Bioresearch Compliance Report
The Insider’s Guide to GCP and GLP Compliance and Enforcement

Online Update Page, March 27, 2006

International

Six study participants could have died due to experimental drug
 
A London-based trial of TeGenero AG’s experimental drug TGN1412 may have caused six male study participants to be hospitalized March 13, but clinical studies at Boston hospitals are continuing, BBC reported March 18.

TGN1412 was developed by Würzburg, Germany-based TeGenero and is being tested by Parexel International, Waltham, MA, to treat such conditions as leukemia and rheumatoid arthritis. The drug product was in the Phase I stage, and was being tested for toxicity in humans, when the deaths occurred.

“This tragic event in England is a bit like a plane crash,” Greg Koski, associate professor of anesthesia, senior scientist in the Institute for Health Policy at Massachusetts General Hospital, told BBC.

“Even if you have a well-developed system for air transportation safety, it doesn’t mean you’re not going to have a really serious tragedy at one time or another. But just because there’s one plane crash, that doesn’t mean everyone stops flying. The system moves on.”

Massachusetts General is one of the Boston-area study sites, and has not halted its part in the ongoing study. Koski is former director of Dept. of Health and Human Services’s (HHS) Office for Human Research Protections. Brigham and Women’s Hospital and Boston Medical Center’s clinical trials also have not been disrupted.

Of the six initially healthy London volunteers given TeGenero’s experimental drug, two remain in critical condition and four are in serious condition.

EU, FDA extend confidentiality agreement

The European Union (EU)-FDA confidentiality arrangement was reviewed March 13 at a meeting in Brussels of the European Commission (EC), the European Medicines Agency (EMEA) and FDA.

All parties agreed to extend the pilot phase for this process, following positive feedback from both regulators and industry that parallel scientific advice can facilitate the development of safe and effective medicines. Another area of particular benefit is pharmacovigilance, where close collaboration on a number of important issues has enhanced patient safety.

This review resulted in an agreement to intensify transatlantic cooperation in the area of medicinal products, with particular focus on vaccines (including preparedness for influenza pandemic), medicines for children, medicines for rare diseases (‘orphans’), oncology and pharmacogenomics. Other public health priority areas will be explored in the coming months, such as, counterfeit medicines.

Other key information from this decision includes:

• The September 2003 public statement together with the text of the Exchange of Letters and the extension to the arrangement in September 2005 between the EC, EMEA and FDA can be found at http://www.emea.eu.int/htms/general/direct/internationcoop.htm.

• The confidentiality arrangement allows the EC/EMEA and the FDA to exchange information as part of their regulatory processes. The types of information covered by the arrangements include legal and regulatory issues, scientific advice, orphan drug designation, inspection reports, marketing authorization procedures and post-marketing surveillance.

• The implementation plan for the confidentiality arrangements as regards medicinal products for human use was agreed and published in 2004 and can be found at http://www.emea.eu.int/pdfs/general/direct/internationalcoop/EMEA-FDAconfidentialityimplement.pdf.

• A pilot program allowing companies to obtain parallel scientific advice from the two agencies (EMEA and FDA) for the development of medicinal products for human use is described in a general principles document that can be found at http://www.emea.eu.int/pdfs/general/direct/internationalcoop/EMEA-FDAScientificAdvice.pdf.

For additional information, please visit http://www.fda.gov/bbs/topics/news/2006/NEW01334.html.

EMEA sees 17% reduction in applications for new drugs in ‘05, but increases seen in future

By Bioresearch Compliance Report Staff

EMEA in 2005 received 43 marketing authorization applications, but had expected 52 — a drop of about 17%, the agency’s 2005 annual report shows. But the report, adopted by the EMEA Management Board’s 50th meeting March 9, forecasts an upward trend for 2006 and 2007, with 62 and 79 initial marketing authorization applications expected respectively, including applications for similar biological and generic medicinal products.

The 2005 annual report also shows that the number of applications for authorization of designated orphan medicines remained strong, with 15 applications received. Orphan designations increased to 118, and requests for scientific advice and protocol assistance for new human medicines were up by almost 60% compared to levels in 2004.

A similar increase in scientific advice requests was seen for veterinary medicines, with twice as many received in 2005 as in 2004 — 10 versus five. The number of marketing authorization applications for veterinary medicines was in line with the forecast, 11 in 2005 vs. eight in 2004. A positive trend is forecast in the coming years for veterinary medicines, with 14 and 16 applications expected for 2006 and 2007, respectively.

The management board also adopted the draft work program for 2007, as well as a preliminary draft budget for 2007 that, once approved by the European Parliament and Council later in 2006, would see EMEA’s total budget rise to €144.1 million ($174.3 million). The current budget is €123.6 million, or $149.5 million.

The board said this increase reflects the forecast increase in number of applications and new workload in 2007, with total fee revenue expected to reach €91.8 million ($111 million).

The EMEA board approved requests for 17 new staff members in 2007, which would take the maximum staff complement to 441.

EMEA priorities for 2007, as outlined in the draft work program, follow the agency’s long-term strategy and build on priorities set in previous years. Priorities for 2007 include:

• Improving the safety of medicines for human and veterinary use.

• Establishing the new Pediatric Committee, which will provide opinions on Pediatric Investigation Plans, plus coordinating a pediatric research network and providing information on pediatric clinical trials, as part of the agency’s implementation of the upcoming legislation on medicines for children.

• Contributing towards the stimulation of research and development in Europe to allow for better access to new and innovative medicines.

• Increasing openness and transparency of the agency’s operations, and providing high-quality and timely information on medicines to patients and health care professionals.

• Increasing international cooperation and interaction with non-EU countries.

The next meeting of the management board is on June 8. The annual report for 2005 should be on the EMEA website, at http://www.emea.eu.int/.

Clinical trials

Drugs cure depression in half of patients, study says; health care has mixed reactions to study findings

Anti-depressants fail to cure the symptoms of major depression in half of all patients with the disease, even if they receive the best possible care, according to a definitive government study released March 22, the “Washington Post” reported.

The $35 million, NIH-funded study was the largest trial of its kind ever conducted — rather than simply asking whether patients were getting better, the study asked what most concerned patients, that is, whether their depression could be made to disappear altogether.

The study revealed that up to one-third of those who added or changed medicines recovered. When viewed with earlier results, the new findings meant that roughly half the people who suffer from serious, long-term depression can get over it — not just improve their symptoms — with adequate medication.

“The goal here was to find treatments that help people to get well, not just better,” said Thomas Insel, M.D., director of NIH’s National Institute of Mental Health (NIMH). “We have safe and effective treatments.”

But to some clinicians, the data provided no clear answers. Although the study showed that patients who do not respond well to one drug could be helped by another, the results were “discouraging for several reasons,” said David Rubinow, a professor and the chair of the psychiatry department at the University of North Carolina–Chapel Hill, who wrote a simultaneous editorial to the study published in the “New England Journal of Medicine.”

First, Rubniow noted, a large numbers of patients continued to have problems, despite treatment. Additionally, the drugs used in the study — Bristol-Myers Squibb’s (BMS) Buspar (buspirone HCI); Forest Labs’s Celexa (citalopram); GlaxoSmithKline’s (GSK) Wellbutrin (bupropion HCI); Pfizer’s Zoloft (sertraline HCI); and Wyeth’s Effexor (venlafaxine HCI) — worked in very different ways yet had roughly equal effectiveness when it came to treating depression.

Specifically, one-third of approximately 3,000 patients taking Celexa — a selective serotonin reuptake inhibitors (SSRI) — recovered, although they generally took higher doses and were monitored more closely than most patients.

Out of the initial group, 727 chose to switch from Celexa to a different medication and were randomly assigned to get either Zoloft , another SSRI; Wellbutrin, a non-SSRI; or Effexor, an anti-depressant made that works on another brain chemical in addition to the one targeted by SSRIs. Roughly, one-fourth became symptom-free within 14 weeks. No big differences were seen in safety or side effects among the drugs.

Another 565 patients chose to “piggy-back” or add a second anti-anxiety drug, particularly Wellbutrin or Buspar, which can boost the effectiveness of SSRIs.

Rubinow, however, did not find it encouraging that only about one in three patients saw their depression symptoms remiss after an initial round of treatment, and that only about half achieved that goal only after only after trying a new round of treatment involving either a new medication or an additional drug.

He found the results to be an “illuminating and disconcerting” window into the affliction that is thought to fuel many of the 30,000 suicides committed each year in the U.S.

But Augustus John Rush, Ph.D., a psychiatrist at the University of Texas Southwestern Medical Center–Dallas, who helped organize the study known as the Sequenced Treatment Alternatives to Relieve Depression, considered the results promising, especially, he explained, when one takes into consideration the many complications that often accompany depression.

