On Target

ON TARGET
COMPLIMENTARY NEWS LETTER OF TARGET HEALTH® INC.

10 May 2008

I. WHAT'S NEW?
Target Health is Moderating a Panel at the Long Island Life Sciences Industry Summit
II. QUIZ - (Fill In The Blanks)
New Switch Regulates Breast Cancer Response To Estrogen
III. HISTORY OF MEDICINE
Sir Archibald Edward Garrod (1857-1936)
IV. GENETICS
Duck-Billed Platypus Genome Sequence Published
V. OBSTETRICS
Elevated Blood Sugar in Non-Diabetics Increases Risk to Newborn
VI. WOMEN'S HEALTH
Smoking and Smoking Cessation in Relation to Mortality in Women
VII. REGULATORY AFFAIRS
Final Guidance on Adverse Events in Clinical Trials Due Soon
VIII. TARGET HEALTH

I. WHAT'S NEW?

Target Health is Moderating a Panel at the Long Island Life Sciences Industry Summit

Dr. Jules Mitchel, President of Target Health Inc., will moderate a panel at the annual meeting of the 2008 Life Sciences Industry Summit. The panel is entitled: "Pre-Clinical Regulatory Strategies: Advancing Into Clinical Trials." The meeting will be held on Thursday, June 5, 2008 from 8am-6pm at the Hilton Long Island,. Let us know if you will be attending. The panelists include:

Don Cilla, PharmD, President and CEO, DCPS
Colleen Dragula Johnson, M.S., D.A.B.T, Independent Toxicology Consultant
Glen Park, PharmD, Senior Director Clinical and Regulatory Affairs, Target Health Inc.
Mary Shatzoff, MS, Senior Manager of Regulatory Affairs, Target Health Inc.

For more information about Target Health or any of our software tools for clinical research, please contact Dr. Jules T. Mitchel or Ms. Joyce Hays. Please visit our Website and Blog.

II. QUIZ (Fill In The Blanks)

New Switch Regulates Breast Cancer Response To Estrogen

Most breast cancers contain estrogen 1) ___, which enable them to grow in the presence of the hormone estrogen. The presence of receptors can determine whether tumors will respond to the estrogen-blocking drug 2) ___. A tiny modification called methylation on estrogen receptors prolongs the life of these growth-driving molecules in breast cancer cells. The finding may help researchers sort out how mutations change the estrogen receptor's function and allow some breast cancers to resist tamoxifen. The problem is that a significant fraction of estrogen receptor positive 3) ___ don't respond to tamoxifen. Development of new drugs that interfere with the methylation of the 4) ___ receptor may be an alternative way to treat those tumors. Until recently, scientists thought methylation enzymes acted only on DNA molecules or on histones, 5) ___ that bundle DNA into spool-like packages. Methylation enzymes add tags called methyl groups to other 6) ___, influencing their ability to turn genes on or off. The scientists found that one of the modification enzymes, called SET7, methylates a flexible part of the estrogen receptor. When they created breast cancer cells with reduced levels of SET7, the estrogen receptor molecules lasted only half as long and were less effective in turning on genes. The research team showed that a mutation in the estrogen receptor found in more aggressive breast tumors interferes with methylation in cells. Also, the methylation appears in exactly the same spot where another protein called BRCA1 adds a different kind of regulatory marking, and may block BRCA1's restrictive effects on the estrogen receptor. Women who inherit a 7) ___ in the gene that encodes BRCA1 have up to an 80% lifetime risk of developing breast cancer, several times the risk of those who don't have it. BRCA1 mutations are estimated to account for about a third of all inherited breast cancers and roughly 2-3% of all breast cancers. Scientists are beginning to look for drugs that could 8) ___ methylation enzymes. Methylation probably affects several other proteins similar to the estrogen receptor. This may be just the tip of the iceberg. Methylation may be just as common as other protein modifications, and even more complicated. The results are published in the May 9, 2008 issue of the journal Molecular Cell.

ANSWERS: 1) receptors; 2) tamoxifen; 3) tumors; 4) estrogen; 5) proteins; 6) molecules; 7) mutation; 8) modulate

III. HISTORY OF MEDICINE

Sir Archibald Edward Garrod (1857-1936)

