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Monitoring International Trends posted April 2013 The NBA monitors international developments that may influence the management of blood and blood products in Australia. Our focus is on: Potential new product developments and applications; Global regulatory and blood practice trends; Events that may have an impact on global supply, demand and pricing, such as changes in company structure, capacity, organisation and ownership; and Other emerging risks that could potentially put financial or other pressures on the Australian sector. A selection of recent matters of interest appears below. Table of Contents Products................................................................................................................................ 1 Regulatory matters ................................................................................................................ 2 Market structure and company news ..................................................................................... 3 Country- specific events ........................................................................................................ 4 Safety and Patient Blood Management ................................................................................. 5 Research………………………………………………………………………………………………5 Infectious Diseases ............................................................................................................... 6 Appendix: Alzheimer’s Research .......................................................................................... 9 1. Products a) At the American Academy of Neurology meeting in March, Shawn Kile from the Sutter Neuroscience Institute in Sacramento reported that recent studies suggested that even a short course of intravenous immunoglobulin (IVIg) could slow brain atrophy in early Alzheimer’s disease and improve cognitive function. Octapharma supported the study. b) Caltech1 engineers, in collaboration with Israeli company LeukoDx have invented a portable device to count white cells of varying types2. The device 1 California Institute of Technology 2 Each of the five subtypes of white cells has a different function. Lymphocytes use antibodies to attack certain viruses and bacteria; neutrophils are combat bacteria; eosinophils target parasites and some infections; monocytes respond to inflammation and replenish white blood cells within bodily tissue; and the rarest subtype, basophils, attack certain parasites. The work is described in the April 7, 2013 issue of the journal Lab on a Chip. 1 c) d) e) f) g) h) 3 4 works on only a pinprick of blood, and gives results in a few minutes, which closely match results from hospitals. A researcher at Washington University in St. Louis has found a way to use light and colour to measure oxygen in individual red blood cells in real time. The technology may have a use in determining how oxygen is delivered to normal and diseased tissues, or the impact of specific treatments on oxygen delivery throughout the body3. Staff at the US Army’s Institute of Surgical Research are developing an “intelligent tourniquet”, which has a pump and sensor system that can be controlled by wireless. When activated it can determine how much pressure it needs on the limb to stop beeding. The wireless vital sign monitor keeps track of heart rate and blood pressure. Wirelessly connected to a laptop, tablet, or smartphone it will give a more detailed readout. The vital signs monitor has been approved by the FDA, but the “intelligent tourniquet” is still in the prototype phase. Entegrion is collaborating with Kedrion Melville, Inc. for clinical development and commercialization of Entegrion’s dehydrated pathogen-inactivated plasma product, Resusix. It is portable and overcomes the cold chain restrictions of fresh frozen plasma (FFP), which is the current standard of care. Entegrion will begin human clinical trials with Resusix in 2013, funded primarily through contracts with the US Department of Defense. Kedrion will make an equity investment. The early development of Resusix was supported from The Office of Naval Research. The program will now be managed by the US Army combat casualty care directorate. The Defense Advanced Research Projects Agency (DARPA) has awarded the Wyss Institute for Biologiclly Inspired Engineering a $US 9.25 million contract to advance its blood-cleansing technology to treat sepsis-bloodstream infections that are the leading cause of death in critically ill patients and soldiers injured in combat. The patient’s blood is mixed with magnetic nanobeads that are coated with genetically engineered human blood protein that bind to a variety of bacteria, fungi, viruses, parasites and toxins. It