“A 50 percent remission rate is extraordinarily good, given the nature of these disorders,” he emphasized. “These individuals have had an average of 16 years of depression. Two-thirds have other concomitant psychiatric conditions and two-thirds have concomitant general medical problems. All of these reduce the chances of remission.”

Although the study has continued to offer treatment for even longer periods, those results are not yet available. Rush said that with chronic problems, most of the benefit is usually seen in the first couple of rounds of treatment, since the remaining patients are those with the most intractable problems.

Psychiatric drugs have been at the center of growing controversy for nearly two years — including concerns that anti-depressants may increase the risk of suicidal behavior among some children and worries that drugs used to treat attention deficit/hyperactivity disorder are overused.

Still, health care providers say they are far more worried about untreated mental illness than any overuse of medications. According to government statistics, depression afflicts 15 million Americans a year. About 189 million prescriptions for anti-depressants were written last year, and the disease costs the nation $83 billion annually because of treatment costs, lost productivity, absenteeism and suicide.

As for safety, the study found no difference among the five drugs tested. All proved similarly effective and relatively safe. The clear message, doctors said, was that anti-depressants should be given a six-to-12-week chance to work and that if one does not help, another should be tried.

FDA management

Bush selects von Eschenbach as regular FDA commissioner

WASHINGTON — President Bush nominated Andrew von Eschenbach, M.D., March 16 to serve as commissioner of FDA, but partisan wrangling over the “morning-after” pill makes it likely the nomination will be stalled indefinitely; von Eschenbach also leads National Cancer Institute (NCI).

Sens. Hillary Rodham Clinton (D-NY) and Patty Murray (D-WA) vowed to block any vote on von Eschenbach’s nomination until FDA decides whether to allow over-the-counter sales of Plan B, an emergency contraceptive known as the “morning-after” pill. The application has been pending for three years. Pro-life groups oppose the application; abortion advocates support it.

The fight comes as FDA is faced with tough decisions about how to track the safety of drugs and medical devices after approval, how to balance competing demands between speedier access to drugs and more information about their safety, and how to approve generic versions of expensive biotech drugs.

Some agency observers believe that only a confirmed commissioner can make such decisions. Political observers nonetheless predict a stalemate.

Von Eschenbach, 64, has been acting FDA chief since September 2005. He succeeded former FDA commissioner Lester Crawford, D.V.M., who resigned less than three months after surviving a tough Senate battle for confirmation.

Norman Ornstein, a scholar at the American Enterprise Institute, said that the Bush administration would allow von Eschenbach’s nomination to languish for years before doing anything that would “anger its allies in the anti-abortion movement,” as an approval for Plan B would.

“It’s not a contest,” Ornstein said. “With the president’s approval rating down even among Republicans, they are not going to enrage their base.”

Last week, an aide to Senate Health Committee Chair Mike Enzi (R-WY) said FDA would need to address the contraceptive issue before the panel acts on a nomination. Enzi issued a statement March 15 praising the nomination but did not address the controversy.

Several industry groups welcomed the nomination, but also tactfully avoided comment on the Plan B controversy. “Dr. von Eschenbach’s experience at the NCI, as a urologic surgeon, medical educator, and cancer survivor makes him keenly aware of the value of medical technology,” said Stephen J. Ubl, president, AdvaMed, in a press statement.

“AdvaMed looks forward to working with him to ensure patients have timely access to safe and effective lifesaving and life-enhancing medical tests and treatments.”

Pharmaceutical Research and Manufacturers of America (PhRMA) issued a press statement as well. “By nominating a permanent FDA commissioner, the President is protecting the health and safety of Americans,” said Billy Tauzin, president and CEO, PhRMA.

“A commissioner nominated by the President, and confirmed by Congress, speaks with greater authority about the resources needed by the FDA to carry out its vital mission.
“A confirmed agency chief can also focus more on long-term programs and needs as well as strategic planning. That is good for FDA stability and the morale of its employees, and good for patients.”

Boyer appointed new head of FDA’s Office of Legislation

David W. Boyer March 15 was appointed as FDA’s assistant commissioner for legislation. In this role, Boyer will manage FDA’s Office of Legislation, oversee the drafting of congressional testimony, respond to congressional inquiries and assist in the development of public health legislation.

Boyer will work closely with the Office of the Commissioner, as well as the six FDA centers.

Boyer has held three senior positions at HHS. He began his HHS career as a special assistant in the Office of the Assistant Secretary for Legislation. Next, Boyer served as a personal aide to the secretary.

In 2005, Boyer returned to HHS as special assistant for oversight in the office of the Assistant Secretary for Legislation.

In addition to his work at HHS, Boyer also has extensive congressional experience. Most recently, Boyer worked with members of Congress as the director of Federal Government Relations for the Biotechnology Industry Organization.

Five new members named to NIH Advisory Committee on Research on Women’s Health

NIH announced March 23 that five new members have been appointed to its Advisory Committee on Research on Women’s Health (ACRWH), which will hold its semiannual meeting on today, March 27.

The new members are:

• Constance Howes, president and CEO, Women and Infants Hospital–Rhode Island, Providence, RI;

• Nancy Norton, founder and president, International Foundation for Functional Gastrointestinal Disorders (IFFGD), Milwaukee;

• Eugene P. Orringer, M.D., executive associate dean for faculty affairs and faculty development, University of North Carolina School of Medicine (UNC), Chapel Hill, NC;

• Susan P. Sloan, M.D., associate professor of medicine and associate residency program director of internal medicine, James H. Quillen College of Medicine, East Tennessee State University, Johnson City, TN; and

• Barbara W.K. Yee, Ph.D., professor and chair of family and consumer sciences, University of Hawaii–Manoa, Manoa Valley, O’ahu, HI.

Howes brings to the ACRWH many years of experience in hospital and health care administration. She is president and CEO of Women and Infants Hospital–Rhode Island, a regional perinatal center affiliated with Brown Medical School. She also has served as general counsel to businesses with concentration in general business and corporate law, administrative law and hospital law; and in the capacity of general counsel of care for the New England Hospital System.

As Founder and President of IFFGD and as chairperson of the Digestive Disease National Coalition, Norton brings the patient, support-group perspective to the ACRWH. She founded IFFGD 14 years ago and continues to serve the digestive disease community in this capacity.

Orringer, a physician with a specialty in hematology/oncology, has extensive experience in research support infrastructure that can provide the ACRWH with the benefit of his long-standing expertise in these areas. As a principal investigator in the Building Interdisciplinary Research Careers in Women’s Health program at UNC, Orringer brings knowledge about the importance of training a new cadre of researchers doing interdisciplinary research on women’s health as well as his unique and successful approaches to mentoring.

Sloan’s expertise and education span the fields of education, law and medicine. She combined her research interest in osteoporosis with her work among the Native American population — most recently by looking at bone density in Native Americans. She also served as secretary of the Assn of American Indian Physicians and as president and committee member of the Assn of Native American Medical Students, a national organization. She received the American Medical Women’s Assn 2005 Local Legend from Tennessee Award as part of the National Library of Medicine “Changing the Face of Medicine” exhibit on women physicians.

Yee’s current research examines how gender, health literacy and acculturation influences health benefits and lifestyle practices across three generations of Vietnamese and Pacific Islanders living in the U.S. She served on the editorial boards of the journals of  “Gerontology: Psychological Sciences, Psychology and Aging” and “Topics of Geriatric Rehabilitation.” She is a member of the Public Health Service Expert Panel of Minority Women’s Health, and the Health Resources and Services Administration. steering committee for the Bright Futures for Women’s Health and Wellness. Yee also is a fellow of the American Psychological Assn and Gerontological Society of America. She was awarded the Okura Community Leadership Award in 2004 from the Asian American Psychological Assn, Okura Mental Health Leadership Foundation, for outstanding community leadership that benefits the Asian-American community.

The NIH Revitalization Act of 1993 charges the advisory committee with giving counsel and recommendations to the director of the Office of Research on Women’s Health on appropriate research activities to be undertaken by the national research institutes with respect to women’s health research.

In all, the committee comprises up to 18 members who are appointed by the NIH director.

Gene research/genomics

Aggression-related gene weakens brain’s impulse control circuits

NIMH announced March 21 researchers have discovered that a version of a gene previously linked to impulsive violence appears to weaken brain circuits that regulate impulses, emotional memory and thinking in humans.

According to NIMH researchers, brain scans revealed that people with this gene version – especially males – tended to have relatively smaller emotion-related brain structures, a hyperactive alarm center and under-active impulse-control circuitry. The study identified neural mechanisms by which this gene likely contributes to risk for violent and impulsive behavior through effects on the developing brain.

