Advancing Precision Medicine: Genomics, Metabolomics, and Clinical Trials
By Dr. Roberta Alexander
San Diego, CA. October 12, 2015
The San Diego Clinical Research Network (SDCRN) organized another great event on October 12. It was held in the Alexandria Building of BIOCOM in the Torrey Mesa area. The building and the auditorium are state of the art, and a perfect match to the excellent program. The event started with a fabulous networking reception sponsored by SureClinical, a company that streamlines the execution of clinical studies by automating different aspects of document processing (www.SureClinical.com).
The program focused on personalized medicine, and brought together important players in the field. After the organizer of the event and founder of SDCRN, Teresa Gallagher, welcomed the attendees, Dr. Arnold Gelb, Senior Medical Director from Halozyme Therapeutics, Inc., introduced the speakers: Drs. Amalio Telenti, Head of Genomics at Human Longevity, Inc.; Steve Watkins, Chief Technology Officer of Metabolon, Inc., and Nicholas Schork, Professor and Director of Human Biology at the J. Craig Venter Institute.
The impact of genetics on disease and treatment options
Although rare diseases caused by a single gene mutation affect, by definition, a small number of individuals, collectively, they affect a large portion of the population. Conversely, numerous diseases that are relatively common may be caused by numerous genetic variations. Osteoarthritis, melanoma, type 2 diabetes, Alzheimer’s disease, Parkinson’s disease, and inflammatory bowel disease, are just some examples of diseases where multiple genetic variations may be implicated. Although some of these variations may have unknown significance and are not actionable, knowledge of the genetic abnormalities present in an individual affected by a certain disease may help drug discovery and development in many ways, from stratification of patients before or after a trial, to understanding unwanted adverse events, to drug repurposing (i.e., lifecycle management).
Metabolomics at the intersection of genetics and environment
It is not all about your genes, as genetic variations may not lead to overt disease, and disease may not be associated with genetic variations. Analysis of metabolic pathways may provide rich information to better understand disease etiology or progression, or drug efficacy and toxicity over time. Metabolomics is the comprehensive measurement of small molecules, including glucose, cholesterol, cortisol, lipids, amino acids, bile acids, etc. Metabolites are at the intersection between genetics and the environment, and their change can be measured over time to provide important information on health and disease.
Metabolites form networks and pathways, and their analysis can improve specificity in precision medicine. For example, one can identify disorders that would be difficult to identify based on genetic analysis; in addition, study of metabolites can identify genetic variations of non-penetrance, i.e., genetic variations that do not lead to disease and alterations in metabolic pathways.
Personalized medicine considerations for drug development
How can one integrate knowledge of genetic and metabolic make-up of an individual in precision medicine? N-of-1 and basket trial designs could help in determining the most appropriate treatment for a patient: if one could pinpoint the mutation that is responsible for breast cancer in a certain individual, one could potentially treat that person with a compound that targets that particular mutation, substantially increasing the likelihood of response. This, assuming that other mutations do not play a major role as well, and assuming that a cause-effect relationship does actually exist and can be established.
Not only drug efficacy, but also toxicity, can be influenced by gene mutations. A classic example is represented by carbamazepine; this compound can lead to a serious skin disease, Stevens-Johnson syndrome, in people who carry a certain HLA mutation. In the case of carbamazepine, the cause-effect relationship was so compelling, and its effects so devastating in people with that mutation, that carbamazepine’s label was changed. Clinical studies to prove a cause and effect relationship in this instance would have been not only unnecessary, but also profoundly unethical.
Another interesting consideration for precision medicine is represented by the so-called personal threshold. For most metabolites, a population threshold, i.e., the reference range in a population, can be established. Assume a person is within the reference range for a certain metabolite, and the level of that metabolite fluctuates only slightly over time. Then, assume that the level changes: it is still within the normal limits, but quite different from the baseline level of that individual. Detection of that change, even if level is still within the population threshold, can help identify a risk of disease in that individual. Identification of perturbations early on, and perturbations of the personal threshold, can lead to action and better health care.
The event ended with a lively panel discussion. Questions from the audience touched on epigenetics, machine learning, and adaptive trials.
Stay tuned and check the SDCRN website (theclinicalresearchconnection.org) for upcoming events!