On Target

ON TARGET
COMPLIMENTARY NEWS LETTER OF TARGET HEALTH® INC.

05 August 2007

I. WHAT'S NEW?
Consulting For NIH
II. QUIZ - (Fill In The Blanks)
Drug Derived From Gila Monster Saliva Helps Diabetics
III. HISTORY OF MEDICINE
Acupuncture
IV. NEUROLOGY
Two Multiple Sclerosis Genes Identified
V. NEUROLOGY
Gene Identified Which Increases Response to Citalopram (Celexa)
VI. NEUROLOGY
Amyotrophic Lateral Sclerosis (ALS) Genes Identified
VII. REGULATORY AFFAIRS
Guidance - Emergency Use of Medical Products
VIII. TARGET HEALTH

I. WHAT'S NEW

Consulting For NIH

Target Health is pleased to announce that its President, Dr. Jules Mitchel, has again been asked by NIH to provide consultations for the evaluation of a proposed clinical program. Dr. Mitchel has been providing these consultations since 2003.

For more information about Target Health, please contact Dr. Jules T. Mitchel. Visit our Blog and Website.

II. QUIZ (Fill In The Blanks)

Drug Derived From Gila Monster Saliva Helps Diabetics

Exenatide is a synthetic form of a 1) ___ called exendin-4 that occurs naturally in the saliva of the Gila monster, a large venomous lizard native to the southwestern United States and northwestern Mexico. The hormone is about 50% identical to a similar hormone in the human 2) ___ tract, called glucagon-like peptide-1 analog, or GLP-1, that increases the production of insulin when blood sugar levels are high. Insulin helps move sugar from the 3) ___ into other body tissues where it is used for energy. The 4) ___ hormone remains effective much longer than the human hormone, and thus its synthetic form helps diabetics keep their blood sugar levels from getting too high. Exenatide also slows the 5) ___ of the stomach and causes a decrease in appetite, which is how it leads to weight loss. Exenatide led to healthy sustained 6) ___ levels and progressive weight loss among people with type 2 diabetes who took part in a three-year study. An average of 11 pounds was also lost over three years. Overweight and weight gain is an almost universal problem for people with diabetes. Exenatide is not intended as a weight-loss drug and it is not approved for that purpose. Only people with type 2 diabetes should take exenatide.

ANSWERS: 1) hormone; 2) digestive; 3) blood; 4) lizard; 5) emptying; 6) glucose

III. HISTORY OF MEDICINE

Acupuncture

Acupuncture was first discussed in the ancient Chinese medical text "Huang Di Nei Jing" (The Yellow Emperor's Classic of Internal Medicine), originating more than 2000 years ago. During the 6th Century, improved transportation and communications within the Asian Continent led to the introduction of Chinese medicine to Japan, and along with Buddhism came in the form of religious medicine. In the 17th century, Waichi Sugiyama, in search of a simple, painless and speedy insertion method, developed the insertion tube, a small cylindrical tube through which the needle is inserted. This insertion method is still used today by practitioners worldwide, and in Japan by over 90% of acupuncturists. Japanese acupuncture has been well established as the primary form of health care for over a thousand years. An acupuncturist's role was comparable to that of a modern physician. When Dutch and German medicine was introduced in the 19th century, the Western modality of medicine quickly became the dominant medical practice. Today in Japan, acupuncture remains an integral part of the health care system, offered in conjunction with medicine. In North America, acupuncture has grown into what is now a common form of pain management therapy in many clinics and hospitals. It is estimated 15 million Americans, or roughly 6% of the American population has visited an acupuncturist and has tried acupuncture for a variety of symptoms including chronic pain, fatigue, nausea, arthritis, and digestive problems. In 1995, the FDA classified acupuncture needles as medical instruments and assured their safety and effectiveness. The medical community for the most part now accepts acupuncture and a growing number of medical schools, such as UCLA, include acupuncture training in their curriculum. In 1997, the US National Institute of Health issued a report titled: "Acupuncture: The NIH Consensus Statement". It stated that acupuncture is a very useful method for treating many conditions. It acknowledges the side effects of acupuncture are considerably less adverse than when compared to other medical procedures such as surgery or pharmaceuticals. In addition, the NIH made the recommendation to U.S. insurance companies to provide full coverage of acupuncture treatment for certain conditions. This momentous advancement in the status of acupuncture in the US has certainly influenced its status elsewhere in the world. Acupuncture treatment is included in many Insurance plans, a sign of acupuncture's acceptance into the mainstream.

