NBA - Monitoring Internation Trends - Prepared February 2012
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MONITORING INTERNATIONAL TRENDS Prepared February 2012 The NBA monitors international developments that may influence the management of blood and blood products in Australia. Our focus is on: •Information that may have an impact on global supply, demand and pricing, such as changes in company structure, capacity, organisation and ownership •Potential new product developments and applications •Global regulatory and blood practice trends, and •Other emerging risks that could potentially put financial or other pressures on the Australian sector.
A summary of current matters of interest appears below. Comments on direct implications for Australia have also been included. Highlights include:
• Baxter is proceeding to a second Phase III trial of its IVIg, Gammagard in Alzheimer’s disease. • Inspiration is seeking approvals for its haemophilia B treatment. • CSL has initiated its PhaseII/III trial of its longer- acting rFIX. • Baxter is trialling its longer- acting rFVIII. • Researchers have found a way to reverse anaemia in mice. • A small study has suggested a single treatment of gene therapy might substantially improve symptoms and quality of life in patients with with hae m oph ili a B. • Scientists have created blood platelet cells by reprogramming stem cells derived from adult cells. • The new Collaborative Biosecurity Research Facility in Geelong will, amongst other things, investigate the origin and treatment of diseases that can be transmitted between humans and animals.
1. Regulatory Matters: a. .The US Food and Drug Administration (FDA) approved Baxter’s Advate for routine prophylaxis to prevent or reduce the frequency of bleeding episodes in patients with haemophilia A. Advate is the only anti-haemophilic factor approved in the US for prophylactic use in both adults and children. The approval is based on a Phase IV prophylaxis study sponsored by Baxter demonstrating that Advate for routine prophylaxis significantly reduced median annual bleed rates from 44 to one compared with an on-demand regimen. Forty-two percent of study patients experienced zero bleeds during one year on prophylaxis. b. Inspiration Biopharmaceuticals applied in October for approval of its drug for haemophilia B in Europe and plans filing an application with the FDA in the first half of 2012. It is also developing a drug to treat patients with either congenital or acquired haemophilia A who have developed inhibitors. French company Ipsen owns 40% of Inspiration and has options to buy more if Inspiration meets a series of milestones. c. Abbott received approval from the FDA for a new Chagas in vitro diagnostic test. The ABBOTT ESA Chagas is the first FDA-approved supplemental test that detects antibodies to Trypanosoma cruzi , a parasite commonly acquired through contact with the blood-sucking triatomine, also known as a "kissing bug." The test will be used as an additional, more specific test on human serum or plasma specimens found repeatedly reactive using a licensed screening test. Amid concerns about the transmission of Chagas disease through blood, the FDA mandated donor screening in 2007. The American Association of Blood Banks (AABB) Chagas Biovigilance Network reports that nearly 1,500 donors with Chagas disease have been identified in the four years since mandatory donor screening was implemented. d. ProMetic's proprietary prion capture resin, PrioClear, is incorporated into Octapharma's manufacturing process for its solvent/detergent treated, prion- reduced, plasma product, OctaplasLG. OctaplasLG, previously approved for
1 A study published Online First by the Archives of Internal Medicin on January 9, 2012 said dabigatran is associated with an increased risk of myocardial infarction (heart attack) or acute coronary syndrome in a broad spectrum of patients when tested against some other medicines. Authors Ken Uchino and Adrian V. Hernandez, of the Cleveland Clinic in Ohio, searched the medical literature for randomized controlled trials of dabigatran that reported on MI or acute coronary syndrome (ACS) as secondary outcomes. Seven trials were selected, involving 30,514 participants, for their meta-analysis. The trials they included were: two studies of stroke prophylaxis in atrial fibrillation, one in acute venous thromboembolism, one in ACS and three trials or short-term prophylaxis of deep venous thrombosis in joint replacement. The control groups included administration of warfarin, enoxaparin or placebo. marketing in 4 countries (Germany, Switzerland, Portugal and Australia), received regulatory approval in November for marketing in several more European Union countries, namely the United Kingdom, Ireland, Belgium, Netherlands, Luxemburg, Sweden