Science Weekly: Memory on trial

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Can we trust the memory of court witnesses?; a sneak preview of a new climate science exhibition; oxygen tasted on another world; and ‘evidence’ we can see into the future

Panel on Integrating Personalized Health Care Into Clinical Practice

Target Health is pleased to announce that our CMO Mark Horn, MD, MPH, and Glen Park, Pharm.D., our Sr. Director Clinical Research and Regulatory Affairs will be participating in a panel entitled: “Integrating Personalized Health Care Into Clinical Practice.” The panel discussion will take place on Thursday, December 2, 2010, between 6:30-8:00 pm at the Mount Sinai School of Medicine, Icahn Medical Institute, 1425 Madison Avenue, NYC (1st Floor Seminar room).

For the program, the Fundamentals of the Bioscience Industry Program (FOBIP) Alumni Network brings together a clinical scientist and two healthcare experts to discuss, debate and identify the current challenges and opportunities for the development of a personalized approach to medicine and healthcare. They will provide perspective from the different participants of the healthcare industry and offer insights into this promising area of medical research. In addition to Drs. Horn and Park, the other panelist will be Paul Chapman, MD. Eric Vieira, PhD will moderate the program. For more information, go to http://fobip.org/alumni/personalized-medicine-seminar.html.

For more information about Target Health contact Warren Pearlson (212-681-2100 ext 104). For additional information about software tools for paperless clinical trials, please also feel free to contact Dr. Jules T. Mitchel or Ms. Joyce Hays. Target Health’s software tools are designed to partner with both CROs and Sponsors. Please visit the Target Health Website.

DNA Drugs Come of Age

After years of false starts, a new generation of DNA vaccines and medicines for HIV, influenza and other stubborn illnesses is now in clinical 1) ___. What’s next for AIDS is new approaches for tackling HIV in the developing world The surprise success, this past summer, of a clinical trial on an antiretroviral-based vaginal 2) ___ provides new traction for efforts to combat AIDS in the developing world. Here are some new directions to expect for treatment and prevention of this widespread killer.

Vaccines and therapies containing DNA rings called plasmids have long held promise for treating and preventing 3) ___, but the plasmids made a weak showing in early tests. Improvements to the plasmids and new methods for delivering them have dramatically enhanced their potency.

DNA vaccines and therapies now used in animals or in late-stage human trials demonstrate that 4) ___ are reaching their potential.

In a head-to-head competition held 10 years ago, scientists at the NIH tested two promising new types of 5) ___ to see which might offer the strongest protection against one of the deadliest viruses on earth, the human immunodeficiency virus (HIV) that causes AIDS. One vaccine consisted of DNA rings called plasmids, each carrying a gene for one of five HIV proteins. Its goal was to get the recipient’s own cells to make the viral proteins in the hope they would provoke protective reactions by 6) ___ cells. Instead of plasmids, the second vaccine used another virus called an adenovirus as a carrier for a single HIV gene encoding a viral protein. The rationale for this combination was to employ a “safe” virus to catch the attention of immune 7) ___ while getting them to direct their responses against the HIV protein.

The test results dealt a major blow to believers in this first generation of DNA vaccines, the plasmids. The DNA recipients displayed only weak immune responses to the five HIV proteins or no response at all, whereas recipients of the adenovirus-based vaccine had robust reactions. To academic and pharmaceutical company researchers, 8) ___ clearly looked like the stronger candidates to take forward in developing HIV vaccines. Source: ScientificAmerican.com, by Morrow & Weiner

 

ANSWERS

 

1) trials; 2) microbicide; 3) disease; 4) plasmids; 5) vaccine; 6) immune; 7) cells; 8) adenoviruses

Francis S. Collins and J. Craig Venter

A decade after the human-genome project, biological science is poised on the edge of something wonderful

Ten years ago, on June 26th 2000, a race ended. The result was declared a dead heat and both runners won the prize of shaking the hand of President Bill Clinton. The runners were J. Craig Venter for the private sector and Francis Collins for the public. The race was to sequence the human genome, all 3 billion genetic letters of it, and as headline writers put it – read the book of life.

