Monitoring International Trendsposted November 2015

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. Highlights include:

Reports on selected papers and posters from the American Society of Hematology (ASH) 57th Annual Meeting and Exposition and the Second International Primary Immunodeficiencies Congress (Section 1)

Reports on new medical deviices which variously diagnose sepsis, diagnose and monitor sickle cell disease, and facilitate cell salvage in seriously under-resourced communities (Section 2)

Advice on approvals for Baxalta’s Obizur for acquired haemophilia A and Baxalta’s Adynovate, built on the full-length Advate model (Section 2)

Financial reports for third quarter 2015 for a number of companies of interest (section 3) Reports of relevant takeover and relocation activity (Section 3) An update on the Scottish National Blood Transfusion Service (SNBTS) National Centre

Project (Section 4) An outline of the discussion of using frozen red cells as more than just a fall-back position

(Section 5) A report on the range of papers and posters presented at the American Heart Association

Scientific Sessions 2015, concerning the Bristol-Myers Squibb/ Pfizer Alliance’s research in non-valvular atrial fibrillation and venous thromboembolism in patients treated with their anticoagulant Eliquis (Section 5)

Research news: including various ways of producing red blood cells, identifying the gene that causes the inflammation leading to sepsis, using genetic modification so pigs can produce albumin, and building artificial blood vessels. (Section 6)

Updates on vaccines and treatments for mosquito borne diseases, influenza, MERS, and tuberculosis, amongst other diseases (Section 7)

Table of Contents

1. Products________________________________________________________________2

Conference presentations__________________________________________________________2

Other___________________________________________________________________________4

2. Regulatory______________________________________________________________6

3. Market structure and company news________________________________________6

4. Country-specific events____________________________________________________9

1

5. Safety and patient blood management______________________________________10

Appropriate transfusion__________________________________________________________10Fresh or frozen red cells?________________________________________________________________10Pathogen reduction____________________________________________________________________12

Treating iron deficiency___________________________________________________________12

Other._________________________________________________________________________13

6. Research______________________________________________________________14

7. Infectious diseases______________________________________________________16

Mosquito-borne disease: dengue, malaria, chikungunya________________________________16

Influenza: strains, spread, prevention and treatment___________________________________18

MERS-CoV (Middle East Respiratory Syndrome-Coronoavirus)____________________________18

Ebola virus disease_______________________________________________________________19

Other diseases: occurrence, prevention and treatment_________________________________19

1. ProductsHere the NBA follows the progress in research and clinical trials that may within a reasonable timeframe make new products available, or may lead to new uses or changes in use for existing products.

Conference presentationsa) The American Society of Hematology (ASH) 57th Annual Meeting and Exposition will

be held in Orlando, Florida from 5-8 December, 2015. All abstracts for the ASH meeting are available online at 2015 ASH Annual Meeting Abstracts . Presentations includei) From Protalex, an abstract highlighting preclinical results from a study of

Staphylococcal protein A (PRTX-100) for the treatment of Immune Thrombocytopenia (ITP)1. The presenter is John W. Semple, of St. Michael's Hospital, Toronto. PRTX-100 was recently granted Orphan Drug Designation in the US and Europe in the treatment of ITP.

ii) From Sangamo Biosciences, a presentation of non-human primate data from its proprietary In Vivo Protein Replacement Platform (IVPRP) program for haemophilia B2, and data from its ZFP Therapeutic haemoglobinopathy programs in collaboration with Biogen3. Edward Lanphier, Sangamo's president and chief

1 The abstract, "Successful Treatment of Thrombocytopenia with Staphylococcal Protein A (PRTX-100) in a Murine Model of Immune Thrombocytopenia (ITP)” is available on the ASH website at http://www.hematology.org and on the company’s website at www.protalex.com.2 “ZFN-Mediated Gene Targeting at the Albumin Locus in Liver Results in Therapeutic Levels of Human FIX in Mice and Non-Human Primates“–Abstract #200, in Session: 801, Gene Therapy and Transfer: Gene Therapy for Hemoglobinopathies and Inherited Bleeding Disorders. Oral presentation by Michael C.Holmes, of Sangamo BioSciences.3 “Genome Editing of the Bcl11A Erythroid Specific Enhancer in Bone Marrow Derived Hematopoietic Stem and Progenitor Cells for the Treatment of Sickle Cell Disease”–Abstract #203, in Session 801. Presenter Siyuan Tan of Biogen; and “Clinical-Scale Genome Editing of the Human BCL11A Erythroid Enhancer for Treatment of the Hemoglobinopathies”–Abstract #204, in Session 801.Oral Presentation

2

executive officer, said: "Our presentations at this year's ASH meeting highlight the breadth of our highly specific genome editing platform in both in vivo and ex vivo therapeutic applications."Data from non-human primates generated in our Factor IX program for hemophilia B demonstrate the potential of our IVPRP strategy to produce clinically beneficial levels of therapeutic protein from a single treatment. We, and our collaborators at Biogen, will also present data from our hemoglobinopathy programs in beta-thalassemia and sickle cell disease, which use an efficient ZFN-mediated knockout approach in hematopoietic stem cells to elevate functional globin to provide a potentially life-long therapeutic effect." 