and Finland. ProMetic noted that it recently received a pu r chase order and binding forecast from Octapharma for approximately $US 3 million of PrioClear resin to be manufactured between December 2011 and June 2012 with further binding forecasts anticipated for the second half 2012. g. In the UK, Jonathan Mason, National Clinical Director for Primary Care and Community Pharmacy at the Department of Health, said in November that the NHS needs to start thinking about the use of medicines as an investment rather than as a spending issue. He told the third annual national Quality, Innovation, Productivity and Prevention (QIPP) symposium in Liverpool: Value-based pricing (VBP) is coming, and we need to think about whether we are willing to spend more on a new drug which will provide better outcomes or keep on going with the cheaper options…..If you focus purely on driving down spending, costs will ultimately increase and quality decreases. But a focus on quality, on continuous improvement, will improve quality and also drive down costs. h. Octapharma reported in mid-November that global sales totalled 1.7 million grams of Octagam® 5% and Octagam® 10% in the first ten months of 2011, an estimated 60,000 treatments, during which there were no reports of thromboembolic events. Also in November, the FDA cleared the way for the US market return of Octagam® 5%. This was based on changes Octapharma has made in the manufacturing process and the company's decision to implement a quality control test on every batch of product released to the marketplace for the absence of thrombogenic potential. Additionally, Octapharma will implement post-marketing studies to ensure product safety. Earlier in 2010, multiple international regulatory agencies authorized the return of Octagam® 5% and Octagam® 10% in important worldwide markets. Octagam® 10% is not approved for marketing in the US. • Octagam was reintroduced with TGA approval in Australia in October 2011. The NBA and the Blood Service worked collaboratively to ensure smooth transition to revised supply arrangements with the reintroduction of Octagam. i. The American Red Cross must pay substantial fines after federal inspectors discovered blood safety violations at the Red Cross Donor and Client Support Center in Philadelphia. That centre coordinates blood donor information from more than 30 collection points around the country. The violations included ineffective donor screening and failure to add new donors with infected blood to the national list of deferred donors. The FDA says these are serious violations, but the nation's blood supply was not compromised. j. The first cord blood storage and research facility in Western Australia was opened in December to store donations from new mothers at King Edward Memorial Hospital. k. CSL Behring announced in January that the FDA had approved a label expansion for self-administration of Berinert, C1 Esterase Inhibitor (Human), a pasteurized, nanofiltered therapy indicated for the treatment of acute attacks of hereditary an g i oede m a (HAE), a rare and potentially fatal g en e t i c d i so r d e r. The FDA has stated that with appropriate training, patients can now self-administer Berinert by intravenous infusion. Also, as part of their label expansion, Berinert is now also indicated to treat life-threatening laryngeal HAE attacks, as well as facial and abdominal attacks. • CSL Bioplasma has submitted Berinert as a Schedule 4 application. Berinert has been approved by the TGA for the treatment of acute attacks in patients with hereditary angioedema. l. Baxter in January submitted a supplemental biologics license application (sBLA) to the FDA for approval of Gammagard Liquid 10% [Immune Globulin Infusion (Human)] for the treatment of multifocal motor neuropathy (MMN). The product, marketed as Kiovig outside the United States and Canada, was approved for the MMN indication in Europe in 2011. The filing is based on a Phase III, randomized, double-blind, placebo-controlled, cross-over, multi-center study of the efficacy, safety, and tolerability of Gammagard Liquid 10% in a total of 44 MMN patients. The study evaluated whether Gammagard Liquid was superior to placebo administration in the primary and secondary endpoints, including grip strength. • Kiovig was selected under the recent IVIg tenders. It is registered in Australia for use as a sub-cutaneous product but is not approved under the supply arrangements for use in this manner. 