There was the drama of a maverick upstart, in the form of Dr Venter and his newly created firm, Celera, taking on the medical establishment, in the form of Dr Collins’s International Human Genome Sequencing Consortium. There was the promise of a cornucopia of new drugs as genetic targets previously unknown to biologists succumbed to pharmacological investigation. There was talk of an era of “personalized medicine” in which treatments would be tailored to an individual’s genetic make-up.

As The Economist observed at the time, the race Dr Venter and Dr Collins had been engaged in was a race not to the finish but to the starting line. Moreover, compared with the sprint they had been running in the closing years of the 1990s, the new race marked by that starting line was a marathon. The competitors ran into numerous obstacles. They found at first that there were far fewer genes than they had expected, only to discover later that there were far more. These discoveries changed the meaning of the word “gene”. They found the way genes are switched on and off is at least as important, both biologically and medically, as the composition of those genes. They found that their methods for linking genetic variation to disease were inadequate. And they found, above all, that they did not have enough genomes to work on. Each human genome is different, and that matters.

One by one, however, these obstacles are falling away and the science of biology is being transformed. It seems quite likely that future historians of science will divide biology into the pre- and post-genomic eras. In one way, post-genomic biology – biology 2.0, has finally killed the idea of vitalism, the persistent belief that to explain how living things work, something more is needed than just an understanding of their physics and chemistry. So it is with the new biology. The chemicals in a cell are the hardware. The information encoded in the DNA is the preloaded software. The interactions between the cellular chemicals are like the constantly changing states of processing and memory chips. Though understanding the genome has proved more complicated than expected, no discovery made so far suggests anything other than that all the information needed to make a cell is squirreled away in the DNA. Yet the whole is somehow greater than the sum of its parts.

The past few weeks have seen an announcement that may turn out to have been as portentous as the sequencing of the human genome: Dr Venter’s construction of an organism with a completely synthetic genome. The ability to write new genomes in this way brings true biological engineering – as opposed to the tinkering that passes for biotechnology at the moment – a step closer. A second portentous announcement, of the genome of mankind’s closest – albeit extinct -relative, Neanderthal man, shows the power of biology 2.0 in a different way. Putting together some 1.3 billion fragments of 40,000-year-old DNA, contaminated as they were with the fungi and bacteria of millennia of decay and the personal genetic imprints of the dozens of archaeologists who had handled the bones, demonstrates how far the technology of genomics has advanced over the course of the past decade. It also shows that biology 2.0 can solve the other great question besides how life works: how it has evolved and diversified over the course of time.

As is often the way with scientific discovery, technological breakthroughs of the sort that have given science the Neanderthal genome have been as important to the development of genomics as intellectual insights have been. The telescope revolutionized astronomy; the microscope, biology; and the spectroscope, chemistry. The genomic revolution depends on two technological changes. One, in computing power, is generic – though computer-makers are slavering at the amount of data that biology 2.0 will need to process, and the amount of kit that will be needed to do the processing. This torrent of data, however, is the result of the second technological change that is driving genomics, in the power of DNA sequencing.

Eric Lander, the head of the Broad Institute, in Cambridge, Massachusetts, which is America’s largest DNA-sequencing center, calculates that the cost of DNA sequencing at the institute has fallen to a hundred-thousandth of what it was a decade ago. The genome sequenced by the International Human Genome Sequencing Consortium took 13 years and cost $3 billion. Now, using the latest sequencers from Illumina, of San Diego, California, a human genome can be read in eight days at a cost of about $10,000. Another Californian firm, Pacific Biosciences, of Menlo Park, has a technology that can read genomes from single DNA molecules. It thinks that in three years’ time this will be able to map a human genome in 15 minutes for less than $1,000.

Even before cheap sequencing became available, huge databases were being built up. In alliance with pathology samples, doctors’ notes and – most valuable of all – long-term studies of particular groups of individuals, genetic information can be linked to what biologists refer to as the phenotype. This is an organism’s outward expression: its anatomy, physiology and behavior, whether healthy or pathological. The goal of the new biology is to tie these things together reliably and to understand how the phenotype emerges from the genotype. That will lead to better medical diagnosis and treatment. It will result in the ability to manipulate animals, plants, fungi and bacteria to human ends and it may help to explain the history of life and what it is to be human. Source: by Geoffrey Carr, The Economist (US). Economist Newspaper Ltd. 2010

Daily Hemodialysis Helps Protect Kidney Patients’ Hearts

When there is a loss of about 90% of usual kidney function, either kidney transplantation or dialysis is required. Nearly 400,000 people in the United States and 2 million worldwide are dependent on dialysis. Despite improvements in dialysis technology, new medications and more than 40 years of experience, mortality rates remain high at 18 to 20% a year. Patients experience frequent hospitalizations and reduced health-related quality of life.