iii) From Global Blood Therapeutics, a presentation of data from the ongoing PhaseI/II GBT440-001 study of GBT440 in sickle cell disease4.

iv) From Genentech, a member of the Roche Group, fifteen oral presentations across a broad range of molecular targets and combinations, as well as different clinical endpoints that Genentech is exploring in various blood diseases and lines of treatment. It offered 30 poster presentations as well. Data was shown for investigational drug ACE910, which was recently granted Breakthrough Therapy designation by the US Food and Drug Administration (FDA) for the prophylactic treatment of people who are 12 years or older with haemophilia A with factor VIII inhibitors.

v) From Alnylam Pharmaceuticals, new results from ongoing clinical studies with two of its subcutaneously administered investigational RNAi therapeutics–ALN-AT3 and ALN-CC55.

b) The VEITH symposium (a conference for vascular specialists) was held in New York City from 17-23 November 20156. The Chief Medical Officer of Humacyte7, presented three sessions on new techniques in human tissue engineered arterial vascular access conduits, and how to optimize outcomes in haemodialysis access8. Humacyte received Fast Track designation for its investigational human acellular vessel (HAV), HUMACYL for vascular access in haemodialysis patients from the FDA in 2014 and has ongoing Phase II trials in the US and EU for patients with End Stage Renal Disease who require vascular access for haemodialysis. Humacyte will soon begin a global Phase III study for HUMACYL.

by Fyodor D. Urnov, of Sangamo BioSciences. A poster will also be presented by Kai-Hsin Chang, of Biogen: “Clonal Analysis of Human Bone Marrow CD34+ Cells Edited by BCL11A-Targeting ZFNs Reveals Clinically Relevant Levels of Gamma Globin Expression in Edited Erythroid Cells”–Abstract #32344 “GBT440, a Potent Anti-Sickling Hemoglobin Modifier Reduces Hemolysis, Improves Anemia and Nearly Eliminates Sickle Cells in Peripheral Blood of Patients with Sickle Cell Disease”- Abstract #542 in Session 114, Hemoglobinopathies, Excluding Thalassemia - Clinical: Promising Therapies in Sickle Cell Disease. Oral presentation by Claire Hemmaway of Queens Hospital, Essex, UK. Also a poster, “GBT440 Demonstrates High Specificity for Red Blood Cells in Nonclinical Species”- Abstract #2172 in Session 113, Hemoglobinopathies, Excluding Thalassemia - Basic and Translational Science5 “A Subcutaneously Administered Investigational RNAi Therapeutic (ALN-AT3), Targeting Antithrombin for Treatment of Hemophilia: Interim Weekly and Monthly Dosing Results in Patients with Hemophilia”. Oral Session: Disorders of Coagulation or Fibrinolysis: Novel Treatment Strategies in Hemophilia. Author: John K. Pasi; “Antithrombin Reduction Corrected Thrombin Generation in Samples from Hemophilia A and B Patients with Inhibitors”. Oral Session: Disorders of Coagulation or Fibrinolysis: Novel Treatment Strategies in Hemophilia. Author: Gili Kenet; and “A Subcutaneously Administered Investigational RNAi Therapeutic (ALN-CC5) Targeting Complement C5 for Treatment of PNH and Complement-Mediated Diseases: Interim Phase 1 Study Results”. Poster session: Bone Marrow Failure. Author: Anita Hill, University of Leeds6 visit http://www.veithsymposium.org7 Jeffrey H Lawson, himself a vascular surgeon8 “Human Tissue Engineered Vessels Are Finally Working as Lower Extremity Bypasses and Dialysis Access: Why and Prospects for the Future”; “Novel Therapies for Hemodialysis Vascular Access Dysfunction”; and “Expanding Role for Endoluminal Anastomosis in Vascular Access Surgery”.

3

c) ADMA Biologics presented a poster for its IVIg product (RI-002) entitled “Protection Against Palivizumab Resistant RSV with an IVIG Containing High Titer Anti RSV Neutralizing Antibodies,” at the Second International Primary Immunodeficiencies Congress9. The poster compared the efficacy of palivizumab with that of RI-002, an IVIg that contains high titre anti-RSV neutralizing antibodies and which prevents RSV infections in the cotton rat after infection with a strain that is resistant to palivizumab. The data also demonstrates the presence of higher anti-RSV neutralizing activity in RI-002 compared with that which is present in palivizumab in this animal model. RI-002, is a polyclonal, intravenous immune globulin derived from human plasma containing naturally occurring polyclonal antibodies10 as well as standardized, high levels of antibodies to respiratory syncytial virus (RSV). ADMA is pursuing an indication for the use of this specialty intravenous immune globulin for patients diagnosed with Primary Immune Deficiency Disease (PIDD). Polyclonal antibodies are proteins that are used by the body's immune system to neutralize microbes, such as bacteria and viruses. Data review indicates that the polyclonal antibodies present in RI-002 support its ability to prevent infections in immune-compromised patients. ADMA’s analysis demonstrated that the Phase III trial met the primary endpoint with no serious bacterial infections (SBI) reported. These results more than meet the requirement specified by the FDA guidance of ≤ 1 SBI per patient-year. A Biological Licence Application was accepted by FDA on 18 September, 2015.

