Science Weekly: Hope for Copenhagen

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An extended programme looking ahead to one of the most important summits in human history

Pfizer Licenses Protalix Treatment for Gaucher’s Disease – Target Health is the Protalix CRO Partner 


Target Health congratulates its client Protalix for this excellent opportunity. 


Pfizer Inc. and Protalix, Ltd. announced last week that they have entered into an agreement to develop and commercialize taliglucerase alfa, a plant-cell expressed form of glucocerebrosidase (GCD) in development for the potential treatment of Gaucher’s disease. Under the terms of the agreement, Pfizer will receive exclusive worldwide licensing rights for the commercialization of taliglucerase alfa, while Protalix will retain the exclusive commercialization rights in Israel. Taliglucerase alfa is the first enzyme replacement therapy derived from a proprietary plant cell-based expression platform using genetically engineered carrot cells.


Target Health is the Protalix CRO partner and together we took this product from toxicology to the pre-IND meeting, IND submission, Phase I, Phase III, Orphan Drug, Fast Track, Expanded Access, multiple FDA meetings and now the eCTD NDA submission. Cato Israel monitored the trial outside of North America. Target e*CRF® and Target Document® were used for the pivotal trial and are now being used in four additional protocols.  This development program was the best case of a Sponsor/CRO/FDA partnership.  The pre-IND meeting took place in June 2004, and last patient last visit was September 2009.  Target Health has prepared and will submit the NDA electronically in eCTD format this month.


Target Health’s team was lead by Glen Park PharmD. Dr. Park joined Target Health in 2005 and since then has been directly involved with approvals of 1 NDA (head lice), 1 MAA (emergency contraception) and 1 PMA (adhesion prevention in the newborn). There are currently 2 NDA submissions in review (emergency contraception and cystic fibrosis).


For more information about Target Health and our software tools for paperless clinical trials, please contact Dr. Jules T. Mitchel (212-681-2100 ext 0) or Ms. Joyce Hays. Target Health’s software tools are designed to partner with both CROs and Sponsors. Please visit the Target Health Website at:

Your Own Stem Cells Can Treat Heart Disease


The largest national stem cell study for heart disease showed the first evidence that transplanting a potent form of adult stem cells into the heart muscle of subjects with severe angina results in less pain and an improved ability to walk. The transplant subjects also experienced fewer 1) ___ than those who didn’t receive stem cells. In the 12-month Phase II, double-blind trial, subjects’ own purified stem cells, called CD34+ cells, were injected into their hearts in an effort to spur the growth of small blood vessels that make up the microcirculation of the heart muscle. Researchers believe the loss of these blood 2) ___ contributes to the pain of chronic, severe angina. “This is the first study to show significant benefit in pain reduction and improved exercise capacity in this population with very advanced heart disease,” said principal investigator Douglas Losordo, M.D., at the Northwestern University Feinberg School of Medicine. Losordo, said this study provides the first evidence that a person’s own stem cells can be used as a treatment for their heart disease. He cautioned, however, that the findings of the 25-site trial with 167 subjects, require verification in a larger, Phase III study. He presented his findings Nov. 17 at the American Heart Association Scientific Sessions 2009. Out of the estimated 1 million people in the U.S. who suffer from chronic, severe 3) ___ — chest pain due to blocked arteries — about 300,000 cannot be helped by any traditional medical treatment such as angioplasty, bypass surgery or stents. This is called intractable or severe angina, the severity of which is designated by classes. The subjects in Losordo’s study were class 3 or 4, meaning they had chest pain from normal to minimal activities, such as from brushing their teeth or even resting. The stem cell 4) ___ is the first therapy to produce an improvement in severe angina subjects’ ability to walk on a treadmill. Twelve months after the procedure, the transplant subjects were able to double their improvement on a treadmill compared to the placebo group. It also took twice as long until they experienced angina pain on a 5) ___ compared to the placebo group, and, when they felt pain, it went away faster with rest. In addition, they had fewer overall episodes of chest pain in their daily lives. In the trial, the CD34+ cells were injected into 10 locations in the heart muscle. A sophisticated electromechanical mapping technology identifies where the heart muscle is alive, but not functioning because it is not receiving enough 6) ___ supply. The study was supported by Baxter Healthcare Corporation


