Target e*PharmacovigilanceTM Integration With Target e*CRF® Coming Soon

Target Health Inc. is pleased to announce that Target e*CRF® (v1.8), will be fully integrated with Target ePharmacovigilanceTM for those who want one-stop shopping for pharmacovigilance for clinical trials. Many aspects of pharmacovigilance will be seamless within EDC and should reduce the duplication of many tasks currently performed by pharmacovigilance departments within the clinical trial space. For example, there should no longer be a need to reconcile the pharmacovigilance database with the EDC database. Target e*PharmacovigilanceTM pulls all the appropriate EDC data into the pharmacovigilance module, allows the site to enter a safety narrative as well as add additional data normally not collected within the clinical trial. It allows the medical monitor to create a safety narrative as well as enter all the additional information needed for both MedWatch Form 3500A and the CIOMS form. Original and followup reports are fully controlled. Most importantly, FDA’s MedWatch has approved our form for any and all safety submissions to FDA. Target ePharmacovigilanceTM joins Target Encoder® (v1.0), Target Document, Target e*CTMS, Target Newsletter® (v1.0) and Target TimeTM (v1.0) family of eClinical trial software. Target eClinical Trial Record (Target e*CTRTM is being released this summer). We know that we have the best eclinical software suite in the industry as well as the most knowledgeable programmers.

For more information about Target Health and any of 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, and if you like the weekly newsletter, ON TARGET, you’ll love the Blog

Drugs that Block Blood-Vessel Growth Could Tackle Obesity

The fat cells that make up 1) ___ tissue can’t grow without blood vessels to nourish them. A Biotech startup based in Cambridge, MA, is developing obesity drugs that starve fat tissue by blocking blood-vessel proliferation. These drugs, which were originally designed to halt tumor growth, cause dramatic weight loss in 2) ___ mice. Both cancer and obesity kill hundreds of thousands of patients each year, but they have more than the Grim Reaper in common. Tumors and excess fat are both unhealthy accumulations of tissue that require elaborate networks of blood 3) ___ to feed them. Obesity could be prevented in the way that cancer researchers have been attacking tumors for decades: using drugs that interfere with its 4) ___ supply. However, anti-angiogenic drugs such as Avastin, used to treat breast, lung, and colon cancer, have unpleasant side effects – especially when used long term – including problems with the reproductive, cardiovascular, and immune systems. Most pharmacological treatments for 5) ___ have focused on controlling food intake. They attack weight gain centrally in the brain by trying to reduce appetite or encourage a feeling of satiety. But the neural mechanisms that regulate 6) ___ intake also can cause side effects. Past weight-loss drug candidates have been discarded for their unwanted effects on mood, wakefulness, reproductive function, and because their efficacy can wear off over time. You push down one thing, but something else pops up. That seems to be the nature of the way that circuits are wired in our brain. This new research approach aims to attack weight gain in the fat tissue – and hope to circumvent the side effects associated with more traditional approaches. Conventional wisdom is that people become obese because they 7) ___. But the fact is that in an environment where people are exposed to the same food supply and lifestyle, some will gain weight and others will not. In animals, those discrepancies seem to correlate with genetically determined differences among individuals’ fat tissue. Animals with so-called hungry adipose tissue with a strong propensity to expand show different expression of 8) ___ that regulate blood-vessel formation than animals that are naturally lean. The scientists aim to alter those natural differences, effectively converting hungry adipose into its more benign cousin, thereby shrinking existing fat stores and preventing the accumulation of new ones. To do so, the company is investigating a class of small molecules originally designed to stop blood-vessel 9) ___ in tumors but abandoned due to their low performance. These agents attach to receptors in the lining of blood vessels, preventing the binding of factors that normally spur those vessels to proliferate. While these drugs proved ineffective for treating 10) ___, they might work for obesity, in which case simply shrinking fat tissue is sufficient. In animal trials, obese mice began to slim down after a few days and reached a normal body weight, usually in three weeks. This process was associated with a dramatic decrease in food consumption. But unlike drugs that cause weight loss by reducing food intake, these compounds seemed to reduce food intake by causing weight loss. As the fat cells shrank, they released free fatty acids that acted as a source of 11) ___ for the body, seeming to partially supersede the need for food calories. As soon as the animals reached a healthy weight, their food consumption returned to normal or even elevated levels, even though they continued to receive the drug. Not only did the mice lose weight, but they also became healthier overall. Their metabolic rate increased, their insulin sensitivity improved, and the fat content of their livers diminished. Within the 12) ___ tissue itself, there was a marked change in the number and architecture of blood vessels. All of these changes were highly reminiscent of those seen with extreme calorie restriction, which has long been known to improve health and extend life span in rodents. The Massachusetts Biotech, plans to start clinical trials later this year, to determine whether the weight loss and health improvements seen in mice will translate to 13) ___. The rodent studies suggest that the doses sufficient for fat loss are lower than that required for tumor suppression, which might reduce the potential for side effects. The company intends its drugs to be used by the 14) ___ obese, and not by those trying to shed a pesky 15 pounds. This is a serious medicine, not a lifestyle drug.