Specifically, Andreas Meyer-Lindenberg, M.D.; Daniel Weinberger, M.D.; and their colleagues at NIMH explained that the gene is one of two common versions that code for the enzyme monoamine oxydase-A (MAO-A), which breaks down key mood-regulating chemical messengers, most notably serotonin.

They said that the previously identified violence-related, or L, version gene, contains a different number of repeating sequences in its genetic code than the other version (H), likely resulting in lower enzyme activity and hence higher levels of serotonin. These, in turn, influence how the brain gets wired during development. The variations may have more impact on males because they have only one copy of this X-chromosomal gene, while females have two copies, one of which will be of the H variant in most cases, the researchers surmised.

Several previous studies substantiate this. For example, a 2002 NIMH study discovered that the gene’s effects depend on interactions with environmental “hard knocks,” that is, men with L were more prone to impulsive violence, but only if they were abused as children. Meyer-Lindenberg and colleagues set out to discover how this works at the level of brain circuitry.

Using structural magnetic resonance imaging (MRI) in 97 subjects, they found that those with L showed reductions in gray matter (neurons and their connections) of about 8 percent in brain structures of a mood-regulating circuit (cingulate cortex, amygdala) among other areas. Volume of an area important for motivation and impulse regulation (orbital frontal cortex) was increased by 14 percent in men only. Although the reasons are unknown, this could reflect deficient pruning — the withering of unused neuronal connections as the brain matures and becomes more efficient, the researchers speculated.

The researchers then looked at effects on brain activity using functional MRI scans. While performing a task matching emotionally evocative pictures — angry and fearful faces — subjects with L showed higher activity in the fear hub (amygdala). At the same time, decreased activity was observed in higher brain areas that regulate the fear hub (cingulate, orbital frontal, and insular cortices) — essentially the same circuit that was changed in volume.

While these changes were found in both men and women, two other experiments revealed gene-related changes in men only. In a task that required remembering emotionally negative information, men, but not women, with L had increased reactivity in the fear (amygdala) and memory (hippocampus) hubs.

Men with L also were deficient during a task requiring them to inhibit a simple motor response; they failed to activate a part of the brain (cingulate cortex) important for inhibiting such behavioral impulses. This region was, conspicuously, the cortex area that was most reduced in volume.

The findings are reported in the March 20 edition of the “Proceedings of the National Academy of Sciences.”

Researchers highlight role of MiRNA in platelet formation

Scientists at the Ohio State University College of Medicine said March 17 they have identified a handful of microRNAs that appear to play a significant role in the development of platelets. The research also suggests that some of these miRNAs, when acting abnormally, may contribute to certain forms of leukemia.

“Basically, we found that a specific set of miRNA genes are turned off in normal platelet development, but turned on in certain platelet-related leukemia cells,” explained lead author Ramiro Garzon, M.D., a clinical instructor at the university.

The MiRNA helps to regulate many key biological processes, including cell growth, death, development and differentiation, explained Garzon.

In the study, which is published in the “Proceedings of the National Academy of Sciences,” the researchers clarify how they previously uncovered substantial evidence linking certain patterns of miRNA to both normal and abnormal blood cell development, especially in diseases, such as, chronic lymphocytic leukemia and lymphoma.

The research team then used microRNA gene chip analysis to identify miRNA expression in normal stem cells and megakaryoctyes. They also studied miRNA expression patterns in four acute megakaryoblastic leukemia (AMKL) cell lines, and discovered that (1) a set of 17 miRNAs are turned off during normal megakaryocyte differentiation and (2) that eight of those genes create a molecular signature that clearly defines a megakaryocyte from any other type of cell.

“We believe this set of genes may contribute to platelet formation,” says Garzon. “We think that when these miRNAs are turned off, it’s a signal to other gene targets to get busy with the normal process of development.” Garzon says just the opposite happens in AMKL, an unusual form of leukemia more often found in children than adults.

Garzon said this enhanced knowledge about miRNA could lead to a new class of targeted therapies that may be helpful in treating leukemia and other diseases. However, much more research is needed before this goal can be realized, he noted.

Structure of human cytochrome P450 2D6 solved by use of Fluidigm technology, GSK says

GlaxoSmithKline (GSK) announced March 17 that it had solved the structure of cytochrome P450 2D6 — an enzyme important in the metabolism of a wide variety of drugs.

GSK said its TOPAZ crystallization chips were used to identify positive conditions for crystallization and subsequently to grow P450 2D6 crystals.

The company researchers worked in conjunction with Fluidigm, South San Francisco, which develops and distributes systems based on the unique properties of integrated fluidic circuits to manipulate fluids on a micro- and nano-volume scale. TOPAZ is GSKs system, which speeds the discovery of protein structure, an essential step in rational drug design.

For this protein target, conventional microplate crystallization trials failed to yield crystals suitable for an X-ray crystal structure determination, according to Paul Rowland, investigator, structural sciences, GSK Discovery Research Group in Harlow, U.K.

The team then turned to TOPAZ preparative chips to further explore crystallization conditions and to scale up those that appeared promising. In the paper Rowland et al. describe the procedure whereby crystals were grown and harvested from the TOPAZ chips and then used to solve the protein structure resulting in the P450 2D6 crystals, which were sufficiently large and well ordered for structural analysis.

“The success of this research bodes well for a chip-based approach, from initial screening of conditions through growth of diffraction-quality crystals,” explained Drake Eggleston, VP, computational, analytical and structural sciences, GSK. “

“The approach provides a number of potential advantages because the TOPAZ system is more efficient than microplates for discovery screening in terms of sample consumption and image analysis.”

The publication of the P450 2D6 structure attests to the value of a long-standing collaboration between GSK and Fluidigm to integrate TOPAZ technology into the drug discovery process, Eggleston emphasized.

He said the P450 2D6 structure is a milestone in ongoing work to determine the structures of various bound substrates and inhibitors related to ligand recognition and specificity in human cytochrome systems.

A relatively large number of genetic polymorphisms have been described for 2D6, some of which are markers for rapid, or conversely, very poor metabolism. A deeper understanding of these polymorphisms as facilitated by three-dimensional structural considerations may lead to safer, more efficacious drugs.

The findings are reported in the March 17 issue of the “Journal of Biological Chemistry.”

Successful cell engineering may lead to BSE prevention, researchers say

Researchers announced March 20 that they have successfully knocked down the expression of possible disease-causing genes in a cloned goat fetus, perhaps preparing the way for breeding disease resistance in other animals, even those genes that might cause bovine spongiform encephalopathy (BSE), commonly known as “mad cow disease.”

The research was a collaboration between scientists at Texas A&M University’s College of Veterinary Medicine and Biomedical Sciences and the Howard Hughes Medical Institute.

The scientists explained how they successfully utilized genetic engineering to produce a goat cell line in which the gene encoding for prion protein (PrP) was targeted for silencing by a process known as RNA interference. They then utilized these cells for nuclear transfer to produce a cloned, transgenic goat fetus that exhibited a greater than 90 percent knock down of PrP.

This is a genetic milestone because previous studies involving mice in which the PrP gene has been silenced have demonstrated the animals to be resistant to prion-mediated diseases, such as, BSE.

“We were able to knock down the genes that are involved with diseases in goats. In cattle, the disease that would most likely be targeted would be BSE, although there are numerous other genes that could be targeted to produce animals resistant to a variety of diseases,” explained Texas A&M researcher Mark Westhusin. “Moreover, the success raises possibilities to develop similar disease-resistance strategies in other animal species.”

BSE, or Mad Cow Disease, is a fatal brain-wasting disease first identified in the U.K. in 1986. BSE affects a cow’s nervous system and causes the animal to lose much of its movement before it eventually dies. More than 180,000 cases of BSE have been confirmed worldwide, including recent cases in the U.S.

BSE also can be passed to humans; more than 100 such cases have been confirmed, mostly in the U.K.

“The next step is to try and avoid the cloning process — to skip that step if possible in developing the disease-resistant animals,” Westhusin said. “That’s where more research is going to be needed and where the process goes from here.”

Their work is published in the current “Proceedings of the National Academy of Sciences.”

Same genes may underlie alcohol and nicotine co-abuse

Vulnerability to both alcohol and nicotine abuse may be influenced by the same genetic factor, according to a recent study supported by NIH’s National Institute on Alcohol Abuse and Alcoholism (NIAAA).

In the study, researcher at Toronto’s Centre for Addiction and Mental Health and the University of Toronto looked at how two genetically distinct kinds of rat — one an innately heavy-drinking strain bred to prefer alcohol (P rats), the other strain bred to not prefer alcohol (NP rats) — learned to give themselves nicotine injections by pressing a lever. Researchers found that P rats took more than twice as much nicotine as NP rats.

