Jeffrey S. Buguliskis Ph.D. Technical Editor Genetic Engineering & Biotechnology News
Focused Genetic Analyses Seek To Improve Patient Care and Streamline Drug Development for Cardiovascular Disease
Sitting still inside a quiet room, in complete silence, place your hands over your ears. Focus on your breathing. Inhale, exhale, and repeat. Soon enough you will begin to feel the rhythmic beating of one of the most active muscles, undoubtedly the most critical, in the human body. Grab a hold of a stethoscope and you’ll be able to hear this muscle’s “song” more clearly: “lub-dub—lub-dub—lub-dub.” It’s a sound that we often take for granted—occurring inside our chests over 100,000 times per day. This rhythmic pulsation beneath the sinewy makings of the thoracic cavity supplies our mass of tissues, organs, and systems with the sanguine elixir that is essential for our daily animation.
It feels only natural to write poetically about a biological process that keeps us functioning on a daily basis while it simultaneously beats the figurative drum toward its demise—which, too often and with little warning, can descend upon us, catastrophically ending our existence.
Taken as a whole, the cardiovascular system is a marvel of biological engineering, yet imperfections in the genetic code can often lie in wait for just the right set of variables—for example, genetic polymorphism + onset of disease + drug cocktail—to initiate a cascade of physiological events leading to clinical emergencies.
Above and Beyond—in Terms of Results, Not Budgets
Invariably, even medications that have widespread success and effectiveness will often display unpredictable levels of efficacy or adverse drug reactions (ADRs) at some point during clinical administration. Pharmacogenomics is one approach the scientific community uses to address genetic variants among the population related to unwanted and potentially life-threating drug effects. Scientists have attempted to couple drug development with new pharmacogenomic discoveries in an effort to improve current regimens or design new therapeutic strategies.
“Pharmacogenomics can help streamline the drug development process by identifying patients who respond favorably to a medication, leading to a larger reduction in clinical event rate and the need for a smaller, less expensive, and perhaps shorter study,” notes Jean-Claude Tardif, M.D., director of the Montreal Heart Institute Research Center and professor of medicine at the University of Montreal. “Integrating pharmacogenomics in drug development holds the potential to reinvigorate this process for cardiovascular compounds—with the goal of yielding more efficacious, safer, and cost-effective medications for targeted populations.”
The pharmaceuticals used to treat cardiovascular disease (CVD) are among the most commonly prescribed medications in the world, underscoring the need for continued pharmacogenomic research to elucidate the molecular mechanisms that regulate the genetic response to active drug compounds. Yet, there has been a trend, in recent years, away from cardiovascular drug development—due in no small part to the sizeable amount of time and financial resources required to assemble large enough clinical trials. However, many research organizations and biopharmaceutical companies are beginning to see the benefit of investing in large-scale pharmacogenomic analyses to update and bolster the cardiovascular drug development process.
“I do believe that pharmacogenomics or targeted approaches could improve cardiovascular drug development,” explains Julie Johnson, Pharm.D., dean, and distinguished professor in the College of Pharmacy at the University of Florida. “In cardiovascular disease, many effective therapies have been documented in the last two or three decades, and so any future drug has to show benefit on top of the already effective therapies. Heart failure is a perfect example of this, where background therapy would almost certainly include beta-blockers, ACE [angiotensin converting enzyme] inhibitors, and likely a diuretic.”
“In an all-comers approach to drug development, it is very hard to show additional benefit on top of these effective therapies. Yet it seems highly likely that there is a subset of the heart failure population who could attain significant benefit from additional treatment—finding a way to identify that subset is the key,” Dr. Johnson adds.
Variants Are the Spice of Genetics
Genetics has played an integral role in the overall fate of many pharmaceuticals after they have already been approved for clinical use by the FDA. One classic example comes from the antiplatelet agent clopidogrel. This drug was approved by the FDA in 1998 to inhibit blood clots and prevent myocardial infarction and stroke. However, just over a decade later, reports began to accumulate concerning clopidogrel’s lack of efficacy for many patients. Researchers found that the liver enzyme P450 2C19 (CYP2C19) was essential for the drug’s bioactivation. Moreover, some studies revealed that specific genetic variants in the CYP2C19 gene made the drug significantly less effective in up to 14% of the patient population.