ANSWERS: 1) adipose; 2) obese; 3) vessels; 4) blood; 5) obesity; 6) food; 7) overeat; 8) genes; 9) growth; 10) cancer; 11) energy; 12) fat; 13) humans; 14) morbidl

The First Neuroscientist, JLW Thudichum (1829-1901)

From 1865 to about 1910, studies of the chemistry of the brain were afflicted by the hypothesis that cerebral lipid matter consisted of a giant molecule from which all the simpler lipids were derived as breakdown products. In 1864, the German pharmacologist Oscar Liebrich presented a paper at a meeting in Giessen arguing that brain tissue was composed of a single giant molecule called “protagon.” Any simpler lipids that chemists were isolating, Liebrich argued, were simply breakdown products of this primary, high-molecular-weight compound. The protagon theory had quite an effect on Johann Ludwig Wilhelm Thudichum, a German-born physician and chemist who was working in London under contract to the medical officer of the Privy Council, John Simon. In an 1868 report to Simon, Thudichum wrote that he wanted to explore the theory further. But when Thudichum started doing his own experiments on brain chemistry, he quickly became disenchanted with Liebrich’s theory. From 1865 to 1871, Thudichum carefully detailed the chemical constitution of the brain. He showed that the elemental composition of protagon was variable and that no carbon-carbon bonds were broken under differential solvent extraction, which indicated that protagon was actually a mechanical mixture of several fatty-like substances, all of which had slightly different solubilities. Thudichum isolated, characterized, and often named various brain-derived compounds, including choline platinochloride, lecithin cadmium chloride, phrenosine, and kerasine. “Thudichum’s ability to employ this procedure to separate compounds with similar, but slightly different, solubility properties marks him out as a genius of the lipid laboratory,” says Theodore Sourkes, a biochemist at McGill University and the author of The Life and Work of J.L.W. Thudichum. For decades, however, the scientific community largely rejected Thudichum’s discoveries. Some accused him of “patent falsification”; others called him a “liar.” Only in 1910, almost a decade after his death, was the protagon theory finally laid to rest when three labs in London, Edinburgh, and New York confirmed that protagon was nothing more than a mixture of simpler lipids.  Thudichum performed chemical analyses on over a thousand brains, both human and animal, and has been called the first English biochemist and the world’s first pathological chemist. His career was characterized by voluminous work, although during his life, he failed to achieve the acclaim he deserved. His greatest work, A Treatise on the Chemical Constitution of the Brain, raised great criticism and garnered outright rejection by the most prominent scientists of the era. Over the years, Thudichum isolated, characterized, and named numerous brain-derived compounds such as cephalin, sphingomyelin, galactose, lactic acid, and sphingosine. He disproved the concept that brain matter was composed of a single giant molecule, protagon, that determined the various specialized properties of the brain. Time, awarded him victory. Ultimate vindication came in the 1930s when samples of his carefully extracted brain isolates were rediscovered, re-analyzed via modern techniques, and found to be both chemically pure and of the molecular composition that he had asserted.

Genomes of Parasitic Flatworms Decoded – Information Could Lead to New Treatments for Schistosomiasis

People become infected with Schistosoma when they wade or bathe in water inhabited by tiny snails that are the parasite’s intermediate hosts. Microscopic fork-tailed parasites released into the water by the snails burrow into a bather’s skin and travel to blood vessels that supply urinary and intestinal organs, including the liver, where they mature. Female worms, which live inside the thicker males, release many thousands of eggs each day. Eggs shed in urine and feces may make their way into snail-inhabited water, where they hatch to release parasites that seek out snails to begin the cycle again. Cases of schistosomiasis (also known as snail fever), top 200 million every year, and some 20 million people are seriously disabled by severe anemia, chronic diarrhea, internal bleeding and organ damage caused by the worms and their eggs, or the immune system reactions they provoke. Though best known for causing chronic illness, schistosomiasis kills some 280,000 people each year in sub-Saharan Africa alone. Since the 1980s, the inexpensive anti-worm medication praziquantel has been administered to people in nationwide schistosomiasis control programs in dozens of tropical countries where the disease is common. While the drug is effective, it does not prevent a person from becoming re-infected through exposure to infested waters.