Researchers have known for some time that people who smoke are more likely to drink alcohol than non-smokers. Similarly, smoking is three times more common in people with alcoholism than in the general population.

Because previous studies also have determined that genetics plays an important role in both alcohol and nicotine addictions, researchers have hypothesized that the same gene or genes may influence the co-abuse of these substances.

However, in the current study, researchers showed that the P rats’ affinity for nicotine could be demonstrated before the animals were ever exposed to alcohol. P rats also were found to be more vulnerable to nicotine relapse than NP rats. Researchers withheld nicotine from the rats until their lever pressing occurred infrequently. Then, both P and NP rats were given a single nicotine injection. P rats, but not NP rats, resumed pressing the lever previously associated with nicotine infusions.

Conversely, the researchers also showed that the P rats’ apparent genetic vulnerability to alcohol and nicotine did not appear to extend to other drugs of abuse. When P and NP rats learned to press a lever to receive cocaine, each group took about the same amount of that drug.

The findings were reported in the “Journal of Neuroscience. “

Genetically engineered mosquitoes show resistance to dengue fever virus

Researchers at University of California–Irvine (UCI) said March 12 they have successfully created a genetically engineered mosquito that shows a high level of resistance against the most prevalent type of dengue fever virus, providing a powerful weapon against a disease that infects 50-million people each year.

According to the article, which was published in the “Proceedings of the National Academy of Sciences,” the researchers exploited a vulnerability of the dengue virus to make the mosquitoes resistant to infection. This vulnerability occurs when the virus replicates and its single strand of RNA briefly becomes double-stranded. At this point, the virus is vulnerable because of a naturally occurring protein called dicer-2.

This protein initially has no effect on a single strand of RNA, but acts like scissors on the double strand, chopping it up and rendering its genetic material useless, the researchers explained. Once this process is started, the single-stranded RNA also becomes vulnerable to dicer-2 and is cut up, thereby preventing further virus replication.

On its own, this process of self-destruction happens only after the virus has already replicated and been transmitted; however, the researchers found a way to control and speed up the process. They cloned a section of the virus’ RNA and injected two inverse copies of it into mosquito embryos. The copies the formed a double-stranded RNA, which, as expected, bound with dicer-2 and was chopped up. The virus never had the opportunity to replicate. As a result, they could inoculate mosquitoes with a form of the virus that would essentially be benign.

Funded by a grant from NIH, the research was conducted in conjunction with UCI by teams from Colorado State University and from Virginia Polytechnic Institute and State University.

The researcher then performed tests on a family of mosquitoes descended from one of the original embryos that survived the procedure. They found that the vast majority of that family was highly resistant to dengue infection. They also were able to detect the engineered RNA in the mosquitoes, a sign that the genetic alteration had been successful and passed down through reproduction. Furthermore, when that genetic modification was reversed, the mosquitoes were as susceptible to the virus as they had been before the procedure.

Dengue fever is endemic in more than 100 countries in Africa, the Americas, the Eastern Mediterranean, Southeast Asia and the Western Pacific.

Research and development

NIH provides $24 million to support Biomedical Informatics Research Network

NIH’s National Center for Research Resources (NCRR) announced March 21 it will provide $24.29 million dollars over five years to UCI for continued support to the Biomedical Informatics Research Network (BIRN).

Currently a consortium of 28 universities and 37 research groups, BIRN is leveraging and sharing distributed tools, software applications, techniques, data and expertise that extend beyond the capacity of most laboratories.

This major NCRR initiative, involving both basic and clinical investigators, is initially concentrating on research involving neuroimaging, but the tools and technologies developed will ultimately be applicable to other disciplines.

UCI is leading the part of the project known as Function BIRN that brings together researchers at 14 institutions for the common purpose of developing and testing interdisciplinary techniques for integrating efforts in functional MRI across multiple sites. The award will allow the Function BIRN team to improve calibration of imaging equipment across sites, develop robust protocols for cognitive assessment, formulate methods for analysis of resulting data and develop a scalable technology toolkit to support such complex studies.

A test project will interpret functional MRI datasets from more than 200 subjects scanned at facilities across the country.

In its initial phase, the Function BIRN focused on developing a shared data storage infrastructure and standard imaging methods for the multiple sites. The project entailed a set of five research participants who traveled to nine sites around the country for brain scans using a common protocol. This formed the first calibration dataset of its kind in the world for systematically studying intersite variability. Software tools were developed to reduce such variability, to automatically correct image distortions, and to manage data for large and diverse neuroimaging research projects. The open-source data and tools are available at http://www.nbirn.net/Resources/Downloads/.

Communicable diseases

HHS launches pandemic flu website

HHS has developed a website, which it says will provide one-stop access to U.S. Government avian and pandemic flu information.

According to the March 23 announcement, the website will provide advice on how to prepare in the event of an outbreak. Visitors to the site can stay up-to-date on plans for responding to an outbreak, learn about current tests, vaccines and medications, and see alerts and advisories for travelers.

In December 2005, President Bush asked Congress for $7.1 billion to fund preparations, and in Congress appropriated $3.8 billion to help the Nation prepare. Of that, $3.3 billion was allocated to HHS. The HHS funding will be used to achieve HHS five primary objectives:

• Monitoring disease spread to support rapid response

• Developing vaccines and vaccine production capacity

• Stockpiling antivirals and other countermeasures

• Coordinating federal, state and local preparation

• Enhancing outreach and communications planning

The website is user friendly and the information is meant to keep the general public educated about flu outbreaks. For example, in terms of the avian influenza (virus H5N1), the site provides maps of confirmed human cases of the flu as well as World Health Organization “situation updates.” Resources include, but are not limited to influenza planning checklists (in both English and Spanish) , as well as other planning tools, risk communications strategies, the National strategy, and the HHS pandemic plan. Furthermore, the site lists upcoming relevant meetings and conferences.

The website can be accessed at http://www.pandemicflu.gov/.

Scientists discover how bird flu spreads

Scientists from the University of Wisconsin–Madison (UWM), with colleagues in Japan, say they found the reason avian influenza is not spreading easily from person-to-person. At present, they said, the virus concentrates itself too deep in the respiratory tract to be spewed out by coughing and sneezing; but experts say the virus could change that behavior by genetic mutation, taking a step toward unleashing a worldwide outbreak of lethal flu. Similar results also were reported from researchers at the Erasmus Medical Center, Rotterdam, Netherlands.

According to their findings, which are reported in the March 23 issue of the journal “Nature,” both research teams used human tissue removed from various parts of the respiratory tract — the region from the nose to the lung — to study where virus infection occurs.

Although, scientists already knew that bird flu viruses use a specific kind of docking site to enter cells they infect, while human flu viruses use a different one, the UWM group found the bird virus docking site appears mostly on lung cells, while being rare on cells found in higher areas like the nose and windpipe. Those higher areas were dominated instead by the human-type docking site.

According to from University of Wisconsin-Madison virologist Yoshihiro Kawaoka, for H5N1 to become a pandemic virus, it would have to mutate in a way that lets it attach to the same docking site human viruses use. Other mutations would be needed as well.

Robert M. Krug of the University of Texas at Austin called Kawaoka’s work an important observation, adding that if H5N1 begins to use the human virus-docking site “we’ve got a lot to worry about.” It is not clear whether that would be enough to produce a pandemic germ, he said.

James Paulson of the Scripps Research Institute, La Jolla, CA, stressed that other viral factors may be important in human-to-human transmission. He believes that once the virus has a foothold in a person, regardless of where it is in the respiratory tract, it may mutate to gain the abilities it needs to start spreading among people.

Iomai receives $1.4 million for flu vaccine research

Iomai Corp., Gaithersburg, MD, announced March 9 that NIH has awarded it $1.4 million for the continued development of its immunostimulant needle-free patch to extend the availability of existing stocks of influenza vaccine in the case of a pandemic.

The award is the second installation of a two-year, $2.9 million grant first announced in January 2005. The grant was awarded under the government’s biodefense initiative.

The patch is based on the company’s transcutaneous immunization technology, which leverages the skin’s unique immune properties as a vehicle for vaccine delivery and enhanced stimulation of the immune system. The immunostimulant patch is designed to be applied at the injection site at the time an adhesive bandage would typically be applied.

The device works by activating immune cells to increase the immune response to the injected vaccine, Iomai explained. The increased immune responses may allow for the use of far smaller doses of injected vaccine to achieve the needed levels for protection. Moreover, the company pointed out, the patch offers the opportunity to be stockpiled in advance of a pandemic event.

A phase I study of a pandemic influenza vaccine by NIH found that a large two-dose regimen of injectable vaccine was required to stimulate what is believed to be an adequate immune response.