IV. NEUROLOGY

Two Multiple Sclerosis Genes Identified

Multiple Sclerosis (MS), caused by a puzzling mix of genes, environment and immunity, affects at least 350,000 Americans. MS typically causes limb weakness, vision loss and problems with coordination, and is the most common disabling neurological disorder of young adults. It's an autoimmune disease, occurring when the body's immune system mistakenly attacks a protective sheath around axons -- the delicate cables that nerve cells use to connect with each other. Various immunosuppressant drugs can reduce symptoms and slow the disease's course, but most MS patients become increasingly disabled with time. Although the trigger for MS is unclear, there's strong evidence for an interplay between genetic susceptibility and some type of environmental factor. Having a relative, especially an identical twin, with MS increases one's risk of developing the disease. In the mid-1970s, researchers discovered that human leukocyte antigens (HLA) account for some of this genetic susceptibility. HLAs are proteins displayed on all the body's cells to help the immune system distinguish self from non-self. A variant of the HLA-DRB1 gene, now widely accepted as the strongest genetic risk factor for MS, increases the likelihood of getting the disease up to four-fold. Still, HLA does not fully explain the genetic basis of MS. A pair of large-scale genetic studies has now revealed that two genes influence the risk of getting MS. These data have been sought since the discovery of the HLA susceptibility gene decades ago. Both studies involved scanning DNA samples from more than 20,000 MS patients and unaffected individuals in the U.S. and Europe, and looking for single nucleotide polymorphisms (SNPs). SNPS are single-letter variations in a gene's DNA code. The studies, simultaneously published online in the New England Journal of Medicine (July 29, 2007) and Nature Genetics (July 29, 2007), demonstrate an association between MS and SNPs in two genes that encode interleukin receptors, proteins that serve as antennae on the surface of immune cells. For the study, gene chip technology was used to scan more than 500,000 SNPs. In total, more than 13,000 DNA samples were analyzed, many of them collected and stored by the Center for Genetic Studies at the National Institute of Mental Health (NIMH) and the U.K.'s Wellcome Trust Case Control Consortium. In the candidate gene study, the researchers scanned DNA samples from four large groups in the U.S, U.K. and Belgium, totaling more than 10,000 people. Both studies revealed an association between MS and a single SNP in the gene interleukin 7 receptor-alpha (IL7R-alpha). The genome-wide scan also found two SNPs in the gene for interleukin 2 receptor-alpha (IL2R-alpha) associated with the disease. Both receptors are known to influence the way that T cells patrol the body for pathogens. IL2R-alpha has previously been implicated in other autoimmune diseases, including type 1 diabetes. Each of the SNPs associated with MS appears to increase the risk of developing the disease by about 20 to 30%.

V. NEUROLOGY

Gene Identified Which Increases Response to Citalopram (Celexa)

According to an article published in the American Journal of Psychiatry (2007;164:1181-1188), it has been demonstrated that a variation in a gene called GRIK4 appears to make people with depression more likely to respond to the medication citalopram (Celexa) than are people without the variation. The increased likelihood was small, but when people had both this variation and one in a different gene shown to have a similarly small effect in an earlier study, they were 23% more likely to respond to citalopram than were people with neither variation. The finding addresses a key issue in mental health research: the differences in people's responses to antidepressant medications, thought to be based partly on differences in their genes. Some patients respond to the first antidepressant they attempt, but many don't. Each medication takes weeks to exert its full effects, and patients' depression may worsen while they search for a medication that helps. The study evaluated DNA provided earlier by patients participating in a recently completed NIMH clinical trial, the Sequenced Treatment Alternatives to Relieve Depression (STAR*D) study. The trial showed that depressed patients who don't benefit from the first medication they try, have a fair chance of being helped by others. After the trial, the DNA codes were collected from 1,297 of the patients who had participated in STAR*D. Results showed that there were 68 genes suspected of being involved in depression,. The genetic material included the occasional variations that occur from person to person. Comparing the DNA codes of those who had responded to citalopram and those who hadn't, it was found that responders were more likely to have a variation in a gene called HTR2A. The protein produced by HTR2A acts as a receptor on brain cells for the chemical messenger serotonin, one of several neurotransmitters that enable the cells to communicate with each other. The discovery that a variation in a serotonin-related gene could affect response to citalopram was not entirely surprising, since the serotonin system is known to be involved in depression. However, GRIK4 makes a protein that acts as a receptor in a different neurotransmitter system, the glutamate system. Recent studies suggest that the glutamate system also is involved in depression, an assertion supported by the new finding. Both of the genes consist of two copies each. The 23% increase in likelihood of response to citalopram occurred in people who carried the favorable variations in both copies of both of the genes. People with fewer of the favorable variations didn't have as high a response rate, but still were more likely to respond than were people with none of the favorable variations.

