On Target

ON TARGET
COMPLIMENTARY NEWS LETTER OF TARGET HEALTH® INC.

2 March 2008

I. WHAT'S NEW?
NDA Submitted - BLA Approved That Used Target e*CRF®
II. QUIZ - (Fill In The Blanks)
Losing Sleep Speeds Up the Aging Process
III. HISTORY OF MEDICINE
HIV/AIDS
IV. PSYCHIATRY
SSRI Plus Therapy Most Successful For Depression - 12 Week Study
V. RHEUMATOLOGY
Cognitive-Behavioral Therapy Improves Health Outcomes in RA
VI. RHEUMATOLOGY
Effect of Glucosamine Sulfate on Hip Osteoarthritis
VII. REGULATORY AFFAIRS
FDA Approves Regeneron's Arcalyst - 1st Approval After 20 Years
VIII. TARGET HEALTH

I. WHAT'S NEW?

NDA Submitted - BLA Approved That Used Target e*CRF®

This past week, FDA announced (http://www.fda.gov/bbs/topics/NEWS/2008/NEW01801.html) the approval of ARCALYST™ (rilonacept, Regeneron Pharmaceuticals) for the treatment of rare inflammatory syndromes. In addition, Ferring Pharmaceuticals announced that it has submitted applications in Europe and the United States for the marketing authorization of its prostate cancer treatment, degarelix, a new GnRH receptor blocker intended for patients in whom androgen deprivation is warranted.

We are very pleased to announce that Target e*CRF® was used for the clinical trials for both submissions. There are now 14 products (NDA-2; PMA-10; BLA-1; and 510k-1) with FDA marketing approval that used Target e*CRF® for their pivotal trials. All of these studies passed FDA pre-approval inspection audits. Currently there is one NDA and one PMA in review.

For more information, please contact Dr. Jules T. Mitchel or Joyce Hays. For new business opportunities, contact Dr. Jules T. Mitchel . Please visit our Website and Blog.

II. QUIZ (Fill In The Blanks)

Losing Sleep Speeds Up the Aging Process

Sleep deprivation research usually focuses on what it does to the 1) ___. Now, new evidence suggests that lack of sleep may also be devastating for the body and may possibly help to bring on 2) ___. In a US study, published in Lancet, researchers found that just one week of sleep deprivation altered subjects' hormone levels and their capacity to 3) ___ carbohydrates. During sleep deprivation, the blood sugar level of the men who participated in the study, took 40% longer to drop, following a high carbohydrate meal during sleep deprivation, compared with during the sleep recovery period. In addition, when deprived of sleep, the men's ability to secrete and respond to 4) ___, dropped by 30%. The men also had higher night time levels of cortisol, which helps to regulate blood sugar and to lower levels of thyroid stimulating 5) ___. Each of these biological responses to sleep deprivation places an individual at greater risk of developing Type II (adult onset) diabetes. The good news, according to the researchers, was that the sleep debt could be made up by spending longer than the normal eight hours in bed, which helped to return the body's 6) ___ balance to normal.

ANSWERS: 1) mind; 2) diabetes; 3) metabolize; 4) insulin; 5) hormone; 6) chemical

