Presentations were given from across the many different fields playing keys roles in driving forward the new era of personalised medicines including: biopharmaceutical industry, health providers, health technology assessment, regulatory, clinical, academia, pharmacy. Only with all these parties working together can the value of merging new technologies be truly obtained. Areas, which attracted particular debate, included the co-development of drugs and companion diagnostics, statistical analysis of stratified medicines trials and the type of data required for health technology assessments.
Companion diagnostics are all the rage
It only takes a cursory glance over the activities of the biopharmaceutical industry to make it clear that the development of companion diagnostics (CDx) is one of the opportunities offered by stratified medicine approaches that is being embraced most readily. This trend was clearly exemplified by speaker Dr Steve Little, who a year previously was the CEO of Manchester-based DxS, and now is Vice President of Personalised Medicine at Qiagen, following the acquisition of DxS by Qiagen in September 2010.
Defining personalised healthcare as ‘the use of a companion diagnostic to predict in advance which patients are likely to benefit from a particular therapy’, Dr Little identified the issues around CDx development from the point of view of both pharma and diagnostic companies. Establishing clinical utility of any new marker requires trials of both the drug and diagnostic. Taking the example of oncology, if an oncology Phase III trial costs $100m, and its companion diagnostic can expect to generate sales in the region of $50m pa, then for most diagnostic companies these costs will necessitate the need to partner to develop a CDx. This is the Qiagen strategy and enables shared development costs. If the drug is approved then there is a market for the diagnostic, and there is the potential for increased sales via co-marketing with the pharma partner. From the pharma perspective most companies do not have the in-house expertise and will be looking to either acquire diagnostic companies or partner. Diagnostic companies, once the cinderella of drug development are now become critical partners in delivering personalised medicines.
And what of the differing development pathways between drug and dagnostic? If development of CDx takes on average four years to US Premarket approval, and drug development considerably longer, good planning and early collaboration is needed to ensure that neither part delays the other. Generation of CDx candidates during the clinical phase is optimal timing, but is not without its challenges, as it is often not until Phase II and the data coming from these trials that defines the markers needed for the development of a diagnostic. Under FDA regulations, any CDx mentioned on a drug label must have FDA approval as a diagnostic in its own right, making the regulatory expertise of the diagnostic partner crucial. In addition, it must be able to provide commercial quantities of the diagnostic globally in order and in time to support the drug launch and ongoing sales.
‘Treatment is from Venus, diagnostic is from Mars’
In order to develop companion diagnostics in an optimal way, there is a clear requirement for better understanding of partners’ needs, according to Peter Keeling of Diaceutics – characterising the situation as ‘Treatment is from Venus, Diagnostic is from Mars’. He believes that the development of CDx is a market with huge potential for the diagnostic industry, citing returns on investment in excess of 60-fold in the case of Herceptin (based on a $70-80m investment in the CDx from 1997-2007 and sales of the drug of $5.3bn over this time period.). There is also the potential to significantly enhance the speed and quantum of diagnostic uptake. With predictions that by 2017 up to 50% of drug earnings will be dependent on personalised medicine, he advocated this to be a key market to be in.
The categories that CDx might fall into, and the advantages and value that could be expected to accrue to the partners were some of the topics covered by James Blakemore of Integrated Medicines. He believes that CDx have the potential to bring faster times through the approval process and to market, reduced time to peak sales, enhanced peak sales and extended product lifecycles. Taking as a measure of the CDx market the sum of drug sales enhancement through the use of companion diagnostics, he puts it at $72bn.
Who claims the lion’s share of this putative revenue uplift, the pharma partner or the diagnostics partner? This is certain to be one of the biggest bones of contention between the players as companion diagnostics move into mainstream drug development, sales and marketing. To a certain extent, this depends on how the CDx is being used. For example, ‘Turnaround”, for a product such as in the case of a severe adverse event in a patient sub-group e.g., GSK’s abacavir and HLA *5701; “Integrated”, co-developed CDx and drug e.g., Pfizer’s Selzentry and Monogram’s Trofile test; “Make-to-order”, market penetration e.g., Merck Serono’s Erbitux and K-RAS tests and “Use-to-order”, market expansion such as in case of generics e.g., AstraZeneca’s budesonide and Prometheus test.
