Paperless Clinical Trials at Target Health Inc.

Target Health Inc. is pleased to announce that it has completed all the programming and testing of its new Clinical Trial Management software, Target e*CTMSTM, and the software will be formally released this month. This web-based software allows for uploading and tracking of Essential Documents, tracking of all study startup tasks and identification of project milestones. Full reports allow individuals, departments and sponsors to know exactly what is due and when. Excel spread sheets are a thing of the past. The next version will be fully integrated with Target e*CRF® to allow for real-time patient information. Target e*CTMSTM now joins Target e*CRF® (v1.7), Target Document® (v1.4), Target ePharmacovigilanceTM (v1.0), Target Encoder® (v1.0), Target Newsletter® (v1.0) and Target TimeTM (v1.0). Target eClinical Trial Record (Target e*CTRTM is being released this Summer). We know that we have the best eClinical software suite in the industry as well as the most knowledgeable programmers.

For more information about Target Health and any of our software tools for paperless clinical trials, please contact Dr. Jules T. Mitchel (212-681-2100 ext 0) or Ms. Joyce Hays (212-876-5000). Target Health’s software tools are designed to partner with both CROs and Sponsors. Please visit the Target Health Website at www.targethealth.com

Oxygen Key to “Cut and Paste” of Genes

An oxygen-sensitive enzyme has been found to play a key role in how 1) ___ create the many different proteins that make up our bodies. The finding shows that the enzyme, termed Jmjd6, directly intervenes in the process in which the DNA of our genes is “cut and pasted” into instructions for the creation of specific 2) ___. The discovery, reported in this week’s Science by a team led by scientists from Oxford University and Ludwig-Maximilians-University, Munich, opens up a new area of molecular research into conditions such as heart disease and cancer. Previous work from Oxford has shown that some of these 3) ___, called oxygenases, affect which genes are expressed in response to low levels of oxygen. “What we have now found is that they also regulate the specific form this expression takes – to give the different proteins that make up everything from heart cells to tumors,” said Professor Chris Schofield of Oxford University’s Department of Chemistry, one of the authors. Genes, stored in the form of DNA, are converted into proteins by a “middleman molecule” called Messenger Ribonucleic Acid – or 4) ___. Individual genes can often give rise to many different proteins because of a process known as mRNA splicing which enables the cutting and pasting of the mRNA that is produced from 5) ___. The proteins that the new oxygenase, termed Jmjd6, act on, are involved in regulating the “cutting and pasting” process. Angelika B?ttger, who led the Munich group, said: “The discovery of a role for an oxygenase in mRNA splicing reveals that it is very likely that 6) ___ levels are involved in regulating almost all steps in the process of gene expression. The challenge now is to determine how the pattern of genes changes in different environments when oxygen is in short supply, enabling us to tackle important questions such as why do tumor 7) ___ respond differently to low oxygen levels than normal cells?” Science, July 3, 2009 , Source: University of Oxford

ANSWERS

1) genes; 2) proteins; 3) enzymes; 4) mRNA; 5) DNA; 6) oxygen; 7) cells

Artemisinin

The plant Artemisia annua, also known as sweet wormwood, has been used by Chinese herbalists for more than a thousand years in the treatment of many illnesses, such as skin diseases and malaria, but had fallen out of common use. The earliest records of use date back to 200 BCE, in the “Fifty two Prescriptions” unearthed from the Mawangdui Han Dynasty Tombs. Artemisinin’s antimalarial application was first described in Zhouhou Beji Fang (“The Handbook of Prescriptions for Emergencies”), edited in the middle of fourth century by Ge Hong. This pharmacopeia contained recipes for a tea from dried leaves, prescribed for fevers (not specifically malaria). Currently, Artemisinin, extracted from the plant is used to treat multi-drug resistant strains of falciparum malaria. Artemisinin can also be synthesized from artemisinic acid. In the 1960s a research program was set up by the Chinese army to find an adequate treatment for malaria. In 1972, Artemisinin was one of many candidates then tested by Chinese scientists from a list of nearly 200 traditional Chinese medicines for treating malaria. It was the only one that was found to be effective, as it cleared malaria parasites from the body faster than any other drug in history. Artemisia annua is a common herb and has been found in many parts of the world, including along the Potomac River, in Washington, D.C.