III. HISTORY OF MEDICINE

HIV/AIDS

AIDS was first reported June 5, 1981, when the CDC recorded a cluster of Pneumocystis carinii pneumonia in five men in Los Angeles. Three of the earliest known instances of HIV infection are: 1) a plasma sample taken in 1959 from an adult male living in Kinshasa, Democratic Republic of the Congo. 2) HIV found in tissue samples from "Robert R “, a 15 year old African-American teenager who died in St. Louis in 1969, and 3) HIV found in tissue samples from a Norwegian sailor who died around 1976. Of the 2 species of HIV that infect humans: HIV-1 and HIV-2, HIV-1 is more virulent and more easily transmitted. HIV-1 is the source of the majority of HIV infections throughout the world, while HIV-2 is not as easily transmitted and is largely confined to West Africa. Both HIV-1 and HIV-2 are of primate origin. The origin of HIV-1 is the Central Common Chimpanzee (Pan troglodytes troglodytes) found in southern Cameroon. It is established that HIV-2 originated from the Sooty Mangabey (Cercocebus atys), an Old World monkey found in Guinea Bissau, Gabon, and Cameroon. Most experts believe that HIV probably transferred to humans as a result of direct contact with primates, for instance during hunting or butchery. A more controversial theory known as the OPV AIDS hypothesis suggests that the AIDS epidemic was inadvertently started in the late 1950s in the Belgian Congo during research into a poliomyelitis vaccine. According to scientific consensus, this scenario is not supported by the available evidence. A 2007 study published in the Proceedings of the National Academy of Sciences by Michael Worobey and Dr. Arthur Pitchenik showed that, based on the results of genetic analysis, HIV probably moved from Africa to Haiti and then entered the US around 1969. Protein has now been identified that enables viruses such as HIV to infect cells and spread through the body. This discovery gives drug developers a target to discover new types of drugs to stop the virus from spreading. HIV is a parasite that does not have enough proteins of its own to complete its life cycle. To survive, the virus needs to use proteins in the cells that it infects. Currently, the drugs that are available to fight HIV act on proteins that the virus itself produces. The downfall of existing HIV drugs is that since the virus is constantly changing, the drugs eventually stop working, and the virus becomes drug resistant. To find these proteins, mutations are first induced in cells through chemical manipulation; this makes random mutations in the DNA of the cell lines. The HIV is then altered so it contained a protein that immediately kills cells, and infects the different mutant cell lines. It was found that some cell lines lived after being infected with HIV. In the cell lines that lived, the HIV is able to get into the cell, but it is attacked. The cell's proteasome, a "machine" in the cell that destroys or chews up proteins, attacks the virus, preventing it from making more copies of itself. Proteasomes are signal dependent machines in the cell, and proteins are typically "tagged" to be destroyed. Finding the switch that turns on the proteasome machine in cells to seek and destroy the virus could be a powerful therapeutic agent in the fight against HIV and in controlling AIDS. By better understanding the newly discovered mechanism, new targets for anti-HIV therapies may be identified. The new cellular factor is called TRIM5α, found in humans and monkeys. The finding shows that the rhesus monkey TRIM5α protein (TRIM5αrh) stops HIV-1 production because it can recognize the virus by its structural protein Gag. TRIM5αrh then destroys the Gag proteins before viral progenies are released from infected cells. This is the first report to show a cellular factor blocking HIV-1 production by actively degrading a viral protein. It is speculated that a subset of the large TRIM family proteins can act as a new group of antiviral factors. Although human TRIM5α cannot block HIV-1 production, it may be possible to develop a drug which influences human TRIM5α to behave like that of rhesus monkeys.

IV. PSYCHIATRY

SSRI Plus Therapy Most Successful For Depression - 12 Week Study

Only about 60% of adolescents with depression show an adequate clinical response to an initial treatment trial with a selective serotonin reuptake inhibitor (SSRI). There are no data to guide clinicians on subsequent treatment strategy. As a result, a study published in the Journal of the American Medical Association (2008;299:901-913), was performed to evaluate the relative efficacy of 4 treatment strategies in adolescents who continued to have depression despite adequate initial treatment with an SSRI. The investigation was a randomized, controlled trial of a clinical sample of 334 patients aged 12 to 18 years with a primary diagnosis of major depressive disorder that had not responded to a 2-month initial treatment with an SSRI. For the study, eligible subjects were switched to 12 weeks of treatment with:

a different SSRI (paroxetine - Paxil; citalopram - Celexa, or fluoxetine - Prozac , 20-40 mg);
a different SSRI plus cognitive behavioral therapy;
venlafaxine - Effexor (150-225 mg);
venlafaxine plus cognitive behavioral therapy.

The main outcome measures were Clinical Global Impressions (CGI) Improvement score of 2 or less (much or very much improved) and a decrease of at least 50% in the Children's Depression Rating Scale-Revised (CDRS-R); and change in CDRS-R over time. Results showed that cognitive behavioral therapy plus a switch to either medication regimen showed a higher response rate (54.8%) than a medication switch alone (40.5%; P = .009). However, there was no difference in response rate between venlafaxine and a second SSRI (48.2% vs 47.0%; P = .83). There were no differential treatment effects on change in the CDRS-R, self-rated depressive symptoms, suicidal ideation, or on the rate of harm-related or any other adverse events. There was a greater increase in diastolic blood pressure and pulse and more frequent occurrence of skin problems during venlafaxine than SSRI treatment. The authors concluded that for adolescents with depression not responding to an adequate initial treatment with an SSRI, the combination of cognitive behavioral therapy and a switch to another antidepressant resulted in a higher rate of clinical response than did a medication switch alone. However, a switch to another SSRI was just as efficacious as a switch to venlafaxine and resulted in fewer adverse effects.