Cash is king, as ever
Katherine Payne of the University of Manchester emphasised the potential of pharmacogenetics and diagnostic tests for the health economist. Defining her role as to ‘provide information about how to allocate scarce healthcare resources such that maximum patient benefit is obtained from every pound spent’, she said that, in theory, pharmacogenetics was the ‘perfect solution’ to this task. She believes that reaching this point is however some way off with a need to develop regulatory systems that lead to a strong evidence base for decision making, more data on factors such as how tests affect the incidence of side-effects and health outcomes, the use of healthcare resources and costs. In short, there is currently not enough evidence for health technology assessment. To this end, a 2008/9 Genomic Medicine report from the House of Lords called for ring-fenced funding of research into genetic and genomic tests within the NHS from an Health Technology Assessment perspective. Looking across the whole product lifecycle
Adam Heathfield of Pfizer looked at the impact of pharmacogenetics over the whole of the product lifecycle, from drug discovery and development through to approval, reimbursement and prescribing. He believes that the impact of pharmacogenetics on research is exciting, while there is ‘less compelling’ evidence for positive effects on the time and cost of development, and the impact on commercialisation is unclear. While there is potential for demonstrating the value of new innovative medicines over cheap generics, there are challenges in study design and in incorporating diagnostics into clinical practice. In the case of clinical trials, for example, the ability to test for a biomarker throws an additional complication and ethical factor into the mix – if a study involves biomarker positive and biomarker negative patients, both of which groups are randomised to drug or placebo, then half of the patients with the marker will not get the drug, and half of those without the marker will be getting the drug. Somewhere, patients may be potentially losing out. Keith Ridge, Chief Pharmaceutical Officer, Department of Health, UK presented the challenges facing the delivery of cost-effective medicines and ensuring patients benefited from the advances being made in novel medication. Being able to more effectively direct medications to those with most need will be critical for the future effective management of health budgets and prescribing practices.
John Whittaker, a statistical geneticist at GSK, also touched on this issue, asking whether it would be common procedure in the future to enrich trial cohorts for genetically defined responders. He also drew attention to another of the obstacles to generating pharmacogenetic data, in that trials are rarely designed with that end-point as a primary objective, and techniques are often applied retrospectively to existing trials.
Recent advances in disease genetics
As well as considering the complex drug development factors that pharmacogenetics and stratified medicine is presenting to the pharma industry, several sessions at the conference highlighted some recent advances in genetics clinical research expected to have significant implications for personalised medicine. Discussing the development of obesity, Dr Alexandra Blakemore of Imperial College London’s Department of Genomics of Common Disease noted that although many factors are known to influence the condition, including a strong environmental factor, genetic factors have also been found to play a key role in an individual’s propensity to become obese and their response to the so called obesogenetic environmental factors. The risk of obesity has also been shown to have a high heritability component.
In common with many other diseases, there are rarer forms of the condition which are monogenic (caused by mutations in a single gene, such as MC4R), as well as polygenic common forms. Mutations in MC4R are the most common singe-gene forms of obesity, but result in only 2-6% of cases. What has been missing until recently has been an understanding of the genetic causes of common obesity – “the mystery of the missing heritability”, as Dr Blakemore called it. Her team has started to solve the mystery by looking at genomic structural variants – areas of the genome in which parts of the sequence may be missing, duplicated, amplified or inverted – since it has been discovered that patients with certain forms of obesity have an increased number of these mutations. Resulting work has identified deletions in chromosome 16 which encompass many genes whose activities makes them candidates for obesity association – and Dr Blakemore believes that this is a ‘promising route’ to finding more obesity-associated genes.
She concluded that there are multiple implications from this work for personalised medicine, in that knowledge of an individual’s obesity-related genetic make-up can guide prescribing decisions around medications that can cause weight gain such as anti-psychotics. In addition, it has been shown that MC4R genotype can influence the result of gastric surgery and so genetic testing might be able to guide surgical treatment decisions. Last but not least, an understanding of new obesity-associated genetic mutations has implications for the development of novel targeted drugs.
