Dawn of Precision Medicine

How Companion Diagnostics (CDx), Pharmacogenomics (PGx) and Genomic Medicine are transforming Healthcare.

Medicine is an ever-evolving field. The classical “one size fits all “approach meant that a standard dose of a particular drug is assumed to work for all patients experiencing similar symptoms. This has major downsides. Standardised dosage may work for some patients whereas, others may not respond to it at all. Few other patients may even experience Adverse Drug Reactions (ADRs), which may lead to extended hospitalizations, development of co-morbidity, additional emergency visits and even fatalities — costing billions of dollars each year.

This differential drug response necessitated the adoption of a more individualized and targeted approach known as the Personalized & Precision Medicine. Precision medicine is a broad term which gets further specialized into Companion Diagnostics (CDx), Pharmacogenomics (PGx) and Genomic Medicine.

While all these approaches leverage the power to genetic testing for precise diagnosis and customized drug therapy, all three approaches are technically unique.

Personalized & Precision medicine

The term personalized medicine was coined in 1999 and is used interchangeably with precision medicine. Both these terms are correct and imply the same meaning. However, the term personalized medicine can be misunderstood as a unique treatment designed specifically for an individual. It is rather a treatment designed for the group of patients harboring similar set of mutations. So the term Precision Medicine (PM) is more appropriate.

Decades of research has shown that DNA (genetic material in Human) and its environmental interactions are the underlying causes of variability in treatment response. The precision medicine approach identifies the mutations (undesirable change in DNA sequence) responsible for causing these variabilities, along with the environmental and lifestyle factors for the diagnosis, treatment and prognosis (likely course) of the disease. PM can be understood as a tool which allows clinicians to dig deeper into your Genome (complete set of DNA) and select the most effective treatment options with minimal side-effects.

The adoption of PM into the clinical practice might sound new but the use ABO Blood typing before performing any blood transfusions is one of its earliest examples.

In 2015, US President Barack Obama announced the Precision Medicine Initiative to encourage its adoption into routine healthcare practices. The initiative encouraged the scientists and research communities, pharma companies, and technology partners to collaborate and work towards revolutionizing healthcare with adoption of PM. Scientists can recognize and develop new targets and biomarkers. Technology partners can help in scaling up to test these markers by incurring least cost and time. The pharma partners can develop and test new specific drugs targeting the identified markers by the scientists.

One can assume PM as a broad umbrella which includes the use of genetic tests to identify the causative mutations in the patient’s DNA to make a diagnosis. Once the mutation profiling is done, the patient populations are categorized into three different cohorts: Likely to be most benefited, likely to have side-effects and finally, the non-responders. The drugs and their appropriate doses are selected on the basis of the first and second categories. However, an alternative line of treatment (if available) is recommended for the third category of non-responders.

PM is mainly used in Oncology (Cancer), Cardiovascular (Heart) and hereditary (passed on from one generation to next) disorders. For example, Cystic Fibrosis is an autosomal recessive disorder with a prevalence of 1 in 2500–3500 births in the US. It is caused by the mutations in CFTR gene. A normal individual has 2 copies of a gene. One copy comes from the mother and the second copy comes from the father. For cystic fibrosis to set in, CFTR gene should have same mutation on both copies of the gene. There are more than 900 different CFTR mutations identified till date. The most common one is the Phe508del, which is responsible for more than 85% of CF cases worldwide. The combination of drugs called Tezacaftor (VX~661) and Ivacaftor (VX~770) has been found to work very effectively in treating the individuals with this particular mutation.

Bill Elder, a family physician from Ohio, USA was diagnosed with CF when he was 8 years old. With clogged air ways, difficulty in breathing and frequent digestive infections, he was expected to not live longer than early adulthood. The genetic test performed using his DNA, identified the causative mutation in the CFTR gene. Based on which he was treated with Ivacaftor which specifically targets G551D mutation in CFTR gene. Innovative use of PM provided Bill and many more like him the new treatment options which were hitherto unavailable.