ANSWERS: 1) deaths; 2) vessels; 3) angina; 4) transplant; 5) treadmill; 6) blood

1890 – On the Death of a Revered NYC Physician (Reported in JAMA on June 14, 1890)


“The most elaborate and gorgeous Chinese funeral services ever seen in this city were those of Dr. Young Doo Hing, a physician of great repute and of high rank in the Masonic order, who died of phthisis a short time since. [Phthisis is a Greek term for tuberculosis. Around 460 BC, Hippocrates identified phthisis as the most widespread disease of the times involving coughing up blood and fever, which was almost always fatal.] Although he is reported to have had a very large practice among his countrymen, he does not seem to have been possessed of any property to speak of at the time of his death; but he was apparently immensely popular in the Celestial community, and when he died, his friends contributed some five thousand dollars to give him a becoming send-off to the realms of almond-eyed blessedness. For days before the funeral, Mott Street, the centre of the Chinese quarter, was thronged with people who made the air resound with the continuous din of firecrackers, gongs, tin pans and various kinds of wind instruments of soul-entrancing melody. The obsequies were conducted in the most approved style of Chinese Masonic splendor, and the funeral procession was a most imposing affair. [Obsequies are the last duty or service/rite to a person, rendered after his death.] The hearse, which was drawn by four black horses, was preceded by a “royal guard’ in glittering helmets, and a body of mounted Masons with many gorgeous banners, accompanied by Chinese and Italian bands of music, and was followed by a line of seventy-five carriages, while it seemed that every Chinaman in New York and all the adjacent cities and towns had come to look at the spectacle. At the completion of the services at the grave, all the personal effects of the deceased were piled up in a heap and burned, in the confident expectation that the various articles would be ready for his use as soon as he arrived at the gates of Paradise.”

Enzyme Replacement Therapy with Agalsidase Alfa in Patients with Fabry’s Disease: An Analysis of Registry Data


Fabry’s disease is an inherited disorder. It is one of a family of hereditary diseases called lysosomal storage disorders that affect the way certain important chemicals are processed in the body. Fabry’s disease is rare and is found in roughly 1 in 117,000 people. The disease was first described in 1898 by Fabry in Germany and Anderson in England. In a lysosomal storage disorder, certain structures in cells, called lysosomes, have trouble metabolizing (breaking down) specific complex fatty molecules. As a result, the lysosomes fill up with these undigested molecules, impairing the cell’s ability to function properly. In the case of Fabry’s disease, cells store up a fatty substance called globotriaosylceramide or GL-3. Over time, excessive build-up of GL-3 in some cell types can cause damage (sometimes severe) in tissues throughout the body. Main symptoms include ongoing burning, tingling pain, and discomfort. This type of pain is called acroparesthesia, and mainly affects the hands and feet. Occasional episodes of intense, burning pain. These usually start in the hands and feet, and can often spread to other parts of the body. These are called “Fabry crises” and can be debilitating. Fabry crises may last anywhere from minutes to several days. Pain can also be brought on by changes in weather, exposure to hot temperatures, stress, exercise, and/or fatigue. Other symptoms include: fatigue, impaired sweating, low tolerance for exercise, dark red skin rashes (angiokeratomas), eye abnormalities (such as corneal whorling) that do not typically affect vision, gastrointestinal, heart and kidney problems. The DNA mutations which cause the disease are X-linked recessive. The condition affects hemizygous males (i.e. all males), as well as homozygous, and potentially heterozygous (carrier), females. While males typically experience severe symptoms, women can range from being asymptomatic to having severe symptoms. This variability is thought to be due to X-inactivation patterns during embryonic development of the female.