then passes through microchannels in the device where magnetic forces pull out the pathogens without removing human blood cells, proteins, fluids, or electrolytes -- similar to how the human spleen does. The cleansed blood then goes back to the patient. The addition of rituximab to a dexamethasone regimen was associated with improved platelet response rates in a cohort of patients with immune thrombocytopenia, according to results of a randomized, open-label, phase III trial. Scientists at Temple University and the University of Delaware have reported4 on the effect of Fucoidan on platelets. Fucoidan is a sulfated polysaccharide, derived from the brown seaweed Fucus vesiculosis, which has demonstrated decreased bleeding and clotting time for people with haemophilia and is now in clinical trials. It activates platelets rather than increases a particular clotting factor. The research was published in PNAS Online Early Edition, March 25, 2013 in the Journal of Biological Chemistry 2 2. Regulatory a) Baxter and Halozyme Therapeutics announced in March that the European Medicines Agency's Committee for Medicinal Products for Human Use (EMA CHMP) gave a positive opinion on the use of HyQvia as replacement therapy for adult patients with primary and secondary immunodeficiencies. HyQvia, a solution for subcutaneous use, combines human normal immunoglobulin (10%) and recombinant human hyaluronidase, which facilitates the dispersion and absorption of the immunoglobulin. b) The European Commission granted CSL Behring marketing authorization for the use of Privigen (immune globulin intravenous [human], 10 percent liquid) in the treatment of patients with chronic inflammatory demyelinating polyneuropathy (CIDP). CIDP is a neurological disorder of the peripheral nerves characterized by progressively worsening weakness in the arms and legs. c) Cangene Corporation of Winnipeg had its botulism antitoxin (heptavalent) approved by the US Food and Drug Administration (FDA). It was developed under a contract with the US Department of Health and Human Services as a precaution against possible bioterrorism. d) Bayer announced CHMP had recommended its anti-clotting drug Xarelto for approval in the European Union when preventing cardiovascular death or stroke after an acute coronary syndrome in adult patients with elevated cardiac biomarkers. e) Fenwal received FDA clearance for a functionally closed disposable set used with the Autopheresis-C system to collect plasma for processing into FFP for transfusion. The closed design permits thawed plasma to be stored for up to an additional four days. f) Terumo BCT in April received 510(k) clearance from the FDA to collect platelets on the Trima Accel system for storage in Isoplate platelet additive solution, which replaces a portion of the plasma in blood products. Blood centres in the US can now collect platelets on the Trima Accel system in 65 percent less plasma volume and store platelets in Isoplate for up to five days, which reduces the single-donor plasma volume in the transfused platelet product. g) Biotest’s Florida plant recalled one lot of Bivigam intravenous immunoglobulin 10% liquid, 100ml vials because visible particles were observed. h) The FDA has granted Acceleron Pharma orphan designation for ACE-536 to treat beta-thalassemia and myelodysplastic syndromes. 3. Company structure and market news a) German company Biotest said in March it is interested in taking over British government-owned Plasma Resources UK (PRUK). The British government reaffirmed in January it would sell most or all of its shares in PRUK. PRUK's Bio Products Laboratory Ltd (BPL) makes plasma products from collections at 32 centres in the US operated by DCI Biologicals Inc. American biopharmaceutical companies and private equity firms are also reported to be interested. b) Biotest’s group sales last year amounted to 422 million euros, up by 4.3 per cent on 2011, while profits after tax rose by 23.5 per cent year-on-year to 23.1 3 c) d) e) f) million euros. The company said it expects the group's sales in the financial year 2013 to grow 10 per cent to 15 per cent year-on- year. CSL Limited on 27 March 2013 closed a new US$500m Private Placement in the US. The Private Placement was foreshadowed in CSL's half year announcement in February 2013. It has four maturity dates, an average life of 8.5 years, and a weighted average interest rate of 2.81 per cent. The proceeds from the Private Placement will be used to fund the Group's capital management plan, including on-market buybacks, and for general corporate purposes. CSL is reviewing its non-plasma businesses, with its incoming CEO Paul Perreault interested in assessing their growth prospects, to see if the businesses need to be improved, spun-off