2. Products a. Baxter announced in January that it would proceed to the second phase III trial using IVIG to treat Alzheimer’s after preliminary results of the first phase III trial showed more than 20% chance of improvement. Enrolment in the first trial was completed in June 2011. • The Data Safety Monitoring Board (DSMB) for the first phase III trial took an initial read of 120 patients at 18 months (from 390) and showed that the trial had a greater than 20% chance of reaching statistical significance in the primary combined endpoints. However, this initial read was conducted only as a “futility analysis’’ to see if the trial was worth continuing, and the full data release is not expected till the first quarter of 2013. • Baxter will now start its second 400-patient phase III trial. This is expected to take three years to complete and is required for FDA approval so this could happen in 2016. The second Phase III trial is identical in design to the first Phase III trial. It is a global, multi-centre trial that will enrol approximately 400 patients. Approximately 80 centres in North America, Europe, Japan and Australia will participate in the study. The primary endpoint of the study is to evaluate the effectiveness of Gammagard Liquid 10% on preserving cognitive performance and functional activities in patients with mild to moderate Alzheimer's disease, as compared with standard of care, over an 18-month period. • This second, confirmatory trial follows a separate, ongoing Phase III Gammaglobulin Alzheimer's Partnership (GAP) trial sponsored by Baxter in collaboration with the Alzheimer's Disease Cooperative Study (ADCS), a clinical trial consortium supported by the US National Institutes of Health. b. Researchers at King's College London have developed a test that uses mass spectrometry to detect various diseases from a single spot of dried blood. The test was developed for the diagnosis of sickle cell disease and inherited metabolic disease in newborns, but has been improved to detect diabetes, kidney disease and heart disease as well. Dried urine spots can also be used for the very early detection of kidney disease, particularly in patients with a high risk of developing renal complications, for example patients with type 1 or type 2 diabetes. The method for sickle cell disease and haemoglobinopathy screening using mass spectrometry was granted an EU patent in 2010. c. In November, the New England Journal of Medicine published results of an evaluation of whether prophylaxis with FEIBA can decrease bleeding events in patients with severe haemophilia A and inhibitors, compared with on-demand therapy. The study reported that patients treated prophylactically over six months experienced a 62% reduction in all bleeds in the prophylaxis period, an average of 5 bleeding events compared with an average of 13.1 during on-demand treatment. d. Baxter announced in January the dosing of the first patients in a Phase I clinical trial of BAX 855, a longer-acting (pegylated) form of a full-length recombinant factor VIII (rFVIII) protein. In terms of manufacturing process, BAX 855 is based on Baxter's Advate. The Phase I trial is a prospective, open-label study that will assess the safety, tolerability and pharmacokinetics of BAX 855 in previously-treated patients aged 12 years or older with severe haemophilia A. When used for prophylaxis, Baxter's Advate requires patients to infuse every two to three days to reduce the occurrence of bleeding episodes. This Phase I trial is the first step in assessing whether BAX 855 can be infused less frequently. e. Amgen wrote two new long-term supply contracts with major dialysis providers DaVita and Fresenius, as it prepares for potential competition for its Epogen. The supply deals come as US Medicare is changing its reimbursement for dialysis to a flat rate. The change has been expected to cut into Epogen sales, because the dialysis providers won't be paid any more for higher doses of the drug than they are for lower doses. Safety questions about higher doses of Epogen continue to mount. Anaemia drug Affymax could be launched in 2012, Roche's Mircera in 2014 and biosimilars as soon as 2015. f. At the 4th Asia Pacific Congress on Controversies in Obstetrics, Gynaecology and Infertility in Bangkok in November there were two oral presentations on the clinical value of the OrSense Ltd NBM 200 non-invasive haemoglobin monitor for maternal health and anaemia- monitoring prior, during and post delivery. g. Data from Baxter’s new phase III clinical trial of HyQ, its combination immunoglobulin product for use in patients with primary immunodeficiencies, was presented at the American College of Allergy, Asthma and Immunology annual meeting. HyQ had already been submitted for approval in the US and Europe. h. AMAG Pharmaceuticals in November announced positive new data from the first head-to-head trial comparing Feraheme (ferumoxytol) Injection for intravenous use to iron sucrose in patients with iron deficiency anaemia and chronic kidney disease. The data were presented in a clinical trials poster session at the American