A study published on line in the Lancet (2 December 2009) analyzed 5-year treatment with agalsidase alfa enzyme replacement therapy in patients with Fabry’s disease who were enrolled in the Fabry Outcome Survey observational database (FOS). Baseline and 5-year data were available for up to 181 adults (126 men). Serial data for cardiac mass and function, renal function, pain, and quality of life were assessed. Safety and sensitivity analyses were done in patients with baseline and at least one relevant follow-up measurement during the 5 years (n=555 and n=475, respectively). Findings In patients with baseline cardiac hypertrophy, treatment resulted in a sustained reduction in left ventricular mass (LVM) index after 5 years (from 71.4?g/m2.7 to 64.1 g/m2.7, p=0?0111) and a significant increase in midwall fractional shortening (MFS) from 14.3% to 16.0% after 3 years (p=0?02). In patients without baseline hypertrophy, LVM index and MFS remained stable. Mean yearly fall in estimated glomerular filtration rate versus baseline after 5 years of enzyme replacement therapy was -3.17 mL/min per 1.73m2 for men and -0?89 mL/min per 1.73m2 for women. Average pain, measured by Brief Pain Inventory score, improved significantly, from 3.7 at baseline to 2.5 after 5 years (p=0?0023). Quality of life, measured by deviation scores from normal EuroQol values, improved significantly, from -0?24 at baseline to -0.17 after 5 years (p=0?0483). No unexpected safety concerns were identified. Acording to the authors, comparison with historical natural history data for patients with Fabry’s disease who were not treated with enzyme replacement therapy, long-term treatment with agalsidase alfa leads to substantial and sustained clinical benefits. The study was funded by Shire Human Genetic Therapies AB.

Mutations in Two Genes Identified That Cause Early-Onset Inflammatory Bowel Disease


The human body is continuously generating local inflammatory responses to control microbial infections and repair damage from other toxins, but if that inflammatory response is not properly controlled tissues may be excessively damaged. According to an article published in the New England Journal of Medicine (2009;361:2033-2045), it has been discovered that mutations in either of two related genes cause a severe and rare form of inflammatory bowel disease (IBD) in young children.  The mutated genes identified in the study encode the proteins IL10R1 and IL10R2, which act together to receive signals from the cytokine IL10. IL10 (interleukin 10) plays a crucial role in keeping the body’s inflammatory responses in check. When either IL10R1 or IL10R2 is mutated, the signals from IL10 cannot be received, and the resulting inflammation causes tissue damage, especially in the gastrointestinal system. Discovery of the genetic mutations allowed the research team to successfully treat one of the study patients with a bone marrow transplant. The patient, who had not responded to other therapies, showed dramatic improvement following the bone marrow transplant and has remained in remission from IBD for more than a year. The successful treatment was built upon a well established treatment approach: that bone marrow transplants can be curative in genetic disorders where the affected gene is normally active in cells derived from the bone marrow. Because of the risks associated with bone marrow transplants, they are used only in cases of severe diseases, where the potential benefits outweigh the risks. Patients with the IBD caused by the genetic mutations identified in this research have very severe disease that meets this general criterion, though each case must be evaluated individually. In order to perform a bone marrow transplant a matched donor is needed. The study patient’s matched donor was a healthy sibling, which is the preferred approach, but bone marrow transplants also can be done using more distantly related or unrelated matched donors. The study is the first to show that a single genetic mutation is sufficient to cause IBD. Other research groups focusing primarily on adult-onset IBD have identified dozens of genes and variants that affect the risk for IBD, but none that singly can cause the disease. This discovery is a milestone in research on inflammatory bowel disease should lead to future therapeutic options not only in children, but potentially also in adult patients with IL10 signaling problems.

