Charles Perry, MBA, MD Joins Target Health as Medical Director
Target Health Inc. is pleased to announce that Charles Perry, MD, MBA, has joined the company as Medical Director. Dr. Perry holds an MD degree from Columbia University School of Medicine and is board certified in internal medicine. He also received an MBA at Columbia and a BS from Duke. Prior to joining Target Health, Dr. Perry spent 2 years at Pfizer where he led cross-functional teams of clinical, regulatory, and commercial experts in analysis and financial modeling of business development efforts, and supported licensing and acquisition due diligence.
Dr. Perry will work closely with Glen Park, PharmD in Clinical Research, Dean Gittleman in Operations, Yong Jong Kim in IT, and with Jules Mitchel, MBA, PhD as part of the Executive Management Team.
Over 15% of our employees are now from Pfizer/Wyeth:
1. Dean Gittleman, MS
2. Ron Harris, RN
3. Mark Horn, MD
4. Judith Schloss Markowitz, MS
5. Jules Mitchel, MBA, PhD
6. Warren Pearlson, RPh
7. Charles Perry, MD
8. Louella White, MS
For more information about Target Health contact Warren Pearlson (212-681-2100 ext. 104). For additional information about software tools for paperless clinical trials, please also feel free to contact Dr. Jules T. Mitchel or Ms. Joyce Hays. The Target Health software tools are designed to partner with both CROs and Sponsors. Please visit the Target Health Website
Marfan Syndrome – Learning to Defuse the Aorta
Dr. Hal Dietz, who found that the blood-pressure drug losartan eased Marfan symptoms
When Dr. Hal Dietz arrived at Johns Hopkins University in the 1980s, he became obsessed with helping children with Marfan syndrome, a rare and often 1) ___ disorder that can cause the aorta, the large blood vessel that carries blood from the heart, to grow and grow until it bursts. These doomed children had a distinctive look that clearly had a genetic basis. They were typically very tall and thin, with long arms, legs and fingers. They often had unusually flexible joints, flat feet and teeth that were crowded in their 2) ___. I decided to study genetics with the sole incentive to identify the 3) ___ for Marfan syndrome and ultimately to understand the mechanism, said Dr. Dietz, now director of the William S. Smilow Center for Marfan Syndrome Research at Johns Hopkins. That journey has led to surprising discoveries about Marfan’s causes and a soon-to-be published clinical trial of a drug that may help its sufferers.
Dr. Dietz’s work also inspired research that may lead to a blood test that detects enlarged aortas, potentially saving thousands of lives, even among those who do not have 4) ___ syndrome. Every year about 10,000 Americans die from ruptured aortas; two victims were the actor John Ritter and the diplomat Richard C. Holbrooke. The hope is that such a test will allow doctors to operate before the aorta bursts, or to quickly identify aortas that have ruptured so 5) ___ can be performed without delay.
Patients whose aortas are breaking apart all need immediate treatment, said Dr. Scott A. LeMaire, a professor of surgery and of molecular physiology and biophysics at the Baylor College of Medicine. The longer you delay the diagnosis, the greater the chance their aorta will 6) ___ while you are trying to figure out what is going on.
For families who have recently learned that a child has Marfan syndrome, Dr. Dietz’s discoveries and the clinical trial he designed have divided their world into before and after, dread and hope. Daniel Speck of Knoxville, Md., was given a diagnosis of Marfan six years ago, when he was 8, after his pediatrician noticed his 7) ___ was curved and suggested a test for scoliosis. It turned out that the curvature was caused by Marfan syndrome. By then, Dr. Dietz and his colleagues had finally found the gene mutation that causes Marfan. It had been a slow and frustrating process: The sequencing machines now used to quickly map DNA had not been invented. Researchers had to sort through every gene in large regions of 8) ___ shared by members of families in which someone had the syndrome. Yet when the researchers first found the mutation, in 1990, it seemed to lead to a dead end. The mutation was in fibrillin-1, a protein in connective tissue, suggesting that the tissue was falling apart because its molecular rivets did not work. And if that was true, Dr. Dietz said, there was nothing you could do to alter the course of the disease. Or as Dr. David Altshuler of the Broad Institute of Harvard and M.I.T., who was not part of the research team, put it, How can we fix the rivets when every rivet in the 9) ___ is broken? Those were the dark days of Marfan research, Dr. Dietz said. But then he began to question the rivet hypothesis. It did not explain some of Marfan’s most notable features: the strikingly long bones of the children’s arms, legs and fingers, their deeply set eyes that slanted downward, their flat cheekbones, small chins, extremely low muscle mass and small amount of body10) ___.