Society of N eph r o l o g y Kidney Week meeting in Philadelphia. i. CytoSorbents Corporation is a New Jersey company using blood purification to treat life-threatening illnesses. Its technology is based on biocompatible, highly porous polymer beads to remove toxic substances from blood and other bodily fluids by pore capture and adsorption. • In 2011, CytoSorb achieved EU CE Mark approval as an extracorporeal cytokine filter2. Its European sepsis trial showed statistically significant mortality benefits in patients treated with CytoSorb in two subgroups at high risk of death – those with very high cytokine levels and patients above the age of 65. CytoSorb reimbursement was established in Germany, addressing a major barrier to sales for most new products. The technology was introduced at medical conferences such as the German Sepsis Society Conference and the International Society of Intensive Care Medicine. The company was awarded its first Phase I Small Business Innovation Research grant from the US Army to develop its technology to help treat trauma patients with rhabdomyolysis. Rhabdomyolysis is the breakdown of muscle fibres that leads to the release of myoglobin into the bloodstream, which can be damaging to kidneys. The US Defense Advanced Research Projects Agency (DARPA) notified the company that it had selected its technology proposal for funding as part of its "Dialysis-Like Therapeutics" program to develop a blood purification device to treat sepsis, pending successful contract negotiations. The company released its new HemoDefend technology platform, which was introduced for out-licensing opportunities at the AABB conference. The company claims HemoDefend has the potential to remove contaminants from the blood supply that can cause transfusion reactions in the more than 30 million blood products administered annually in the US alone. It says Hemodefend removes antibodies, free haemoglobin and inflammatory mediators. j. At the 53rd Annual Meeting of the American Society of Hematology (ASH) in San Diego, Symphogen presented final Phase II data demonstrating that its recombinant polyclonal antibody drug candidate rozrolimupab exhibited a favourable safety profile and induced a rapid increase in blood platelets in patients with Immune Thrombocytopenia Purpura (ITP). Products currently used in ITP include immunoglobulin, Promacta and NPlate. k. CSL Behring announced that the first site (Vienna) has been initiated in its global phase II/III, multi-centre study to evaluate the safety, efficacy and pharmacokinetics of recombinant fusion protein linking coagulation factor IX with recombinant albumin (rIX-FP). The prospective, open-label study will enrol patients aged 12-65 years who have haemophilia B. CSL Behring, in collaboration with its parent company, CSL Limited, is developing rIX-FP for the prophylaxis and treatment of bleeding episodes in patients with congenital Factor IX (FIX) deficiency as part of the PROLONG-9FP clinical study program. To date, the PROLONG-9FP program has established study sites in Austria, Bulgaria, France, Germany, Italy, Spain and Israel. In coming months additional trial sites will be established in the United States, Japan and Russia. • This study follows a Phase I pharmacokinetic trial which the company says showed "very promising" half-life extension results. CSL Behring and CSL have
2 The company says that the overproduction of cytokines or "cytokine storm" is widely acknowledged to play a causal role in the development of organ failure, immune suppression, and secondary infections, the leading causes of death in the ICU from life-threatening illnesses such as infection and sepsis, burn injury, trauma, acute respiratory distress syndrome, pancreatitis and others. It says that physicians continue to affirm that there are no effective "active" therapies available to treat these conditions and that they continue to rely on supportive care therapies such as mechanical ventilation, vasopressors, and dialysis to help keep patients alive. The voluntary worldwide withdrawal of Xigris by Eli Lilly in late October, previously the only approved therapy in the US and Europe to treat sepsis, has highlighted the lack of therapies available. engineered rIX-FP to extend the half- life of Factor IX while minimizing any tolerability issues. In the process, recombinant albumin--a protein with an inherently long half-life--is used as a fusion partner. A specifically designed linker connects the recombinant factor IX and recombinant albumin as a means of optimizing the efficacy of rIX-FP. • The Phase II/III study consists of a screening period, a pharmacokinetic evaluation period, followed by an approximately 12-month safety and efficacy evaluation period with rIX-FP. A surgical prophylaxis sub-trial is included.