Otherd) Pulse Therapeutics’ of St Louis aims to use magnets to help clear the blood clots that

can cause strokes11.e) Scientists at Sunnybrook Research Institute in Toronto used focused ultrasound to

breach the blood-brain barrier and effectively deliver chemotherapy into the brain tumour of a patient.

f) Halozyme Therapeutics announced that the first healthy subject had been dosed in a Phase I clinical trial evaluating the safety, tolerability and pharmacokinetics of a subcutaneous formulation of rivipansel, a compound discovered by GlycoMimetics, and being developed by Pfizer, using Halozyme's ENHANZE formulation. Rivipansel is being evaluated as an intravenous formulation in a Phase III study for the treatment of patients hospitalized with vaso-occlusive crisis of sickle cell disease. Halozyme's ENHANZE technology is based on a proprietary recombinant human enzyme (rHuPH20) that targets hyaluronan, a glycosaminoglycan, which is a chain of natural sugars throughout the body and component of the extracellular matrix, to aid in the dispersion and absorption of injected therapeutic compounds.

g) Chimerix initiated dosing in SURPASS12, one of the two Phase III trials in the brincidofovir kidney transplant program. Both the SUSTAIN13 and SURPASS trials are evaluating brincidofovir for the prevention of cytomegalovirus (CMV) disease in

9 held 5-6 November, 2015 in Budapest, Hungary. The abstract and poster can be found on the ADMA Biologics website (www.admabiologics.com) under the drug development tab, abstracts, posters and publications.10 Such as Streptococcus pneumoniae, H. influenza type B, cytomegalovirus (CMV), measles, and tetanus11 Pulse CEO Sean Morris says: “Alongside (the clot busting drug) we inject iron particles that are smaller than red blood cells,” he said. “They’re made to be extremely magnetic. So now these particles are flowing through the blood pool. And little by little by virtue of a small, portable and rapidly spinning magnet placed by the patient’s head, the particles are being pulled out of circulation and into the stagnant column of flow that precedes a clot. As we spin the magnet at 180 RPM’s, we make little magnetic rotors within the stagnant column of blood, and they’re constantly spinning by virtue of this magnetic field. It helps mix the drug that’s in the main blood pool into the clot. Those particles are helping deliver the drug, and they’re constantly mixing in new drug.”12 ClinicalTrials.gov ID: NCT0243995713 ClinicalTrials.gov ID: NCT02439970

4

kidney transplant recipients; both trials are now actively enrolling. Brincidofovir is an oral nucleotide analog. It has demonstrated in vitro antiviral activity against the five families of DNA viruses that affect humans, including herpes viruses and adenovirus, and created a clinically and statistically significant reduction in CMV infection in a Phase II trial in hematopoietic cell transplant (HCT) recipients. Chimerix then conducted the SUPPRESS trial for the prevention of clinically significant CMV infection in patients undergoing HCT. This completed enrolment in June, and topline data is expected early in 2016.

h) ProMetic Life Sciences reported on 4 November that its plasma-derived plasminogen14 replacement therapy, currently in a Phase 1 clinical trial in the US, had succeeded in treating a plasminogen-deficient infant in critical condition in an intensive care unit at the Altona Children's Hospital in Hamburg. The plasminogen was administered by a team from the Department of Paediatric Haematology and Oncology at the University Medical Centre, Hamburg-Eppendorf. Diagnosed with severe plasminogen deficiency at 4 weeks of age, the patient had suffered respiratory failure requiring ventilatory and circulatory support in the ICU. Administration of plasma was not successful in raising his plasminogen to an effective level. ProMetic's plasminogen was provided under the Named Patient Program, a German initiative which enables physicians, healthcare regulators and manufacturers to coordinate the provision of drugs that are not yet commercially available. ProMetic has received orphan drug designation from both the FDA and EMA for its plasminogen therapy for the management of patients with plasminogen deficiency. ProMetic is currently completing its single ascending dose clinical trial to demonstrate safety, tolerability and pharmacokinetics of the product.

i) ProMetic began enrolling the first of 75 patients with primary immunodeficiency diseases ("PIDD") in a Phase III clinical trial, an open label, single arm, two-cohort15 multicentre study that is investigating the safety, tolerability, efficacy and pharmacokinetics of ProMetic's plasma purified IVIg.

j) T2 Biosystems, which develops diagnostic equipment in the US, has built a new system for diagnosing sepsis where it is caused by the fungus called candida. T2, unlike traditional methods, is similar to magnetic resonance imaging, and would take only five hours. The detector measures changes in the magnetic properties of the water molecules in a sample of blood. Magnetic nanoparticles are mixed with the sample -- if a fungus is present, the particles will attach to it, thus changing the magnetic properties of the blood. By applying magnetic pulses to the sample the device is able to determine whether or not the virus is present. The technique detects this particular pathogen in 96 per cent of cases, compared with 60 per cent in blood culture tests. Six US hospitals have adopted the technology so far.