About 10 years ago, he and his colleagues discovered the answer in another protein, T.G.F.-beta, short for transforming growth factor beta, which tells cells how to behave during development and is used in repairing wounds. The protein’s function depends on fibrillin-1, the very protein that is altered in Marfan syndrome. Normally, fibrillin-1 hooks T.G.F.-beta to connective tissue. But in someone with Marfan, the researchers discovered, the fibrillin-1 is defective, and the process goes awry. Instead of attaching to the connective tissue, T.G.F.-beta drifts away from it. Floating free in the bloodstream, it makes cells behave abnormally, leading to many of the problems caused by Marfan, including excessive growth of the aorta. In short, the rivet model was entirely wrong. That, Dr. Dietz said, was one of the few ?aha’ moments in my life. He tested his theory in mice, giving them the mutated fibrillin-1 gene. Sure enough, levels of the T.G.F. 11) ___ were very high. The mice showed Marfan symptoms, including emphysema, weak skeletal muscles and a thickening of the mitral valve in the heart. He then sought a way to block the function of T.G.F.-beta and found a widely used blood pressure drug, losartan, that did just that. In the mice, the drug prevented features of the syndrome, including ballooning of the aorta. Instead of dying of aortic aneurysms by three months of age, the mice lived a normal life span of two years.
In 2006, the National Heart, Lung, and Blood Institute started a randomized trial based on Dr. Dietz’s work in which some children with Marfan got the drug and others got the standard treatment, with a beta blocker that slows the 12) ___ rate. But Dr. Dietz worried about the children who were most severely affected. Most died in the first few years of life. By the time he finished the clinical trial, they would be dead. They had an unrelenting growth of the aorta, he said. If the drug worked, it could save their lives immediately. I felt compelled to treat them. One morning in 2006, Kari Dostalik of Urbandale, Iowa, whose daughter, Haley, has the disorder, went to a lecture by Dr. Dietz at the annual Marfan syndrome conference. He showed a slide of a boy who had a severe form of Marfan and had been given losartan outside the clinical trial. Ms. Dostalik had met the child and his family at a previous conference. Before treatment, the boy looked weak and tired. But after having taken the drug, she said, he was grinning ear to ear. Even better, Dr. Dietz told the group, as soon as the boy and other children took the drug, their aortas stopped growing. And losartan appeared to reverse some of the disease’s effects. When we heard the word ?reversed,’ Ms. Dostalik said, our first gut reaction was, ?How soon can we get Haley enrolled?’ The study was just beginning, and children would be in it for three years. Neither the families nor the doctors would know which drug they were taking, losartan or the beta blocker. As tempting as it was to just give Haley losartan, Ms. Dostalik said, she and her husband worried about possible side effects, and they wanted to help science find an answer. This was our chance to help the Marfan community, she said. Two years later, Dr. Dietz and his colleagues published data in The New England Journal of Medicine on 17 severely affected children who were given the drug outside the clinical trial. Before they took it, their 13) ___ were growing about three and a half millimeters a year; afterward, the rate slowed to half a millimeter a year.
Some researchers worried that publishing the data might doom efforts to persuade parents to enroll children in the trial when they could get a drug like losartan on their own. But over the next three years, 604 families joined the study, with results expected in the coming months. The Specks enrolled Daniel, and suspect he got 14) ___. His mother said the family saw wonderful changes – everything started to stabilize. Daniel’s aorta had been growing astronomically, she said, and that growth slowed so much that he would not qualify if he tried to enter the trial today. He also developed better muscle tone and more body fat.
