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Printable Handouts
Navigable Slide Index
- Introduction
- 5 Challenges
- Challenge 1 - Identifying new targets
- Conventional therapeutic targets in CVD
- How to find new targets?
- GWAS: A source of novel targets (1)
- Large-scale association analysis
- Challenge 2 - Validating new targets
- Target validation takes place late in the pipeline
- Using genetics for causal inference
- Mendelian randomisation: a ‘natural’ RCT
- Mendelian randomisation in target development
- Is the IL-6–CHD association causal?
- Tocilizumab inhibits signaling at IL-6R
- A genetic proxy for IL-6R inhibition
- Validation of IL6R SNP as a proxy for tocilizumab
- IL6R SNP is associated with lower CHD risk (1)
- IL6R SNP is associated with lower CHD risk (2)
- sPLA2 inhibition and CHD prevention
- sPLA2-IIA
- sPLA2-IIA Mendelian randomisation
- The PLA2G2A variant and sPLA2-IIA mass
- Specificity of the PLA2G2A variant
- Expected PLA2G2A SNP and MVE association
- Observed PLA2G2A SNP and MVE association
- Genetics can help prioritise drug targets
- Challenge 3 - Avoiding adverse drug effects
- Mechanisms of adverse drug effects
- Torcetrapib – the ILLUMINATE trial
- Genetic investigation of torcetrapib and BP
- Challenge 4 - Making better use of existing drugs
- Pharmacogenetics
- Scenarios in stratified medicine
- Clopidogrel
- Clopidogrel treatment efficacy
- Clopidogrel and myocardial infarction
- Clopidogrel and major bleeding
- Clopidogrel pharmacokinetics
- CYP2C19* alleles
- Systematic reviews of CYP2C19* alleles (1)
- Meta-analysis of CYP2C19
- Systematic reviews of CYP2C19* alleles (2)
- Genetic effect on intermediate phenotypes
- Association between CYP2C19 alleles and CVD
- Possibility for publication bias
- CYP2C19 alleles and the response to clopidogrel
- CYP2C19-clopidogrel conclusions
- Challenge 5 - New approaches & drug development
- Integration into the drug development pipeline
- Acknowledgements
- Thanks
Topics Covered
- Conventional therapeutic targets in CVD
- Identifying new targets (GWAS and association analysis)
- Validating new targets (Mendelian randomisation; IL6R, CHD and tocilizumab; sPLA2 inhibition and CHD prevention)
- Avoiding adverse effects (The ILLUMINATE trial, Torcetrapib and blood pressure)
- Making better use of existing drugs (Pharmacogenetics of Clopidogrel and CYP2C19)
- New approaches & drug development
Links
Series:
Categories:
Therapeutic Areas:
Talk Citation
Swerdlow, D. and Holmes, M.V. (2014, March 5). Key drug discovery challenges in cardiovascular medicine [Video file]. In The Biomedical & Life Sciences Collection, Henry Stewart Talks. Retrieved December 6, 2024, from https://doi.org/10.69645/LCDJ2666.Export Citation (RIS)
Publication History
Financial Disclosures
- Dr. Dan Swerdlow has not informed HSTalks of any commercial/financial relationship that it is appropriate to disclose.
- Dr. Michael V. Holmes has not informed HSTalks of any commercial/financial relationship that it is appropriate to disclose.
A selection of talks on Genetics & Epigenetics
Transcript
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0:00
Hello.
This is Daniel Swerdlow
and Michael Holmes.
And welcome to this talk
about some of the challenges
faced in developing new
drugs for the treatment
and prevention of
cardiovascular disease.
0:15
This talk will concentrate
on pharmacological therapy
for the principal areas of
cardiovascular disease--
coronary heart disease
including myocardial infarction
and related conditions, stroke
and other cerebrovascular
disease, and peripheral
vascular disease.
As the global burden of
cardiovascular disease
continues to grow and novel
therapeutic strategies are
relatively scarce, we will
address five key challenges faced
in finding new
approaches to treating
and preventing
cardiovascular disease.
First, the identification of new
therapeutic targets beyond those
modulated by conventional therapy.
Second, we will examine methods
for validating potential targets
early in drug development process.
Safety of new medicines
is increasingly important
and is subject to growing
external regulation.
We consider techniques for
predicting and evaluating
adverse drug effect in order to
prevent and reduce patient harm.
Fourth, we discuss the use of
pharmacogenetics, an expanding
approach that uses
a patient's genotype
to optimize their
pharmacological therapy.
And finally, we propose a strategy
for integrating new techniques
into the drug development pipeline
in order to expedite the transfer
of safe, effective new therapies
into clinical practice.
1:28
Our first challenge is the
identification of new targets
for treating and preventing
cardiovascular disease.
1:40
There is currently a large range
of pharmaceutical agents used
for the prevention and treatment
of cardiovascular disease.
There are, however,
a relatively limited
number of therapeutic targets.
Conventional therapy aims to
reduce cholesterol, blood pressure,
and to some extent
inflammation and to inhibit
coagulation and thrombosis.
It is likely, however, that many
more targets and pathological
mechanisms lie undiscovered that
could be valuable novel targets for
the cardiovascular
disease prevention.
And it is the identification
of those targets that
is the first challenge
we will examine.