Sir Archibald Edward Garrod, an English physician, brought forward the scientific study of inborn errors of metabolism. Garrod's concept of 'chemical individuality' with no awareness of genes more than 100 years ago is an amazing example of futuristic thinking. Garrod also provided insight into a number of scientific concepts and modern thinking. Garrod introduced a paradigm, new for its day, in medicine: Biochemistry is dynamic and different from the static nature of organic chemistry. It led him to think about metabolic pathways and to recognize that variation in Mendelian heredity could explain an 'inborn error of metabolism'. At the time, Garrod had no idea about the nature of a gene. Born in London, Archibald was the fourth son of Sir Alfred Baring Garrod, a physician at King's College Hospital, who discovered the abnormal uric acid metabolism associated with gout. In 1885 Garrod obtained his BM and MA from Oxford, and became a member of the Royal College of Physicians, London. Garrod was a proponent of scientific research as the foundation of medical practice, and published on a variety of diseases and topics throughout his career, including An Introduction to the Use of the Laryngoscope (1886) and A Treatise on Rheumatism and Rheumatoid Arthritis (1890). Garrod developed an increasing interest in chemical pathology, and investigated urine chemistry as a reflection of systemic metabolism and disease. This research, combined with the new understanding of Mendelian inheritance, evolved from an investigation of a few families with an obscure and not very dangerous disease (alkaptonuria) to the realization that a whole territory of mysterious diseases might be understood as inherited disorders of metabolism. Garrod studied the recurrence patterns in several families, realized it followed an autosomal recessive pattern of inheritance, and postulated that it was caused by a mutation in a gene encoding an enzyme involved in the metabolism of a class of compounds called alkaptans. Over the next decade he developed an understanding of the possible nature of inherited diseases of metabolism. He formulated the "one gene, one enzyme" hypothesis and described the nature of recessive inheritance of most enzyme defects. Garrod died in 1936, at the age of 79.

IV. GENETICS

Duck-Billed Platypus Genome Sequence Published

Fans of TV nature shows will remember that the duck-billed platypus, native to Australia, is one of the few mammals that lays eggs. However, platypus peculiarity does not end there. For example, these odd animals boast what looks like a duck's bill, which houses an electrosensory system used when foraging for food underwater, along with thick fur coats adapted for the icy waters in which it resides. Males also possess hind leg spurs that can deliver venom powerful enough to wound territorial competitors during mating season or cause excruciating pain in other mammals, including humans. According to an article published in the journal Nature (2008;453:175-183), a high-quality draft genome sequence of Glennie, a female platypus from Australia has been analyzed. The platypus genome sequence is publicly available from NIH's National Center for Biotechnology Information. Once the sequence was produced, the research team began comparing the genome of the platypus, whose ancestors split from the rest of mammalian lineage some 166 million years ago, with the well-characterized genomes of the human, mouse, dog, opossum and chicken, as well as the draft genome sequence of the green anole lizard. The chicken genome was chosen because it is descended from the ancestral group of egg-laying animals, including extinct reptiles, which passed on much of their DNA to animals like the platypus. Scientists were particularly interested in finding features within the platypus genome that could explain the odd mix of characteristics seen in the platypus, those that were more like reptile and birds and those which were like mammals. The team found that the platypus genome contains about the same number of protein-coding genes as other mammals -- approximately 18,500. The platypus shares more than 80% of its genes with other mammals whose genomes have been sequenced. Next, researchers combed the platypus genome looking for genetic evidence of sequences unique to platypuses, which have been lost from mammalian genomes. While the female platypus lays eggs, a reptilian characteristic, it also produces milk to nourish its young, which is a mammalian characteristic. Interestingly, the platypus genome harbors both reptilian and mammalian genes associated with fertilization of eggs. However, it was discovered that, like other mammals, the platypus genome contains a tightly clustered set of genes that produce the casein proteins that make up milk. When the research team began analyzing the genetic sequences responsible for venom production in the male platypus, they made a surprising finding. They discovered that venom produced by the male platypus arose from duplications in certain genes over the course of evolutionary time which had been passed on from ancestral reptile genomes. The reptilian lineage displays a similar duplication of venom genes, but that duplication appears to have occurred independently during the evolution of reptiles, giving them similar abilities to produce venom.

