(complimentary Newsletter from Target Health Inc.)
Monday, January 5, 1998
All of the staff at TARGET HEALTH wishes you and your families a healthy and successful New Year.
We are actively looking for a good statistician/programmer to join our growing biostatistics group. Ph.D. would be desirable, but a strong M.S. level candidate would be acceptable. It will be a excellent opportunity for the right person.
New Readers
This week we would like to welcome Jake Rand (Mt. Sinai School of Medicine), Robert Bender (Micropulse), M. Walden (Australia), David Stevens (Wilson Soncini), James Gourzis (Parexel). Please forward ON TARGET to your friends and colleagues so that we may add them to our ever-growing list. If you know any friends and colleagues who might want to receive ON TARGET, please ask them to e-mail their address to info@targethealth.com, so that we may add them to our ever-growing list. We welcome you to visit our website weekly to see new additions which is being designed by our Manager of Data Management, Vanessa Hays.
As a result of the flu crisis in Hong Kong, two new Internet links have been discovered. One is the link to the Hong Kong Health Department Health (www.info.gov.hk/dh/new/bullet.htm) and a website on emerging diseases (www.outbreak.org).
The avian strain of influenza virus has caused, as of a January 2, 15 confirmed and 6 suspected cases of human influenza in Hong Kong. Hong Kong Health officials were so worried about the virus, that on Monday they began slaughtering all 1.2 million chickens in the territory. Why should so few cases cause such drastic measures locally and apprehension globally? The main reason is the strain's novelty for humans, its unknown mode of transmission, and it's high lethality. To date, four of the 16 confirmed cases have resulted in death. Health officials also reported the first evidence of the probable transmission of the strain from one person to another. A 3-year-old boy who died in May apparently transmitted the virus to his doctor, but the doctor did not develop symptoms and seems not to have spread the virus to others.
As a reminder to all of us: a worldwide influenza epidemic like the one that killed 21 million people in 1918 and 1919 could strike again without warning. Influenza virus has known to do the unexpected. The virus mutates every few years, altering certain components on its surface. Some changes have minor effects, while others have catastrophic consequences. Even minor changes can allow the virus to keep one step ahead of the fresh vaccines that are prepared each year. Such changes also allow influenza viruses to evade naturally occurring antibodies primed by earlier infections, produced to protect against repeat attacks.
Scientific ignorance does not stem from a lack of effort. Years ago, the World Health Organization established a network of experts to detect and cope with any potential pandemic. In 1993, the CDC developed a plan to deal with an influenza pandemic.
The first case of the flu, A(H5N1) avian strain, was first detected in a 3-year-old boy who died in May. The thinking at the time was that this was an isolated odd phenomenon in nature where a boy gets infected by a virus that should not normally be infecting humans. Some scientists even thought that the virus was a contaminant that often popped up in a laboratory. Nevertheless, at that time, the WHO alerted countries to increase surveillance for the strain.
The Hong Kong cases are the first in which avian influenza has gone directly from birds to people without passing through other animals. In the past, viral strains that cause influenza in birds have produced outbreaks in horses, pigs and other animals before moving on to people. It is apparently the close proximity of these animals which is a main transmission problem.
The formula for influenza vaccines is changed each year as experts guess what strains are likely to be most prevalent in the next flu season. The choices are made by late winter so millions of doses can be prepared by fall, before most flu seasons begin in the United States. Not surprisingly, some guesses have been wrong.
At least six publications prepared by Target Health are due out this year in the area of infectious diseases. They will be used, in part, to support the launch of a new major antibiotic.
NEUROLOGY BACK TO TOPAs a reminder, Anita Islam, Ph.D. (Neurobiology) is now on the staff of TARGET HEALTH and already has established her presence with an IND submission on December 24.
The discovery of two human genes that cause a form of epilepsy is expected to throw light on the nature of the disease as well as on the general principles by which the brain operates. It is hoped that by establishing a genetic basis for the mysterious and often alarming disease, it will remove the stigma that often is associated with it.
At least one form of the disease can now be attributed to defects in genes that make a critical component of the electrical circuitry of brain cells. The defective component probably delays the recharging process in nerve cells that have fired off an electrical message to their neighbors. The delay presumably interferes with the brain's intricate timing pattern and somehow triggers the widespread lock-step firing of nerve cells that is the hallmark of an epileptic seizure.
