The path from genomic insight to clinical applications

Centre-Logo for articleSome of the key messages raised at the ‘Translational Genomics’ meeting; 15th January 2013 at the Royal College of Physicians

What is translational genomics?
Translational genomics refers to the exploitation of the information generated by research into the genetic make-up of the biological world for useful applications.  In healthcare this involves translating genetic insights for the development of new healthcare interventions, most notably the development of (i) better drugs, (ii) improved disease prevention strategies and (iii) better diagnostic methods.

The meeting brought together key-stakeholders in genomic medicine, ranging from leading researchers making the discoveries to drug regulators, health technology assessors (NICE), health economists, practicing clinicians, educators and patient representatives.  This group recognises the fact that to maximise the potential gains of translational genomics, collaboration of all stake-holders is essential.  Even at the industry level collaboration is necessary.  Dr Mike Hardman, Vice President of R&D Science relations at AstraZeneca commented, ‘What’s abundantly clear is that drug development in stratified medicine cannot be done entirely within one pharma “house”.’

What the meeting aimed to show was that there was a continuum from gene to effector protein, and therapeutic interventions can range from gene therapy (to replace or repair a defective gene) to improving the function of defective protein gene-products.  This was illustrated by Dr Van Goor’s (Vertex, USA) talk on a novel cystic fibrosis drug (ivacaftor) that helps activate the chloride channel, the cystic fibrosis transmembrane regulator (CFTR).

Pharmacogenetics at the patient interface
One area that holds particularly great promise is that of developing new drugs for prescribing according to the patient’s genetic make-up, including somatic gene mutations.  For example in advanced countries women with breast cancer are now tested for specific tumour genetic abnormalities, before being prescribed an intervention.  Moreover it is also possible to identify subjects who carry genes associated with greater risk of some cancers, so that better targeted surveillance strategies can be developed for the individual patient and their close relatives.

Professor Munir Pirmohamed, NHS Chair of Pharmacogenetics, illustrated this aspect with an overview of the outcomes of research in this area.  His talk highlighted how (i) HLA-B*57:01 testing could identify most patients who should not be given the drug abacavir, (ii) how testing for variants of two genes (CYP2C9 and VKORC1) could potentially make warfarin-dosing safer, and (iii) how testing for mutations in gene BRAF (a gene encoding an intracellular signaling molecule) could identify likely responders to a new drug, verumafenib, that has transformed the management of metastatic melanoma.

Validating biomarkers
For every biomarker such as those that Professor Munir Pirmohamed highlighted, there are several that fail clinical validation tests.  Even with CYP2C9 and VKORC1, the evidence is not robust enough for their testing to be required currently prior to prescribing warfarin.  Dr Rose McCormack, of AstraZeneca described how biomarkers that seemed obvious at the start of a study may fail to be validated and that extensive work needed to be undertaken, ideally prospectively to ensure that a predictive biomarker be established.  Such work eventually led to the validation of mutation of the epidermal growth factor receptor as a response predictor for gefitinib, a drug that has transformed the therapy of patients with non-small-cell lung cancer.

Monoclonal antibodies
Monoclonal antibodies make up some of the most successful drugs on the market with a large number having annual sales of over $1 billion (blockbuster status).  Professor Martin Glennie, Director of Cancer Sciences Division at Southampton University, illustrated how monoclonal antibodies can be harnessed to activate T cells to engulf cancer cells.  Manipulation of T-cell co-receptors by monoclonal antibody targeting has already led to successful drugs such as ipilimumab.  Challenges remain on how to identify likely responders to such therapy.  However although monoclonal antibodies were first introduced for therapeutic use many years ago, the best is yet to come.

Big Pharma
In addition to Dr Rose MacCormack and Dr Mike Hardman from AstraZeneca, big pharma was also represented by Professor Lon Cardon, Senior Vice-President from GlaxoSmithKline. In his view Pharma was ‘turning towards development of stratified medicine’.  He also described the significant resources invested by GSK to develop such medicines for subgroup of patients; often so few in numbers that the drugs are referred to as orphan drugs.

Regulatory evaluation of genomic medicines
The path from molecular discovery to a licensed drug therapy is a long, expensive one.  Just how difficult was illustrated by Joern Aldag of the small Dutch company UniQure, a company that grew out of a university spin-off through various transformations.  He described the long arduous task of validating a gene therapy (the first to be licensed in the Western world), as regulators insisted on larger sample sizes when the patients were just not there given the rarity of the condition.  The expense led to the company going into liquidation before being rescued by venture capital.  However, as Dr June Raine of the Medicines and Healthcare Products Regulatory Agency indicated, ‘regulation is changing’ to take account of these difficulties, to ensure that innovations can reach the market in a timely manner although clearly safety has to continue to be a prime concern.

Fair returns for innovators
It is estimated that taking a drug from scientific insight to the market costs over £500m.  Therefore the prices charged by the innovators for their products are also high.  A new drug targeting a specific cancer-cell abnormality (a targeted drug) typically costs over £10k per annum per patient.  A prostate cancer vaccine can cost over £100k per course. Yet there is a need to ensure that the NHS gets value for money.  Dr Elizabeth George, Associate Director of appraisals at NICE described how they undertook a health technology assessment of a companion diagnostic that is required prior to use of a targeted drug.  Such assessments are used to inform the NHS about the cost-effectiveness on genomic medicines.  Professor Adrian Towse, Director of the Office of Health Economics suggested that there might be a need to use different approaches for valuing genomic medicines that provided a lifetime cure (e.g. a therapeutic cancer vaccine or gene therapy) to those that prolonged survival for a short time.  Professor Bobby Gaspar from UCL’s Institute of Child Health provided an example of a gene therapy directed at severe combined immunodeficiency that provided an apparent cure for some patients.  He wondered whether industry would have an incentive to develop such therapies for such rare diseases (considerably rarely than the gene therapy for lipoprotein lipase deficiency that Joern Aldag described).

Funding trials
The good use made of the generous donations of the public to advance drug research was illustrated by Professor Peter Johnson, Chief Clinician of Cancer Research UK.  He talked about the charity’s coordination of major projects to validate biomarkers for stratified medicine.  In a major initiative that involves the UK government’s technology strategy board, AstraZeneca and Pfizer, they hope to recruit 9000 patients with various solid cancers, with a view to testing the feasibility of detailed gene sequencing in clinical practice to inform the management of patients’ personalised targeted treatment.

Future outlook
It is still often perceived that genomic medicine is for the future.  It is hoped that the cases presented at this meeting have shown that the future is now.  As Professor Lon Cardon remarked in his talk, ‘personalised oncology medication isn’t “the future”,  it is happening today’. The case-examples highlighted by the various speakers provided useful lessons on how we might become better at developing genomic medicines and rolling them out for the benefit of patients in as cost-effective a way as possible.  Alastair Kent, Director of Genetic Alliance UK commented ‘optimising health gain from genomic medicines requires the creation of a framework where patients and families have a real role in establishing what matters about the condition and its impact on their lives’.

Dr Vanessa Potter, a practising consultant oncologist, predicted ‘the number of mutations with “drugs to match” is only going to increase so planning the expansion of molecular services is required’.