medicine in pharma
- Exposure – Does the compound get to the site of action?
- Mechanism – Does the compound cause its intended pharmacological/functional effects?
- Efficacy – Does the compound have beneficial effects on disease or clinical pathophysiology?
- Safety – What is the therapeutic window (how safe is the drug)?
- Responders – How do sources of variability in drug response in target population affect
efficacy and safety?
Pharma strategy based on personalized medicine
- Right target
- Right tissue
- Right safety
- Right patients
- Right commercial potential
1
,Role of molecular (omics) biomarker data in personalized healthcare
The power of omics in diagnostics
- Increase diagnostic yield
- Put biomarker change in context
Personalized healthcare in rare metabolic disorders
- Technology innovation is driving impact in personalized healthcare
- Crucial to combine different molecular views to understand human health and disease (X-
omics)
- Fast translational of biomarker research to implementation needed
- On personalized diagnosis
o Metabolic screening adds strongly to genetic screening in identifying mechanisms of
disease
- On personalized medicine
o Impressive effects of uridine therapy
o Increase quality of life for patient and family
o Frequent issues regarding expensive medication versus cheap supplements
- Advantages in using holistic omics methods in clinical diagnostics
Moving to personalized health(care)
- People are more than linear pathways
- Different genetic make-up and lifestyles
- Different environments
- Different risk factors
- Different preferences
3 key aspects of personalized health(care)
- What to measure?
- How much can it change?
- What should be the follow-up for me?
3 translational innovation gaps
- Research to research
- Research to diagnostics
- Research to society
2
,Translation is key in personalized healthcare
Personalized health(care) model
Afterthought: there is no single one reflection of health
- Funhouse mirror effect
- Multiple sources of your data
o Multiple omics
o Clinical chemistry
o Electronic patient dossier
o Wearables
o Digital biomarkers
o Commercial health tests
o Social media
o Surrounding
- Each are a skewed image of you
- How to deal with all of this for your personal health(care)?
Pharmacology and drug disposition
Pharmacology
- The science that is concerned with the use, effects, and modes of action of chemicals on the
function of living system
Pharmacotherapy
- What does the patient with the drug? → pharmacokinetics
3
, - What does the drug with the patient? → pharmacodynamics
Rational vs. evidence-based pharmacotherapy
- Rational pharmacotherapy → mechanism-based pharmacotherapy
- Evidence-based pharmacotherapy → it does not matter how it works, as long as it works
Pharmacological phases in pharmacotherapy
- Exposition phase → behavior of a substance in the environment, changes in the application
form, available for uptake
- Toxicokinetic phase → absorption, distribution, metabolism (toxification, detoxification),
excretion (ADME)
- Toxicodynamic phase → interactions with receptors or other (macro) molecules at the site
of the operation
Classification of pharmacological effects
Classical drug-receptor-interactions
4