V. OBSTETRICS

Elevated Blood Sugar in Non-Diabetics Increases Risk to Newborn

Diabetes results from difficulty transferring sugar (glucose) from the blood to the body's tissues. It occurs in roughly 5% of all pregnancies in the US. Mothers with diabetes during pregnancy are also at increased risk for preeclampsia, a potentially fatal disorder involving dangerously high blood pressure. Babies born to mothers with diabetes -- when they reach adulthood -- are at higher risk for obesity as well as diabetes, high blood pressure, and heart disease. It is well known that high blood sugar levels characteristic of the diabetes that occurs during pregnancy present risks for expectant mothers and the infants born to them. These problems included a greater likelihood for Cesarean delivery and an abnormally large body size at birth. Infants born to women with higher blood sugar levels were also at risk for shoulder dystocia, a condition occurring during birth, in which an infant's shoulder becomes lodged inside the mother's body, effectively halting the birth process. According to a study published in the New England Journal of Medicine (2008; 358:1991-2002), pregnant women with blood sugar levels in the higher range of normal -- but not high enough to be considered diabetes -- are more likely than women with lower blood sugar levels to give birth to babies at risk for many of the same problems seen in babies born to women with diabetes during pregnancy. The current study is the first to document that higher blood sugar levels, not high enough to be considered diabetes, also convey these increased risks. The seven-year study involved more than 23,000 pregnant women at 15 centers in 9 countries. For the study, an oral glucose tolerance test was performed on each woman, from the 24th through the 32nd week of pregnancy. For the test, the women fasted, after which their blood glucose level was measured. Next, the women drank a glucose solution, and then their blood glucose was measured at predetermined intervals. Women with blood sugar levels high enough to raise safety concerns were referred for treatment and were not included in the study. The remaining women were observed throughout the study until they gave birth. Results showed that the higher the mother's blood sugar levels, the greater the chances that they would deliver by Cesarean section. In addition, the higher the mother's blood sugar levels, the more likely the infants were to have high insulin levels and low blood sugar levels at birth. Both conditions indicate exposure to high glucose levels in the womb. Moreover, the higher the mother's blood sugar levels, the more likely the women were to develop preeclampsia, and the more likely their infants were to be born prematurely, and to experience shoulder dystocia. So, for example, women with the lowest fasting blood sugar levels gave birth to abnormally large babies roughly 5% of the time, while women with the highest blood sugar level gave birth to large babies 26% of the time.

VI. WOMEN'S HEALTH

Smoking and Smoking Cessation in Relation to Mortality in Women

It is well known that smoking is associated with an increased risk of total and cause-specific death, but the rate of mortality risk reduction after quitting compared with continuing to smoke is uncertain. There is inadequate or insufficient evidence to infer the presence or absence of a causal relationship between smoking and ovarian cancer and colorectal cancer. As a result, a study published in the Journal of the American Medical Association (2008;299:2037-2047) was performed to assess the relationship between cigarette smoking and smoking cessation on total and cause-specific mortality in women. The investigation was a prospective observational study of 104,519 female participants in the Nurses' Health Study with follow-up from 1980 to 2004. The main outcome measure was the hazard ratios (HRs) for total mortality, further categorized into vascular and respiratory diseases, lung cancer, other cancers, and other causes. Compared with never smokers, current smokers had an increased risk of total mortality (HR, 2.81) and all major cause-specific mortality. The HR for cancers classified by the 2004 surgeon general's report to be smoking-related was 7.25 and 1.58 for other cancers. Compared with never smokers, the HR for colorectal cancer was 1.63 for current smokers and 1.23 for former smokers. A significant association was not observed for ovarian cancer. Significant trends were observed for earlier age at initiation of smoking for total mortality (P = .003), respiratory disease mortality (P = .001), and all smoking-related cancer mortality (P = .001). The excess risk for all-cause mortality decreases to the level of a never smoker 20 years after quitting, with different time frames for risk reduction observed across outcomes. Approximately 64% of deaths among current smokers and 28% of deaths among former smokers were attributable to cigarette smoking. According to the authors, most of the excess risk of vascular mortality due to smoking in women may be eliminated rapidly upon cessation and within 20 years for lung diseases. Postponing the age of smoking initiation reduces the risk of respiratory disease, lung cancer, and other smoking-related cancer deaths but has little effect on other cause-specific mortality. These data suggest that smoking is associated with an increased risk of colorectal cancer mortality but not ovarian cancer mortality.

VII. REGULATORY AFFAIRS

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.

Final Guidance on Adverse Events in Clinical Trials Due Soon

The FDA will soon issue a final guidance distinguishing between adverse events and unanticipated problems in clinical trials, clarifying when the former have to be reported to an institutional review board (IRB). It is the sponsor’s responsibility to report serious and unexpected adverse events to the FDA. While clinical investigators are not required to report adverse events that do not fall into this category to the IRB, they must record all adverse events on case report forms and submit them to the FDA in annual reports. The regulations on devices stipulate that clinical investigators must report unanticipated adverse device effects within 10 working days to the sponsor and the IRB. In federally funded trials, even a serious adverse event might not have to be reported to HHS’ Office for Human Research Protections if it were anticipated, but it still would have to be reported to the FDA. The FDA’s draft guidance can be viewed at www.fda.gov/OHRMS/DOCKETS/98fr/07d-0106-gdl0001.pdf.

For more information about our expertise in Regulatory Affairs, please contact Dr. Jules T. Mitchel or Dr. Glen Park.

VIII. TARGET HEALTH

TARGET HEALTH INC. (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, IDE, NDA, PMA and 510(k) submissions, execution of Clinical Trials, Project Management, Biostatistics and Data Management, Web Trials, utilizing Target e*CRF®, our proprietary Internet-based Clinical Trial System, and Medical Writing. 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.

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Dr. Jules T. Mitchel, President
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