HHS awards $1.7B in Ryan White CARE Act grants for HIV/AIDS care for low-income people

HHS March 4 announced 174 grants totaling nearly $1.7 billion for states, territories and cities to provide care and services for low-income HIV-positive people.

According to the press release, the grants are provided under three titles of the Ryan White CARE Act. The 51 Title I grants, totaling $587 million, will help eligible metropolitan areas provide essential HIV/AIDS care and support services to HIV-positive patients who are uninsured or underinsured.

The 59 Title II grants, totaling $1.06 billion, will support state and territory AIDS Drug Assistance Programs, including funding for the purchase of antiretroviral drugs, as well as the Minority AIDS Initiative.

The 64 Title III grants, totaling $25.7 million, will help community-based organizations provide outpatient care services, including testing, referring and counseling, as well as medical evaluation and clinical care, according to the release.

People

Ezekowitz, internationally-recognized physician and researcher, joins Merck R&D

Merck announced March 16 that R. Alan B. Ezekowitz, Ph.D., has been named senior VP and franchise head, Immunology, Respiratory and Endocrine, Merck Research Laboratories (MRL).

Ezekowitz, 52, assumes his new role on April 1. He came to MRL from Massachusetts General Hospital, where he served as chief of pediatric services and chaired the Executive Committee On Research.

Ezekowitz helped to create the MassGeneral Hospital for Children, a ‘hospital within a hospital,’ which provides world-class care for infants, children and adolescents.

He also has been chief of Pediatric Services for Partners HealthCare System, Boston, and the Charles Wilder professor of pediatrics at Harvard Medical School.

Prior to joining the staff of Massachusetts General Hospital in 1995, Ezekowitz served on the staff of Children’s Hospital–Boston for 11 years.

In this newly-created position with MRL, Ezekowitz will have overall responsibility for scientific direction across the drug discovery and development process for Merck’s key therapeutic areas of immunology, respiratory disease and endocrine disorders. He will be based at Merck’s research facility in Rahway, NJ.

SurModics names Shoup VP quality, regulatory and clinical affairs

SurModics, Eden Prairie, MN, March 13 announced that Michael J. Shoup joined the company as VP of quality, regulatory and clinical affairs.

Shoup has more than 20 years of experience in quality assurance and manufacturing, including over 15 years in the medical device industry at St. Jude Medical, Acorn Cardiovascular and Boston Scientific SciMed. Most recently, he was director of quality and design assurance for St. Jude Medical’s Cardiac Surgery Division.

Shoup teaches medical device design and manufacturing as an adjunct professor in the School of Engineering at St. Thomas, and regularly lectures for the Center for Business Excellence.

Trial news updates

Avicena Group, Palo Alto, CA, announced March 22 that FDA has granted orphan drug designation to HD-02, the company’s proprietary drug candidate for the treatment of Huntington’s disease (HD). The company recently announced the publication of positive Phase I/II data for HD-02 in the journal “Neurology.” The findings showed that the drug was safe and well-tolerated by patients at a dose of eight grams/day, while resulting in elevated serum and brain levels of creatine. Additional findings demonstrated that HD-02 reduced serum 8-hydroxy-2’-deoxyguanosine (serum 8OH2’dG) levels, which are markedly elevated in HD patients.

CuraGen Corp., Branford, CT, announced March 22 the initiation of patient dosing in a Phase Ib/II proof-of-concept trial to evaluate PXD101, a small molecule histone deacetylase (HDAC) inhibitor, in combination with Velcade (bortezomib) for the treatment of relapsed, refractory multiple myeloma (MM). The goal of the Phase Ib portion of this trial is to establish the maximum-tolerated-dose (MTD) of PXD101 in combination with Velcade in up to 30 patients who have failed at least two prior lines of therapy for MM. Following determination of the MTD, the study will enter Phase II and enroll up to 15 additional patients with relapsed, refractory MM who have failed at least one prior therapy. The Phase II portion of the study will further evaluate the safety, pharmacokinetics, pharmacodynamics, and anti-tumor activity of PXD101 in combination with Velcade. Patients will be enrolled at multiple sites in the U.S. PXD101 is a promising small molecule HDAC inhibitor being investigated for its role in the treatment of a wide range of solid and hematologic malignancies either as a single-agent, or in combination with other active anti-cancer agents. HDAC inhibitors represent a new mechanistic class of anti-cancer therapeutics that target HDAC enzymes and have been shown to: arrest growth of cancer cells (including drug-resistant subtypes), induce apoptosis, promote differentiation, inhibit angiogenesis and sensitize cancer cells to overcome drug resistance when used in combination with other anti-cancer agents. Preliminary results from this open-label, multi-center study are expected by mid-2007.

Elan, Dublin, Ireland, and Biogen Idec, Cambridge, MA, announced March 22 that a decision on their currently suspended multiple sclerosis (MS) drug, Tysabri (natalizumab), has now been delayed by FDA until June. At that time, the companies expect FDA to make a decision on or before June 28 on whether to permit Tysabri to return to the market. Initially, FDA was to have made a decision this week. The drug was withdrawn from the market in February 2005 after three people taking Tysabri in clinical trials contracted a rare, often fatal brain disease called progressive multifocal leukoencephalopathy; two died.

GSK announced on March 14 that it will undertake a clinical study of a preventive vaccine for human papillomavirus (HPV) infection starting in April. The vaccine is indicated for cervical cancer, which is the second most common cancer in women. In clinical studies conducted in Japan, the vaccine showed benefits against HPV16 and 18 types of infections. The vaccine is approved in the EU under the trade name Cervarix.

Nabi Biopharmaceuticals, Boca Raton, FL, announced March 21 it will continue development of its gram-positive program, led by StaphVAX [Staphylococcus aureus Polysaccharide Conjugate Vaccine] and Altastaph [Staphylococcus aureus Immune Globulin Intravenous (Human)]. The decision was based on conclusions from an outside advisory panel’s review of the company’s assessment of the StaphVAX confirmatory Phase III clinical study results, the company said. The assessment revealed marked differences in the effectiveness of the lot of vaccine used in this study compared to the lot used in the previous Phase III clinical study. On Nov. 1, 2005, Nabi announced that this study had failed to meet its primary endpoint. Because these results were not consistent with previous positive clinical data for StaphVAX, the company developed an investigation plan and formed an outside advisory panel of experts to conduct an assessment to determine the factors that led to the unexpected results. This panel was tasked with three main objectives: review and revise the plan; analyze the data; and provide direction for the future development of the company’s Gram-positive infections program. In collaboration with the panel, Nab reached two important conclusions related to the future development of StaphVAX and Altastaph: (1) the quality or functional characteristics of the antibodies generated by the vaccine used in the confirmatory clinical study was inferior to those antibodies generated by vaccine lots used in previous and subsequent clinical studies; and (2) medical factors associated with kidney disease in dialysis patients impaired their immune response to the vaccine. When considered in combination with an increase in the virulence of the bacteria, these factors also contributed to the observed lack of protection in this study population. Nabi said data from the company’s review have defined subtle, significant changes in elements of the manufacturing process for the lot used in the confirmatory Phase III study. These changes resulted in differences in the capsular polysaccharide structure itself that are believed to be important for producing high-quality and high-affinity antibodies. Nabi also noted that it has developed a new laboratory assay capable of distinguishing these findings about antibody quality. “This new assay will be used to ensure that future vaccine and antibody product lots generate antibodies of optimal quality prior to initiating additional clinical studies,” the company said in a statement.

Neurobiological Technologies, Emeryville, CA, March 22, announced the initiation of its second Phase III study of Viprinex (Ancrod) in patients with acute ischemic stroke. The overall clinical development program for both trials will enroll 1,300 patients, divided equally between the two trials. The program will be global in nature recruiting patients in the U.S., Europe, the Pacific Rim and South Africa. This second Phase III trial, known as Ancrod Stroke Program-II (ASP-II), will evaluate the dichotomized modified Rankin Scale as the primary endpoint. The dichotomized modified Rankin Scale measures independent day-to-day function of patients 90 days post-stroke. Secondary endpoints include other analyses of the Rankin and the Barthel Index. ASP-II is a randomized, double-blind, placebo-controlled trial of patients who will receive a brief intravenous infusion of Viprinex or placebo within six hours of the onset of stroke. The dosing of Viprinex in both ASP-I and ASP-II will be approximately one-tenth of the dosing used in prior Viprinex clinical programs conducted by Knoll AG. This is based on a single one-day infusion, as opposed to either five or seven days used in previous clinical trials.