Two international research teams have determined the complete genetic sequences of two species of parasitic flatworms that cause schistosomiasis. Schistosoma mansoni and Schistosoma japonicum are the first sequenced genomes of any organism in the large group called Lophotrochozoa, which includes other free-living and parasitic flatworms as well as segmented roundworms, such as the earthworm. The research was supported in part by the National Institute of Allergy and Infectious Diseases (NIAID), and is published in the current issue of Nature (DOI: 10.1038/nature08160 2009; DOI: 10.1038/nature08140 2009).  The genomic information obtained through these sequencing projects suggests ways to design drugs or other compounds targeted specifically at proteins or other gene products required by the parasite to find or survive in its human or snail host.  Finding new drug targets was a key goal of the team that sequenced the S. masoni genome. For the study, the research group determined the sequence of 363 million nucleotides, encoding 11,809 genes. Analysis of the genes and the proteins they encode revealed the loss of some types of genes (and proteins) and expansion of other gene families relative to corresponding genes found in non-parasitic worms. These genetic gains and losses are tied to the parasitic lifestyle of Schistosoma. For example, the researchers detected a large percentage of genes encoding proteases (enzymes that break down proteins.) Parasites, like Schistosoma, that must bore through skin and other tissues to invade their hosts require many such enzymes. Befitting a parasite that must navigate murky waters to find its intermediate host and later must travel through several tissue types in its human host, Schistosoma flatworms have sophisticated neurosensory systems that allow them to, for example, detect chemical, light and temperature levels in water or inside their hosts. Genes that encode signaling proteins involved in these neurosensory processes made up a significant proportion of both S. masoni and S. japonicum genomes. The team responsible for the S. masoni genome also used bioinformatic computational techniques to translate genetic sequence information into maps of over 600 enzymatic reactions arrayed in multiple metabolic pathways. The analysis revealed 120 flatworm enzymes that could potentially be targeted with drugs that would disable the enzyme and inhibit the parasite’s metabolism. Finally, in an effort to find currently marketed drugs (such as protein or enzyme inhibitors) that might also be deployed against schistosomiasis, the researchers compared information about parasite proteins to a database of drugs directed at other human diseases. They found 66 instances of currently marketed drugs that might also be effective against schistosomiasis. NIAID research on schistosomiasis and other neglected tropical diseases can be found at http://www3.niaid.nih.gov/topics/tropicalDiseases/default.htm.

Novel Drug Discovery Tool Could Identify Promising New Therapies For Parkinson’s Disease

Parkinson’s disease attacks cells in a part of the brain responsible for motor control and coordination. As those neurons degenerate, the disease leads to progressive deterioration of motor function including involuntary shaking, slowed movement, stiffened muscles, and impaired balance. The neurons normally produce a chemical called dopamine. A synthetic precursor of dopamine called L-DOPA or drugs that mimic dopamine’s action can provide symptomatic relief from Parkinson’s disease. Unfortunately, these drugs lose much of their effectiveness in later stages of the disease, and there is currently no means to slow the disease’s progressive course. In most cases, the cause of Parkinson’s disease is unknown, but there are recent, tantalizing clues. Investigators have discovered that vulnerable brain cells in patients with Parkinson’s disease accumulate a protein called alpha-synuclein. Moreover, genetic abnormalities in alpha-synuclein cause a rare familial form of the disease. Previous studies showed that when yeast cells are engineered to produce large amounts of human alpha-synuclein, they die.

Researchers funded by the National Institutes of Health have turned simple baker’s yeast into a virtual army of medicinal chemists capable of rapidly searching for drugs to treat Parkinson’s disease. In a study published online in Nature Chemical Biology (13 July 2009), it was demonstrated that yeast cells can be rescued from toxic levels of a protein implicated in Parkinson’s disease by stimulating the cells to make very small proteins called cyclic peptides. Two of the cyclic peptides had a protective effect on the yeast cells and on neurons in an animal model of Parkinson’s disease. For the study, the research team tested whether yeast could make cyclic peptides that would save them from alpha-synuclein’s toxicity. Cyclic peptides are fragments of protein that connect end-to-end to form a circle. Although cyclic peptides are synthetic, they resemble structures that are found in natural proteins and protein-based drugs, including pain killers, antibiotics and immunosuppressants. Cyclic peptides that suppress alpha-synuclein toxicity could be candidate drugs for Parkinson’s disease, or they could help researchers identify new drug targets for the disease. The research procedure involves exposing yeast cells to short snippets of DNA that the cells can absorb and use to make cyclic peptides. Then, a genetic switch is flipped in the lab that causes the cells to produce toxic levels of alpha-synuclein. If the yeast make cyclic peptides that suppress alpha-synuclein toxicity, they live; if not, they die. This simple assay enables testing millions of cyclic peptides simultaneously in millions of yeast cells. The process is extremely rapid and much less expensive compared to other techniques used to screen large number of chemicals with an eye toward new drugs. The research team collaborated with other researchers to test these two cyclic peptides in C. elegans, a millimeter-long worm with a small number of dopamine-producing neurons that are easy to examine and count. Those neurons are vulnerable to alpha-synuclein toxicity, but they were less vulnerable and more likely to survive in worms that were genetically modified to make either of the two cyclic peptides.