k) Biomedical engineers from the University of Connecticut and colleagues from Yale, MIT, and Harvard have developed a simple, cheap and rapid technique for diagnosing and monitoring sickle cell disease, for use where advanced medical technology and training are in short supply. The technique uses a 3D-printed device. The key to the new device is magnetic levitation. Sickle cells, because of their unique crescent moon or sickle-like shape, tend to be denser than healthy red blood cells and therefore float at a lower height when the cells are placed in a paramagnetic solution and subjected to a magnetic field." This approach enables a binary (yes/no) decision for identification of sickle cell disease, even by the naked eye," said team leader Savas Tasoglu..

l) US start=up Sisu Global Health plans to launch a series of low-cost medical devices in under-resourced communities. It has developed a device it calls the Hemafuse: a hand-pump that sucks up blood from a chest or abdominal injury. Then, when you

14 Plasminogen is a naturally occurring protein that is synthesized by the liver and circulates in the blood.15 Cohort 1 is 50 adults, Cohort 2 is 25 children.

5

push down again, the blood passes through a one-way valve to a blood bag for later use. There's also a filter for cleaning out clots and particulates.

2. RegulatoryThe NBA monitors overseas regulatory decisions on products, processes or procedures which are or may be of relevance to its responsibilities.

a) The European Commission granted marketing authorization for Baxalta's Obizur to treat adult patients with acquired haemophilia A caused by antibodies to Factor VIII (FVIII). Results from a Phase II/III open-label clinical trial of Obizur demonstrated a positive response and clinical improvement, with FVIII activity levels at 20 per cent or more at 24 hours following the first infusion. The development of antibodies to porcine factor VIII was the only adverse reaction reported in over 5 per cent of patients. Obizur is also approved in the US and Canada and is under regulatory review in Switzerland, Australia and Colombia.

b) The FDA approved Adynovate [antihaemophilic Factor (recombinant), PEGylated], an extended circulating half-life recombinant Factor VIII (rFVIII) treatment for haemophilia A. Adynovate is built on the full-length Advate [antihaemophilic Factor (recombinant)] molecule. Advate has more than 12 years of real-world patient experience. Currently, studies are ongoing in previously treated patients (PTPs) with severe haemophilia A undergoing surgery and in paediatric PTPs under the age of 12 with severe haemophilia A, the latter necessary before Baxalta applies for marketing authorisation in Europe. Baxalta will also initiate a study in previously-untreated patients (PUPs) with severe haemophilia A. Baxalta has filed for regulatory approval of the treatment in Japan.

c) Gauss Surgical won CE Mark approval in the European Union for its Triton mobile real-time surgical blood loss monitoring system. The device works with Apple‘s iPad system. The device scans surgical sponges and blood bearing canisters and estimates the amount of blood contained in them. The system was FDA approved for sponge blood loss calculation in May 2014, and received 510(k) clearance for suction container blood loss calculation in March 2015.

3. Market structure and company newsThe NBA’s business intelligence follows company profitability, business forecasts, capital raisings or returns, mergers and takeovers, arrangements for joint research and/or development, contracts for supply of manufacturing inputs, and marketing agreements. Companies considered include suppliers, potential suppliers and developers of products which may be of interest.

a) Swedish Orphan Biovitrum (Sobi) announced revenue for the third quarter 2015 increased 18 per cent year on year. "The third quarter results support the themes from the first half year with solid momentum across the commercial portfolio and achievement of significant additional milestones for our extended half-life haemophilia franchise." said Geoffrey McDonough, CEO and President.

b) Biogen reported third quarter 2015 results. Revenue increased 11 per cent compared with the third quarter of 2014. Biogen also announced a corporate restructuring, which included the termination of a number of pipeline programs and an 11 per cent reduction in workforce.

c) Baxalta reported strong third quarter financial results, exceeding its previously-issued sales and earnings guidance. Baxalta also raised its outlook for the second half of 2015 and provided preliminary 2016 guidance. Baxalta’s haematology and immunology businesses generated double-digit sales growth (excluding the impact of

6

foreign currency) in the quarter. Haematology revenues of $US 935 million increased 10 per cent (excluding the impact of foreign currency). Key drivers of growth include heightened demand for ADVATE [Antihaemophilic Factor (Recombinant)], a treatment for haemophilia A, and FEIBA [Anti-Inhibitor Coagulant Complex], an inhibitor treatment. A benefit from newly launched products, such as RIXUBIS [Coagulation Factor IX (Recombinant)] for the treatment of haemophilia B, and OBIZUR [Antihaemophilic Factor (Recombinant), Porcine Sequence], for the treatment of acquired haemophilia A, also contributed to performance. Immunology sales of $US 626 million advanced 13 per cent (excluding the impact of foreign currency) on a pro forma basis. The company continued to capitalize on its broad and differentiated portfolio of immunoglobulin therapies, including HYQVIA [Immune Globulin Infusion 10% (Human) with Recombinant Human Hyaluronidase], and is driving strong sales of specialty biotherapeutics. Baxalta says it continues to make progress toward its goal of achieving 20 new product launches by 2020.

