NHS Chair of Pharmacogenetics Clinical Pharmacogenomics: Implications of New Developments for the NHS Munir Pirmohamed NHS Chair of Pharmacogenetics Department of Molecular and Clinical Pharmacology Institute of Translational Medicine University of Liverpool

Prediction is very difficult, especially about the future The Next 20 Years Prediction is very difficult, especially about the future Niels Bohr, Danish Physicist The best way to predict the future is to invent it Alan Kay, American Computer Scientist

Definitions Pharmacogenetics Pharmacogenomics (after Vogel, 1957) The study of the genetic basis for the difference between individuals in response to drugs Pharmacogenetics (after Vogel, 1957) Use of population genetic information for drug research, design and development Clinical management of drug therapy (drug dosing and drug choice) Pharmacogenomics (after Marshall, 1997)

Evolution of Clinical Pharmacogenomics Phenotype Probe drug Metabolite: parent drug ratio Individual genes PCR-based Current Standard GWAS Increasing use Robust findings Sequencing Future? Implementation

Thiopurine Methyl Transferase (TPMT): A Phenotypic Test Metabolises azathioprine and 6-mercaptopurine Thioguanine accumulation inversely related to TPMT activity Associated with severe haemopoietic toxicity Molecular basis defined Phenotyping assays available and still used PATCHY UPTAKE and dependent of specialty

Evolution of Clinical Pharmacogenomics Phenotype Probe drug Metabolite: parent drug ratio Individual genes PCR-based Current Standard GWAS Increasing use Robust findings Sequencing Future? Implementation

Incidence before and after testing for HLA-B*5701 Technology-Based Reduction in the Burden of ADRs: The Case of Abacavir Hypersensitivity Association with HLA-B*5701 Clinical genotype Clinical phenotype Incidence before and after testing for HLA-B*5701 Country Pre testing Post testing Reference Australia 7% <1% Rauch et al, 2006 France 12% 0% Zucman et al, 2007 UK (London) 7.8% 2% Waters et al, 2007

Effect of Pharmacogenetics on Drug Usage

Evolution of Clinical Pharmacogenomics Phenotype Probe drug Metabolite: parent drug ratio Individual genes PCR-based Current Standard GWAS Increasing use Robust findings Sequencing Future? Implementation

Evolution of Clinical Pharmacogenomics Phenotype Probe drug Metabolite: parent drug ratio Individual genes PCR-based Current Standard GWAS Increasing use Robust findings Sequencing Future? Implementation

Malignant Melanoma and BRAF Inhibitor: Baseline and 2 Weeks After

Evidence What type of evidence is required for demonstration of clinical utility?

Warfarin Pharmacogenetics: Controversy Regarding Genotyping Change in warfarin label (2007) and dosing tables (2010) We genotyped 201 warfarin-treated patients for five common polymorphisms in and around VKORC1, and all covaried significantly with warfarin dose. VKORC1 has a larger impact on warfarin dose than CYP2C9, which affects dosing through polymorphic metabolism of warfarin.

Pharmacogenetic-Based Dosing: Warfarin Randomised Controlled Trial FP7 sponsored EU trials 3 trials: warfarin, phenprocoumon, acenocoumarol 400-450 patients in each %TIR as primary outcome measure Point of Care test for genotyping European Union Pharmacogenetics of AntiCoagulant Therapy

HLA Genotyping to Prevent Serious Adverse Drug Reactions Since 2001, 22 new alleles associated with serious immune-mediated adverse drug reactions have been identified Many of these have been based on genome wide association studies with initial results being replicated Examples include: Carbamazepine: HLA-B*1502 and Stevens-Johnson Syndrome Carbamazepine: HL-A*3101 and hypersensitivity syndrome Allopurinol: HLA-B*5801 and serious cutaneous adverse reactions Flucloxacillin: HLA-B*5701 and cholestatic hepatitis Are we going to require RCTs for all of these association? Can we afford it?

“Hierarchies of evidence should be replaced by accepting—indeed embracing—a diversity of approaches..... ...It is a plea to investigators to continue to develop and improve their methods; to decision makers to avoid adopting entrenched positions about the nature of evidence; and for both to accept that the interpretation of evidence requires judgment.”

Evidence standards differ between non-genetic and genetic tests 3 examples given: Drug exposure Prevention of adverse drug reactions Health technology assessment

Drug Exposure: Differential Evidential Standards Example: Aztreonam SmPC “after an initial usual dose, the dosage of aztreonam should be halved in patients with estimated creatinine clearances between 10 and 30 mL/min/1.73 m2” Many different examples in hepatic and renal impairment with dose instructions based on PK studies and occasionally PK-PD modelling No need for RCTs – in fact, would be impractical However, a genetic polymorphism leading to same degree of change in drug exposure is often ignored and/or RCT data are required for implementation

Differential Evidence Standards Unfamiliarity with genetic tests Lack of experience in interpretation Perceived cost of genetic testing Lack of availability of tests Poor turnaround time recommendations on dosing evaluation in patients with polymorphisms in known metabolic pathways

The Future? 10 years A whole genome costs less than £100 Only needs to be done once Good visualisation software Patient who requires a drug metabolised by CYP2D6 Absent in 8% of the population Are you going to ignore the genetic data in the patient’s medical record?

Patient Empowerment

Translation into Clinical Practice Lost in Translation Major on-ongoing advances Identify evidence needs Consistency in evidence standards Streamlined processes for adoption into NHS Innovation into practice a major driver for the AHSN Poste, Nature, 2011

Acknowledgements Collaborators Wellcome Trust Sanger Institute (Panos Deloukas, Stephane Bourgeois, Trevor Lawley, Gordon Dougan) University of Bangor (Dyfrig Hughes) Epigen, DILIGEN, iSAEC Funders Department of Health (NHS Chair of Pharmacogenetics), NIHR programme, MRC, EU-FP7, Wellcome Trust Dept of Pharmacology Ana Alfirevic, Dean Naisbitt, Andrea Jorgensen, Dan Carr, Mas Chaponda, Fabio Miyajima, Kevin Park plus many others