Results published online in the New England Journal of Medicine (20 November 2010) showed that frequent hemodialysis improved left ventricular mass (heart size) and self-reported physical health compared to conventional hemodialysis for kidney failure. The trial, called the Frequent Hemodialysis Network (FHN) Daily Trial, was funded by the National Institutes of Health and the Centers for Medicare & Medicaid Services.

The study showed that six hemodialysis treatments per week improved left ventricular mass and physical health compared to conventional, three weekly dialysis therapy sessions. Frequent hemodialysis was also associated with improved control of high blood pressure and excessive phosphate levels in the blood, a common problem in patients on hemodialysis. There were no significant effects on cognitive performance, self-reported depression, or the use of drugs to treat anemia.

Previous observational data suggested that the dose of hemodialysis correlates directly with patient survival. However, results from the HEMO Study published in 2002, showed no added benefit of increasing the per-treatment dose of hemodialysis in the conventional three times per week method. However, since that time a few small, single-center studies found that the dialysis dose could be greatly increased by adding more dialysis sessions. Those findings led FHN researchers to test the hypothesis that almost daily treatment would improve both objective and subjective, or patient-reported, outcomes.

The FHN Daily Trial involved 245 patients at 10 university and 54 community-based hemodialysis facilities in North America between Jan. 2006 and March 2010. Patients were randomly assigned to receive either conventional three weekly dialysis treatments or six treatments a week.

Patients in the frequent-hemodialysis group averaged 5.2 sessions per week; the weekly standard Kt/Vurea (the product of the urea clearance and the duration of the dialysis session normalized to the volume of distribution of urea) was significantly higher in the frequent-hemodialysis group than in the conventional-hemodialysis group (3.54+0.56 vs. 2.49+0.27). Frequent hemodialysis was associated with significant benefits with respect to both coprimary composite outcomes (hazard ratio for death or increase in left ventricular mass, 0.61; hazard ratio for death or a decrease in the physical-health composite score, 0.70). Patients randomly assigned to frequent hemodialysis were more likely to undergo interventions related to vascular access than were patients assigned to conventional hemodialysis (hazard ratio, 1.71). Frequent hemodialysis was associated with improved control of hypertension and hyperphosphatemia. There were no significant effects of frequent hemodialysis on cognitive performance, self-reported depression, serum albumin concentration, or use of erythropoiesis-stimulating agents.

According to the authors, frequent hemodialysis, as compared with conventional hemodialysis, was associated with favorable results with respect to the composite outcomes of death or change in left ventricular mass and death or change in a physical-health composite score but prompted more frequent interventions related to vascular access.

Pre-Exposure Chemoprophylaxis for HIV Prevention in Gay Men

Antiretroviral chemoprophylaxis before exposure is a promising approach for the prevention of human immunodeficiency virus (HIV) acquisition. To study this approach, a study published in the New England Journal of Medicine (23 November 2010), randomly assigned 2,499 HIV-seronegative men or transgender women, who reported to have intimate physical relations with men, to receive a combination of two oral antiretroviral drugs, emtricitabine and tenofovir disoproxil fumarate (FTC-TDF), or placebo once daily. All subjects received HIV testing, risk-reduction counseling, condoms, and management of sexually transmitted infections.

The study subjects were followed for 3,324 person-years (median, 1.2 years; maximum, 2.8 years). Of these subjects, 10 were found to have been infected with HIV at enrollment, and 100 became infected during follow-up (36 in the FTC-TDF group and 64 in the placebo group), indicating a 44% reduction in the incidence of HIV (P=0.005). In the FTC-TDF group, the study drug was detected in 22 of 43 of seronegative subjects (51%) and in 3 of 34 HIV-infected subjects (9%) (P<0.001).

In terms of safety, nausea was reported more frequently during the first 4 weeks in the FTC-TDF group than in the placebo group (P<0.001). The two groups had similar rates of serious adverse events (P=0.57).