OXiGENE, Waltham, MA, March 23 announced that the company has successfully completed patient enrollment in a Phase II clinical trial for the treatment of imageable solid tumors. The trial, which is being conducted in the U.S. under OXiGENE’s IND application on file with FDA, is designed to evaluate the safety and anti-cancer activity of the triple combination of Combretastatin A4P (CA4P) — OXiGENE’s lead therapeutic candidate — together with widely-used chemotherapy agents, carboplatin and paclitaxel. OXiGENE expects the presentation of top line data later in 2006, as patients enrolled in this trial are continuing to receive prolonged therapy. The Phase II clinical trial, which received clearance to commence in December 2004, is a randomized, open-label trial designed to evaluate the triple combination of Combretastatin A4P, carboplatin and paclitaxel in patients with solid tumors. The objectives of the trial are to assess the safety of several doses of CA4P in combination with the two chemotherapeutic agents, gather data on anti-tumor activity and establish a recommended Phase II/III dose. Additionally, the study will assess, by MRI, changes in tumor blood flow, which may provide additional insight into the biological activity of CA4P.

Teva Pharmaceutical Industries, Jerusalem, March 21 said it has halted development of an oral version of its MS drug Copaxone (glatiramer acetate). Teva and its partner, Lundbeck A/S, Copenhagen, Denmark, began clinical trials of oral Copaxone in 2000 but the results were not “statistically significant,” the company said. Now, based on further results received in March 2006, Teva and Lundbeck will not continue the development of this formulation, Teva said in a filing to U.S. Securities and Exchange Commission (SEC). “Nevertheless, Teva is considering future development of Copaxone in various non-parenteral formulations and will make its decision in the context of its entire MS portfolio,” the company added in the SEC filing.

Wyeth Pharmaceuticals announced March 16 its decision to discontinue the Horizon Phase III clinical trial program of its investigational drug temsirolimus oral tablets in combination with Femara (letrozole), a currently approved breast cancer therapy, for first-line use in postmenopausal women with hormone-receptor positive metastatic breast cancer. This decision was based upon the recommendation of an independent Data Monitoring Committee (DMC) after review of data from a planned interim analysis. The Horizon study compared the combination of temsirolimus oral tablets and letrozole versus letrozole alone. The DMC advised that continuation of the trial was unlikely to achieve the targeted level of efficacy for the combination therapy compared to letrozole alone. The DMC concluded, therefore, that the risk/benefit ratio for treatment of metastatic breast cancer did not favor continuation and recommended that the trial be discontinued. Wyeth said that although the Phase III trial for women with hormone-receptor positive metastatic breast cancer involved an oral formulation of temsirolimus is discontinued, two other Phase III clinical trials studying temsirolimus in renal cell carcinoma and mantle cell lymphoma using an intravenous formulation are continuing. After a recent review of the data, the DMC for the renal cancer study indicated that study continue as planned, the company added. Temsirolimus is a targeted investigational drug that specifically inhibits mTOR (mammalian target of rapamycin) kinase, a protein critical for tumor growth and cell survival. Anti-tumor activity with this agent has been previously reported in Phase I and Phase II studies.

Trial briefs

AnorMED, Vancouver, announced March 17 that preliminary clinical data on AMD070, an HIV entry inhibitor, showed the drug candidate is active, generally safe and well tolerated in HIV patients. The open label dose finding study, XACT, funded by AnorMED, involves dosing of AMD070 twice daily for 10 consecutive days. There are up to four cohorts with a total of 12 patients per cohort. Activity and safety data from the first eight HIV patients enrolled in the first dose cohort, showed four out of eight had significant reductions in CXCR4 viral load with an average reduction of 1.3 log. Based on this data, enrollment into the first cohort will be completed and the next dose cohort will be initiated. More detailed activity and safety data will be announced in September 2006, the company said. HIV entry inhibitors may become a new treatment paradigm in the management of HIV. In order to enter and infect healthy cells HIV must bind to either the CXCR4 or CCR5 receptor. AnorMED’s HIV Entry Inhibitor Program is focused on the discovery and development of drugs that target both receptors.

AstraZeneca announced March 22 results from two clinical trials, which will be published in the April edition of the “American Journal of Gastroenterology,” which indicate that Nexium (esomeprazole magnesium) can reduce the incidence of gastric ulcers in patients at risk of developing gastric ulcers and who regularly take either non-selective nonsteroidal anti-inflammatory drugs (NSAIDs) or COX-2-selective NSAIDs. Pooled data from the double-blind, randomized, six-month trials showed that significantly fewer patients taking either Nexium 20 mg or Nexium 40 mg, in addition to their regular non-selective NSAID/COX-2-selective therapy, developed an ulcer at six months, compared to those taking a placebo (5.2% and 4.6%, respectively, vs. 17%). These differences were seen as early as the first month of treatment and maintained throughout the study duration. In the first trial, known as Verification of Esomeprazole for NSAID Ulcers and Symptoms, or VENUS, a significantly smaller percentage of patients taking Nexium 20 mg or 40 mg developed a gastric or duodenal (occurring in the beginning of the small intestine) ulcer, compared to patients on placebo (5.3% and 4.7%, respectively, versus 20.4%). In the second trial, Prevention of Latent Ulceration Treatment Options, or PLUTO, the ulcer rates were 5.2% and 4.4% for patients on Nexium 20 mg and 40 mg, respectively, versus 12.3% for those on placebo.

Cell Therapeutics, Seattle, March 22 presented preliminary results of a phase I/II clinical trial of pixantrone in 64 patients with relapsed aggressive non-Hodgkin’s lymphoma who had previously failed one or two prior chemotherapy regimens, including the CHOP regimen. The two-part study was designed to determine the MTD and evaluate the drug’s effectiveness in a combination known as CPOP, in which pixantrone replaces doxorubicin in the standard CHOP regimen. All patients on the study had received prior doxorubicin therapy and as such were at risk for developing severe cardiac toxicity with additional anthracycline therapy. The CPOP regimen was highly effective, with complete response/unconfirmed complete response rates of 41% (14 of 34 patients) and 43% (13 of 30 patients) and overall response rates of 71% (24 of 34 patients) and 77% (23 of 30 patients) in the Phase I and II component of the study, respectively. Predominant side effects were blood-related and included 60% to 75% grade-4 neutropenia and 23% febrile neutropenia. Grade-3 infections were observed at the 150 mg/m2-dose level (10%), but no grade-3 infections have been reported to date at the 180 mg/m2-dose level. There was one case of congestive heart failure reported, which was felt by the investigator to be related to the patient’s underlying cardiac disease.

Genmab, Copenhagen, Denmark, March 21 announced additional data from the HuMax-CD20 Phase I/II study to treat patients with active rheumatoid arthritis. In patients who received two doses of HuMax-CD20, 38% (10/26) achieved ACR50 and 15% (4/26) achieved ACR70. There were three dose levels in the study with results as follows: — In the 300-mg dose group — 25% (2/8) of patients achieved ACR50 — 13% (1/8) achieved ACR70 — In the 700-mg dose group — 44% (4/9) achieved ACR50 — 22% (2/9) achieved ACR70 — In the 1000-mg dose group — 44% (4/9) achieved ACR50 — 11% (1/9) achieved ACR70 After re-examination of the previously reported ACR20 data, it appears one of the responders in the 300 mg dose group had received only one dose of HuMax-CD20, thus 73% (19/26) of patients treated with two doses of HuMax-CD20 achieved ACR20. The intent to treat analysis remains the same, with 63% of patients achieving ACR20.

GW Pharmaceuticals, Porton Down, U.K., March 17 announced preliminary results from a Phase III study of Sativex in the relief of spasticity in people with MS. This study is one of a number of Phase III studies that are currently taking place to support approval of Sativex across Europe in a range of target indications. Analysis of the per protocol population (i.e., those patients that complied with the study protocol) showed a positive and statistically significant improvement in the primary outcome measure (p<0.05). Analysis of the intent-to-treat population (i.e., all study patients regardless of whether they complied with the protocol) was in favor of Sativex but not to a degree that reached statistical significance (p>0.05). The trial was a randomized placebo-controlled parallel group study in 335 people with spasticity due to MS. All patients entering the study were taking best available anti-spasticity medication and remained on such medication through the trial. Hence, any improvements seen in the trial were obtained over and above currently available treatment. The primary outcome measure was the improvement in spasticity as measured on a 0-10 numeric rating scale. The duration of treatment in the study was 14 weeks. The primary endpoint, and two key secondary endpoints (the Responder Analysis and the Carer Global Impression of Change), in the per protocol analysis achieved statistical significance, whereas the outcomes in the intent-to-treat analysis were positive but non-significant. The lack of significance in the intent-to-treat analysis was not due to a lack of effect of Sativex, but rather was due to a larger than expected placebo response, the researchers explained, thus reducing the size of the difference between the two groups. Had the placebo response been the same as in GW’s previous completed Phase III spasticity study, the intent-to-treat analysis in this new study would also have been statistically significant, GW said. Separately, a pooled analysis across the three Sativex MS spasticity studies now completed, incorporating a total of 652 patients, showed Sativex to be significantly superior to placebo (p<0.05). As in previous studies, adverse event data in this latest trial showed the medicine to be generally well tolerated.