When his time in the trial ended, the Specks were told Daniel could take losartan or the older drug, whichever they preferred. Ms. Speck did not want to take any chances. They chose both. Daniel, now 15, continues to do well.
The Marfan discoveries are starting to affect a bigger group – those without Marfan but whose aortas have bulged and torn, a life-threatening emergency. Symptoms of a torn aorta can vary enormously, depending on which of the arteries branching from it are disrupted. The aorta begins at the heart and runs all the way down to the abdomen, feeding blood to more than a dozen major arteries. If a tear interferes with branches that deliver blood to the heart, it can look like a heart attack. If it interferes with branches that deliver blood to the brain, it can look like a 15) ___. People come in with this life-threatening condition and are either misdiagnosed or there is a long delay in diagnosis, Dr. LeMaire said. Once the vessel ruptures, the operation to fix it is risky. Patients have to be put on a heart-lung machine, and their torn aortas repaired with a piece of synthetic fabric. The stretched and torn aorta has become something akin to tissue paper. Even the most experienced surgical teams lose as many as a quarter of their patients. But it appears that these patients may have the same telltale molecular signals as Marfan patients. When an aorta ruptures, it releases high levels of the Marfan protein, fibrillin-1, into the blood. That led Lynn Sakai, a biochemist at the Shriners Research Centerin Portland, Ore., to suggest using fibrillin-1 levels as a blood test for aortic ruptures. She, Dr. LeMaire and their colleagues studied blood and tissue samples, stored at the Baylor College of Medicine, that belonged to patients with ballooning or ruptured aortas. In a recent paper, they reported that fibrillin-1 levels in the blood of patients with bulging aortas were two and a half times higher than in those who did not have enlarged aortas. And high fibrillin-1 levels were three times as common in those with tears in their aortas as in those whose aortas were bulging but not torn. Dr. LeMaire and his colleagues say they need to validate their results with blood tests from many more emergency room patients. They hope that such tests can be used to predict who is at risk for an aortic aneurysm or needs emergency surgery. We’d like to round up all the people who come to an emergency room with some symptom of chest pain, Dr. Sakai said, people like John Ritter, who died because the emergency room guy did not recognize that he was having an aortic dissection. Steve Marpman, of Queens, 42, director of social work for a managed care company, could have used a blood test when he went to an emergency room and almost died of an aortic aneurysm. He was training to be a policeman and passed several physical exams without trouble. Then one day he was dizzy and had a hollow feeling in his chest. His vision blurred. His speech became incoherent. By the time he got to an emergency room, he was near death – vomiting blood, going in and out of consciousness, with a weak pulse and rapid heartbeat. A cardiology intern came in, looked at Mr. Marpman’s long legs and fingers, and said, Marfan. Mr. Marpman had never heard of the syndrome.
An adult aorta is normally three to four centimeters, or 1.2 to 1.6 inches, in diameter. When it reaches five centimeters, doctors often suggest elective surgery. Mr. Marpman’s aorta was 10 centimeters wide, and had split open. His heart was spilling 16) ___ into his abdominal cavity and lungs. He had emergency surgery and awoke from the 12-hour operation intubated and strapped to a bed.
Losartan, the blood pressure drug, has not been tested on adults with Marfan, but Mr. Marpman has begun taking it. His baby boy inherited the Marfan gene. And if the clinical trial turns out to prevent excessive growth of the aorta, son will join father in taking the drug. Sources: The New York Times (By Gina Kolate, Published: December 2, 2013), Johns Hopkins Medical School, Wikipedia
Click on this link, to hear a presentation by Dr. Hal Dietz
Dr. Hal Dietz, Victor A. McKusick Professor of Institute of Genetic Medicine and Professor of Pediatrics and Investigator of Howard Hughes Medical Institute at The Johns Hopkins Hospital and Chair of the Loeys-Dietz Syndrome Foundation Medical Advisory Council (MAC), presents Research Update on Loeys-Dietz Syndrome at the 2012 LDSF Conference in Baltimore, Maryland, USA. Dr. Dietz discusses the latest on LDS mice model research findings.
