UCL Institute of Cardiovascular Science

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Otto Wolf Lecture: Using genetics to make impersonal medicines

Speaker: Prof. Aroon Hingorani, Director, UCL Institute of Cardiovascular Science

Date: 11th February

Time: 13.00. Tea and coffee available on the balcony from 12.40

Location: Kennedy Lecture Theatre, UCL Institute of Child Health, 30 Guilford Street, London WC1N 1EH

Cost: Free

Bringing a new drug to market is protracted (~10 years), expensive (estimated costs are currently ~$4-11 billion), and uncertain (only a small fraction of the thousands of newly-synthesised compounds emerge as licensed drugs. A compound can fail at any point but a late-stage (phase IIb/III) failure has serious financial repercussions. Notable recent examples in cardiometabolic disease include avasimibe, lapaquistat , torcetrapib, muraglitazar, varespladib and niacin. These have contributed to job losses, plant closures and R&D stagnation in a therapeutic area where the bar is already high, because new drugs must prove incremental efficacy over established therapies in large and expensive outcome trials. Innovative methods are therefore needed to de-risk and accelerate drug development.

Phase III RCTs, which test the safety and efficacy of a new molecule, serve as the most rigorous target validation experiment during drug development. This is because the randomised allocation of the intervention balances treated and control groups except for the exposure to the drug, leading to abolition of confounding, while assessment of outcome post intervention overcomes reverse causation. The problem is that this decisive experiment comes last not first. Before an RCT can be undertaken, there must be the financial and strategic commitment to a potential drug, yet it is the RCT itself that is the final arbiter of target validity – in effect a “Catch -22”. Can an alternative source of randomised human evidence be deployed ahead of critical decision points in the drug development pathway, before committing substantial resource to a specific target or molecule?

Unlike other naturally occurring differences between individuals, genotype is determined by a randomised allocation at conception according to Mendel’s second law (Mendelian randomisation) and is also unaffected by disease. Thus, genetic association studies form a special category of observational study that can be viewed as a natural RCT. This talk reviews the concept and application of genetic studies as natural RCTs and looks ahead to how genetic information might be used to aid drug development in the future.

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