Epilepsy, said to affect 2 percent of people at one time or another in their lives. Some forms of epilepsy are caused by damage to the brain from infection or trauma, but 40 percent of cases are thought to be genetic in origin. The two new genes have been detected by studying the pedigrees of several families who suffer from a rare but intriguing form of epilepsy. The findings have been published in the journal Nature Genetics. The type of epilepsy is called benign familial neonatal convulsions because it runs in families and occurs in babies a few days old. The disease is termed benign because, in 84 percent of cases, it mysteriously disappears after a few weeks.
Possibly, the nerve cells affected by the mutant genes cause neighbor cells to take some action that reverses the effects of the defect after a few weeks of life. Another explanation is that the gene in question is only used for a brief period in the infant's development, much like the gene that produces a special form of hemoglobin, known as fetal hemoglobin. The normal role of the new genes is to make critical components of nerve cells known as voltage-gated potassium channels. Nerve cells are able to transmit electrical signals because of channels, embedded in their membranes, that maintain an electrical imbalance between the nerve fiber and its surroundings. The channels allow sodium and potassium ions, which are atoms that have lost an electron, to cross the membrane in different directions.
A nerve signal is transmitted when the imbalance is reversed at the nerve's body, and the reversal propagates all the way down the nerve's fiber. The imbalance must quickly be restored for the cell to fire again, and the restoration is the role of the potassium channels, which open to let potassium ions rush across the membrane and restore the previous state of imbalance.
In the affected families, the genes that specify the design of the potassium channel protein have changes or deletions in the sequence of chemical letters that make up their DNA. These variations from the correct sequence presumably cause defects in the potassium channel proteins. An epilepsy-associated gene was also discovered last year in Finland, but this gene causes general nerve degeneration. The new genes are the first pure epilepsy-causing genes to be found in humans. Identification of these genes through their ability to cause epilepsy should help to understand what they do in the human brain.
The FDA approved the first gene-based test for predicting whether a cancer will recur. The test, for breast cancer, is based on how many copies of a particular gene a patient has. The test also seemed to indicate whether some treatments would help a patient. Although the test was approved as only a prognostic device, its manufacturer, ONCOR INC. of Gaithersburg, Md., said it was conducting research on the test's ability to indicate the value of specific therapies for different patients and would amend its filing with the FDA to include this data as they became available.
More than 180,000 cases of breast cancer occur in the United States each year, according to the American Cancer Society. While 120,000 of those patients are told when they are initially treated for breast cancer that the cancer has not spread, more than 40,000 women annually find that their cancer has come back. The chances of the cancer recurring are reported to be higher for patients with five to 10 copies of the HER-2/neu gene per cell; most people have two copies per cell.
In clinical trials of the Oncor test, 31 percent of the patients with localized breast cancer but an elevated number of copies of the HER-2/neu gene died within five years of surgery, while 97 percent of the patients with normal levels of the gene survived at least five years. Because patients with higher levels of HER-2/neu do not respond to estrogen-blocking treatments, more potent chemotherapies could be prescribed earlier.
The HER-2/neu gene prompts the production of a protein that is believed to help cancer cells reproduce. Recent clinical trials have shown that a genetically engineered copy of an antibody produced by GENENTECH INC. can block the action of the protein, leading to remissions in some advanced breast cancer cases after conventional chemotherapy had failed. The Oncor test could be used to determine which patients would be candidates for this drug, which is expected to be submitted for FDA approval later this year.
The Oncor Inform HER-2/neu test, expected to cost about $200, is not limited to newly found breast cancer. Because the test is applied directly to breast cancer cells, cancer survivors can ask their doctors to perform it on tissue samples that have been kept on record, even if the samples are many years old.
The FDA is now not only requiring a clinical rationale for new diagnostics but also clinical data looking at test results as a function of treatment and clinical outcome. The key is to meet with FDA to discuss all clinical development plans to assure FDA and sponsor concurrence.
TARGET HEALTH INC. is a full service CRO with staff dedicated to all aspects of Regulatory Affairs, Clinical Research, Biostatistics, Data Management, Strategic Planning and Drug and Device Development. TARGET HEALTH also has a group of specialized advisors in the areas of Toxicology, Analytical Methods Validation, Product and Process Development, Quality Assurance, Manufacturing and Animal Health.
TARGET HEALTH INC.
310 Madison Avenue, 22nd Floor, New York, NY 10017
Phone (212) 681-2100 - Fax (212) 682-0151
JulesMitchel@targethealth.com
(Dr. Jules T. Mitchel, President)
JoyceHays@targethealth.com (Ms. Joyce
Hays, CEO)