According to the authors, oral FTC-TDF provided protection against the acquisition of HIV infection among the subjects and that detectable blood levels strongly correlated with the prophylactic effect.

Effects of Long-Term Etanercept Treatment on Growth in Children with Selected Categories of Juvenile Idiopathic Arthritis

According to an article published in Arthritis & Rheumatism (2010;62:3259–3264), a study was performed to evaluate the effects of long-term etanercept treatment, with or without methotrexate, on growth in children with selected categories of juvenile idiopathic arthritis (JIA).

For the study, a 3-year, open-label, nonrandomized registry was conducted with 594 patients with polyarticular or systemic JIA treated with etanercept only, etanercept plus methotrexate, or methotrexate only. Height, weight, and body mass index (BMI) were assessed at baseline and at years 1, 2, and 3, using percentiles derived from US Centers for Disease Control and Prevention standardized growth charts.

Results showed statistically significant increases in the mean height percentiles from baseline in etanercept-treated patients at year 3 (4.8 percentile points) and in patients treated with etanercept plus methotrexate at years 1, 2, and 3 (2.4, 3.3, and 5.6 percentile points, respectively). Statistically significant increases from baseline in the mean weight percentiles were observed at years 1, 2, and 3 in both the etanercept group (7.4, 10.0, and 13.0 percentile points) and the etanercept-plus-methotrexate group (2.9, 6.9, and 8.4 percentile points, respectively). Statistically significant increases from baseline in the mean BMI percentiles were observed in both the etanercept group (range 9.6-13.8 percentile points) and the etanercept-plus-methotrexate group (range 2.1-5.2 percentile points). The mean height, weight, and BMI percentiles did not change significantly in patients in the methotrexate-only group.

According to the authors, etanercept treatment, with or without methotrexate, may contribute to the restoration of normal growth in children with JIA.

TARGET HEALTH excels in Regulatory Affairs and Public Policy issues. Each week we highlight new information in these challenging areas.

FDA Approves Xgeva to Help Prevent Cancer-Related Bone Injury

Xgeva (denosumab) is a monoclonal antibody that targets a protein involved in cancer-related bone destruction called human RANKL (Receptor Activator for Nuclear Factor κ B Ligand). RANKL also known as TNF-related activation-induced cytokine (TRANCE), osteoprotegerin ligand (OPGL), and ODF (osteoclast differentiation factor), is a molecule important in bone metabolism.

The FDA has approved Xgeva to help prevent skeletal-related events (SREs) in patients with cancer that has spread (metastasized) and damaged the bone. Skeletal-related events include bone fractures from cancer and bone pain requiring radiation. Other FDA-approved drugs for similar conditions include Zometa (zoledronic acid) and Aredia (pamidronate disodium).

Xgeva’s safety and effectiveness were confirmed in three randomized, double-blind clinical studies in 5,723 patients comparing Xgeva with Zometa. One study involved patients with breast cancer, another in patients with prostate cancer, and a third included patients with a variety of other cancers. The studies were designed to measure the time until occurrence of a fracture or spinal cord compression due to cancer or until radiation or surgery for control of bone pain was needed.

In patients with breast or prostate cancers, Xgeva was superior to Zometa in delaying SREs. In men with prostate cancer, the median time to an SRE was 21 months with Xgeva compared to 17 months with Zometa. In patients with breast cancer, the median time to an SRE was 26 months with Zometa and has not yet been reached with Xgeva. In patients with other solid tumors, time to development of an SRE was similar for both Xgeva and Zometa. The most common solid tumors were non-small cell lung cancer, multiple myeloma, kidney (renal) cancer, and small cell lung cancer.

The most serious side effects experienced with Xgeva were low calcium levels in the blood (hypocalcemia), and osteonecrosis of the jaw, a severe disease resulting from reduced blood flow to areas of the jaw and exposed jaw bone, causing pain, swelling, numbness, or infection.

Denosumab was originally approved under another trade name, Prolia, in June 2010. Prolia is indicated to treat postmenopausal women with osteoporosis who are at high risk for bone fractures. Xgeva is administered using a higher dose and with more frequent dosing than Prolia. Denosumab has a different safety profile in patients with osteoporosis than in patients with cancer and bone metastases.

Xgeva is marketed by Thousand Oaks, Calif.-based Amgen.

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