Theraputic approaches to AD Flashcards
How long is the preclinical stage
10-20 years
What are PSEN1/2 and APP
Rare autosomal dominant genes- 100 percent penetrance
Describe the amyloid cascade hypothesis
The amyloid cascade hypothesis was initially suggested in 1992. This theory postulates that the initial event which triggers neuronal degradation in Alzheimer’s disease is enhanced amyloid-β generation and aggregation. It suggests that if the amount of Aβ generated is greater than the amount that is degraded, accumulation occurs, resulting in plaque formation, tau tangle formation, cell death, and the associated symptoms of Alzheimer’s disease.
Therefore, it has been suggested that boosting the non-toxic, non-amyloidogenic processing pathway or reducing the toxic amyloidogenic processing pathway may lead to less amyloid-β production and reduce the progression of Alzheimer’s disease. However, research into β- and γ-secretase inhibitors and α-secretase enhancers have shown that reducing the activity of these enzymes can lead to cancers and further neuronal dysfunction.
What are the currently prescribed drugs for symptomatic AD treatments
Symptomatic treatments
* Cholinesterase inhibitors
* Donepezil, galantamine, rivastigmine
* Cholinergic deficits in AD
* Potentiates cholinergic synapses
* Glutamate receptor antagonist
* Memantine
* Blocks channel of NMDA type glutamate
receptor
* Treatments for other symptoms
* e.g. depression, sleep, hallucinations, pain
What is the issue with the symptomatic treatments of AD?
Prescribed too later into clincial onset so do not reduce disease affect.
What are the disease modyfying treatments for AD?
- Emerging new monoclonal antibody therapies.
- Aducanumab (withdrawal)
- Lecanemab* (approved USA and UK)
- Donanemab* (approved USA and UK)
(return) What stages of Amyloid beta plaque progression does the 3 disease odyfying drugs target?
Lecumab- protofibrils
Aducanumab & Donanemab- Ab plaques
Disadavntages of Lecanemab & Donanemab and Aducanumab
L& D:
* FDA and the Medicines and Healthcare products Regulatory Agency (MHRA)
* Efficacy:
Slow the progression of Alzheimer’s disease in some individuals
* Side effects:
Amyloid-related imaging abnormalities (ARIA)
Aducanumab
* Approved by the FDA in 2021 (with some concerns from the scientific community)
* Withdrawal in 2024
What factors need to be considered for monoclonal antibody therapies?
- Amyloid beta is a target with strong biological rationale and human genetics
support - Mechanism of action of therapeutic matters and time of intervention
- Cognitive decline slowed – opportunities for improvement
What are the 3 pillars of drug development & discovery?
Pharmakinetics
Pharcodynamics
Biomarkers
What is pharmakinetics
(what the body does to the drug) Drug needs to be at the site of action over the desired time/period
What is pharmadynamics?
(What the drug does to the body) Drug needs to bind
to the target
What are biomarkers?
Biomarkers:
Characteristic that is objectively measured and evaluated as an indicator of healthy or pathological processes
* In drug discovery it can be used to measure pharmacologic response/ clincial response to a therapeutic intervention.
Why did Ab aggregation inhibitor fail trails
- In vivo data mixed, lack of
quantitative estimates of insoluble
Ab; dose–response relationship
not established - Rationale for clinical doses not
clear - Phase 2 - reduction in CSF Ab
seen - an increase in CSF Ab
would have been anticipated - Phase 3 - no evidence of
clinical benefit
Why did NSAID gamma -secreatase modulator fail?
- In vitro data demonstrating gsecretase modulator robust
- In vivo data demonstrating effects
on brain Ab levels in Tg mouse
models not convincing - Tarenflurbil did not penetrate the
brain to sufficient concentration at
doses used to achieve a
pharmacological effect (Tg mice or
man)
Why did NSAID g-secretase
inhibitor fail
- Preclinical & clinical development
robustly prosecuted - Target engagement definitively
established in man - Therapeutic index limited given the
mechanism & the associated
Notch inhibition. Max dose
progressed (140 mg/day) did not
show any effect on CSF Ab. T1/2
short – once a day dosing
insufficient - Unexpected worsening of AD in
treated patients has closed this
approach - trials were highly
informative
Why did Ab Mabs fail?
Strong preclinical in vivo data on
the mAb
* Doses in the clinical program
limited by vascular edema - target
engagement unclear
* Efficacy not seen, therapeutic
benefit of clearing plaque from the
brains of AD patients remains to be
tested with this antibody
(return) What is the role of TREM2 in AD and where are clincial trials for it thus far
A Phase I clinical trial: is the drug safe for humans?
* First time that a new drug is tested in human study participants.
* Phase I trials are usually conducted in healthy volunteers.
What are the different points medicine need to address for targets/mechanisms?
Medicines for all patients
Medicines that target different aspects of disease biology
Medicines that are easy to access
Medicines that are more effective
Medicines with less side effects
What makes a good drug? 5 things
- Solubilty
- Activity
- Metabolic profile/toxciity
- Half-life
- Oral Bioavilabilty
What are the 5 Rs?
Rights:
1.Paitent
2.Tissue
3.Safety
4.Commercial potential
5.Target
What are the 6 stages of the drug discovery process?
- Basic research
- Non-clincial studies
- Clinical studies
- New drug applications and review
- Approval and Lauch
- Post marketing surveillence and clincial studies
In Stage 1 & 2 of drug discovery what are the steps taken?
Target identification
Target validation
Screening
Medicinal chemistry to find candidate gene
What is a good target? 3 parts
Specific
Safe
‘Druggable’
Target Product profile
Outlines the desired ‘profile’ of a target product
Target validation
Demonstrate that the target is involved in the disease
* Expression in disease-relevant tissue/cells
* Its modulation has a therapeutic effect
Approaches for target validation
* Antisense oligonucleotides
* Small interfering RNA
* Transgenic animals and cell models
KO and KI Assay development
Screening types
Screening is the process by which we identify molecules with the desired
activity
Types of Screening:
1. HTS
2. Physiological screening
3. Focused screening
Assay development
- A critical part of the “hit” discovery process
- Key consideration in assay development:
➢3 R’s : Relevance, Robustness,
Reproducibility
➢Practicality
➢Cost
➢Automation
Types of assay? 2
1.Cell-free
➢Target based
➢Measure function of a purified target
➢Identify compounds that modulate
activity / binding of the target protein
2.Cell based
➢Measure function of the target in the
context of the cell
➢Measure expression of the target
➢Provide a functional read-out of
compound activity
Hit to lead
Process by which hit compounds are characterised and optimise
* The goal is to identify the most promising compounds through limited structureactivity relationship (SAR)
* Goal to generate a lead compound to use in vivo with reasonable ADME
properties (Absorption, distribution, metabolism, and excretion