d) Reporting to an investor conference in London on 5 November, Roche described ACE910 (factor IXa/X biMAb) as “an investigational bispecific antibody specifically engineered to support the interaction between factors IXa and X and hence mimic factor VIII, a protein essential to blood clotting. It is being developed for use in people with haemophilia A, irrespective of inhibitor status. Following encouraging phase I results, Roche plans to initiate a phase III trial of ACE910 in patients with factor VIII inhibitors by the end of 2015, a phase III trial in patients without inhibitors in 2016, and a study in paediatric patients (0–12 years) in 2016”. Roche is relying on new drugs, including its ACE-910 investigational treatment for people with haemophilia, to offset competition from biosimilar versions of its older drugs starting in 2017 as their patents expire.

e) Shire, which has been bidding to acquire Baxalta, announced on 2 November that it would acquire Dyax for $US 37.30 cash per Dyax share for aggregate upfront consideration of approximately $US5.9 billion16. Dyax shareholders may receive additional value through a non-tradable contingent value right (CVR) that will pay $US 4.00 in cash per Dyax share upon approval of DX-2930 in hereditary angioedema (HAE)17, representing a potential additional $US 646 million in aggregate contingent consideration. DX-2930 is a Phase III-ready, fully humanized, injectable, long-acting, prophylactic monoclonal antibody targeting pKal with proof-of-concept Phase IB efficacy data. This data demonstrate a > 90% reduction in HAE attacks compared with placebo in the 300mg/400mg arms in patients with > 2 attacks in the 3 months prior to study entry. DX-2930 has received Fast Track, Breakthrough Therapy, and Orphan Drug designations by the FDA and has also received Orphan Drug status in the EU. It offers patent protection and anticipated regulatory exclusivity beyond 2030. It is expected to enter Phase III clinical trials by year-end 2015. If approved for the prevention of Type 1 and Type 2 HAE, DX-2930 could generate annual global sales of up to $US 2.0 billion.

f) Cerus Corporation signed a new agreement with Fresenius Kabi. The ten year contract extends and reinforces the existing partnership for the production of INTERCEPT Blood System kits at the manufacturing facility in La Châtre, France. Now Fresenius Kabi has committed to investing in the La Châtre facility. A number of investments are planned to foster automation and install new equipment. Additional future investments will expand capacity and reduce costs. La Châtre is designated in the agreement as the primary site of production. Should volume expectations require,

16 The transaction has been unanimously approved by the Boards of Directors of both Shire and Dyax and is expected to close in the first half of 2016. The transaction is subject to approval by Dyax shareholders and customary closing conditions and regulatory approvals.17 HAE is a rare, debilitating genetic inflammatory condition, which causes episodes of swelling in the face, extremities, and GI tract and can be life threatening. It is underdiagnosed and prophylaxis is underutilized, so it offers good growth opportunities.

7

a second manufacturing facility would be identified and qualified. Finally, under the new agreement, the current licence agreement with Fresenius Kabi will convert to a royalty-free licence and Cerus will no longer be required to pay royalties on the sale of INTERCEPT kits.

g) Cerus signed a multi-year sales agreement with OneBlood for the INTERCEPT Blood System for platelets and plasma. OneBlood distributes blood products to more than 200 hospitals and healthcare facilities throughout most of Florida, parts of Southern Georgia, Alabama and South Carolina.

h) Vertex Pharmaceuticals made a $US 105 million commitment to gene editing company CRISPR Therapeutics, targeting a potential cure for cystic fibrosis and sickle cell disease. Vertex will pay $US 75 million in an upfront investment and $US 30 million in an equity investment, in exchange for exclusive rights to license up to six CRISPR-Cas9-based treatments that result from the collaboration.

i) China Biologic Products released its earnings results on November 3rd. The company reported $US 0.82 earnings per share for the quarter, beating the consensus estimate of $US 0.81. The firm earned $US 78.80 million during the quarter, compared with the consensus estimate of $US 75.30 million. China Biologic Products’ revenue was up 14.4 per cent compared with the same quarter last year. Equities analysts forecast that China Biologic Products will post $US 3.49 earnings per share for the current fiscal year. China Biologic Products18 CEO David Gao has been reported as selling significant numbers of shares in the company, as illustrated below:

Date No of shares Average price Total transaction20 October 258 $105.00 $27,090.0026 October 59,542 $105.22 $6,265,009.24.29 October 71,118 $110.21 $7,837,914.782 November 12,891 $112,26 $1,447,143.6619

4 November 95,991 $115.60 $11,096,559.60

j) Pfizer's bid for $US 113bn Dublin-based drug maker Allergan was the biggest potential merger of the year. It was seen as potentially good news for the Irish exchequer, although the US has been hoping to end tax inversions, the foreign takeover deals that have allowed US corporations to transfer their tax residence overnight to low-tax regimes. Post inversion, the US firm will still be charged 35 per cent tax on US profits, but global earnings can qualify for the lower tax regime abroad.

