Drug Discovery Fundamentals II Flashcards
Disease-modifying
Drugs which change the course of the disease
e.g., amyloid lowering antibodies
Symptomatic
Drugs which help the symptoms of the disease
e.g., cholinesterase inhibitors
Cure
A treatment which restores normal function and reverses the damage
Target Engagement Biomarkers
Measure that the drug has bound to its target
Include PET, fMRI, neurophysiology, fluid analytes (CSF/blood)
Disease Biomarkers
Measure the effect the drug has on the disease
Includes fMRI, neurophysiology, myography, transmagnetic stimulation, respiratory/muscle strength
Critical Aims of Biomarkers in Drug Development
- Stratifying patient populations
- ensures that the right drug goes to the right patient - Defining disease stage and monitoring progression
- Demonstrating target engagement and biological effect of drug
- Acts as a surrogate for efficacy and safety endpoints
- e.g., if a drug raises NfL you know this is a safety concern even if there are no adverse effects
Reasons for Drug Development Failure
- Wrong population
- eligibility criteria may not reflect real world scenarios - Wrong stage of disease
- need to give an intervention as early as possible before irreversible damage occurs - Wrong target
- possibly multiple targets - Wrong trial design
- possibly not long enough to see an effect
Biomarker
An objectively measured characteristic which can be:
- an indicator of normal biologic processes
- an indicator of pathologic processes
- a measure of a biological response
Different types of biomarker exist, including cognitive, structural, functional and fluid
AD Biomarkers
Amyloid - particularly Ab1-42/1-40 ratio
Phospho-tau - secreted and phosphorylated in response to amyloid pathology (more specific for AD than total tau which reflects general neuronal damage)
Hypothesis Free Biomarkers
Use mass spectrometry to analyse proteins in the tissue
- digest proteins into peptides and separate with liquid chromatography
- can detect which peptides are present in which conditions with the hope of using them as biomarkers
BUT requires time and money - may need to deplete abundant proteins which hide others, there is huge range in values
Proteomics for Biomarkers
Can now quantify over 1000 proteins from an individual cell
Can look at 100 proteins in one assay
Helps to detect many markers which may be relevant to AD
TREM2
A variant was identified which significantly increases AD risk
It causes glial dysregulation
Soluble TREM2 can be measured using CSF
Complement and Synaptic Proteins
First seen to co-localise with amyloid plaques in post-mortem brains
GWAS implicate CR1 and CLU
Blood Assays
Technological advancements mean some brain derived proteins can now be detected in blood
GFAP has a larger effect size in blood than in CSF
NfL
Released from injured/dying axons so can be used as a marker of neurodegeneration
Can be used as diagnostic, prognostic (higher levels at start of disease = quicker deterioration), treatment response (reduced levels in response to effective drugs)