ONCOLOGY

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Imaging Technique Monitors Protein Changes In Mouse Tumors

The HER2 protein is overexpressed (produced at higher-than-normal levels) in approximately 20 to 25 percent of breast cancers. Tumors that overexpress HER2 are more aggressive and more likely to recur than tumors that do not overexpress the protein. Current targeted therapies directed against HER2 can slow or stop the growth of tumors that overexpress it. Currently, HER2 expression is measured in biopsy specimens – that is, in tumor samples that have been removed from the body. However, expression of HER2 in these samples may not accurately represent HER2 expression in the tumor as a whole. Moreover, follow-up biopsies are not routinely performed after the initial diagnosis, and there are no means to evaluate how long a targeted therapy takes to reach its target, how effective it is, and how long its effects last. According to an article published in The Journal of Nuclear Medicine (2009 50:1131-1139), a new imaging technique can monitor, in living mice, the HER2 protein that is found in above-normal amounts in many cases of breast cancer, as well as some ovarian, prostate and lung cancers. This new approach could provide a real-time noninvasive method for identifying tumors in humans who express HER2 and who would be candidates for targeted therapy directed against this protein. It may also provide real-time information that will help clinicians optimize treatment for individual patients. For the study, an imaging compound was used that consists of a radioactive atom (fluorine-18) attached to an Affibody molecule. The radioactive atom allows the distribution of the Affibody molecules in the body to be analyzed by positron emission tomography (PET) imaging. In general, affibody molecules are scaffold proteins, having a common frame of amino acids determining the overall fold or tertiary structure, but with each member characterized by a unique amino acid composition in an exposed binding surface determining binding specificity and affinity for a certain target. Affibody molecules represent a new class of affinity proteins based on a 58-amino acid residue protein domain, derived from one of the IgG binding domains of staphylococcal protein A. Initially, the radiolabeled Affibody molecule was used to visualize tumors that expressed HER2 in mice. The mice were injected under the skin with human breast cancer cells that varied in their levels of HER2 expression, from no expression to very high expression. After three to five weeks, when tumors had formed, the mice were injected with the Affibody molecule and PET images were recorded. The levels of HER2 expression as determined by PET were consistent with the levels measured in surgically removed samples of the same tumors using established laboratory techniques. To determine whether their method could be used to monitor possible changes in HER2 expression in response to treatment, the team next injected the Affibody molecule into mice with tumors that expressed very high or high levels of HER2 and then treated them with the drug 17-DMAG, which is known to decrease HER2 expression. PET scans were performed before and after 17-DMAG treatment. Results showed thatHER2 levels were reduced by 71% in mice with tumors that expressed very high levels of HER2 and by 33% in mice with tumors that expressed high levels of HER2 in comparison with mice that did not receive 17-DMAG. These reductions were confirmed by using established laboratory techniques to determine the concentrations of HER2 in the tumors after they were removed from the mice.

Schizophrenia and Bipolar Disorder Share Genetic Roots 

A trio of genome-wide studies, with a combined sample of 8,014 cases and 19,090 controls, and published online in Nature (1 July 2009), have pinpointed a vast array of genetic variation that cumulatively may account for at least one third of the genetic risk for schizophrenia. One of the studies traced schizophrenia and bipolar disorder in part, to the same chromosomal neighborhoods. All three studies implicate an area of Chromosome 6 (6p22.1). This hotspot of association might help to explain how environmental factors affect risk for schizophrenia. For example, there are hints of autoimmune involvement in schizophrenia, such as evidence that offspring of mothers with influenza while pregnant have a higher risk of developing the illness. Among sites showing the strongest associations with schizophrenia was a suspect area on Chromosome 22 and more than 450 variations in the suspect area on Chromosome 6. Statistical simulations confirmed that the findings could not have been accounted for by a handful of common gene variants with large effect or just rare variants. This involvement of many common gene variants suggests that schizophrenia in different people might ultimately be traceable to distinct disease processes. Nevertheless, most of the genetic contribution to schizophrenia, which is estimated to be at least 70% heritable, remains unknown. The consortium pinpointed an association between schizophrenia and genes in the Chromosome 6 region is known to harbor genes involved in immunity and controlling how and when genes turn on and off. For example, one of the strongest associations was seen in the vicinity of genes for proteins called histones that slap a molecular clamp on a gene’s turning on in response to the environment. Genetically rooted variation in the functioning of such regulatory mechanisms could help to explain the environmental component repeatedly implicated in schizophrenia risk. The study also found an association between schizophrenia and a genetic variation on Chromosome 1 (1p22.1) which has been implicated in multiple sclerosis, an autoimmune disorder. The study also found significant evidence of association with variation on Chromosomes 11 and 18 that could help account for the thinking and memory deficits of schizophrenia. The new findings could eventually lead to multi-gene signatures or biomarkers for severe mental disorders. As more is learned about the implicated gene pathways, it may be possible to sort out what’s shared by, or unique to, schizophrenia and bipolar disorder.