or sold. The Commonwealth Serum Laboratories were established during World War I when Australia became isolated from global supplies. CSL was incorporated in 1991 and listed on the Australian Stock Exchange in 1994. bioCSL, which was formed in January, includes vaccine, pharmaceutical and diagnostics businesses. It is the only manufacturer of flu vaccine in the Southern Hemisphere; its other vaccines include a vaccine for Q fever. The company produces anti-venom for Australian snakes and spiders. CSL sells the Gardasil human papilloma virus vaccine, which protects against cervical cancer, in Australia and earns royalties on Merck’s sales of the vaccine overseas. Cerus Corporation announced that the TILAK, University Clinics, Regional Hospital Innsbruck (LKI) in Austria and ZIT GmbH Hamburg in Germany, signed one and four year purchase agreements, respectively, for the INTERCEPT Blood System for platelets. Implementation of the latter agreement is expected to occur upon ZIT Hamburg’s receipt of regulatory approval from the Paul-Ehrlich-Institut to produce INTERCEPT-treated platelets. Prices charged by the three largest producers of plasma therapies- CSL, Baxter and Grifols have 70 per cent of the market- have increased in the US by up to 4 per cent for the second consecutive year and analysts are predicting further price rises. Julien Dormois, a Paris-based analyst at Exane BNP Paribas, noting a 5 per cent rise in Grifols share price in response to predictions of more price increases, raised his stock- price estimate by 21 per cent to $45. 4. Country- specific events United States a) A 9-year-old Georgia boy has developed a rare tick-borne bacterial infection called ehrlichiosis from a blood transfusion, according to the Centers for Disease Control and Prevention (CDC). The infection is serious and can be fatal. It can remain undetected because routine tests don't look for it, and many people do not realize they were bitten by a tick. In this case, the boy's condition deteriorated for ten days before a pathologist identified the condition. Ehrlichiosis is easily treatable with the antibiotic doxycycline, but as this is not a powerful drug it is not always the first choice when doctors are dealing with a serious but unknown infection. In this case the boy was treated 4 with broad-spectrum antibiotics on admission to hospital, but remained ill. The infected donor was traced, but had no symptoms.5 b) Memorial Blood Centers in April announced the receipt of a second round of funding from The Foundation for America's Blood Centers to continue research on blood donor safety. The Iron Depletion and Replacement in Donors Study is a two year study being conducted jointly with the Mississippi Valley Regional Blood Center. Across the US, a low haemoglobin level is the most common medical reason for donor deferral. Previous studies have evaluated the efficacy of iron replacement in deferred donors but this study includes testing of ferritin--a measure of iron stores--and also offers iron replacement to donors who qualify for donation but may be at risk of iron deficiency. Participant data is being compared with data collected under current testing protocols to discover if education and iron replacement reduce rates of subsequent donor deferral. c) At the National Kidney Foundation’s 2013 Spring Clinical Meetings, researchers reported that red blood cell transfusion rates have increased since the introduction of the Medicare prospective payment system (“bundling”) for end-stage renal disease care and changes to drug labelling for erythropoiesis stimulating agents. Canada d) Health Canada is opening up a comment period on its website for people to express support or concern about paid plasma donations and their potential impact on the nation’s blood system. Canadian Plasma Resources wishes to operate commercial collection centres in Toronto and Hamilton. Health Canada’s responsibilities include the safety of the blood supply. Whether donors are paid falls under provinicial legislation. As part of its consultation, Health Canada convened a meeting in Toronto on 10th April with key stakeholders, including patient advocacy groups, academia, provincial and federal government representatives the Canadian Blood Services, the nonprofit agency that oversees the blood supply in Canada, except Quebec. Also participating was Héma-Québec, which oversees the blood system in Quebec. e) On April 17th, World Haemophilia Day, the Canadian Haemophilia Society marked its sixtieth anniversary as the World Federation of Haemophilia celebrated its fiftieth. Both were founded in Montreal by Frank Schnabel, a businessman with haemophilia. Other f) In New Zealand, a decline in the demand for red blood cells from District Health Boards means the New Zealand Blood Service has been able to reduce the number of times a year it calls on some donors. The Auckland DHB, for instance, has run a campaign on "Why use two when one will do?" g) In India, the proposal from five years ago to set up the National Blood Transfusion Authority (NBTA), to streamline regulations in the blood banking sector, appears to have been dropped by the government. 