k) Grifols is investing $US 100m in Ireland. The company's facility at Grange Castle Business Park in Dublin is due to open early in 2016. It will be the centre for Grifols decision-making on commercial policy, research and development and the supply chain needs of its Bioscience Division. The facility will also store plasma and carry out the labelling, packaging and final conditioning of the product. Grifols announced that it would move its corporate treasury from Barcelona to Dublin. From there,

18 China Biologic Products, Inc. (NASDAQ:CBPO) is a biopharmaceutical firm, principally engaged in the research, development, manufacturing and sales of human plasma -based biopharmaceutical products in China. The Company’s principal products are human albumin and immunoglobulin for intravenous injection (IVIG). China Biologic manages its business through two subsidiary companies, specifically, Shandong Taibang Biological Products Co. Ltd. and Guizhou Taibang Biological Products Co., Ltd. The business also holds an interest in Xi’a Huitian Blood Products Co., Ltd., a plasma products company. The Company’s products contain thymopolypeptides shot, human immunoglobulin, IVIG, human albumin, human hepatitis B immunoglobulin, human rabies immunoglobulin, human tetanus immunoglobulin, placenta polypeptide, Factor VIII and individual prothrombin complex concentrate. 19 This left him with 472,991 shares of the company’s stock, valued then at $53,097,969.66.

8

Grifols will manage all its global payments, including taxes. The announcement came shortly after the Irish government announced a new business-friendly corporate tax category.

l) Grifols announced that intermediate results from its AMBAR study support its continuation. AMBAR (Alzheimer Management By Albumin Replacement) is a Phase III clinical trial that explores the combination of plasma extraction and replacement with albumin to stabilize Alzheimer's disease. The company says the intermediate results show the tolerability and safety of the treatment, meeting the necessary conditions for patients to undertake it and for the continuation of the AMBAR study. The recruitment process is expected to be completed in 2016, with preliminary results to be presented in 2017, once all patients have completed the study.

m) Blubird Bio suffered a drop in its share price when it announced that the first patient with beta-thalassemia, treated with an earlier version of its gene therapy technology back in 2007, had recently required two blood transfusions. The patient had gone seven years without needing one, Bluebird made clear the vectors its using now are far superior—meaning, presumably, treatment should last longer. But that remains to be seen.

n) Dimension Therapeutics did not make quite the share price it had hoped on its initial public offering. Dimension is working on gene therapies for both haemophilia A and haemophilia B. Its haemophilia B program (DTX-101) is its most advanced and is expected to begin clinical testing by the end of this year. There are at least six other gene therapy treatments for haemophilia B being worked on at present.

o) CSL Ltd announced that Its influenza business is operating under the name Sequiris following the merger of the recently acquired Novartis influenza business and its existing vaccines and pharmaceutical business bioCSL20.

4. Country-specific eventsThe NBA is interested in relevant safety issues which arise in particular countries, and also instances of good practice. We monitor health issues in countries from which Australia’s visitors and immigrants come.

a) In the US, Centres for Medicare & Medicaid Services (CMS) has given permanent Healthcare Common Procedure Coding System (HCPCS) Level II codes for pathogen-reduced platelet and plasma components. At the moment, Cerus’ INTERCEPT Blood System is the only FDA-approved system for pathogen reduction of platelet and plasma components, intended to reduce the risk of transfusion transmitted infections.

b) From May 2016, as part of the FDA's final rule, “Requirements for Blood and Blood Components Intended for Transfusion or for Further Manufacturing Use,” the minimum haemoglobin for male blood donors in the US will increase to 13.0 g/dL While the minimum requirement for female donors will remain 12.5 g/dL., a variance will be possible for female donors to be permitted to donate at 12.0 g/dL, if additional steps are taken to assure donor safety.

c) In the US, Diplomat Pharmacy secured the right to dispense Coagadex (coagulation factor X, human) to its patients from Bio Products Laboratory Limited (BPL). Coagadex was approved by the FDA on 20 October, 2015. Coagadex is the only FDA-approved product to treat hereditary factor X deficiency, and is the only factor X concentrate available in the US.

d) The construction phase of the Scottish National Blood Transfusion Service (SNBTS) National Centre Project (at the Heriot-Watt Research Park site) is at the halfway

20 Sequiris is the world's second largest provider of influenza vaccine with operations in more than 20 countries in the US$ 4 billion global industry.It is based in Maidenhead (UK).