APOE Genotype for Risk of Alzheimer’s Disease

The apolipoprotein E (APOE) genotype provides information on the risk of Alzheimer’s disease (AD), but the genotyping of patients and their family members has been discouraged. As a result, a study published in the New England Journal of Medicine (2009;361:245-254), was performed to examine the effect of genotype disclosure in a prospective, randomized, controlled trial. For the study, 162 asymptomatic adults who had a parent with AD were randomly assigned to receive the results of their own APOE genotyping (disclosure group) or not to receive such results (nondisclosure group). Symptoms of anxiety, depression, and test-related distress were measured 6 weeks, 6 months, and 1 year after disclosure or nondisclosure. Results showed there were no significant differences between the two groups in changes in time-averaged measures of anxiety (4.5 in the disclosure group and 4.4 in the nondisclosure group), depression (8.8 and 8.7, respectively), or test-related distress (6.9 and 7.5). Secondary comparisons between the nondisclosure group and a disclosure subgroup of subjects carrying the APOE 4 allele (which is associated with increased risk) also revealed no significant differences. However, the 4-negative subgroup had a significantly lower level of test-related distress than did the 4-positive subgroup (P=0.01). Subjects with clinically meaningful changes in psychological outcomes were distributed evenly among the nondisclosure group and the 4-positive and 4-negative subgroups. Baseline scores for anxiety and depression were strongly associated with post-disclosure scores of these measures (P<0.001 for both comparisons). The authors concluded that disclosure of APOE genotyping results to adult children of patients with AD did not result in significant short-term psychological risks but that test-related distress was reduced among those who learned that they were APOE 4-negative. Persons with high levels of emotional distress before undergoing genetic testing were more likely to have emotional difficulties after disclosure.

TARGET HEALTH excels in Regulatory Affairs and works closely with many of its clients performing all FDA submissions. TARGET HEALTH receives daily updates of new developments at FDA. Each week, highlights of what is going on at FDA are shared to assure that new information is expeditiously made available.

FDA Approves Opioid Pain Reliever with Required Risk Reduction Plan (REMS)

The FDA has approved Onsolis, a medication intended for certain patients with cancer to help manage breakthrough pain, i.e. severe flares of pain that break through regular pain medication. Onsolis is in a class of drugs that deliver the potent opioid fentanyl through the mouth’s mucous membranes. Onsolis delivers fentanyl via an absorbable film that sticks to the inside of the cheek. The drug is indicated for the management of breakthrough pain in patients with cancer, ages 18 and older, who already use opioid pain medication around the clock and who need and are able to safely use high doses of an additional opioid medicine. Such patients are considered opioid tolerant because of their current opioid medication use. Because fentanyl is subject to abuse and misuse, Onsolis was approved with a Risk Evaluation and Mitigation Strategy, or REMS, which is a required plan for managing risks associated with a drug or biological product. The Food and Drug Administration Amendments Act of 2007 (FDAA) gave the FDA the authority to require that drugs and biological products have a REMS to ensure that the benefits of a drug or biological product outweigh its risks. As part of the REMS, Onsolis will only be available through a restricted distribution program called the FOCUS program. Under this program, only those prescribers, patients and pharmacies registered with the program will be able to prescribe, dispense, and receive Onsolis. The FOCUS program will provide training and educational materials to prescribers and pharmacy personnel, and a counseling call will be placed to patients prior to dispensing to ensure they have been adequately educated about the appropriate use of the drug. Prescription orders will be filled only by participating pharmacies that send the product directly to the patients’ homes. Onsolis was approved with a boxed warning, which states that the medication should not be used for the management of migraines, dental pain, or postoperative pain or by patients who use opioids intermittently, or on an as-needed basis. It also warns that the drug should be kept out of the reach of children and should not be substituted for other fentanyl products. In February, the FDA announced that it would require a REMS for a different class of opioids that offer long-acting and extended-release medication. The FDA has held a series of meetings with stakeholders, including a large public meeting, and also solicited written public comments to hear more about how to develop this REMS. Onsolis is manufactured by Aveva Drug Delivery Systems, Miramar, Fla., and marketed under license from BioDelivery Sciences International Inc. of Raleigh, N.C., by Meda Pharmaceuticals Inc., based in Somerset, N.J.

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

Target Health (www.targethealth.com) is a full service eCRO with full-time staff dedicated to all aspects of drug and device development. Areas of expertise include Regulatory Affairs, comprising, but not limited to, IND (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.