Companion diagnostics (CDx)

The term was first used in 2006 and falls under the umbrella of PM. US-FDA defines Companion Diagnostics as an in-vitro medical device (IVD) or an imaging tool which can provide essential information about safe and effective use of drugs or a developed biological/therapeutic product. To simplify, CDx is a device or an imaging tool or a genetic test to identify specific genetic errors. These errors are then targeted by the special drugs to get the precise therapy outcomes.

There are a myriad of biomarkers and platforms used for developing CDx assays (group to analytes which are investigated as a panel in laboratory for the presence/absence), which can be either diagnostic (to identify the nature of cancer) or prognostic (to evaluate the likely course of cancer).

CDx assays can measure protein expression (changes in cellular protein levels), gene mutations (errors in gene) and gene fusions (2 different genes break and fuse together to make a new gene). These changes combine to help Cancer prosper and metastasize (spread) into other parts of the body. The knowledge of these molecular changes helps in precise diagnosis and selection of specific and efficacious therapy.

Various platforms used to identify these changes are- Immunohistochemistry (IHC: use of antibodies to confirm the presence/levels of a protein biomarker), qPCR (quantitative PCR to measure the amount of DNA), Sanger sequencing (gold standard technology to sequence the DNA fragments and identify mutations and variations) and Next Generation Sequencing (NGS: advanced sequencing technique where numerous DNA fragments are sequenced in parallel to identify various mutations in several patients simultaneously).

Based on the CDx test results, the patient populations are classified into different subsets. First, benefited by the use of therapeutic product, and will respond well towards the treatment. Second, likely to have severe side effects with the use of same therapeutic product/device. This knowledge is utilized to administer treatments with high efficacy, least side effects and targeted outcomes.

Initially the concept of CDx was confined to one analyte/gene per drug. This changed in 2017 with the approval of Next GS based multiple target oncology panel by US-FDA.

The first CDx assay was approved in 1998 for Breast Cancer treatment. It was a semi-quantitative IHC analysis based HERcep Test with its therapeutic product HERCEPTIN (chemical name: trastuzumab). HER2 is a gene also called the Human Epidermal Growth Factor Receptor 2. It codes for HER2 proteins which are the receptors on the breast cells responsible for healthy breast cell growth, division and repair. However, in some breast cancers HER2 gene amplifies by making more copies. A healthy person has 2 copies of the gene but a HER2 positive cancer patient can even have 4 copies leading to its protein over-expression and stimulation of uncontrolled cell division. This makes breast cancer as one of the most aggressive type of Cancer.

HERcep test measures the HER2 protein expression levels. Over expressed HER2 proteins are treated with the FDA approved Herceptin. The drug targets the surface of the cancer cells by blocking the chemical signals which invigorate uncontrolled cell growth. This is how a CDx test and the associated drug are used collectively to treat one of the most complex and aggressive cancer types.

There are more than 17 FDA approved CDx tests for Breast Cancer alone, making it the highest number for a single cancer type. This is followed by more than 15 CDx assays for Lung Cancer. The count of approved assays goes on for colon cancer, ovarian cancer, hematologic cancers, melanomas, and sarcomas. While most research is done on cancer, some CDx assays are also developed for infectious diseases like HIV. The growing success of CDx assays to provide targeted results has made it an indispensable part of medicine and has carved its way into clinical practice.

Pharmacogenomics (PGx)

Pharmacogenomics is a branch of PM which studies the inter-genomic variations in genes associated with drug response and metabolism. To understand these variations lets first see how similar are we when it comes to our genome?

Between any 2 humans, there is only 0.1% variation in the genome. This small difference makes each one of us unique, so that no two humans can be identical. In fact variations are seen in the DNA of identical twins as well. These variations have provided us our unique appearance, capabilities, features and our uniqueness in metabolizing food and drugs.

A PGx test leverages the technology of genotyping to identify the variations in genes associated with drug metabolism to decipher protein activity responsible for transportation, metabolism and excretion of drugs from the body. Based on the PGx test results an individual is categorized into normal, inter-mediate or poor metabolizer for a given drug. Based on these categories, the appropriate drug and its right dosage are tailored for an individual. FDA till date has approved more than 100 drugs which come with PGx information on the label to assist clinicians. The dosing guidelines are maintained and updated by the Clinical Pharmacogenetics Implementation Consortium (CPIC).These approved drugs fall under the broad categories of Analgesics, Antivirals, Cardiovascular and Anti-cancer drugs.