9

point. Keys are expected to be handed over in November 2016 and full transfer to the facility is expected to be complete by mid-2017.

e) A draft report21 reveals wide variances in medical treatments across Australia: the rate of prescribing drugs for attention deficit and hyperactivity disorder to children varies by 75 times between the Taree-Gloucester region and the area with the fewest prescriptions. In Mount Druitt, residents have greater access to CAT scans than anywhere else, even though experts warn against routine scanning. Men in the New -England and northwest region of NSW are more likely to have their prostate removed after a cancer scare, perhaps due to other treatment options being unavailable, while the rate of antipsychotic drug use in Victoria’s Yarra suggests some older people with mild dementia are being medicated unnecessarily. Even surgery rates differ greatly. Hospital admissions for knee arthroscopies varied by 4.2 times, once outliers were removed, and the draft suggests “many of these people will have degenerative disease in their knees and will not benefit from this intervention”. There was also three times the difference in rates of MBS-funded cataract surgery, once the outliers were removed, and significant variation in rates of tonsillectomies for children. Women living in regional areas were up to five times more likely to undergo a hysterectomy or endometrial ablation than those living in metropolitan areas, and the draft recommends patients be given more information on their options, the risks and benefits. In 2012-13 there were 8496 radical prostatectomy admissions to hospital, which represents 150 admissions per 100,000 men aged 40 and over. Yet rates ranged from 69 to 282 per 100,000, and the draft suggests the lack of specialist surgeons might be the cause.

f) China established the world's largest mosquito factory in northern Guanzhou province to tackle dengue fever by releasing a million sterile mosquitoes every week. The Indian Government is reported to have been considering a Chinese proposal to introduce genetically modified mosquitoes to mate with dengue carrying females of the same species.

5. Safety and patient blood managementWe follow current issues in patient safety and achieving favourable patient outcomes.

Appropriate transfusion

Fresh or frozen red cells?a) Freezing of red blood cells for transfusion has been a secondary system to storing

liquid blood for short-term delivery. Frozen red cells have been seen as for people with rare blood types or blood diseases, or for military personnel overseas. However, some current discussion suggests wider use is warranted-particularly at times of mass trauma.

b) “A large prospective, randomized trial would provide more impetus for greater change in our blood system, but the people who really affect that change the most are the blood bankers,” said Col. Martin A. Schreiber, professor of surgery at Oregon Health & Science University, in Portland, and of the Army Medical Corps with the US Army Reserve. “We’d need their support. Surgeons can exert pressure, but the decisions are made by the blood bankers.”

c) Studies have demonstrated that frozen red cells yield equivalent clinical outcomes to liquid red cells when used in transfusions for trauma patients. In1968 US Navy doctors successfully transfused 307 units of frozen red cells into 36 severely injured

21 The final report is is being prepared by the Australian Commission on Safety and Quality and Health Care and the National Health Performance Agency, assisted by experts and health groups.

10

defence personnel injured in the Vietnam War22. More recent studies confirm these results, although they have not been large-scale.

d) Studies have also reported that frozen red cells achieve superior tissue oxygenation to fresh red cells and possess a better biochemical profile.23

e) Probably the most important characteristic of frozen red cells is that they can be stored for up to 10 years without deterioration in quality while liquid red cells can be stored for a maximum of 42 days. There are even some studies that suggest the quality of liquid blood cells decreases after the first two weeks of storage, although there is not complete agreement about this. Dr Schreiber and others argue that the long shelf-life means cryopreserved blood products could help prevent shortages of blood, particularly in mass-casualty situations24, and could reduce the wastage of blood products deemed too old for use25.

f) In 2013, Dr Schreiber and colleagues completed a prospective, randomized, double-blind study of 57 patients who received frozen or liquid red blood cells26 . The study showed that frozen packed red blood cells have a superior biochemical profile, with an absent inflammatory response, attenuated fibrinolytic state and increased 2,3-diphosphoglycerate concentrations compared with liquid red blood cells.

g) In 2015 at the 136th annual meeting of the American Surgical Association, Dr Schreiber presented updated data from the trial, the largest yet focussed on liquid versus frozen red blood cells.

h) Investigators from five level 1 trauma centres across the US randomly assigned 256 patients to transfusions with young red blood cells (<14 storage days), old red blood cells (≥14 storage days) and frozen red blood cells. The patients were well matched for injury severity and demographics, and underwent near-infrared spectroscopy to assess tissue oxygenation for 12 hours after their first transfusion, with additional blood tests after each transfusion. Patients in all groups received a median of two units of blood. The study demonstrated that transfusion of frozen red blood cells was as safe and effective as transfusion of young and old red blood cells, with no significant difference in tissue oxygen saturation across all the groups. Clinical outcomes, too, were similar with no difference in organ failure, infection rate or mortality on the basis of the type of blood given.

i) Frozen red blood cells contained significantly less α2-macroglobulin, haptoglobin, C-reactive protein, serum amyloid P and free haemoglobin than the other groups (P<0.001). Interleukin-2 was elevated in patients who received frozen red blood cells compared with old, but not young, red blood cells (P=0.04).

j) Survey data from fourteen America’s Blood Center members about prices of blood units suggest the average price in 2014 for a frozen, thawed, deglycerolized red blood cell unit was $US 398 compared with $US 223 for regular liquid red cells.

k) In 201427 three Australian military physicians and American Red Cross representatives argued that a cryopreserved packed red blood cell trial would require more than 2,500 patients to establish an absolute risk reduction of 5 per cent. That is the threshold needed to change practice, according to the standard used in the ABLE trial to assess the effects of prolonged fresh red blood cell storage on clinical outcomes.28

22 The patients’ post-transfusion haemoglobin, platelet count and creatinine clearance rate were similar to those receiving liquid blood cells, according to the report in The New England Journal of Medicine (1968;278:747-752).23 J Trauma Acute Care Surg 2014;77:20-27; J Trauma Acute Care Surg 2013;74:371-37624 Frozen units could be available in ninety minutes25 For example, in the hours following the 9/11 attacks, nearly 300,000 extra units of blood were collected. 50,000 were eventuallydiscarded, having expired before they could be used. Only 9,500 were frozen.26 J Trauma Acute Care Surg 2014;77:20-2727 In a letter to The Journal of Trauma and Acute Care Surgery, (2014;77:1004).