VI. NEUROLOGY

Amyotrophic Lateral Sclerosis (ALS) Genes Identified

Approximately 90% of persons with amyotrophic lateral sclerosis (ALS) have the sporadic form, which may be caused by the interaction of multiple environmental factors and previously unknown genes. As a result, a study published online in the New England Journal of Medicine (July 29, 2007; DOI: 10.1056/NEJMoa073493), performed a genomewide association analysis using 766,955 single-nucleotide polymorphisms (SNPs) found in 386 white patients with sporadic ALS and 542 neurologically normal white controls (the discovery series). Associations of SNPs with sporadic ALS were confirmed in two independent replication populations: replication series 1, with 766 case patients with the disease and 750 neurologically normal controls, and replication series 2, with 135 case patients and 275 controls. The study identified 10 genetic loci that were significantly associated (P<0.05) with sporadic ALS in three independent series of case patients and controls and an additional 41 loci that had significant associations in two of the three series. The most significant association with disease in white case patients as compared with controls was found for a SNP near an uncharacterized gene known as FLJ10986. The FLJ10986 protein was found to be expressed in the spinal cord and cerebrospinal fluid of patients and of controls. Specific SNPs seem to be associated with gender, age at onset, and site of onset of sporadic ALS. It was concluded that variants of FLJ10986 may confer susceptibility to sporadic ALS and that FLJ10986 and 50 other candidate loci warrant further investigation for their potential role in conferring susceptibility to the disease.

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.

Guidance - Emergency Use of Medical Products

The Emergency Use Authorization (EUA) authority recently granted by Congress allows the FDA Commissioner to strengthen the public health protections against biological, chemical, radiological, and nuclear agents that may be used to attack the American people or the U.S. armed forces. Under section 564 of the Federal Food, Drug, and Cosmetic Act (FD&C Act) (21 U.S.C. 360bbb-3), which was amended by the Project BioShield Act of 2004 (Public Law 108-276), the FDA Commissioner may allow medical countermeasures to be used in an emergency to diagnose, treat, or prevent serious or life-threatening diseases or conditions caused by such agents, when there are no adequate, approved, and available alternatives. This new guidance explains FDA's policies for authorizing the emergency use of medical products. The document is intended to inform industry, government agencies, and FDA staff of the Agency's general recommendations and procedures for issuance of EUAs. FDA expects that requests for consideration for an EUA would be submitted by government agencies (e.g., the Department of Health and Human Services or the Department of Defense (DoD)) or private entities. FDA may seek additional data and information on a case-by-case basis to ensure that the statutory criteria for issuance of an EUA are met. The declaration of an emergency based on one of the following grounds:

The Secretary of Homeland Security determines that there is a domestic emergency, or a significant potential for a domestic emergency, involving a heightened risk of attack with a specified biological, chemical, radiological, or nuclear agent or agents;
The Secretary of Defense determines that there is a military emergency, or a significant potential for a military emergency, involving a heightened risk to United States military forces of attack with a specified biological, chemical, radiological, or nuclear agent or agents;
The Secretary of a public health determines that there is an emergency under section 319 of the Public Health Service Act (PHS Act) that affects, or has the significant potential to affect, national security, and that involves a specified biological, chemical, radiological, or nuclear agent or agents, or a specified disease or condition that may be attributable to such agent or agents.

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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