In 2010, the FDA added a black box warning to clopidogrel so that patients and healthcare providers were acutely aware of the poor-metabolizing-variant population, which was at 3.5 times greater risk for adverse cardiovascular events, such as heart attack, stroke, and even death. A growing amount of data continued to identify an ever-increasing number of CYP2C19 variants, highlighting the need for more pharmacogenomic studies, as well as the importance of genotyping patients that were currently on or getting ready to begin clopidogrel therapy.
Routine use of pharmacogenomic methodologies for CVD patients starting the process of determining the most effective treatment for management of their disease is seemingly an idea whose day should have already come. However, a number of obstacles still prevent this the translation of this approach from a laboratory tool into a full clinical mainstay.
“A key issue for instituting pharmacogenomics in cardiovascular medicine is the demonstration of improved hard cardiovascular outcomes (death, myocardial infarction, stroke) with genetically guided therapy in an adequately powered prospective clinical trial,” Dr. Tardif states. “Clinicians and payers indeed want to know that a pharmacogenomic test is affecting therapeutic effects on clinical outcomes favorably and significantly before its implementation.”
Dr. Tardif continues, “This is the reason why we are conducting the ongoing Dal-GenE study, an international Phase III randomized controlled trial of 5000 patients with a recent acute coronary syndrome and the appropriate genotype.”
Eric Topol, Ph.D., director of the Scripps Translational Science Institute and cardiologist with the Scripps Clinic, says that “there is major unmet need to reduce heart attacks, heart failure, heart rhythm disorders, and more. Each drug development program should have ‘omics’ embedded into it, including exome or whole genome sequencing.” Dr. Topol adds that currently “at the clinic level it is the lack of practicality, i.e., it costs too much and takes too much time to get the results needed.”
Historically, pharmacogenetic modalities have been hampered by fiscal, regulatory, and logistical considerations; however, a notable shift seems to be taking place at the pharmaceutical drug discovery and development phases. Companies have started to move away from the model of developing a single drug for a large population and are edging toward strategies that focus on a much narrower populace through the use of specific genetic panels that contain an array of disease variant biomarkers. This targeted approach should lead to reduced development costs and increased drug safety and efficacy.
Pharmacogenomics Predicts the Future by Creating It
A steadily growing amount of data is linking ever more genetic variants to variable drug responses. The prospect of incorporating pharmacogenomic analysis into routine diagnostic care in the interest of improving clinical outcomes is a foundation of personalized medicine, and many researchers believe that there will be new discoveries and novel pharmacogenomic biomarkers for testing drug toxicity and efficacy—especially for CVD.
“Using genetic information to guide treatment decisions or dose selection in cardiovascular disease is likely to increase in the future,” says Dr. Johnson. “This is in part due to the fact that for many situations in cardiovascular disease there are numerous therapeutic choices that have documented efficacy in a population—though a specific therapy may be less effective in an individual.”
There are those who firmly believe that pharmacogenomics is the tip of the spear in the battle for full acceptance of precision medicine initiatives. Having a greater appreciation for the interactions between our genomes and the medications being administered will not only improve patient outcome but will also strengthen patient confidence in the medical and pharmaceutical community. This increased assurance will allow researchers to expand their work beyond the inherited aspects of our genome and dive into even more nuanced areas of genomics, such as the transcriptome, epigenome, metabolome, and even the microbiome (which is increasingly being viewed as a having a significant impact on drug metabolism and overall health—but we’ll save that story for a future issue of Clinical OMICs).
“Pharmacogenomics could very well become an important aspect of precision medicine for cardiovascular disease,” states Dr. Tardif. “We are aiming for greater benefits from a pharmacogenomics-guided therapy to be targeted toward a distinct subset of patients, compared to the standard one-size fits-all approach. This paradigm shift will be welcomed by patients, physicians, healthcare systems, regulators, and payers.”
This article was originally published in the June 2016 issue of Clinical OMICs. For more content like this and details on how to get a free subscription to this digital publication, go to www.clinicalomics.com.