5 The case report was published in the journal Clinical Infectious Diseases, March 19, 2013. 5 5. Safety and patient blood management a) Vel-negative blood contains an antibody that can cause violent rejection of transfused blood, and further transfusions can trigger kidney failure and death. The blood type has been difficult to identify and supply. Scientists led by Bryan Ballif of the University of Vermont and Lionel Arnaud of the French National Institute of Blood Transfusion have found the culprit, a small protein molecule called SMIM1, and identified two rapid DNA tests for identifying Velnegative blood in patients6. b) At the 15th International Haemovigilance Seminar in Brussels, Swissmedic and the Swiss Red Cross presented the results of a haemovigilance study reflecting two years of experience with routine transfusion of 62,500 INTERCEPT-treated platelet components. Dr. Markus Jutzi told the meeting: “As expected, in routine use, we observed that INTERCEPT-treated platelet components prevented septic transfusion reactions. Furthermore, we detected no increased risk for pulmonary adverse events. The introduction of the INTERCEPT procedure also obviated the need for gamma irradiation.” 7 c) In the US, the Cleveland Clinic is using new protocols to make doctors think again before ordering transfusions. Costs for external blood purchases dropped to $US26.4 million in 2012 from $US35.5 million in 2009. Savings elsewhere in the hospital included blood storage and processing costs and the cost of transfusion-related complications. Robert Lorenz, medical director of blood management for the Cleveland Clinic, says the guidelines encourage physicians to give some patients iron before surgery, and to accept some level of anaemia and a higher heartbeat before resorting to transfusions. The Cleveland Clinic uses low volume test tubes when samples are collected and minimizes the number of blood draws performed on patients. 6. Research a) Scientists at the Albert Einstein College of Medicine of Yeshiva University and the Icahn School of Medicine at Mount Sinai have discovered in mice that macrophages -- white blood cells essential in the immune response -- also help to produce and eliminate the body's red blood cells. The findings could lead to novel therapies for human conditions where the red blood cell production is out of balance such as haemolytic anaemia and polycythaemia vera, bone marrow transplants and chemotherapy8. b) A team at Lund University (Sweden) have rejuvenated the blood of mice by re- programming the stem cells that produce blood. "Our ageing process is a consequence of changes in our stem cells over time", said Martin Wahlestedt, lead author of the report in the journal Blood. "Some of the changes are 6 Their results were published online in the journal EMBO Molecular Medicine on March 18, 2013. The poster abstract has been published as P-11 in Blood Transfusion, Supplement No. 1, February 2013, ISSN 1723-2007 and is available for download at http://www.bloodtransfusion.it/scarica.aspx?tipo=A&id=002454&riv=81. 7 8 Andrew Chow et al, "CD169+ macrophages provide a niche promoting erythropoiesis under homeostasis and stress." Nature Medicine, 2013 DOI: 10.1038/nm.3057. Another study reported in the same issue by Stefano Rivella and colleagues at Weill Cornell Medical College will also be of interest. 6 irreversible, for example damage to the stem cells' DNA, and some could be gradual changes, known as epigenetic changes, that are not necessarily irreversible, even if they are maintained through multiple cell divisions. When the stem cells are re-programmed, as we have done, the epigenetic changes are cancelled." c) A team led by Dr Anna Randi at the National Heart and Lung Institute, Imperial College London used a new approach to investigate von Willebrand disease (vWD). This disease is caused by a deficiency of von Willebrand factor (vWF), a blood component essential to clotting. vWF is produced by endothelial cells, which line the blood vessels. Dr Richard Starke, lead author of the study, took blood samples from eight patients, extracted stem cells called endothelial progenitor cells, and grew them in the lab to yield large numbers of endothelial cells. The team then analysed each patient’s disease. Dr Randi believes that endothelial progenitor cells could become an invaluable resource for testing new drugs for vWD and other diseases. “We will be able to test the effects of a range of compounds in the patients’ own cells, before giving the drugs to the patients themselves,” she said. Professor Mike Laffan, in charge of patients with VWD at Hammersmith Hospital in West London, hopes to apply the team’s findings to reduce severe bleeding in these patients. 