Drug Development Flashcards
93% clinical trials (Phase II) fail - why?
Poor translation of neuroscience research into medicines due to a lack of good preclinical animal models
The aetiology of many brain disorders remain unknown - therefore struggle to produce animal models with good construct validity
The treatments for brain disorders liable to serious side effects which limits their use
ie. headaches, nausea, seizures
Many trials fail because the drug cannot cross the blood-brain barrier - restricts availability to the CNS; the delivery of drugs to the CNS is a major issue
Chasing more complex issues - all the ‘easy’ CNS disorders have drugs!
Some disorders require early diagnosis for successful treatments
- Diagnosis = too later; disease has developed
- Require good biomarkers!!!
Some neurodegenerative diseases often require long clinical trials
ie. AD preventative drugs
The ‘patent’ cliff
A patent lasts ~ 20 years
~20 years to turn a drug from a lead compound + put through all approval processes
~13 years to develop a CNS drug, therefore only have 7 years to convince pharmaceutical companies that the drug is worth investing in/make a profit
After 20 years - other pharmaceutical companies can produce the same drug (the patent has expired) - replicate + sold at cheaper prices
Drug discovery process
CNS ~ 17 years
Preclinical:
Target discovery –> target to lead compound –> lead optimisation –> LADMET
Target to lead compound = highly regulated, structured process; requires robust, well reproducible data using animals to get to the LADMET stage
Clinical:
Phase 1 - Phase III
Registration
Target Discovery
Identify sensible targets for drugs to act at!!!
EXPRESSION ANALYSIS - analysis protein expression to see if they are up- or down-regulated during disorders
Use qRT-PCR = quantification of RNA = gold-standard for accurate measurement
IN VITRO FUNCTION in cell culture using knock-down transgenics or drugs
See how up- or down-regulating drugs has an effect on a tissue
Tissue banks are important at this stage - pathological tissues can reveal interesting results!
IN VIVO TARGET VALIDATION - animal models of disease
- Superior to in vitro validation
Different approaches to drug delivery
Target Discovery
Pathology to a drug
- Chromosome walking/positional cloning
- Develop some understand of the pathology of disease
- Identify a pathophysiological pathway; select novel targets
- Create an animal model; introduce a drug and see how it responds
- Understanding the pathway = validation of NOVEL drug targets
Reverse translation
- No idea about the pathophysiological pathway involved
- Look at patient symptoms + examine existing drugs
ie. Depression + the chance discovery of its drugs - Understanding current pharmacological therapies used for treating symptoms of a disease, to use to identify the mechanism of action
- Drug candidates arising from this approach should have similar properties to existing drugs, but with some efficacy and/or tolerability
- IMPROVED drug!
Target to lead compound
Use a large, diverse chemical library
Identify a target via high-throughput assays (HTA) - crude + broad = produce a HIT compound
HIT conformation - pick compounds for further validation; more selective + refined testing = produce lead compounds
Examples of high-throughput testing
Radioligand binding = characterise the binding of a drug to its target receptor; information of the affinity + mode of interaction (ie. competitive, non-competitive)
FRET-based functional assays = indicates proximity
Reporter-gene assays = study drug-induced changes in gene expression
Ion flux assays = used to study ion flux; very broad and basic information
Radiolabelled substrate conversion by enzyme targets = check enzymatic activity
Crystal modelling of ligand binding sites
Predict structures of other compounds based on crystal structures of other identified compounds
ie. Predict structures of VGKCs based on Kv1.2, KcsA, MthBK
In silicons drug binding = identify where a drug binds to a receptor
ie. Apamin onto SK channel
Used to understand which amino acids of lead compounds are essential for interactions with targets!
BAD
Difficult to crystallise structures - very complex + variable (crystallised in aqueous solutions; hard for receptors which are membrane-bound)
Often need to lock receptors into conformations using agonists/antagonists or study in the desensitised form
X-Ray diffraction studies
Once have a crystallised product…
Produce Angstrom resolution = 0.1nm (1 A)
Used to determine the atomic and molecular structure of a crystal = crystalline structures cause a beam of x-rays to diffract into many specific directions
Need this level of information to develop highly selective profiles!
Mutagenesis studies
Predict which amino acids are crucial for interactions using mutant receptors
Lead optimisation
Perform SAR analysis to improve the potency of the drug
Adapt structure, undergo multiple testing + modifications to accumulate knowledge of the drug and understand of its target
Optimise structure to facilitate access in vivo
ie. Route of administration + brain penetration
Pre-clinical candidate LADMET testing
Liberation - how the drug is released from its formulation
Absorption
Distribution - where the drug goes in the body
Metabolism
Excretion
Toxicology
Prior to clinical trials
Highly regulated and structured testing
Involved multiple animal models
Clinical Development
Phase 0 = microdosing - gather preliminary pharmacodynamics + pharmacokinetics
Phase I = testing in healthy humans; 20-100 volunteers
Phase II = blind testing; see whether a drug actually works
MOST DRUGS FAIL HERE
Proof of concept - information about the effect of the medicine on the actual disease
Phase III = looks at the efficacy of the drug
Large scale randomised trials
Registration
Phase IV = see if it delivers unexpected side effects
ie. TB drug = improved moods of Ps –> anti-depressant!
See whether the prescription could be broadened!
Why do drugs fail?
How can we address this?
Lack of efficacy; the ability to produce the desired effect Phase II
Improved understanding of the disease (aetiology)
Improved understanding of basic biology
Better animal models (better construct/face/predictive validity)
Pharmacogenetics - precision medicine to match patient with the correct type of medication; not all medications are suitable
ie. MS = not every patient reacts well to the drugs
Translational research: bench-to-bedside
How can we do this?
Interface of basic research + clinical trials
Harnessing the results from the lab (the “bench”) and translating them into new drugs/devices/treatment options for Ps (the “beside”)
How can we do this?
- Develop disease biomarkers
- Use technologies that can be applied to both humans + animal models for greater comparison to see whether disease intervention is working
ie. MRI, EEG
- Use human tissue (preferably diseased) for labs = important to raise awareness of the importance of tissue donation to brain banks
- Use better, more valid animal models of disease
= better animal models (increased validity) should lead to better drugs (increased predictive validity) and reduce Phase II attrition therefore MORE DRUGS