Hearing Improvement after Avastin in Patients with Neurofibromatosis Type 2

Neurofibromatosis Type II is a genetic disease whose main manifestation is the development of symmetric, non-malignant brain tumors in the region of the cranial nerve VIII, which is the auditory-vestibular nerve that transmits sensory information from the inner ear to the brain, thus contributing to hearing loss. Most people with this condition also experience problems in their eyes. NF II is caused by mutations of the “Merlin” gene, which, it seems, influences the form and movement of cells. The principal treatments consist of neurosurgical removal of the tumors and surgical treatment of the eye lesions. There is no current medical treatment. According to an article published online in the New England Journal of Medicine (8 July 2009), a study was performed to evaluate response to therapy of bevacizumab (Avastin, Genentech) in patients with Neurofibromatosis Type 2. Initially, the expression pattern of vascular endothelial growth factor (VEGF) and three of its receptors, VEGFR-2, neuropilin-1, and neuropilin-2, was determined in paraffin-embedded samples from 21 vestibular schwannomas associated with neurofibromatosis type 2 and from 22 sporadic schwannomas. Ten consecutive patients with neurofibromatosis type 2 and progressive vestibular schwannomas who were not candidates for standard treatment were then treated with Avastin, an anti-VEGF monoclonal antibody. An imaging response was defined as a decrease of at least 20% in tumor volume, as compared with baseline. A hearing response was also defined as a significant increase in the word-recognition score, as compared with baseline. Results showed that VEGF was expressed in 100% of vestibular schwannomas and VEGFR-2 in 32% of tumor vessels on immunohistochemical analysis. Before treatment, the median annual volumetric growth rate for 10 index tumors was 62%. After Avastin treatment in the 10 patients, tumors shrank in 9 patients, and 6 patients had an imaging response, which was maintained in 4 patients during 11 to 16 months of follow-up. The median best response to treatment was a volumetric reduction of 26%. Three patients were not eligible for a hearing response. Of the remaining seven patients, four had a hearing response, two had stable hearing, and one had progressive hearing loss. There were 21 adverse events of grade 1 or 2. According to the authors, VEGF blockade with Avastin improved hearing in some, but not all, patients with neurofibromatosis type 2 and was associated with a reduction in the volume of most growing vestibular schwannomas.

TARGET HEALTH excels in Regulatory Affairs and works closely with many of its clients performing all FDA submissions. TARGET HEALTH receives daily updates of new developments at FDA. Each week, highlights of what is going on at FDA are shared to assure that new information is expeditiously made available.

FDA Approves Effient to Reduce the Risk of Heart Attack in Angioplasty Patients

During an angioplasty, a balloon is used to open the artery that has been narrowed by atherosclerotic plaque. Often, a tiny wire mesh scaffold (stent) is inserted into the blood vessel to help keep the artery open after the procedure. Platelets in the blood can clump around the procedure site, causing clots that can lead to heart attack, stroke, and death. The FDA has approved the blood-thinning drug Effient tablets (prasugrel) to reduce the risk of blood clots from forming in patients who undergo angioplasty. Effient was studied in a 13,608-patient trial comparing it to the blood-thinning drug, Plavix (clopidogrel), in patients with a threatened heart attack or an actual heart attack who were about to undergo angioplasty. Results of the study showed that the fraction of patients who had subsequent non-fatal heart attacks was reduced from 9.1% in patients who received Plavix to 7.0% in patients who received Effient. While the numbers of deaths and strokes were similar with both drugs, patients with a history of stroke were more likely to have another stroke while taking Effient. In addition, there was a greater risk of significant, sometimes fatal bleeding in patients who took Effient. According to the FDA, Effient offers physicians an alternative treatment for preventing dangerous blood clots from forming and causing a heart attack or stroke during or after an angioplasty procedure. However, physicians must carefully weigh the potential benefits and risks of Effient as they decide which patients should receive the drug. The drug’s labeling will include a boxed warning alerting physicians that the drug can cause significant, sometimes fatal, bleeding. The drug should not be used in patients with active pathological bleeding, a history of mini-strokes (transient ischemic attacks) or stroke, or urgent need for surgery, including coronary artery bypass graft surgery. Effient is manufactured by Eli Lilly and Company of Indianapolis, in partnership with Tokyo-based Daiichi Sankyo Ltd.

Target Health (www.targethealth.com) is a full service eCRO with full-time staff dedicated to all aspects of drug and device development. Areas of expertise include Regulatory Affairs, comprising, but not limited to, IND (eCTD), IDE, NDA (eCTD), BLA (eCTD), PMA (eCopy) and 510(k) submissions, Management of Clinical Trials, Biostatistics, Data Management, EDC utilizing Target e*CRF®, Project Management, and Medical Writing. Target Health has developed a full suite of eClinical Trial software including 1) Target e*CRF® (EDC plus randomization and batch edit checks), 2) Target e*CTMSTM, 3) Target Document®, 4) Target Encoder®, 5) Target Newsletter®, 6) Target e*CTRTM (electronic medical record for clinical trials). Target Health ‘s Pharmaceutical Advisory Dream Team assists companies in strategic planning from Discovery to Market Launch. Let us help you on your next project.