Sleep Quality and Immune Mediators in Asthmatic Children


Asthmatic children have been reported to complain about poor sleep quality and recent research has demonstrated a relationship between sleep and circulating cytokines. As a result, a study published in Pediatrics and Neonatology (2009;50:222-229), was performed to assess the relationship between serum cytokine levels and sleep quality in asthmatic children. For the study, after an initial screening phase at allergy clinic visits, 90 asthmatic children aged 6-12 years were enrolled to complete the Chinese version of the (Childhood) Asthma Control Test (ACT). A questionnaire assessing sleep quality of asthmatic children was also administered to all subjects and parents. Serum levels of interleukin (IL)-4, IL-6, IL-10, IL-12, total immunoglobulin (Ig) E, and prolactin were determined at enrollment. For the analysis, subjects with an ACT score > 20 were assigned to the well-controlled group and those with a score of < 19 were assigned to the inadequately controlled group. Results shoed that in the well-controlled group, good sleepers had a significantly lower mean level of IL-10 and a higher mean ratio of IL-12/IL-10 compared with the poor sleepers. Furthermore, the serum prolactin level was significantly greater in the good sleeper subgroup. In both subgroups, the concentrations of IL-6, IL-12 and total IgE were not significant different. According to the authors, as good sleep is associated with a lower IL-10 level, a higher prolactin concentration, and a higher IL-12/IL-10 ratio, prolactin may have a potential role in this immunity shift. Thus, further insight into the functional role of cytokines on the sleep quality of asthma sufferers will result in the identification of novel therapeutic perspectives.

First Human Embryonic Stem Cell Lines Approved For Use Under New NIH Guidelines 


NIH Director Francis S. Collins, M.D., Ph.D., announced the approval of the first 13 human embryonic stem cell (hESC) lines for use in NIH-funded research under the NIH Guidelines for Human Stem Cell Research adopted in July 2009. Children’s Hospital Boston developed 11 of the approved lines and Rockefeller University in New York City developed two of the approved lines. An additional 96 lines have been submitted to NIH for either internal administrative review or consideration by the external Working Group for Human Embryonic Stem Cell Eligibility Review and the NIH Advisory Committee to the Director (ACD), including more than 20 that will be considered by the ACD on December 4, 2009. The working group provides findings to the ACD, which makes recommendations to the NIH Director, who decides whether the hESCs may be used in NIH-funded research and lists those deemed eligible on the NIH Human Embryonic Stem Cell Registry. Research using hESCs is already yielding information about the complex events that occur during human development. Researchers hope that eventually cells differentiated from hESCs may be used to treat a myriad of diseases, conditions, and disabilities and to test the safety of new drugs in the laboratory. On March 9, 2009, President Obama issued Executive Order 13505: Removing Barriers to Responsible Scientific Research Involving Human Stem Cells. The executive order states that the Secretary of Health and Human Services, through the Director of NIH, may support and conduct responsible, scientifically worthy human stem cell research, including human embryonic stem cell research, to the extent permitted by law. The NIH Guidelines for Human Stem Cell Research were published on July 7, 2009, and are available at <>. The guidelines implement the executive order, as it pertains to extramural NIH-funded stem cell research, establish policy and procedures under which the NIH will fund such research, and help ensure that NIH-funded research in this area is ethically responsible, scientifically worthy, and conducted in accordance with applicable law. Children’s Hospital Boston and Rockefeller University submitted information about the informed consent process for embryo donation to the NIH administrative review process, which confirms that the submissions met specific requirements regarding informed consent for embryo donation as detailed in the guidelines. More than 30 NIH grants funded in the 2009 fiscal year totaling more than $20 million proposed to use hESCs; these grants have been restricted until approved lines became available on the NIH registry. With today’s announcement and following NIH approval, these principal investigators may obtain registry-listed hESCs, if they are appropriate for their project, from the owners of the lines and proceed with their research. This group of grants includes research using hESCs for the therapeutic regeneration of diseased or damaged heart muscle cells, developing systems for the production of neural stem cells and different types of neurons from hESCs in culture, and developing a cell culture system for the large scale production and self-renewal of hESCs.


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

Target Health ( 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 (eCTD), IDE, NDA (eCTD), BLA (eCTD), PMA (eCopy) and 510(k) submissions, Management of Clinical Trials, Biostatistics, Data Management, EDC utilizing Target e*CRF®, Project Management, and Medical Writing. Target Health has developed a full suite of eClinical Trial software including 1) Target e*CRF® (EDC plus randomization and batch edit checks), 2) Target e*CTMSTM, 3) Target Document®, 4) Target Encoder®, 5) Target Newsletter®, 6) Target e*CTRTM (electronic medical record for clinical trials). 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.