Category Archives: pharmacogenomics

Largest Trial of EGFR-Mutated NSCLC Patients Promises New Personalized Treatment Option

Captured by GenomeWeb

Using a pharmacogenetic strategy to home in on a molecularly defined non-small cell lung cancer patient population, researchers have shown in a clinical trial that the investigational EGFR inhibitor afatinib significantly prolongs survival in patients with EGFR-mutated tumors.

Researchers from Boehringer Ingelheim and elsewhere presented data at the American Society of Clinical Oncology’s annual meeting this week on the LUX-Lung 3 trial, which they heralded as the “largest and most robust” trial performed to date in the EGFR-mutation positive NSCLC population. Sponsor Boehringer Ingelheim will likely seek approval for afatinib as a first-line therapy for this subset of lung cancer patients.

The data, presented by lead study author James Chih-Hsin Yang of National Taiwan University Hospital, also showed that patients who harbor two of the most common EGFR mutations respond especially well to afatinib.

In the LUX-Lung 3 trial, study investigators enrolled 345 patients from 130 sites in 25 countries. Patients with Stage IIIB/IV adenocarcinoma and EGFR-positive tumors were randomized to receive either afatinib or the most effective chemotherapy regimen containing cisplatin and pemetrexed. The primary endpoint of the study was independent reviewer-assessed progression-free survival, or the period of time patients were alive without their disease advancing. Secondary endpoints included overall survival, disease control rate, tumor shrinkage, patient-reported outcomes, and safety. Study participants were previously untreated for advanced NSCLC.

The data from LUX-Lung 3 showed that patients receiving afatinib lived for a median of 11.1 months without their cancer progressing, while patients receiving cisplatin/pemetrexed lived for a median of 6.9 months. The overall survival data in the study are not yet mature.

After 12 months, “47 percent of patients in the study who received afatinib had not progressed, [while] 22 percent of people who received chemotherapy have not progressed,” Yang said. “With this simple measurement, you can tell that the patients who received afatinib enjoyed a longer progression-free survival time compared with chemotherapy.”

Patients on the afatinib arm had around a 40 percent less chance of dying than patients on the chemotherapy arm. According to an assessment by independent reviewers, tumors shrank in 56 percent of patients following treatment with afatinib, compared to 22.6 percent of patients in the chemo arm.

Between 30 percent and 40 percent of Asian adenocarcinoma patients and between 5 percent and 15 percent of Caucasian adenocarcinoma patients harbor EGFR mutations. Although this molecularly targeted population is small, the incidence of NSCLC is so high that many patients stand to potentially benefit from a personalized medicine treatment approach, Yang said during his presentation.

Throughout the world, there are approximately 1.6 million new cases of lung cancer each year, 85 percent of which are the non-small cell type. For the majority of lung cancer patients, their diagnosis comes too late for surgery to be an option. Chemotherapy regimens have shown to prolong survival for about one year. In the US, 15 percent of lung cancer patients survive for five years after diagnosis.

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AssureRx Health Launches Personalized Medicine Test for ADHD

Captured by PR Newswire 

AssureRx Health, Inc. announced it has launched a personalized medicine test for the growing number of children and adults diagnosed with attention deficit hyperactivity disorder (ADHD). The new pharmacogenomic test can assist clinicians with important medication decisions that result from genomic differences in how individual patients tolerate ADHD medications.

GeneSightRx ADHD analyzes variations in three genes that influence how a patient might metabolize certain medications used to treat ADHD in children and adults. Understanding a patient’s unique genomic profile may help a clinician individualize a patient’s medication selection and avoid side effects that often occur with these medications. The test provides objective, evidence-based information for clinicians to personalize medication selection for each patient.

The GeneSightRx ADHD analysis is based on pharmacogenomics, FDA-approved manufacturer’s drug labels, published peer reviewed research, and proven pharmacology. The new ADHD test adds to the company’s treatment decision support products that include GeneSightRx Psychotropic, a psychiatric pharmacogenomic product that tests important genomic variants affecting metabolism to psychiatric medications for individual patients.