ANSWERS: 1) fatal; 2) mouth; 3) gene; 4) Marfan; 5) surgery; 6) rupture; 7) spine; 8) DNA; 9) body; 10) fat;; 11) protein; 12) heart; 13) aortas; 14) losartan; 15) stroke; 16) blood
Marfan and Loeys-Dietz Syndromes – Antoine Marfan MD, Harry (Hal) C. Dietz MD, Bart Leo Loeys MD, PhD
Antoine Marfan; portrait by Henry Bataille
Antoine Bernard-Jean Marfan (June 23, 1858 – February 11, 1942) was a French pediatrician. He was born in Castelnaudary (d?partement Aude, Languedoc-Roussillon) to Antoine Prosper Marfan and Adelaide Thuries. He began his medical studies in Toulouse, where he stayed for two years before moving to Paris. He graduated in 1886, his education having been interrupted by a period of military service. In 1914 he became a professor of infantile hygiene in the pediatric clinic of the University of Paris. During the same year, he became a member of the Acad?mie de M?decine.
In 1896, Marfan described a hereditary disorder of connective tissue which became known as Marfan syndrome. The term Marfan’s syndrome was first used by Henricus Jacobus Marie Weve (1888-1962) of Utrecht in 1931. Today, it is thought that Marfan’s patient (a five year old girl named Gabrielle) was affected by a condition known as congenital contractural arachnodactyly (Beals syndrome), and not Marfan’s syndrome.
Further eponymous medical conditions named after Antoine Marfan include:
1. Dennie-Marfan syndrome
2. Marfan’s hypermobility syndrome
3. Marfan’s law
4. Marfan’s sign
5. Marfan’s symptom
6. Marfan-Madelung syndrome
Marfan also had interests in the pediatric aspects of tuberculosis, nutrition and diphtheria. With Jacques-Joseph Grancher (1843-1907) and Jules Comby (1853-1947), he was co-publisher of Trait? des maladies de l’enfance. From 1913 to 1922, he was publisher of the journal Le Nourrisson.
Harry (Hal) C. Dietz MD
Loeys-Dietz syndrome is a recently discovered autosomal dominant genetic syndrome which has many features similar to Marfan syndrome, but which is caused by mutations in the genes encoding transforming growth factor beta receptor 1 (TGFBR1) or 2 (TGFBR2). It was identified and characterized by American physician Harry C. Dietz and Belgian physician Bart L. Loeys, for whom it is named. There are currently two forms of Loeys-Dietz syndrome which are further subdivided into another two forms.
A de novo mutation in TGFB3, a ligand of the TGF beta pathway, was identified in an individual with a syndrome presenting partially overlapping symptoms with Marfan Syndrome and Loeys-Dietz Syndrome.
The main clinical characteristics include:
1. Widely spaced eyes (orbital hypertelorism)
2. Cleft palate orbifid uvula(a split in the tissue that hangs down in the back of the throat)
3. Aortic and arterial aneurysms/dissections with tortuosity (corkscrew structure) of the arteries.
Other findings can include:
1. Scoliosis or Kyphosis
2. Indented or protruding chest wall (pectus excavatum or pectus carinatum)
3. Contractures of fingers and toes (camptodactyly)
4. Long fingers and lax joints
5. Club foot
6. Premature fusion of the skull bones (craniosynostosis)
7. Joint hypermobility
8. Congenital heart problems including patent ductus arteriosus (connection between the aorta and the lung circulation) and atrial septal defect (connection between heart chambers)
9. Translucency of the skin with velvety texture
10. Abnormal junction of the brain and medulla (Arnold-Chiari malformation)
11. Bicuspid aortic valves
Many of the physical findings typical in Loeys-Dietz syndrome are also found in Marfan syndrome cases, including increased risk of ascending aortic aneurysm and aortic dissection, abnormally long limbs and fingers, and dural ectasia (a gradual stretching and weakening of the dura mater that can cause abdominal and leg pain). However, it also has some additional traits not typical of Marfan patients, including widely spaced eyes, a split uvula in the back of the throat, and skin findings such as easy bruising or abnormal scars.