7. Infectious diseases Mosquito- borne diseases a) Arbovax has completed its pre-clinical trial of its single-dose tetravalent dengue vaccine in primates. Inviragen has completed the first stage of its phase II study of its two-dose DENVAx. A vavccine developed by the US National Institutes of Health (NIH) is entering phase II.9 b) The CDC published findings that a 2010 dengue outbreak in Florida came from a unique local strain of the virus. c) Wageningen University in the Netherlands, the Erasmus Medical Centre and TI Pharma have worked jointly to develop a prototype vaccine against chikungunya10. d) Researchers have discovered the precise structure of the chikungunya virus while it is bound to antibodies, showing how the infection might be neutralized. Michael Rossmann, Purdue University's Hanley Distinguished Professor of Biological Sciences, said "This is the first time the structure of an alphavirus has been examined in this detail." Chikungunya is an alphavirus. The research was reported in the journal eLife. e) Dengue has been found in Innisfail and Townsville, following the Cairns outbreak. f) Researchers from the University of Oxford and the Wellcome Trust reported in the journal Nature that nearly 400 million people annually are infected with dengue, more than triple the current estimate by the World Health Organization (WHO). 9 Co developers came from Johns Hopkins University and the University of Vermont. The The study appeared in the March 15, 2013 issue of the Journal of Infectious Diseases. 10Reported in the Public Library of Science journal, PloS Neglected Tropical Diseases 7 g) Hawaii Biotech has acquired from Merck, ownership of a family of patents to West Nile virus vaccine technology, and a nonexclusive license to related technologies. Hawaii Biotech is developing a Crimean-Congo haemorrhagic fever vaccine through a grant from the National Institute of Allergy and Infectious Diseases; a malaria vaccine in collaboration with academic researchers at the University of Hawaii at Manoa; and a tick-borne flavivirus vaccine. Influenza h) The flu reports currently of most interest globally concern the emergence of H7N9 in China. The disease does not seem to be particularly challenging to birds, but has a significant fatality rate in humans. There is at the time of writing still debate on its source, its geographic extent, on whether it is capable of human to human transmission, on how fast the world can prepare for mass vaccination against a possible pandemic, on whether it is resistant to available treatments, on how fast it is likely to mutate and even on how to detect it in birds as well as humans. Chinese health officials report the disease attacks the lungs, causing suffocation and organ failure. i) The CDC has begun vaccine preparation for H7N9, using synthetic DNA, teaming up with Novartis and the J.Craig Venter institute to reverse engineer the virus sequence. j) Sanofi Pasteur’s quadrivalent flu vaccine has been accepted for review for approval in Europe k) A new vaccine effective against the H5N1 avian influenza virus, in mice and ferrets, and also effective against the H9 subtype of avian influenza, was reported online ahead of print in the Journal of Virology. The print version will appear May 2013. l) Australian researchers say a new strain of swine flu has been detected that is resistant to antivirals like Tamiflu, although the strain was sensitive to Relenza. The speaker at the Annual Scientific Meeting of the Australasian Society for Infectious Diseases was lead investigator Dr. Aeron Hurt of the World Health Organization Collaborating Centre for Reference and Research on Influenza in Melbourne. m) A CSIRO Australian Animal Health Laboratory (AAHL) project is creating genetically modified chickens to breed H5N1 resistant offspring. n) Both common sense and Canadian research (by Dr Kamrahn Khan of St Michael’s Hospital, Toronto) suggest that if flu screeining at airports is to be used to slow a pandemic, then screening before travel from areas of threat is essential, although it may be politically difficult. Other o) At 26 March, the World Health Organization (WHO) had been informed of 17 confirmed cases of human infection with the novel coronavirus, of whom 11 had died. Human to human transmission is thought to have occurred in a family treated in the UK after one member had travelled to Pakistan