ADHD diagnoses increased 66 percent from 6.2 million in 2000 to 10.4 million in 2010, according to a study published in the March/April 2012 issue of Academic Pediatrics. ADHD is the most common childhood disorder and can continue into adulthood. Symptoms of ADHD include an inability to stay focused or pay attention, difficulty controlling behavior, and hyperactivity.

“ADHD is a neurobehavioral disorder affecting millions of children and adults. With the introduction of GeneSightRx ADHD, clinicians now have an objective, evidence-based tool for individualizing ADHD medications,” said James S. Burns, president and CEO of AssureRx Health. “Our goal is to build a portfolio of innovative pharmacogenomic and other treatment decision support products to help physicians individualize the treatment of patients with neuropsychiatric and other disorders.”

When a clinician orders the test, a DNA sample is taken from the patient with a simple, non-invasive cheek swab. The specimen is sent overnight to AssureRx Health’s CLIA-certified and CAP-accredited laboratory. The ordering clinician receives the patient report via a secure online portal that presents the patient’s genomic information in an easy-to-read and clinically actionable format. Read more…

Panel to report on ethical issues regarding genome sequencing

Captured by Genetic Engineering & Biotechnology news

The U.S. Presidential Commission for the Study of Bioethical Issues is grappling with many of the ethical issues arising from the falling price—and resulting potential for increased use—of whole genome sequencing in clinical care. The aim is to find the balance between researchers’ use of such data and the privacy of individuals whose genomes are under study.

Addressing the committee on February 2, speakers offered varied perspectives on key questions: How is genetic information collected and stored? Who will interpret this genetic data? Is it ethical to allow healthcare providers to interpret the data without a health systems infrastructure to help them interpret it? What will be the privacy protections for patients?

The commission plans to discuss its recommendations publicly and come to consensus views at its August meeting. Recommendations are to be finalized in a report to President Barack Obama set to be completed this fall.

“The Norman Rockwell model or Marcus Welby model that your doctor knows and remembers everything and can do it all right is hopelessly inadequate for this era of data-intensive healthcare,” said Daniel R. Masys, M.D., affiliate professor of biomedical and health informatics at the University of Washington School of Medicine. “Our ability to acquire person-specific DNA data far exceeds our understanding of this information.”

“Is it even ethical to allow our healthcare system to practice without a systems infrastructure for decisions support?” Dr. Masys asked. “Is it ethical to discard person-specific DNA data with data of unknown significance? And lastly, how does genomic consent differ from standard consent? How does consent change when person lacks genetic health literacy, when a health condition does not yet exist but is a future probability?”

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OSU Wins NIH Funds for Statin-focused PGx Study

Captured by a GenomeWeb staff reporter

Scientists at The Ohio State University Medical Center will use a $1 million grant from the National Institutes of Health to uncover various genetic factors involved in patients’ responses to statin medications, the widely-used drugs that are used to lower cholesterol and prevent heart attack and stroke.

Statins are the most commonly prescribed medication class in the US for lowering cholesterol, but they do not benefit some patients, while others experience adverse reactions, such as headaches, sleep problems, and muscle and liver problems.

“Our primary goal is to develop pharmacogenomic patient-selection strategies for improving statin efficacy and cost-effectiveness, and for reducing the incidence of associated adverse effects,” investigator Joseph Kitzmiller, a research assistant professor of pharmacology and biomedical engineering at OSU, said in a statement.

Kitzmiller plans to use the funding to become an independent investigator focusing on using pharmacogenomics in personalized medicine applications. Specifically, he wants to develop multi-gene models for use in patient-selection strategies for improving the efficacy and cost-effectiveness of statins and to reduce the incidence of adverse effects.

Kitzmiller will partner with fellow OSUMC researchers Wolfgang Sadee, director of the Program in Pharmacogenomics, and Rebecca Jackson, director of the Center for Clinical and Translational Sciences, and he will combine resources with the Pharmacogenomics Research Network and the Clinical and Translational Science Consortium.

The five-year grant from the National Institute of General Medical Sciences was awarded under the Translational Scholar Career Award in Pharmacogenomics and Personalized Medicine program.