As there is no known cure, Loeys-Dietz syndrome is a lifelong condition. Due to the high risk of death from aortic aneurysm rupture, patients should be followed closely to monitor aneurysm formation, which can then be corrected with vascular surgery. Previous research in laboratory mice has suggested that the angiotensin II receptor antagonist losartan, which appears to block TGF-beta activity, can slow or halt the formation of aortic aneurysms in Marfan syndrome. A large clinical trial sponsored by the NIH is currently underway to explore the use of losartan to prevent aneurysms in Marfan syndrome patients. Both Marfan syndrome and Loeys-Dietz syndrome are associated with increased TGF-beta signaling in the vessel wall.
Bart Loeys is a Professor in the Institute of Genetic Medicine and at the University of Ghent in Belgium. He was intimately involved in the recognition and characterization of the Loeys-Dietz syndrome. He continues to work on the genetic basis of aortic aneurysm conditions.
Risk Stratification at Diagnosis for Children with Hypertrophic Cardiomyopathy
Hypertrophic cardiomyopathy (HCM) is a condition in which the heart muscle becomes thick. Often, only one part of the heart is thicker than the other parts. The thickening can make it harder for blood to leave the heart, forcing the heart to work harder to pump blood.
According to an article published in The Lancet (2013;382:1889-1897), treatment of children with hypertrophic cardiomyopathy might be improved if the risk of death or heart transplantation could be predicted by risk factors present at the time of diagnosis.
The study analyzed data from the Pediatric Cardiomyopathy Registry, which collected longitudinal data for 1085 children with HCM from 1990 to 2009. The goal of the study was to understand how patient factors measured at diagnosis predicted the subsequent risk of the primary outcome of death or heart transplantation. The Kaplan-Meier method was used to calculate time-to-event rates from time of diagnosis to the earlier of heart transplantation or death for children in each subgroup. Cox proportional-hazards regression was used to identify univariable and multivariable predictors of death or heart transplantation within each causal subgroup.
Results showed that at 2 years, the poorest outcomes were recorded for the 69 children with pure HCM with inborn errors of metabolism, for whom the estimated rate of death or heart transplantation was 57%. Children with mixed functional phenotypes also did poorly, with rates of death or heart transplantation of 45% for the 69 children with mixed hypertrophic and dilated cardiomyopathy and 38% for the 58 children with mixed hypertrophic and restrictive cardiomyopathy. For children diagnosed with hypertrophic cardiomyopathy at younger than 1 year, the rate of death or transplantation was 21%. For children diagnosed with HCM and a malformation syndrome, the rate of death or transplantation was 23%. Excellent outcomes were reported for the 407 children who were diagnosed with idiopathic HCM at age 1 year or older, with a rate of death or heart transplantation of 3%. The risk factors for poor outcomes varied according to HCM subgroup, but they generally included young age, low weight, presence of congestive heart failure, lower left ventricular fractional shortening, or higher left ventricular end-diastolic posterior wall thickness or end-diastolic ventricular septal thickness at the time of cardiomyopathy diagnosis. For all HCM subgroups, the risk of death or heart transplantation was significantly increased when two or more risk factors were present and also as the number of risk factors increased.
According to the authors, in children with HCM, the risk of death or heart transplantation was greatest for those who presented as infants or with inborn errors of metabolism or with mixed hypertrophic and dilated or restrictive cardiomyopathy. Risk stratification by subgroup of cardiomyopathy, by characteristics such as low weight, congestive heart failure, or abnormal echocardiographic findings, and by the presence of multiple risk factors allows for more informed clinical decision making and prognosis at the time of diagnosis.
Overweight Adolescents and Life Events in Childhood
According to an article published in Pediatrics (2013;132:1506-1512), a study was performed to 1) test the association of life events in childhood with overweight risk in adolescence; 2) examine the effects of chronicity, timing, intensity, valence, and type of life events; and 3) test potential moderators.
