LE Intro
The pharmaceutical R&D phases
Research (discovery and optimization)
Development (human phases and registration)
Marketing (production and market)
Forward translation = from inhibitor to clinic
Reverse translation = learning from the clinical and then reposition the
drug, back to basic research
Biomarkers = characteristics that is objectively measured and evaluated
as an indicator of normal biological processes, pathogenic processes, or
pharmacologic responses to a therapeutic intervention
Molecular biomarkers can provide a molecular impression of a
biological system (cell, animal, human)
Biomarkers can be various analytes
Rational selection: 5Rs assessment
Right- target, -tissue, -safety, -patients and -commercial potential
Need for P-medicines = personalized medicines
Insufficient efficacy as the most frequent reason
Safety issues
Subapproaches of P-Medicine
Using biomarkers and molecular profiling for P medicine
Pharmacogenetics
Patient selection is key
Drug development:
1. Target discovery (identification and validation)
2. Lead discovery (hit 2 lead)
3. Lead optimization
4. Human studies
2 routes
You know the target
o Target identification
o Target discovery
o Target validation
o Lead discovery
You have a drug and a desired effect (you do not know target, earlier
days)
o Target deconvolution
o Lead discovery (function of phonotypic based screening)
Hit-2-lead (target validation)
The end of the target validation phase
, o Fragment library screening
o Compound library screening
o Epitope mapping - antibody/protein library screening
Lead finding
Beginning of the pharmaceutical development
o Start with a hit, scaffold
o First exploration on
Biochemical
Toxicity
Solubitlity and absorption
Feasibility (chemical/biochemical)
o Need for biomarkers and screening assays
Ends with 2 to 3 leads which can be explored and optimized
Lead optimization
Iterative process
o Optimalization of
Biochemical properties
Cellular efficacy
Physico-chemical optimalization
Metabolism and toxicity (ADME absorption distribution
metabolism excretion)
In vivo efficacy in disease models
Clinical candidate
Are models translational to humans
Very important = scalability (from mouse to human, mg > kg, is that
feasible)
Pharmacokinetics = what the body does to the drug
ADME
Pharmacodynamics = what drug does to the body
Drug resistance and regrowth tumor (side screening to avoid these
problems)
Reasons:
Molecular heterogeneity in diseased tissue
o Escaping cell regrow, or metastasize
Cells adapt by
o Amplification
o Activation escape pathways
LE Genetic therapies
Target identification
4 steps of diagnosis: from mechanism to therapy
1. A detailed clinical characterisation (single/multi-organ)
Clinical read out (diagnosis)
Syndromic (multiple tissues are affected) vs non-syndromic
The pharmaceutical R&D phases
Research (discovery and optimization)
Development (human phases and registration)
Marketing (production and market)
Forward translation = from inhibitor to clinic
Reverse translation = learning from the clinical and then reposition the
drug, back to basic research
Biomarkers = characteristics that is objectively measured and evaluated
as an indicator of normal biological processes, pathogenic processes, or
pharmacologic responses to a therapeutic intervention
Molecular biomarkers can provide a molecular impression of a
biological system (cell, animal, human)
Biomarkers can be various analytes
Rational selection: 5Rs assessment
Right- target, -tissue, -safety, -patients and -commercial potential
Need for P-medicines = personalized medicines
Insufficient efficacy as the most frequent reason
Safety issues
Subapproaches of P-Medicine
Using biomarkers and molecular profiling for P medicine
Pharmacogenetics
Patient selection is key
Drug development:
1. Target discovery (identification and validation)
2. Lead discovery (hit 2 lead)
3. Lead optimization
4. Human studies
2 routes
You know the target
o Target identification
o Target discovery
o Target validation
o Lead discovery
You have a drug and a desired effect (you do not know target, earlier
days)
o Target deconvolution
o Lead discovery (function of phonotypic based screening)
Hit-2-lead (target validation)
The end of the target validation phase
, o Fragment library screening
o Compound library screening
o Epitope mapping - antibody/protein library screening
Lead finding
Beginning of the pharmaceutical development
o Start with a hit, scaffold
o First exploration on
Biochemical
Toxicity
Solubitlity and absorption
Feasibility (chemical/biochemical)
o Need for biomarkers and screening assays
Ends with 2 to 3 leads which can be explored and optimized
Lead optimization
Iterative process
o Optimalization of
Biochemical properties
Cellular efficacy
Physico-chemical optimalization
Metabolism and toxicity (ADME absorption distribution
metabolism excretion)
In vivo efficacy in disease models
Clinical candidate
Are models translational to humans
Very important = scalability (from mouse to human, mg > kg, is that
feasible)
Pharmacokinetics = what the body does to the drug
ADME
Pharmacodynamics = what drug does to the body
Drug resistance and regrowth tumor (side screening to avoid these
problems)
Reasons:
Molecular heterogeneity in diseased tissue
o Escaping cell regrow, or metastasize
Cells adapt by
o Amplification
o Activation escape pathways
LE Genetic therapies
Target identification
4 steps of diagnosis: from mechanism to therapy
1. A detailed clinical characterisation (single/multi-organ)
Clinical read out (diagnosis)
Syndromic (multiple tissues are affected) vs non-syndromic