Coverage Policy for Genetic Tests Should Reflect Clinical Utility

Captured by Managed Healthcare Executive magazine
December issue

Medical science has progressed exponentially in recent years, but the challenge for insurers continues to be determining coverage policies. Clay Marsh, MD, executive director of the Center for Personalized Health Care at The Ohio State University, says some forms of genetic tests are more commonly accepted than others such as the test that looks for BRCA1 or BRCA2 genes in women who have breast cancer. Marsh says some of the earliest research in genetic testing has been done in the area of pharmacogenomics to identify how patients with certain genetic profiles will respond to a drug.
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Recent Developments in Pharmacogenomics

Lawrence Lesko

Lawrence Lesko, a 20-year veteran of the U.S. Food and Drug Administration who is now with the University of Florida, offered a summary of some issues scientists encounter during the drug review and approval process at the FDA.

“A lot of us were concerned about safety,” he noted, and those concerns were driven by the burden of adverse events, which cause patients harm and drive up costs. Of 21 older drugs withdrawn from the market recently, several had a genetic component. Had researchers known that at the time of their approval, he said, there might have been a different outcome related to adverse events associated with those drugs.

In the case of a drug that treats a condition associated with Huntington’s disease, FDA scientists conducted dose response studies and a drug interaction study, performed simulations, and determined proper dosing – all of which influenced how the drug was labeled. That process became a blueprint for the next drug to come along in the approval process.

“We developed a pattern of using models and simulation rather than clinical trials to update drugs when it comes to safety events,” Lesko said.

In a breakdown of new biologics in the pharma pipeline, 40 percent are addressing indications for cancer and metastases. A large percentage of drugs are also in development for infectious diseases and autoimmune disorders. Fifty percent of the drugs are related to conditions for which a biomarker is identified in the causal pathway, which could lead to even more targeted therapies.

And of 21 drugs approved in a six-month period in 2010, none was a targeted therapy, but almost half of the diseases being addressed and one-fourth of the drugs had a genetic component – meaning “there’s a lot of opportunity for targeted therapies,” Lesko said.

Targeted therapy development could become a little easier under a recent FDA reorganization – a new report issued by the agency noted that the FDA plans to build out infrastructure to drive and support personalized medicine, enable a rapid development pathway for target therapies, and improve consistency and clarity in the device review process.

Advances in the Prevention and Treatment of Chronic Disease

Three clinician-researchers described their work in using individual patient information to guide the treatment of disease.

End-stage kidney disease

A golden age of anemia treatment in end-stage renal disease once existed, launched with a drug became commercially available in 1989. The drug, recombinant erythropoietin, or EPO, prevented iron overload in patients who received blood transfusions, replacing those treatments with an IV injection during dialysis. Quality of life appeared to be dramatically improved.

That golden age ended, however, with the discovery that EPO was associated with an increased risk for cardiovascular events, said Jon Klein, professor of medicine and holder of the Endowed Chair in Proteomics at the University of Louisville. Eventually, the drug was subject to a black-box warning from the FDA and a CMS mandate to use the lowest dose needed to prevent the need for a transfusion.

“Clinicians didn’t know what to do with this,” Klein said. Should they lower the dose dramatically, or consider stop giving the drug altogether? Klein and colleagues sought to provide optimal dosing information via the analysis of proteins that influence patient sensitivity to the drug.

Using a series of extractions of plasma, the researchers tracked several pools of information from fragments of proteins, intact proteins, proteins bound together and microparticles. Two proteins emerged as biomarkers of sensitivity to the drug.

Applying computational intelligence, the researchers developed an algorithm-driven dose optimizer that guided clinicians in the continued use of EPO. The model-guided treatments helped patients reach their target hemoglobin levels within 20 weeks, compared with 50 weeks using a more traditional trial-and-error clinical approach.

Heart failure

A key to keeping heart failure patients out of the hospital is regulating their intra-cardiac and pulmonary artery pressure. When it’s too high, they are at risk for arrhythmia. When it’s too low, they might pass out. Getting it right can dramatically reduce hospitalization and improve patients’ quality of life.