3. Market structure and company news: a. In November ProMetic Life Sciences announced that its expanded partnership with Wuhan Institute of Biologic Products and its parent company China National Biotech Group had resulted in the successful completion of the first milestones associated with the scaling up of the Plasma Protein Purification System (PPPS)3 in the Wuhan facility. This had created critical knowledge which will lead to further cost reduction for ProMetic's own facility in Laval, Canada. b. Novo Nordisk will no longer use live animals to test production batches of its biological products. It will use cells from hamsters and other animals to test its production batches for biological activity. Novo Nordisk says these methods produce a narrower range of results with more precision and reliability. The transition has involved amending thousands of registration dossiers to satisfy health authorities worldwide. The use of live organisms in the production of biologics raises concerns about batch-to-batch variability and the potential for contamination. As a result, potency and safety testing are typically required for each individual batch of a biological to maintain quality control. This often involves animal tests rather than in vitro assays used for quality control of small-molecule drugs. The number of animals needed for biological control tests, as well as the types of tests required, are determined by the regulatory requirements of the countries in which Novo Nordisk sells its products. c. Alnylam Pharmaceutical (headquartered in Cambridge, Massachusetts) is continuing its "Alnylam 5x15" program, which was launched in January 2011 to have five RNAi therapeutic programs in clinical development by the end of 2015. The company explains that RNAi is a natural process of gene silencing that could lead to a new class of medicines, RNAi therapeutics. Among the company’s plans are programs in haemophilia and refractory anaemia. d. Canadian company Cangene announced in January that it is cutting 120 jobs, or about 17 per cent of its total workforce. It has, however, signed a collaborative research agreement with the University of British Columbia to develop immune-based therapies for Alzheimer's disease.
4. Overseas events a. The Scottish National Blood Transfusion Service is to build its new national headquarters in Edinburgh, at the Heriot-Watt University Research Park. b. Debate continues over Canadian Blood Services’ decision to close its production facility in St John, in favour of a consolidated operation in the Maritime Provinces.
3 Prometic says that the Plasma Protein Purification System allows for the targeting and removal of multiple high- value proteins from a single plasma sample at unprecedented activity levels using ProMetic's Mimetic Ligand adsorbent technology. This system also provides for the recovery of new biotherapeutics as they are discovered and identified. The effect of this process is to reduce the significant losses incurred when using the more conventional Cohn precipitation process. Some support continues for the notion of an independent blood agency in New Brunswick. Suggestions have also been made of partnering with Héma-Québec . c. Michael Mosley filmed for a BBC series, Frontline Medicine, in the main hospital in Camp Bastion, the headquarters of the British forces in Afghanistan. In an article for the Mail Online in November he wrote “The survival rate amongst wounded troops in Afghanistan is up to 90 per cent, which makes it the highest in the history of warfare….. For my new series I wanted to find out what they were doing on the frontline that was making the difference and how what was being learnt could be used to improve physical-injury care in Britain”. These included: • the single- handed tourniquet, issued to all the troops on the ground. • soldiers being taught to stuff a wound with Celox - bandages impregnated with chitosan, a substance found in shrimp shells. • the intraosseous needle: The Medical Emergency Response Team on an evacuation helicopter can drill into bone (usually the humeral head) so blood is transfused into the bone’s soft marrow interior. This is easier in a moving helicopter than searching for a vein collapsed through blood loss. 4 • transfusing with a unit of plasma for every unit of red cells d. Europe's health is suffering, with around 80,000 cases of tuberculosis infection a year and serious problems with measles, HIV and threats from "superbug" infections, an annual health report on the region said in November. e. 15,000 newborn babies at two of Bahrain's main hospitals will be screened for genetic and metabolic disorders within the next two years. It will take place as part of a major study being launched in January by the non-profit Al Jawhara Centre for Genetic Diagnosis and Research. Diagnostic services managing director, Dr Jamal Golbahar said it was imperative such a screening programme was introduced because the risk of babies with genetic disorders increases in consanguineous marriage (marriage between relatives), which are between 60% cent and 70% in the region. In general there is a one in 2,000 chance of a child being born with a metabolic disorder, but it is only one in 50,000 to 60,000 in the US and Europe, said Dr Golbahar. The pilot study screening will be conducted by taking a blood spot from the baby's heel by prick test when it is two days old. It will be tested for 50 genetic disorders, including blood disorders such as sickle cell anaemia and thalassaemia. Those found to have a disorder will be followed up by a team of experts who will treat their condition.
5. Safety Issues: a. A study in the Townsville region has confirmed seropositivity of the causative agent of Q fever, Coxiella burnetii, in over 20% of domestic dogs. This may have public health implications for both dog owners and veterinarians. b. New mothers at Bathurst Base Hospital in 2009 received blood transfusions at a rate of more than four times the state average, new figures show. c. Many premature infants suffer a life-threatening destruction of intestinal tissue called necrotizing enterocolitis (NEC). Now a Loyola University Medical Center study5 has identified a major risk factor for NEC. Premature newborns with the AB blood type who develop NEC are nearly three times as likely to die from it as those with other blood types. The authors say neonatal ICUs typically give Type O in transfusion, the
4 A study involving 22 centres in England and Wales is assessing how changing the mix of blood components given can affect outcomes.