V. RHEUMATOLOGY

Cognitive-Behavioral Therapy Improves Health Outcomes in RA

According to an article published in Arthritis Care & Research (2009;59:311-316), a study was performed to investigate whether cognitive-behavioral therapy (CBT) administered early in the course of rheumatoid arthritis (RA) has long-term effects on health care use. For the study, files were reviewed of 47 of the original 53 patients with early RA who volunteered for a randomized controlled trial comparing CBT with no psychological intervention. Occasions of service provision associated with RA were documented and health care use was compared between groups. Results showed that the CBT group used fewer health care resources than the control group in the 5 years following intervention. Significant differences were observed for the number of inpatient nights, physiotherapy referrals, injections, and for total health care use. There was a trend that closely approached significance toward fewer episodes of surgery and orthopedic referrals in the CBT group. The authors concluded that the results suggest that CBT administered early in the course of RA can reduce health care use for the first 5 years after treatment and that brief psychological treatments can have long-term effects.

VI. RHEUMATOLOGY

Effect of Glucosamine Sulfate on Hip Osteoarthritis

The effectiveness of glucosamine sulfate as a symptom and disease modifier for osteoarthritis is still under debate. As a result, a study published in the Annals of Internal Medicine (2008;148:268-277), was performed to assess whether glucosamine sulfate has an effect on the symptoms and structural progression of hip osteoarthritis during 2 years of treatment. The investigation was a randomized, controlled trial. For the study, 222 patients with hip osteoarthritis were recruited by their general practitioner. Patients were eligible if they met the American College of Rheumatology clinical criteria for hip osteoarthritis. The intervention was 2 years of treatment with 1500 mg of oral glucosamine sulfate or placebo once daily. The primary outcome measures were Western Ontario and McMaster Universities (WOMAC) pain and function subscales over 24 months and joint space narrowing after 24 months. The main secondary outcome measures were WOMAC pain, function, and stiffness after 3, 12, and 24 months. At baseline, both groups were similar in demographic and clinical variables. Overall, WOMAC pain did not differ (mean difference [glucosamine sulfate minus placebo], –1.54, nor did WOMAC function (mean difference, –2.01). Joint space narrowing also did not differ after 24 months (mean difference, –0.029). Only 1 of the sensitivity analyses, based on extreme assumptions regarding missing assessments due to total hip replacement, provided results consistent with a glucosamine effect. Some of the limitations of the study was that 20 patients had total hip replacement during the trial and half of the patients had a Kellgren and Lawrence score of 1 which represents mild disease. According to the authors, glucosamine sulfate was no better than placebo in reducing symptoms and progression of hip osteoarthritis.

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.

FDA Approves Regeneron's Arcalyst - 1st Approval After 20 Years

The FDA has approved Arcalyst (rilonacept, an Interleukin-1 blocker) to help ease the suffering faced by those with certain chronic inflammatory diseases. Arcalyst is approved for the long term treatment of two Cryopyrin-Associated Periodic Syndromes (CAPS) disorders: Familial Cold Auto-Inflammatory Syndrome (FCAS) and Muckle-Wells Syndrome (MWS). Target e*CRF® was used for the clinical trials.

Symptoms of both of these disorders include inflammation such as joint pain, rash or skin lesions, fever and chills, eye redness or pain, and fatigue in both children and adults. However MWS is associated with more severe inflammation and may include hearing loss or deafness. In addition, some MWS patients may also be affected by the buildup of a protein substance that damages organs and tissue (amyloidosis). Fifty percent of CAPS cases are associated with a gene mutation in the CIAS 1 gene. The FCAS and MWS disorders affect about 300 people in the US and have been designated as an Orphan Drug. The Orphan Drug Act - now in its 25th year - has been tremendously successful in delivering effective treatments to patients with extremely rare, but serious, diseases. Arcalyst blocks interleukin-1 which is a signaling protein secreted by certain immune-related cells in the body. Interleukin-1 acts as a messenger to regulate inflammatory responses, but in excess it can be harmful and has been shown to be key in the inflammation seen in CAPS sufferers with FCAS or MWS. The FDA based its approval on a clinical study conducted by the manufacturer, which demonstrated the drug’s safety and effectiveness. Using a daily diary questionnaire, 47 patients rated the following five signs and symptoms of CAPS: joint pain, rash, feeling of fever/chills, eye redness/pain, and fatigue, each on a scale of zero (none/no severity) to 10 (very severe). Patients noted initial onset of relief of symptoms in their diaries within several days. The most commonly reported side effects associated with use of Arcalyst were injection-site reactions and upper respiratory infections. The FDA granted the drug a priority review, which speeds the review process for patients who have unmet medical needs. Arcalyst is manufactured by Regeneron Pharmaceuticals Inc., Tarrytown, N.Y.

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.

TARGET HEALTH INC.
261 Madison Avenue
24th Floor
New York, NY 10016
Phone: (212) 681-2100; Fax (212) 681-2105

http://blog.targethealth.com
www.targethealth.com
Dr. Jules T. Mitchel, President
Ms Joyce Hays, CEO