For the study, mothers of children enrolled in the Eunice Kennedy Shriver National Institute of Child Health and Human Development Study of Early Child Care and Youth Development responded to the Life Experiences Survey at ages 4, 9, and 11 years. Using logistic regression analysis, the authors tested the association of experiencing many negative life events with being overweight at age 15 years, controlling for child gender, race/ethnicity, maternal education, and maternal obesity. Child gender, maternal education, maternal obesity, child’s ability to delay gratification for food, and maternal sensitivity were tested as moderators.
Results showed that among the 848 study children (82% non-Hispanic white), experiencing many negative life events was associated with a higher risk of overweight (odds ratio: 1.47). Greater chronicity and negative valence of the event were associated with greater overweight risk; timing of exposure and maternal reported impact of the event were not. The association was more robust for events related to family physical or mental health and among children of obese mothers and children who waited longer for food.
According to the authors, children who experience many negative life events are at higher risk of being overweight by age 15 years. The authors added that future work should investigate mechanisms involved in this association, particularly those connected to appetitive drive and self-regulation, and that these mechanisms may hold promise for obesity prevention strategies.
TARGET HEALTH excels in Regulatory Affairs. Each week we highlight new information in this challenging area.
FDA Approves Sovaldi for Chronic Hepatitis C
Hepatitis C is a viral disease that causes inflammation of the liver that can lead to diminished liver function or liver failure. Most people infected with HCV have no symptoms of the disease until liver damage becomes apparent, which may take several years. Some people with chronic HCV infection develop scarring and poor liver function (cirrhosis) over many years, which can lead to complications such as bleeding, jaundice (yellowish eyes or skin), fluid accumulation in the abdomen, infections or liver cancer. According to the Centers for Disease Control and Prevention, about 3.2 million Americans are infected with HCV.
The FDA has approved Sovaldi (sofosbuvir) to treat chronic hepatitis C virus (HCV) infection. Sovaldi is the first drug that has demonstrated safety and efficacy to treat certain types of HCV infection without the need for co-administration of interferon. Sovaldi is a nucleotide analog inhibitor that blocks a specific protein needed by the hepatitis C virus to replicate. Sovaldi is to be used as a component of a combination antiviral treatment regimen for chronic HCV infection. There are several different types of HCV infection. Depending on the type of HCV infection a patient has, the treatment regimen could include Sovaldi and ribavirin or Sovaldi, ribavirin and peginterferon-alfa. Ribavirin and peginterferon-alfa are two drugs also used to treat HCV infection.
Sovaldi’s effectiveness was evaluated in six clinical trials consisting of 1,947 participants who had not previously received treatment for their disease (treatment-naive) or had not responded to previous treatment (treatment-experienced), including participants co-infected with HCV and HIV. The trials were designed to measure whether the hepatitis C virus was no longer detected in the blood at least 12 weeks after finishing treatment (sustained virologic response), suggesting a participant’s HCV infection has been cured.
Results from all clinical trials showed a treatment regimen containing Sovaldi was effective in treating multiple types of the hepatitis C virus. Additionally, Sovaldi demonstrated efficacy in participants who could not tolerate or take an interferon-based treatment regimen and in participants with liver cancer awaiting liver transplantation, addressing unmet medical needs in these populations.
The most common side effects reported in clinical study participants treated with Sovaldi and ribavirin were fatigue and headache. In participants treated with Sovaldi, ribavirin and peginterferon-alfa, the most common side effects reported were fatigue, headache, nausea, insomnia and anemia.
Sovaldi is the third drug with breakthrough therapy designation to receive FDA approval. The FDA can designate a drug as a breakthrough therapy at the request of the sponsor if preliminary clinical evidence indicates the drug may demonstrate a substantial improvement over available therapies for patients with serious or life-threatening diseases. Sovaldi was reviewed under the FDA’s priority review program, which provides for an expedited review of drugs that treat serious conditions and, if approved, would provide significant improvement in safety or effectiveness.
Sovaldi is the second drug approved by the FDA in the past two weeks to treat chronic HCV infection. On November 22, the FDA approved Olysio (simeprevir).
Sovaldi is marketed by Gilead, based in Foster City, Calif. Olysio is marketed by Raritan, N.J.-based Janssen Pharmaceuticals.