Professor Mark Caulfield of Barts and the London gave an update on progress in deciphering the genetic influences on hypertension, a widespread condition that is often poorly controlled. Recent data coming from the International Collaboration for Blood Pressure and MRC British Genetics of Hypertension study has identified several novel genetic loci, many encoding genes not previously thought to influence blood pressure – and therefore throwing up ‘credible targets that industry can reconsider’. Other talks presented included Dr Hugh Brady, Reader in immunology from Imperial College London providing new insights into natural killer call regulation and their implications for health and disease, Dr Stefano Fedele from University College London Eastman Dental Institute providing an up-date on his research investigating genetic predictors of jaw osteonecrosis associated with bisphosphonate treatment and Aroon Hingorani, Professor of Genetics Epidemiology of Cardiovascular disease, University College London presenting data on the application of genetics to identify new disease pathways and drug target in atherosclerosis. Arthur Holden, CEO, International Serious Adverse Event Consortium (iSAEC) further exemplified the important role of academia and in particular working in association, presenting the work of the iSAEC and academic-industry partnerships to investigate the genetic basis of drug-related adverse events.
These findings strengthen the growing recognition of the importance of open innovation and the critical role academic research has to play in the discovery of new targets, their clinical validation and clinical development. Industry - academic collaboration has to be a model of working for the biopharmaceutical industry in order to harness the opportunities and novel findings arising out of these groups working at the cutting edge of science.
The future’s bright....
And what of the future? It is clear that pharmacogenetics and personalised medicine are both here to stay and are being fully embraced by the biopharmaceutical sector. One of the biggest challenges now is gaining the acceptance of healthcare sector in its biggest sense – from payors all the way to the end user, be it the clinician or the patient. London Genetics’ 2011 conference, held on 8-9th November, will be debating these issue along with other hot topics with speakers from key players in the field including regulatory, health insurance, clinical, diagnostic, payor regulatory landscape as well as and often overlooked, the ethical implications of an era of personalised medicine.
Conference speakers in order of presentation:
Elizabeth Foot, CEO, London Genetics Limited; Dominique Kleyn, former CEO, London Genetics Limited; Krishna Prasad, EMA Pharmacogenetic Working Party, and Medicines and Healthcare products Regulatory Agency; Felix Frueh, VP, R&D Personalized Medicine, Medco Health Solutions, Inc.; Andrea Jorgensen, Research Assistant, Wolfson Centre of Personalised Medicine, University of Liverpool; Arthur Holden, CEO, International Serious Adverse Event Consortium; Angela Flannery, Lead Technologist for Stratified Medicine, UK Technology Strategy Board; Alex Blakemore, Reader in Genomic Medicine, Imperial College London; Hugh Brady, Reader in Immunology, Imperial College London; Mark Caulfield, Director of William Harvey Research Institute & NIHR Cardiovascular Biomedical Research Unit, Barts and The London Medical School; Centre for Clinical Pharmacology; Steve Little, VP, Personalised Healthcare, Qiagen; John Whittaker, Director, Statistical Genetics, GSK; Peter Keeling, CEO Diaceutics; Stefano Fedele, Clinical Senior Lecturer, Oral Medicine Unit, UCL Eastman Dental Institute, London; Aroon Hingorani, Professor of Genetic Epidemiology of Cardiovascular Disease, Rayne Institute, University College London; Steve DeCherney, Professor of Medicine, Division of Endocrinology, University of North Carolina School of Medicine, Chapel Hill, North Carolina; Adam Heathfield, Science Policy Director, Europe, Pfizer; Keith Ridge, Chief Pharmaceutical Officer, Department of Health, UK; Katherine Payne, Professor of Heath Economics, University of Manchester; James Blakemore, Senior Consultant, Medical Diagnostics, Team Consulting Ltd. and Associate Consultant, Integrated Medicines Limited.