Human Genome Sciences (HGS), Rockville, MD, March 14 announced 12-week interim data from a Phase IIb clinical trial to evaluate the efficacy and safety of Albuferon (albumin-interferon alpha IIb) in combination with ribavirin in patients with genotype 1 chronic hepatitis C virus (HCV) who  are naive to interferon alpha-based treatment regimens. The results to date demonstrate that Albuferon in combination with ribavirin was safe, well tolerated and showed robust antiviral activity. The interim data will be presented in detail April 29 at the European Association for the Study of the Liver [See details under “Conferences”]. In a separate press release also issued March HGS reported the interim results of a Phase II clinical trial of Albuferon in combination with ribavirin in treatment-experienced patients with chronic HCV. HGS said that based on the 12-week virologic response data from the Phase IIb study, Albuferon appears capable of meeting this target at doses of 900-1200 mcg every 14 days. The company believes that the interim data at the 1200-mcg dose administered every two weeks show a trend for greater antiviral activity for Albuferon, compared with Hoffman La Roche’s Pegasys (peginterferon alfa-2a), administered every seven days, with 75% of the patients in this group exhibiting a level of HCV viral load below the level of quantitation, compared with 66% in the treatment group receiving 180 mcg of Pegasys at seven-day intervals. Response rates were somewhat lower at 12 weeks for the treatment group receiving 1200-mcg doses of Albuferon every 28 days, which suggests that higher doses will be required to optimize a 28-day dosing schedule, the company concluded. In other Phase II studies, HGS said it is evaluating Albuferon doses of 1500 mcg and 1800 mcg. Interim results show that these doses are well tolerated when given every 14 days and may have greater antiviral activity than the 900-mcg and 1200-mcg doses on the same schedule.

Merck / Schering Plough announced March 13 that Vytorin (ezetimibe/simvastatin) significantly reduced LDL “bad” cholesterol by an average of 52.5% and C-reactive protein (CRP) by an average of 31.0%, compared to averages of 38.0% and 14.3%, respectively, achieved with Merck’s Zocor (simvastatin). These results were observed in a combined post-hoc analysis of three studies involving patients with high cholesterol. C-reactive protein, a marker of inflammation, is considered an emerging risk factor for cardiovascular disease (CVD), according to the American Heart Assn. This post-hoc analysis pooled data from three similar randomized, placebo-controlled, double-blind studies that included a total of 3,083 patients with primary hypercholesterolemia. After a six to eight week washout period and a four week recommended cholesterol-lowering diet, investigators randomized patients with LDL cholesterol levels between 145-250 mg/dL equally into one of the following drug regimens for 12 weeks: Merck / Schering Plough’s ZETIA (ezetimibe) 10 mg; Zocor 10, 20, 40 or 80 mg, Vytorin 10/10, 10/20, 10/40 or 10/80 mg; or placebo. Overall, in a pooled analysis across all doses of Vytorin and Zocor that included all patients with valid baseline and endpoint LDL cholesterol and CRP measurements, the geometric mean CRP level declined in patients taking Vytorin by 31% as compared to a 14.3% reduction in the group of patients taking Zocor. The mean LDL cholesterol level declined in patients taking Vytorin by 52.5% as compared to a 38% reduction in the group of patients taking Zocor. In three placebo-controlled, 12-week trials, the incidence of consecutive elevations in serum transaminases were 1.7% overall for patients treated with Vytorin and 2.6% for patients treated with Vytorin 10/80 mg. In controlled long-term (48-week) extensions, which included both newly-treated and previously-treated patients, the incidence of consecutive elevations in serum transaminases was 1.8% overall and 3.6% for patients treated with Vytorin 10/80 mg. These elevations in transaminases were generally asymptomatic, not associated with cholestasis and returned to baseline after discontinuation of therapy or with continued treatment. The safety and effectiveness of Vytorin with fibrates have not been established; therefore, co-administration with fibrates is not recommended, the company added.

NIH’s National Eye Institute (NEI)-researcher concluded that a single dose of azithromycin taken by mouth after surgery reduces by one-third the recurrence of a vision-threatening eyelid condition called trichiasis. This is in contrast to the usual six-week regimen of tetracycline ointment applied directly to the eye. In this study, called Surgery for Trichiasis, Antibiotics to Prevent Recurrence (STAR), eye infection with the bacterium that causes trachoma was present in 19% of the adults with trichiasis in Wolayta Zone, Ethiopia, the location of the clinical trial. More than 77% of the patients were women, who have four times the rate of trichiasis than men. Women often contract trachoma repeatedly by taking care of infected children. For this trial, the researchers from Wilmer Eye Institute at Johns Hopkins, Baltimore, collaborated with ORBIS International, New York, a nonprofit organization that works to eliminate blindness in developing countries. ORBIS trained Integrated Eye Care Workers (IECWs) to perform the eyelid surgeries, and Wilmer Eye Institute certified them, following WHO guidelines to ensure quality. The surgeries performed by the IECWs were as successful as those performed by ophthalmologists, and recurrence rates overall were low. Pfizer, through the International Trachoma Initiative that it co-sponsors with the Edna McConnell Clark Foundation, provided the azithromycin used in the trial. The study is published in the March 2006 issue of “Archives of Ophthalmology.”

PeriCor Therapeutics, New York, announced March 14 positive results of its novel cardioprotective agent, acadesine. The study was funded by the Ischemia Research and Education Foundation, San Bruno, CA and conducted in collaboration with the Multicenter Study of Perioperative Ischemia (McSPI) Research Group. The study found that among patients undergoing coronary artery bypass graft (CABG) surgery who experienced post-reperfusion myocardial infarction (MI), acadesine significantly reduced two-year mortality by 77% as compared to placebo. The principal benefit, which was observed in the first 30 days following MI, was sustained over the two-year period. This is the first large study to demonstrate prospectively an important reduction in mortality from ischemia/reperfusion injury in any setting of clinical revascularization and this benefit was maintained over two years. In the study of 2698 patients, post-reperfusion MI engendered a significant risk of long-term mortality that was mitigated by acadesine. Perioperative myocardial infarction, which occurred in 100 patients, conferred a 4.2-fold increase in 2-year mortality over patients who did not have an infarction (p<0.001). However, acadesine treatment reduced that mortality by 4.3-fold: from 27.8% (15/54; placebo) to 6.5% (3/46; acadesine) (p=0.006) with the principal benefit occurring over the first 30 days following myocardial infarction. Multivariate analysis confirmed these findings, with no other differences between the groups confounding this relationship. The current study investigated the effects of acadesine on long-term mortality after perioperative MI. It was prospectively designed to monitor all-cause mortality for two years among those patients enrolled in the acadesine 1024 trial who had suffered MI around the time of their CABG surgery. It was randomized, placebo-controlled, and double-blinded. The original in-hospital Phase IIIa 1024 trial was also double-blinded, placebo-controlled, and randomized. It compared the effects of acadesine and placebo on myocardial infarction, through four days following CABG surgery. The drug was administered intravenously at 0.1 mg/kg/min for seven hours continuously, starting 15 minutes prior to the induction of anesthesia. The study was conducted at 54 institutions in the U.S. and Canada, enrolling 2,698 patients with 1,346 receiving placebo and 1,352 receiving acadesine. Although the original study showed a trend that acadesine reduced the incidence of perioperative MI, the difference was not statistically significant. Acadesine is an adenosine regulating agent (ARA), which has been shown to amplify the body’s broad-spectrum protective response during an ischemic event. By augmenting a patient’s own adenosine release in ischemic tissue, acadesine appears to protect heart muscle from ischemic damage. Preclinical studies have shown that ARAs increase endogenous adenosine release in an event-specific and site-specific fashion, remaining pharmacologically silent in the absence of net ATP breakdown. This novel, first-in-class, cardioprotective compound has been shown to be safe and well tolerated in studies of over 4,000 patients across five key clinical studies in the setting of CABG surgery.