“If we wait until patients are symptomatic or their weight increases, the window of opportunity to intervene relatively short,” said William Abraham, chief of the division of cardiovascular medicine at Ohio State University Medical Center. “So if we can only measure the right signal and respond to it in a proactive way, we might be able to reduce hospitalizations and improve patients’ quality of life or well-being.”

Abraham has been an investigator on trials testing the safety and effectiveness of implantable devices that monitor pulmonary artery pressure. They have no batteries or moving parts, and are delivered by catheterization. Trials have tested a variety of methods of monitoring, and a clear message has emerged. When patients are guided to monitor their pressure, report the levels to a clinician and titrate their medications accordingly, hospitalizations are reduced and their quality of life improves.

“This is an example of how we are exploiting knowledge of individual patients’ physiology to develop new approaches to heart failure management,” he said.

LDL cholesterol response to statins

It is known that how patients will respond to statin therapy to lower their bad cholesterol is a strong predictor of their reduced risk for cardiovascular problems. But do genes drive that response? Researchers are trying to find out how influential genes might be, said Daniel Chasman, director of computational biology at Brigham and Women’s Hospital and Harvard Medical School.

Candidate genes identified in the past were tied to a number of effects: They might affect uptake of the drug, inhibit production of cholesterol, stop its transport or degrade it altogether.

Chasman and colleagues ran an enormous genome-wide analysis of almost 7,000 patients for whom statin treatment had been highly effective. The analysis produced 820,000 single nucleotide polymorphisms, or SNPs (pronounced snip). Each gene contains two alternative forms – called alleles  – that are identical in most people. However, when the activity level, or expression, of one allele differs from its partner allele in a single gene, that small difference is called a SNP. The SNP affects a gene’s protein-producing process.

The researchers found a total of three SNPs associated with the lowering of LDL cholesterol in the population studied. A placebo group showed no such associations. It remains unclear just how powerful these genetic variants are in influencing a patient’s response to statins, but the more that is known, the closer clinicians will come to prescribing the right dose or the right medication for the right patient on a routine basis.

Virtual Health Clinics and Pharmacogenomics Focus on Wellness

Amy Sturm

Post by Amy Sturm, Human Genetics, The Ohio State University’s Center for Personalized Health Care

Ohio State Medical Center genetic counselors Amy Sturm and Kevin Sweet and medical geneticist Kandamurugu Manickam, MD, along with Center for Personalized Health Care(CPHC) staff members, are currently working on the development of a new Virtual Genomics Clinic, which will offer genomic counseling through telemedicine vehicles. This genomic counseling service will focus on wellness and keeping healthy individuals from developing disease.  The virtual clinic will also provide genetic counseling services for a wide array of single-gene disorders and common, complex diseases.  This comprehensive risk assessment will include medical history, family history, behavioral and environmental risk factor analyses, as well as genetic testing services when applicable.  Those individuals interested in participating may also pursue different types of genomic testing services.

Pharmacogenomics (PGx)

An especially important area of P4 Medicine is pharmacogenomics, or the study of genetic variants that influence a person’s response to certain drugs. The metabolism of many different drugs is influenced by one’s genetic background. Among the most common are the Cytochrome P450 (CYP) genes, which encode enzymes that control the metabolism of more than 70 percent of prescription drugs.   People who carry variations in certain CYP genes often do not metabolize drugs normally, and this can influence response in many ways.  Knowing whether a person carries any of these genetic variations can help the healthcare team individualize drug therapy, decrease the number of adverse drug reactions, and increase the effectiveness of drugs.

Members of CPHC are collaborating on a new project with Wolfgang Sadee, PhD, chair of pharmacology at Ohio State, and Peter Embi, MD, MA, associate professor of biomedical informatics at Ohio State, to facilitate the use of genetic variant analysis to determine a patient’s response to certain prescription drugs, and to have this information available in the Ohio State Medical Center electronic medical record (IHIS). The initial focus will target a genetic variant known as CYP2C19 that influences how patients respond to the drug clopidogrel (Plavix). Plavix is a platelet inhibitor used in the treatment and prevention of a number of cardiovascular diseases.  Plavix must be metabolized into its active form by the cytochrome P450 enzyme, CYP2C19, and certain genetic variants can alter a patients’ response.  Some people are slow metabolizers, leading to an increased risk for heart attack.  Having this test available, and the use of advisory flags in IHIS to readily alert the healthcare team for when the drug is prescribed will lead to more effective treatments and safer applications.

