L5: Cardiovascular Drug Development Flashcards
Why do we need clinical trials?
-Because we need Evidence based medicine = The integration of best research evidence with clinical expertise and takes into account patient values
EBM:
-Requires latest scientific evidence to be applied to clinical practice
-Involves assessment of research in terms of category and level of evidence
-Category and level is used to define strength of recommendation
Levels of evidence
Drugs used to treat cardiovascular disease
Time taken for developing new medicine
- Pre-discovery phase: certain protein associated with the disease or is upregulated in disease and is thought to contribute to disease pathology – it would be considered a target to perhaps down regulate this target or inhibit – this process usually takes decades before enough evidence is gathered on whether this target is worth targeting in drug development
- Drug discovery: Candidate molecules chosen on basis of pharmacological properties
Compound screening occurs where libraries of compounds are screened for whether they initially bind to the target + then through various assays (preclinical development), where the compounds of interest are narrowed down further and further at each stage depending on whether or not they work in pre-clinical models and then in clinical settings - Preclinical development: Non-human studies; Toxicity testing (side effects); Pharmacokinetic analysis (pK + pD, metabolised, excreted) and formulation (how drug is going to be in an acceptable format for patients)
- Clinical development: Volunteers and patients; Efficacy testing, side-effects and potential dangers;
- Post marketing surveillance: Drugs monitored for long term side effects and long-term efficacy
costs 1billion USD investment to get a drug to market
- Drug discovery - what is assessed in this stage?
- “Druggable” targets include: small molecules/enzymes such as kinases (which phosphorylate proteins to switch them on/off, generally some sort of active site which can be switched off
- “non-druggable targets include: Transcription factors (not amenable to inhibition but recently this thinking is changing)
Drug Discovery - once the target is discovered, what happens next?
Lead Finding and Optimisation:
Target identified -> processes to assess whether drugs developed will work against target. This is done via:
- Cloning of target protein: produce it as a purified protein
- Set up Assay to measure functional activity: involves setting up high throughput screening systems where compound libraries (with various different drug compounds) are screened for whether they initially bind to the target and induce effect
- Automated systems to allow for speed & economy (cost-effectiveness)
- High-throughput screening of large compound libraries
- Compound libraries are: Natural products, fungal, plants, bacteria e.g. antibiotics and sirolimus (rapamycin – inhibits mTOR proteins) - Lead optimisation occurs where chemistry of drug is altered to increase drug potency, selectivity & stability
what is assessed during stage 2 - preclinical development?
What occurs during stage 3 (Clinical Development?)
Are all drug discovery for small molecule inhibitors?
NO
Other types of drug discovery targets can include:
Biopharmaceuticals: Proteins, antibodies & oligonucleotides (siRNA used to down-regulate transcription of a gene) as therapeutic agents
E.g. Insulin= protein drug
Tissue plasminogen activator (clot buster – breaks down fibrin) = protein drug
Example of a new drug targeting cholesterol homeostasis
PCSK9 inhibitors
PCSK9 =protein which targets LDL receptors for degradation -> Decreases ability to uptake LDL in liver+ remove from circulation (so can be detrimental in this case)
PCSK9 mAbs (inhibitors) prevent LDLR degradation, promote recycling + less degradation of receptor = more cholesterol uptake by liver (helpful in promoting cholesterol homeostasis)
Relatively new target – with its timeline for drug development being quite short
Definition of clinical trial
“Application of experimental variable (treatment to person or group of persons) + observation during or following treatment to measure its effect”
What is a clinically meaningful endpoint to a trial?
An outcome measure may be death, occurrence or recurrence of morbid condition,
or difference indicative of change e.g. BP measurement (BP related to onset of CVDs thus measuring BP might be suitable to use as marker for change) (direct measurement of hypertensive drug)
Types of clinical trials
Problematic areas in design issue of clinical trials that may affect outcome include:
- who will the drug be trialled on? E.g. trials cannot be performed on pregnant women (e.g. problem with thalidomide), age range needs to be considered, ethnicity, diversity (both female and males), trialling on prisoners, introducing incentives for joining a clinical trial (not allowed now – but this would take advantage of people living in poverty and even students have been targeted). – protecting patients is the key aim of this
- Whether blinded study: single or double (double = both participant + researcher do not know)
lack of masking = placebo effect = introduce bias - Ensuring no bias in terms of which group is receiving a drug
- must always consider data from even those that have dropped out – should not remove data from study because person dropped out halfway
- endpoints are surrogate markers (what are u going to measure) + required to inform scientists whether there is an effect of the drug or not (efficacy)
- Cannot run forever, too long + costly.
endpoints need to be used and considered carefully (linked to 7.) - traditional = is drug better than current gold standard at treating
equivalence = does drug have same effectiveness as the current gold standard + but has other benefits ie low costs/fewer side effects
How is analyse + evaluation of clinical trials undertaken?
- in a non-biased manner
Key Design Issues for human clinical trials/questions to ask yourself
What is systematic error in clinical trials and the types
= Bias
How do we analyse & present clinical trial results?
What are the factors that can influence interpretation of clinical trials from conception to dissemination of the results?
Areas where there tends to be a lot of bias, and the following individuals can influence bias:
-Authors
- Reviewers: might not have the right expertise or they don’t give a good quality review so poor data gets published in the literature
- Editor
- Doctor
- Media/public: patient populations can sometimes drive the approval of certain drugs for certain conditions
- Other investigators
The use of imaging in diagnosis of CVD, drug discovery & development
Imaging of CVD: Diagnosis
Diagnostic imaging at molecular level example
ATHEROSCLEROSIS
- Development of imaging techniques that identify whether VCAM was expressed on endothelial cells so we can detect it via imaging and see that it is overexpressed + thus know it’s involved in monocyte retrieval (early stages of development of atherosclerosis).
- Detection of other receptors =Integrins, detection present on new blood vessels -> angiogenesis important in plaque instability – effects how the fishers break up + cause that plaque to be instable thus ruptures through endothelium, thus forming thrombus, so would be good to detect this.
What evidence is needed for imaging to be a surrogate for clinical endpoints?
Examples of imaging techniques in cardiovascular drug development:
- IVUS: measure coronary artery wall to identify how much atherosclerosis is ongoing + whether any potential drug is inhibiting the development of the atherosclerotic lesion
- PET: positron-emitting radioisotopes that can be linked to a ligand and then used to identify hotspots within a tissue and can be combined with CT.
Example of how imaging can be useful in drug discovery