Stem Cell Therapeutics, Calgary, ON, Canada, March 16 reported positive results from its Phase I pharmacokinetic clinical trial in support of its lead therapeutic program for stroke, NTx- 265. The trial demonstrated that, for the two drugs administered to healthy volunteers, no drug related adverse events were encountered and both drugs were detected in the cerebrospinal fluid (CSF) following intramuscular administration. The study was conducted on SCT’s behalf by Medicon A/S, Birkerod, Denmark. This Phase I clinical trial permitted characterization of the relationship between intramuscular administration and passage into blood and subsequent transport into the CSF. The study also generated new evidence that these two neural stem cell (NSC) proliferation inducing drugs reach the CSF when administered to human subjects with an intact blood-brain barrier. The results of this clinical trial demonstrated that no drug related adverse events were observed for either NSC proliferation inducing drug at the administered dose; and, transport of the two different NSC proliferation inducing drugs into the CSF was detected in healthy subjects. Moreover, when comparing the two NSC proliferation inducing drugs, there was no statistically significant difference in the pharmacokinetic distribution or transport of drug into the blood and CSF. The primary aim of this trial was to demonstrate that intramuscular administration of either of the two drug forms results in the passage of drug into the blood and then subsequently on into the CSF in age-matched healthy, human volunteers. As NSCs in the adult human brain are in close proximity to the CSF, drug transport into the CSF would support SCT’s planned therapeutic strategy of providing drugs by peripheral administration in order to achieve benefit in the brain. Healthy subjects are expected to have an intact blood brain barrier and therefore permit less transport of drug from blood to the CSF than occurs in stroke patients. This limited transport occurs because stroke patients experience a transient loss of integrity of the blood brain barrier following acute onset of the disease. The administered dose of the two different drug forms was similar to that planned for future clinical studies in stroke patients. As the volunteers in the Phase I trial were healthy and had not suffered a recent stroke, there was no possibility of deriving data to demonstrate efficacy and therefore no efficacy endpoints were included in the Phase I trial’s design. NTx-265 is a therapeutic regimen of two drugs being developed by SCT for the treatment of stroke. The first drug administered in the regimen increases the number of NSCs located in the brain of a patient suffering from a recent stroke, which is accomplished by the systemic administration to the patient of an NSC proliferation inducing drug.

Valeant Pharmaceuticals, Costa Mesa, CA, March 16 reported 48 week results from a Phase II study of its oral anti-viral compound, pradefovir. Valeant is evaluating the safety and efficacy of pradefovir for the treatment of compensated chronic hepatitis B (HBV). Pradefovir is a pro-drug of adefovir that was licensed from Metabasis Therapeutics. Pradefovir uses Metabasis’ HepDirect technology, which enables higher concentrations of the drug in the liver, the primary site of HPV viral replication. The Phase II study is an open-label, randomized, multiple dose study with 242 patients enrolled at 21 sites in the U.S., Taiwan, Singapore and Korea. Approximately half of the patients had been previously treated with interferon or an antiviral and are considered to be more difficult to treat. Seventy percent of the patients were HBeAg positive. The Phase II study consisted of five treatment groups: pradefovir — 5, 10, 20 and 30 mg/day (QD), and Gilead Sciences’s, Foster City, CA, Hepsera (adefovir dipivoxil) — 10 mg/day (QD), with an overall treatment duration of 48 weeks. In the Phase II study, 10, 20 and 30 mg of pradefovir had a statistically superior viral load reduction compared to 10 mg of Hepsera. The study results revealed an HBV DNA decline from baseline with a mean decline compared to HBV DNA in Hepsera and an HBV DNA Control. The percentage of patients with HBV DNA of less than 400 c/mL were 45%, 63%, 56%, and 71% for the pradefovir 5 mg, 10 mg, 20 mg, and 30 mg groups, respectively, and 36% for the Hepsera group. No patient demonstrated an increase in serum creatinine levels over baseline of greater than or equal to 0.5 mg/dL, a marker for the severe renal toxicity associated with higher doses of adefovir. Renal safety was comparable between all treatment groups. There were no serious adverse events related to treatment. The most frequently reported adverse events were similar across all treatment groups, including Hepsera. No dose-related trends regarding safety were identified and no events resulted in a patient being withdrawn prematurely from treatment.

Conferences

ExpertBriefings.com Audioconference. Keeping vCJD/BSE Out of Blood Products! April 4, 2:00-3pm (EST). For more than 20 years David Asher, M.D., supervisory medical officer and laboratory chief in FDA’s Office of Blood Research and Review FDA has been concerned about a theoretical risk that the fatal progressive neurological illness Creutzfeldt-Jakob disease (CJD) — a transmissible spongiform encephalopathy (TSE or prion disease) — might be transmitted by human blood, because the blood of animals with TSEs sometimes contains the infectious agent. Until recently, epidemiological studies yielded little evidence that CJD had been transmitted from person-to-person by blood. Since December 2003, however, three vCJD infections have been recognized in recipients of red blood cells transfused from apparently healthy donors who later came down with the disease. David Asher, M.D., supervisory medical officer and laboratory chief in FDA’s Office of Blood Research and Review, who has been involved in CJD research and public health policy for almost 40 years, will explain current understanding of transfusion-transmitted vCJD and other iatrogenic forms of CJD, and then review FDA’s efforts to reduce the risk. For more information, visit http://www.fdainfo.com/expertbriefings//index.html.

Experimental Biology, April 1-5, San Francisco. Sponsored by Federation of American Societies for Experimental Biology. For more information, visit http://www.faseb.org/meetings/eb2006/call/default.htm.

15^th Annual Partnership with CROs, April 3-5, The Mirage Hotel, Las Vegas. For more information, visit http://www.iirusa.com/cropartners/index.cfm.

Clinical Geonomics, Proteomics, and Bioinformatics Research Course, April 4-8, Westin San Francisco Airport, San Francisco. For more information, visit http://www.gennexttech.com.

12^th National HIPAA Summit, April 9-11, Hyatt Regency on Capitol Hill, Washington. For more information, visit http://www.HIPAASummit.com.

Therapeutic Insight 2006, April 24-26, Boston. Sponsored by Defined Health and Communitech. For more information, visit http://www.therapeuticinsight.com.

PEGS: The Protein Engineering Summit, April 24-28, Boston. 2nd Annual PEGS, a weeklong series of meetings dedicated to protein research. For more information, visit http://www.healthtech.com/2005/pegs/.

Modeling and Simulation to Better Predict Clinical Outcomes, May 1, Hyatt Regency, Reston, VA, Sponsored by EXL. For more information, visit http://www.exlpharma.com/events/ev_brochure.php?ev_id=28.

PharmaDiscovery2006, May 10-12, Bethesda North Marriott, Bethesda, MD. Sponsored by Elsevier’s Science & Medical division. For more information, visit http://www.pharmadiscovery2005.com/images/100304/FinalBrochure1.pdf.

Bridging the Regulatory Gap: Biomedical & Social/Behavioral Research Are Closer Than You Think, May 16, Notre Dame, IN. Sponsored by Office of Human Research Protection. For more information, visit http://www.hhs.gov/ohrp/education/conference.html#upcoming.

Clinical Trials Design, May 16-17, Milan, Italy. For more information, visit https://www.clinicaldevice.com/RegistrationForm.htm or call (773) 489-5706.

Project Management for Clinical Trials, May 18-19, Milan, Italy. For more information, visit https://www.clinicaldevice.com/RegistrationForm.htm or call (773) 489-5706.

17th International Contracting & Negotiating Clinical Trials, May 21-24, Hyatt Regency Philadelphia at Penn’s Landing, Philadelphia. Sponsored by Strategic Research Institute. For more information, visit http://www.srinstitute.com/conf_page.cfm?instance_id=27&web_id=776&pid=384.

Apoptosis Research & Drug Development, May 22-23. Estancia La Jolla Hotel & Spa, La Jolla, CA. Sponsored by EXL. For more information, visit http://www.exlpharma.com/events/ev_brochure.php?ev_id=28.

Mitigating Drug Development Risk, March 27-28, Hyatt Regency, Princeton, NJ. Sponsored by EXL Pharma. For more information, visit http://www.exlpharma.com/events/ev_descrip.php?ev_id=28.

41st Annual Meeting of the European Assn for the Study of the Liver, April 26-30, Vienna, Austria. For more details, visit http://www.easl.ch/easl2006/.

OHRP: Special Populations/Special Research Situations, June 1-2, Denver. Co-sponsored by Office of Human Research Protection (OHRP); the University of Colorado Health Sciences Center School of Medicine and its Colorado Multiple Institutional Review Board; and seven regional academic institutions and hospitals in Denver. For more information, visit http://www.ohrpmeetings.org/Denver/default.html.

World Transplant Congress 2006, July 22-27, Hynes Convention Center, Boston. For more information, visit http://www.wtc2006.org/.

Crossing the Line: How Much Risk is Acceptable? Sept 25-26, Durham, NC. Sponsored by Office of Human Research Protection. For more information, visit http://www.hhs.gov/ohrp/education/conference.html#upcoming.

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