For example, genotyping results from VKORC1 together with CYP2C9 help to determine the ideal dosage for Warfarin. Warfarin, sold under the brand name Coumadin, is an anti-coagulant (blood thinning medication) given in various thrombotic (blood clot) disorders. Slight differences in dose can affect plasma levels, causing concentration dependent ADRs. So it is very crucial to tailor the dose before prescribing it to a patient. FDA label provides 2 sets of warfarin dosing recommendations to optimize the initial dose. First, is based on when the VKORC1 and CYP2C9 genotypes are known and the second set, when they are not known (in this case the clinical history is taken into account).

Each year billions of dollars are spent on treatment of illness caused due to ADRs. A simple and quick PGx test can make prescription medication safer and efficient by preventing ADRs and thus reducing the spending which can then be better utilized on other critical healthcare concerns.

Genomic medicine (GM)

Genomic medicine is a subset of PM which utilizes an individual’s genomic information (mutations, variations and re-combinations) across the whole human genome to navigate diagnostic, therapeutic and health outcomes into clinical care. The major advantage of GM over the other approaches is its robustness of scanning the whole genome (coding and non-coding stretches of DNA) or the whole exome (protein coding stretches of all the genes) for mutations and variations. The deeper coverage into the genome can pick up variants which can be missed by other approaches. It can also identify the novel, previously unknown mutations helping to diagnose diseases which remained undiagnosed before.

Completion of Human Genome project in 2003 and simultaneous advancements in technology led to the development of many High Throughput platforms which could accurately perform tests on more samples and analytes (genes) in the shortest time spans ever. This in-turn led to substantial increase in development of genetic tests which are now readily available for clinical use. As of May, 2020, the genetic testing registry maintains the record of 65,384 genetic tests for 15,266 different conditions. These tests can be categorized into Breast Cancer panels, Cancer and Somatic mutation panels, Single gene panels, Whole Genome and Whole Exome panels.

GM is extensively used for hereditary disorders and the predictive genetic testing (genetic test which predicts the chances of developing a disease before its actual onset).

Nic Volker, a young boy from Wisconsin, USA was born in 2004 with a severe form of inflammatory bowel disease. For first 5 years he suffered excruciating pain due to the holes in his intestine and could only be fed with tubes and intravenous injections. In 2009, a team of doctors and geneticists decided to put an end to his sufferings by doing the Whole Exome Sequencing (WES) analysis by using NGS. WES analysis pinpointed towards one mutation which caused his immune system to attack his own digestive track and weakened him to fight infections. Further investigation and literature search indicated that the bone-marrow transplant can be the only life-saving treatment for him. After serious contemplation, bone-marrow transplant was performed on him. Use of GM provided the miraculous cure and extricated him from the suffering.

GM is the answer to correctly diagnose the genetic disorders which were hitherto undiagnosed or misdiagnosed. However, the major road block is the cost to carry out such expensive diagnosis. Continuous efforts to make these advances in the technology affordable and reachable to all are going on worldwide.

Conclusion

These innovative medicine approaches are transforming healthcare by uncovering the power of DNA testing. Despite so many success stories, there is still a lack in translation of the newly discovered variants into actual clinical use. In future, advancement in healthcare software, updated databases and easier accessibility to information will address this lack and aid in faster bench to bedside translation. PM will also envision the amalgamation of genetic profiles into the clinical data to complete medical information required for advance diagnosis. In forthcoming years PM will access patient’s genetic profile and predict the signs of disease before its actual emergence. Longitudinal follow ups will prevent the onset of many diseases before their overt emergence, leading to reduced healthcare costs, improved disease management and lifestyles. The use of genetics will also advance nutrition, immunotherapy, health and preventive care transforming them into precision nutrition, precision immunotherapy, precision health, precision preventive care, and thereby touching every aspect of human healthcare.