Medical geneticist Kandamurugu Manickam, MD and genetic counselors Kevin Sweet and Amy Sturm are leading the clinical implementation of pharmacogenomics at Ohio State.

The Ghost of Personalized Medicine

Captured by The Scientist

The US Food and Drug Administration recommends that doctors genotype patients before prescribing more than 70 commonly-used medications for specific genetic biomarkers. These tests, the agency suggests, can help physicians identify those in which the drug is less efficacious, poorly metabolized, or dangerous. But medicine is still far from a day when drugs and treatment regimes are fitted precisely to a patient’s genomic profile.

According to a 2008 survey conducted by the American Medical Association (AMA) and Medco Research Institute, even though 98 percent of physicians agreed that the genetic profiles of their patients may influence drug therapy, only 10 percent believed they were adequately informed about how to test their patients for biomarkers that may predict the safety and/or efficacy of a particular drug.

“Less than 1 percent of all opportunities are being realized with respect to genetic testing,” said Felix Frueh, president and head of genomics initiatives at Medco. “There’s a long way until this new technology is going to see the translation.”

Indeed, while new biomarkers are identified everyday, and researchers are continuing to collect more and more information about genetic variants that confer some amount of disease risk or predict a specific response to a treatment, that information has yet to be widely implemented in the clinic. The AMA states on its website that physicians today can use more than 1,200 genetic tests for more than 1,000 different diseases to help diagnose and treat their patients, but only 13 percent of the 10,000 doctors who responded to the survey had ordered a genetic test for a patient in the preceding 6 months.

But while physicians by and large have been slow to adopt the practice of screening patients to search for genetic information of relevance to drug treatments, known as pharmacogenomics, neither research nor regulation has stalled, as evidenced by the FDA’s relabeling of dozens of approved drugs with biomarkers that affect their safety or efficacy in specific patient populations. “Pharmacogenomics is probably an area where personalized medicine is really able to deliver,” Frueh said, “and it is able to do so because those are tests that can be clearly associated with a particular therapy.” Read more…

OSU Medical School Adds Personalized Medicine Curriculum with P4 Program for New Doctors

Captured by GenomeWeb (PGx Reporter)

Twenty students from the Ohio State University College of Medicine’s class of 2014 are spending the summer in a pilot program with an emphasis on genomics as well as lower-tech methods to individualize care.

Led by Kandamurugu Manickam, a geneticist at OSU’s Center for Personalized Health Care, the inaugural class takes place this summer as a pilot project to determine how to integrate P4 — short for predictive, preventive, personalized, and participatory medicine — material into the medical school’s new curriculum beginning in 2012.

Manickam told PGx Reporter this week that many universities are interested in adding programs in personalized medicine, but that OSU’s P4 approach sets the program apart. “Places have talked about doing [this], but [they have placed] most of the emphasis on genetics, which is why we are really unique, in looking at all these factors,” he said.

P4 medicine is the brainchild of Leroy Hood, president of the Institute for Systems Biology, which partnered with OSU in 2009 to form the P4 Medical Institute (PGx Reporter 10/7/2009). The program’s goal is to transform healthcare “from a reactive system to one that predicts and prevents disease, and tailors diagnosis and therapy to the individual consumer.”

P4 encapsulates a broad approach that includes an emphasis on low-tech and low-cost preventative measures in addition to ‘omics based personalization, according to Manickam. ” I’m a geneticist, but one of the things we’ve kind of recognized is that genetics is expensive to do, but there are less expensive ways to get good outcomes,” he said. However, genomics is still a large part of P4, he explained, and will become more and more so, as pharmacogenomics and genetic testing develop further.

OSU plans to explore P4 through a variety of clinical programs and the pilot course is a separate push by the university to integrate P4 principles into its educational programs. “We’ve been trying a lot of clinical ideas at Ohio State in this area,” Manickam said. “But we wanted to [provide] a little more education [on the P4 paradigm] for medical students.” Read more…