Mewburn Ellis writes:
Historically, drugs have been developed on a ‘one size fits all’ basis, in which all patients with a particular disease receive substantially the same treatment. We have known for some time that this approach is imperfect - a drug that works well for some patients may have only negligible therapeutic benefit for others, or may cause substantial side effects. However, clinicians often have little option but to try a patient on a drug and hope for a good outcome. Today, with advances in data collection and analysis, our understanding of the physiological and genetic variance between patients is increasing, allowing us to understand why different patients respond differently to the same treatment. This is the emerging model of ‘precision medicine’ - in which medical decisions, treatments, practices and products are tailored to the individual patient.
The International Human Genome Mapping Consortium completed the first genome sequence in 2001, facilitating advances in our understanding of the genetic basis of disease and likely responsiveness to treatment, and these advances have been critical to the emergence of precision medicine. The importance of other technologies should not be overlooked, however, with advances in proteomics, metabolomics and cell biology, as well as informatics, biosensors and artificial intelligence all playing a part in this exciting field.
Advantages of precision medicine
The combination of conventional investigative procedures with these new approaches offers the potential to create a unique, precise picture of the medical condition of an individual patient, and to tailor their treatment accordingly. The objective is for all patients to receive precisely the right medical care that will benefit them most, as individuals.
Improving diagnosis accuracy
Oncology has been at the forefront of the movement. We now understand that malignant tumours have significant heterogeneity, both within and between tumours. The classification of these and other heterogeneous diseases into more precise subtypes, by powerful detection methods and analysis tools, integrated with more traditional clinical diagnostic tools, enables clinicians to develop more accurate diagnosis, prognosis and therapeutic strategies for different disease subtypes.
For example, some tests can help to distinguish different types of cancer based on tumour genetic profiles. Such profiles are helping researchers to distinguish patients with a good prognosis from those unlikely to respond. This enables clinicians to change the treatment strategy, switching to a different drug, or increasing the dosage to improve the chances of a good outcome. A number of commercialised diagnostic precision technologies are now available, and many more are in the pipeline. This type of profiling would have been the stuff of science fiction just 10 or 20 years ago – now, it is an established part of diagnosis for several types of cancer.
An example is the BRCA gene test which is often made available to women with a family history of ovarian or breast cancer. Arming women with the knowledge about whether they too carry a mutation associated with increased risk of developing cancer allows them to take preventative action, such as undergoing radical surgery, to try to prevent them developing the disease, or help them catch it earlier, when it may be more readily treatable.
Optimising treatment
When a genetic or molecular signature of a disease is discovered, an obvious and productive area of research involves looking for drugs that can target this specifically. This is one of the central approaches of the burgeoning field of immunotherapy, in which components of the immune system such as antibodies, T-cells and B-cells are engineered to specifically recognise and destroy those cells exhibiting a particular genetic change.
Genetic profiling of cancer cells has identified thousands of mutations, many of which play little or no role in causing those cells to be cancerous. Whilst targeting these mutations may not directly impact the fundamental biological processes of the cancer, if presented on the surface of cancer cells these mutations can provide a useful label to identify the cell as cancerous. The patient’s own immune cells can them be re-educated to identify these “neoantigen” labels, targeting the cells for destruction.
The cancer drug trastuzumab (Herceptin), for example, targets the HER2 receptor found at high levels on the surface of some cancer cells, known as HER2 positive cancers. An important first step in the treatment of stomach or breast cancers is therefore genetic testing to identify whether the patient is one of the 1 in 5 patients that has a breast or stomach cancer that is HER2 positive, and hence might benefit from trastuzumab treatment.
Another exciting development is the prospect of therapeutic gene editing. The CRISPR/Cas9 system has received significant press coverage since its discovery in 2015, but research into other gene editing systems is more advanced; treatments with Zinc Finger Nucleases (ZFNs) are already being tested in the clinic, attempting to replace a faulty enzyme gene in patients with Hunter syndrome.
As well as targeting the efficacy of drug treatments, precision medicine can help clinicians identify treatments that might have the best safety or tolerability profile for a particular patient. Variations in the amount, or structure, of particular enzymes or signalling molecules in an individual may affect the way a patient responds to, or processes, a particular drug. For example, patients who naturally have a particularly high level of certain enzymes may metabolize a drug more quickly than other patients, leading to a higher peak concentration which could be associated with an adverse reaction in that individual. Armed with this information, the treating physician may opt for a lower dose in that patient, or a different treatment altogether.
Driving forces
There has been widespread political support for precision medicine, as governments recognise the potential for improved outcomes and reduced healthcare costs – an ever-increasing goal in the face of an ageing world population. Currently, there is significant waste of resources in the use of ineffective treatments. Clearly, if treatment can be optimised to enhance efficacy, not to mention avoiding the costs of managing adverse reactions (difficult to quantify, but estimated in 2004 to cost the UK’s NHS £466 million per year), significant savings could be made. Optimised therapy might also encourage more patients to comply with their treatment regimens, saving the NHS £500+ million per year.