5 The study was published online ahead of print in the Journal of Perinatology. Senior author is Jonathan Muraskas, MD, co-medical director of Loyola's neonatal ICU. universal donor type. This practice may inadvertently cause an enhanced immune reaction.
6. Research: a. Once-monthly peginesatide, an investigational peptide-based erythropoiesis stimulating agent (ESA), is similar to epoetin administrated one to three times weekly in maintaining mean haemoglobin levels in the 10-12 g/dL range in hae m o d i a l y s is patients with anae m i a, according to study findings presented in Philadelphia in November at Ki dn e y W e ek 201 1. b. Researchers at Children’s Hospital Boston have found a way to reverse anaemia in lab mice. They discovered that genetically engineered blood vessels were successful in secreting drugs into the bloodstream. If the method succeeds in delivering other therapeutic proteins on demand, it could be used for patients with haemophilia to deliver Factor VIII and Factor IX proteins; with hepatitis C to deliver alpha interferon; and with multiple sclerosis to deliver interferon beta, all according to Juan Melero-Martin, the study’s principal investigator from the Department of Cardiac Surgery at Children’s Hospital, Boston.6 c. A novel immunoglobulin replacement therapy that uses hyaluronidase to facilitate dosing with gammaglobulin has shown good efficacy in preventing infections in people with primary immunodeficiency disease (PIDD), according to a study presented in a poster session at the American College of Allergy, Asthma & Immunology 2011 Annual Scientific Meeting in November. It may also enable reducing the frequency of dosing from monthly to weekly. d. Medical researchers in Canada and the US recently published their joint findings that fatal prion diseases, which include BSE or "mad cow disease," have a hidden signature. In the journal Public Library of Science (PLoS) Pathogens, they demonstrate that up to seven months before an animal showed physical signs of having a prion infection, a particular prion protein in the brain was being eradicated. This is known as shadoo protein. The researchers suggested that the brain cells are in fact trying to get rid of the fatal prion protein and as a consequence, this bystander shadoo protein is being destroyed unintentionally. e. In December, China launched a research program on the treatment of beta thalassemia, a predominant type of Mediterranean anaemia, in Guangzhou, the capital city of south China's Guangdong province. f. Erythropoietin, considered a "performance enhancing" substance for athletes, may increase risk of vascular problems in the brain, Swiss researchers said. The study, published by the Journal of the Federation of the American Societies for Experimental Biology, found that prolonged EPO administration increased haematocrit – the concentration of red blood cells in blood – while acute administration did not. The study found both groups had increases in blood vessel constriction and higher blood pressure. g. Preoperative autologous blood donation during posterior lumbar spinal surgery is associated with preoperative anaemia, and a lower transfusion threshold than allogeneic blood use, according to a study in Spine (15 December 2011). h. New research shows that transfusions did not speed recovery or reduce the risk of dying among more than 2,000 elderly people who had hip surgery. The study appears online in the New England Journal of Medicine (15 December 2011). i. The annual meeting of the American Society of Hematology in San Diego in December was told that hydroxyurea, approved for use in adults with severe sickle cell anaemia, can also help young children with the disease. j. Six haemophilia B patients given a single treatment of gene therapy enjoyed substantially improved symptoms and quality of life. Their livers were infused with a
6 November 17 issue of Blood correct version of the gene that makes Factor IX. Four were able to stop receiving FIX up to the time of the report and the other two increased the time period between receiving FIX. The patients ranged in age from 27 to 64.7 The first patient who received the gene has maintained steady levels of the FIX protein for more than 18 months. • Altering the disease from severe to mild may be harder for haemophilia A because the missing protein is much larger and therefore more difficult for a vector virus to deliver to the liver. Hemophilia A is also thought more likely to generate an immune response. Two of the gene therapy patients with hemophilia B suffered mild immune responses that required steroid treatment.