and Saudi Arabia. p) Researchers continue with viral engineering which without adequate safeguards may pose a risk to public health. Work to make H1N1 transmissible between humans had its moratorium lifted, and a Dutch scientist 8 q) r) s) t) u) v) w) x) was reported to have proposed similar experiments with other avian flu viruses and with the new coronavirus. German and Swiss scientists reported they had engineered the canine distemper virus to grow in human cells. Researchers at the University of Alberta have discovered a tiny change in the makeup of prions which appears to allow mad cow disease to adapt and spread in other animals. Public health experts are concerned about the threat from a tuberculosis epidemic on Queensland’s northern border. A woman from Papua New Guinea, who died in Cairns Base Hospital in March of extensively drug resistant TB, is seen as the first of a wave of medical refugees entering Queensland for treatment. Between late December and 26 March, health authorities in Perth had confirmed 30 cases of mumps. Most were older teenagers or young adults who had been partially or fully vaccinated against mumps. A Queensland boy has become Australia's third victim of the bat-borne lyssavirus. He is thought to have been bitten by a bat while in the Whitsundays. A man who became Maryland’s first fatal case of rabies in nearly 40 years contracted the infection from a kidney transplant. Australian infectious diseases experts, like their overseas colleagues, are increasingly concerned about the emergence of antibiotic–resistant superbugs not only in hospitals but in the community. Victoria had 485 cases of cryptosporidiosis notified to the health department this year to April 1, compared with 88 for the same period last year. At the annual meeting of the Australasian Society for Infectious Diseases in Canberra in March, West Australia Health Department researchers presented their study of the state’s visitors to Bali which showed that increased travel to the island has resulted in a rising number of serious diseases. Dengue fever was the disease most commonly brought back from Indonesia in 2012, with 415 notifications, 80 per cent of all WA dengue cases. Other diseases acquired in Indonesia in 2012 included salmonella gastroenteritis with 263 cases, campylobacter gastroenteritis with 157 cases, chlamydia with 95 cases and gonorrhoea with 37 cases. Also contracted were hepatitis A, HIV, legionaires' disease, malaria, typhus and typhoid fever. 157 people needed rabies prophylaxis after incidents with animals in Bali. 8. Appendix: Research on Alzheimer’s Disease a) In the US, the CDC released data showing the risk of dying from Alzheimer’s disease rose 39 per cent between 2000 and 2010 as mortality rates for cancer, heart disease and stroke fell. b) ORM-12741 is the first drug to target a specific subtype of adrenergic receptors (alpha-2C) in the brain. These are thought to be involved in modulation of brain functions under stressful conditions. In a clinical trial with 100 patients it appeared to have some positive effect on memory11. 11 Study author Juha Rouru, MD, of Orion Pharma in Turku, Finland. Published in American Academy of Neurology, March 2013. 9 c) H. Lundbeck A/S and Otsuka Pharmaceutical Co announced a license and development agreement for Lu AE58054, a selective 5HT 6 receptor antagonist. The compound met its primary endpoint in a fixed dose, randomized, placebo-controlled, 24-week clinical study in 278 patients with moderate Alzheimer's disease, with Lu AE58054 administered as an add-on to donepezil. The clinical data from the phase II study will be presented at the annual Alzheimer's Association International Conference (AAIC) in Boston in July 2013. d) US researchers have identified two drugs already approved for human use that act against prion disease. Astemizole is an antihistamine that crosses the blood-brain barrier and works effectively at a relatively low concentration. Tacrolimus is an immune suppressant used in organ transplantation. However, although it acts as an anti-prion drug, it may cause problems with neurotoxicity. Both compounds reduce the amount of the normal form of the prion protein at the cell surface12. e) Researchers at the Max Planck Florida Institute for Neuroscience reported in The Journal of Neuroscience that the presence of amyloid beta triggers increased levels of a signalling protein called centaurin-a1, that appears to cause neuronal dysfunction. The FDA has granted Acceleron Pharma orphan designation for ACE-536 to treat beta-thalassemia and myelodysplastic syndromes. 12 The study, led by Professor Corinne Lasmezas of The Scripps Research Institute, will be published in the journal Proceedings of the National Academy of Sciences. 10