Pharmaceutical companies are similarly keen to embrace the new approach. Identification and analysis of biomarkers is becoming an essential part of prospective drug development programmes, with biomarker-based approaches being integrated in more than 40% of new programmes. This has the potential to markedly increase success rates for new drug approvals, as higher response rates in specific populations can be achieved. Therefore, precision medicine offers pharmaceutical companies a smoother path to market, increased uptake of the drug (due to magnified treatment effects), and the potential to extend patent protection for the drug by obtaining patent protection for its use in selected patient populations.
Although precision medicine provides significant opportunities and advances for medical science, there are a number of ethical questions that cannot be ignored. Now we have the ability to sequence every child born at birth, should we so? The US National Human Genome Research Institute (NHGRI) is tackling this very issue right now, evaluating the potential benefits of every new baby undergoing extensive DNA sequencing and analysis. A chief issue of concern is the fact that genomic information is personal data, which is subject to personal data protection laws, and could have considerable ethical implications. This debate is unlikely to be resolved any time soon. We discuss these ethical issues further in our blog, Precision medicine: ethics, regulation and patent law.
What has made all this possible?
When the International Human Genome Mapping Consortium’s sequencing project published their findings in 2001, their sequencing project had taken many years to complete; now, this massive undertaking could be completed in a matter of days. A number of genomic assays are already mainstream, making this type of technology accessible to practising doctors.
Thanks to industrial and academic advances, frequently supported by governmental initiatives across the world, new tests and applications for precision medicine are being developed all the time. This is one of the most fast-moving and innovative fields of medical technology.
It is interesting to see how governments are encouraging industry down this path. The UK government was one of the first to realise the potential of precision medicine, launching Genomics England as part of the NHS 65th birthday celebrations in 2013. The project initially sought to collect the genome sequence of 100,000 individuals, generating a sequence database that could be used to diagnose patients with extremely rare diseases, some of whom may have lived their whole life without a diagnosis. The UK government has recently expanded this scheme, and will now offer whole genome analysis to all seriously ill children suspected of suffering a genetic illness or cancer, as part of their routine care.
The UK is not alone in wanting to win the precision medicine race. In the USA, the Precision Medicine Initiative is working to generate the evidence needed to take precision medicine to clinical practice. The initiative is focussing initially on cancer treatment but the ultimate aim is to transform all areas of health and healthcare. A key component of this initiative is the “All of Us” research program. That study is the largest longitudinal study ever conducted in the USA, collecting and collating biological samples, lifestyle data and medical records from 1 million volunteers into a centralised database that is available for researchers to analyse.
China is also investing heavily in precision medicine technologies, prioritising genomic research as part of the government’s current Five Year Plan. In addition to providing substantial funding for collecting and sequencing genomic information, the government is also investing in projects to develop the computer infrastructure necessary to manage and process genomic data. Coupled with having a large population available to analyse, this investment in data collection, analysis and infrastructure is likely to place China in a prime position when it comes to new precision medicine technologies.
Intellectual property
Mimicry might be the sincerest form of flattery, but precision medicine is a high-investment, high-yield field of research, and these innovations need to be protected. This is a complex and diverse area of domestic and international law, with different countries holding differing perspectives on patenting precision medicine technologies.
For example, while the US Patent and Trademark Office (USPTO) is usually considered applicant-friendly, it can be a challenging office for innovators in this field. The US Supreme Court’s 2013 Prometheus and Myriad decisions resulted in a dramatic shift in the USPTO’s approach, prohibiting protection for innovations in this field that were previously patentable. In many countries ‘methods of diagnosis’ are excluded from patent protection if practised directly on the human or animal body rather than in vitro, but some countries, notably China, take this further and will not grant patents to any method of diagnosis at all. The European Patent Office (EPO), on the other hand, is one of the more applicant-friendly patent offices for this field of technology. The specific requirements of each of the different patent offices around the world should be factored in from an early stage.
In addition to the challenges presented by the different approaches taken by the different patent offices, innovators must also consider how the technology will be ultimately be used, if the protection afforded by the granted patents is to provide useful coverage. Methods of diagnosis are, for example, increasingly performed across international borders, with samples sent internationally to centralised processing facilities. In these cases, it may be difficult to demonstrate that a single entity is undertaking the entire method, from sample to diagnosis, or providing any overarching control. It is therefore imperative that the way in which the technology will be implemented, and more importantly how it might be used by third parties, is considered from the beginning of patent process.
When seeking professional advice in this area, it is therefore vital that the legal team has the breadth of experience and knowledge required to build a patent portfolio that provides optimum protection for your invention.
Conclusions
The future of medicine lies in precision, and the field offers a wealth of opportunities for innovators and inventors working in this space. It is an exciting and innovative field, and both the technology and the IP landscape are continuously evolving.