7. On the horizon a. MIT researchers have described the key role of platelets in spreading cancer through secondary tumours. Cancer research professor Richard Hynes and his team published in Cancer Cell, pointing to chemical signals from the platelets leading tumour cells to spread into other locations. Platelets were found to contribute to metastatic cells after coming in contact with tumour cells. Metastasis may be responsible for up to 90% of cancer deaths. • This may in the longer term change cancer treatment processes given that a large proportion of platelet transfusions are given to people undergoing chemotherapy or bone marrow transplantation. b. In a high-stakes experiment funded by the US Defense Department, the University of Pittsburgh Medical Center is to test a hypothermia strategy on a handful of trauma victims who are bleeding so badly from gunshots, stab wounds or similar injuries that their hearts stop beating. Get cold enough and "you do OK with no blood for a while," says lead researcher Dr. Samuel Tisherman. He calls the rescue attempt "emergency preservation and resuscitation", EPR instead of CPR. His team plans to begin testing it early this year. • Before the first candidates are chilled, the scientists face a hurdle: The law requires that patients consent to be part of medical experiments after they're told the pros and cons. That's impossible when the person is bleeding to death. There won't even be time to seek a relative's permission. So the Pittsburgh team is beginning a campaign required by the FDA to educate area residents about the study instead — with signs on city buses, video on YouTube, a web site and two town-hall meetings. Residents worried about possible risks, such as brain damage, could sign a list saying they'd opt out if they ever were severely injured. c. Scientists have created blood platelet cells by reprogramming stem cells derived from adult cells, offering the potential for a renewable supply. Researchers at the Centre for iPS Cell Research and Application at Kyoto University presented data at a meeting of the American Society of Hematology in December showing they were able to create the cells in the laboratory and confirm they had the same life span as normal human platelets when infused in mice. Induced pluripotent stem cells, or iPS cells, are produced by manipulating ordinary human skin or blood cells back to a state in which they are able to differentiate into a number of different cell types.
7 The study was presented in December at the annual meeting of the American Society of Hematology in San Diego, and was published concurrently in the New England Journal of Medici 8. Infectious diseases: a. Mosquito- borne diseases • Inviragen in November announced the start of Phase 2 trials of DENVax, its investigational dengue vaccine. The trials will test the safety and immunogenicity of the vaccine in multiple age groups in countries where dengue fever is endemic – Puerto Rico, Colombia, Singapore and Thailand. The testing follows the successful completion of Phase I trials of the vaccine, conducted in Colombia. • A group of researchers led by Novartis has discovered novel malaria compounds that may prove to be more efficient than currently available treatments and could be used as a prophylactic. This new class of antimalaria treatments targets infections both in the blood and in the liver, thus reducing the risk of a disease relapse. b. Influenza/Avian Influenza • Inovio Pharmaceuticals announced in November that a single intradermal (ID) electroporation boost of its SynCon avian influenza vaccine generated hemagglutination inhibition (HAI) titres against six different, unmatched strains of H5N1 – a distinct new clinical achievement on the global research community's path to develop universal influenza vaccines. This single synthetic vaccine generated a four-fold or greater rise in HAI titres in 50 per cent of boosted subjects in its Phase I clinical study. These results were presented at the 5th WHO Meeting on Influenza Vaccines that Induce Broad Spectrum and Long-Lasting Immune Responses. • According to research published in the November Journal of Virology, vaccinating children annually against influenza virus could interfere with their development of cross-reactive killer T cells to flu viruses. Lead author Rogier Bodewes of Erasmus Medical Center, Rotterdam, and his collaborators warn of potentially conflicting outcomes from annual flu shots. "Annual flu vaccines are effective against seasonal flu, but could leave people more vulnerable to novel pandemics", said Bodewes. "Induction of virus-specific killer T cells caused by childhood flu infection may reduce morbidity and mortality rates from pandemic influenza viruses." • Sustained community transmission of oseltamivir-resistant A(H1N1) 2009 pandemic viruses have been identified in Australia. Relevant samples were obtained in the Hunter New England region of NSW between May and August 20118. • A review of oseltamivir (Tamiflu) raised questions about both the efficacy of the medication and the commitment of its maker to supply enough data for claims about the drug to be evaluated by independent experts9. • Science and Nature jointly published a l e tt er on 20 January declaring a voluntary two- month suspension of research into transmission of H5N1 highly pathogenic avian influenza. The letter, signed by 39 influenza researchers around the world, acknowledges that before research continues, there should be informed, global discussions regarding its regulation and publication. The move came after the news that H5N1, which so far has not evolved transmissibility between humans, had been
8 N. Engl. J. Med., 2011; 365:2541-2542
9 Je f f e r s o n T , et a l " N eu r a m in id as e inh i bi t o rs f or p r e v e n t i n g a nd tr e a t i n g in f lu e n z a i n he a l t hy adu l ts a nd ch i ld r e n" C och r a n e D a t ab a s e o f S y s t e m a t i c R e v ie w s 2011 ; 12 . Art. N o .: CD 008 9 65. transformed in lab experiments into a virus that is aerosolized and easily transmitted between ferrets, the animal model that best mimics human influenza infection. On 20 December, the US N a t i onal S c i ence A d v i so r y B oa r d f or Bi osecu r i t y (NSABB) recommended that details of the mutations which evolved this new transmissibility be redacted before publication, sparking a heated debate among the scientific community regarding how to share the results of such potentially dangerous research, and whether or not to do i t i n t he f i r s t p lace. • In December, the first US facility for making influenza vaccine in cell culture was opened in North Carolina. The Novartis plant had 49% of its construction funded by the US Health and Human Services Department. Cell culture is seen as somewhat faster than conventional, egg-based production of flu vaccine. There is some suggestion that chicken-based egg production might be vulnerable to an avian flu pandemic. The facility uses cultured canine kidney cells to grow influenza vaccine. c. vCJD • An international team of researchers identified two Swiss cows with a new form of “mad- cow disease”. Previously, scientists had uncovered three prion variants, but when the current team examined the prions of the two cows, they found a fourth variant10. d. Other • In November, Senator Kim Carr opened the new Australian Animal Health Laboratory (AAHL) Collaborative Biosecurity Research Facility (ACBRF) in Geelong. The facility, which is a part of the CSIRO’s AAHL, will research viruses that threaten people, livestock and wildlife. It will be used to investigate the origin and treatment of ‘zoonotic’ diseases – that is, diseases that can be transmitted between humans and animals. • A recent study11 published in the Medical Journal of Australia examined whether premigration screening for tuberculosis is worth undertaking in visa applicants, and whether screening resources are being appropriately directed towards intending migrants at highest risk of tuberculosis. The authors report that the overseas screening program is detecting substantial numbers of people with active tuberculosis who otherwise would have travelled to Australia. Premigration screening detected 519 people who required treatment for active tuberculosis in the 2009–10 financial year. It is uncertain if this is typical, although at May 2011 nearly 400 cases had been identified in the 2010–11 program year. The prevalence of tuberculosis found (137 per 100 000 population) compares with that found in people in Australian immigration reception and processing centres (157 per 100 000).12 These rates are high compared with the estimated prevalence of tuberculosis in Australia of 7.9 per 100 000 population in 2009.13 • Almost 4000 cases of whooping cough were reported last year to the WA Health Department, compared with 1458 cases for the whole of 2010. • British troops are returning from Afghanistan with the desert boils disease leishmaniasis. They develop crater-like skin boils that erupt and are very slow to heal. The treatment is
10 in the journal Emerging Infectious Diseases, published by the U.S. Centers for Disease Control and Prevention, January 2012.
11 Author details Kathleen King BSc(Hons), MB ChB, FRCPath, formerly Senior Medical Adviser , Global Health Branch, Dept of Immigration and Citizenship, Sydney. Paul J Douglas MB BS, MHA, FRACMA, Chief Medical Officer and Global Manager Health, Immigration. Ken Beath BE, MAppStat, PhD, Lecturer, Dept of Statistics, Macquarie University.
12 King K, Vodicka P. Screening for conditions of public health importance in people arriving in Australia by boat without authority. Med J Aust 2001; 175: 600-602.
13 World Health Organization. Global tuberculosis control. WHO report 2010. Geneva: WHO, 2010: 183. intravenous dosing with sodium stibogluconate. Cutaneous leishmaniasis, the common form among soldiers, is a disease spread by the bite of the female sandfly. It can eventually cause parts of the nose and lips to wear away if left untreated.