11

Pathogen reductionl) Terumo BCT completed the first clinical trial to demonstrate that the Mirasol PRT

system29 can effectively reduce the incidence of transfusion transmitted infection (TTI) with malaria30. Whole blood showed a statistically and clinically significant reduction in TTI of malaria compared with the subject group that received untreated whole blood. The incidence of adverse events from the transfused blood was similar between the treated and untreated groups31. Studies are continuing to support an application by Terumo BCT to gain FDA approval for the clinical use of red blood cells derived from treated whole blood. If the application is approved, the Mirasol PRT system will be used in applications such as field hospital settings to support transfusions for military personnel under austere conditions. Terumo BCT has applied for the CE Mark for the Mirasol PRT system for treatment of whole blood32.

Treating iron deficiencym) Investigational drugs that produce effects in the body similar to what occurs at high

altitudes may offer a new way to stimulate red blood cell production and treat patients with anaemia, according to studies in the Journal of the American Society of Nephrology (JASN)33. The findings may lead to safer alternatives than currently used anaemia medications34.

28 Transfus Med Rev 2011;25:197-205.29 Terumo BCT’s Mirasol pathogen reduction technology system for treatment of whole blood was developed with the support of the US Department of Defense (DoD) through grants and contracts with the US Army Medical Research and Materiel Command, Fort Detrick, Maryland. The Mirasol PRT system uses a combination of riboflavin (vitamin B2) and ultraviolet light to inactivate viruses, bacteria, parasites and white blood cells that may be present in collected blood products.30 Ray Goodrich, Chief Scientific Officer for Terumo BCT, said: “The success of the AIMS trial is due to the collaboration of Terumo BCT, Cambridge University, Komfo Anokye Teaching Hospital and the Republic of Ghana. The Mirasol PRT system can enable blood centers to provide safer transfusions despite challenges with access to the blood supply and testing of blood products. This trial is the first to demonstrate significant pathogen reduction in whole blood, marking an important milestone in blood safety.”31 The AIMS trial was a prospective, randomized, double-blind, controlled, single-center study in which patients received ≤2 transfusions of either Mirasol-treated fresh whole blood (MIR-WB) or fresh WB prepared by standard-of-care methods In the AIMS trial, 223 subjects received trial-related blood transfusions; 111 subjects received MIR-WB and 112 subjects received WB prepared by standard-of-care methods. Subjects were followed for 28 days post-transfusion.32 The Mirasol pathogen reduction technology system is used to treat platelets and plasma across 18 countries in Europe, the Middle East, South America, Central America and Asia.33 The article "Roxadustat (FG-4592): Correction of Anemia in Incident Dialysis Patients," appeared online at jasn.asnjournals.org/ on October 22, 2015. The editorial, "The Dawning of a New Day in CKD Anemia Care?" appeared online at jasn.asnjournals.org/ on October 22, 2015. 34 Anatole Besarab, (FibroGen) and his colleagues enrolled 60 dialysis patients in a Phase II randomized clinical trial. They received no iron, oral iron, or intravenous iron while treated with roxadustat (also known as FG-4592) for 12 weeks. Roxadustat increased erythropoietin and concomitantly improved several processes that increased the availability of iron for incorporation into haemoglobin in red blood cells. Roxadustat with only moderate oral iron supplementation corrected anaemia (as assessed by patients' haemoglobin levels) as well as roxadustat with intravenous iron. "As anemia is associated with an increased risk of cardiac events and death as well as decreased quality of life, the availability of such an oral therapy could change the landscape of treatment of anaemia in kidney failure patients," said Dr. Besarab. In two other Phase II trials Louis Holdstock, and Alexander Cobitz (GlaxoSmithKline) and their team enrolled 73 non dialysis patients with chronic kidney disease and 83 haemodialysis patients to test the effects of GSK1278863 (0.5mg, 2mg, or 5 mg) compared with control (placebo for the non dialysis study; continuing on recombinant human erythropoietin for the haemodialysis study). In the non dialysis study, GSK1278863 produced dose-dependent effects on haemoglobin, with the highest dose resulting in an average increase of 1 g/dl at week 4. In the haemodialysis study, treatment with GSK1278863 in the 5-mg arm maintained average

12

Other.o) Bristol-Myers Squibb and Pfizer presented 22 abstracts at the American Heart

Association (AHA) Scientific Sessions 2015, held November 7-11 in Orlando, Florida. The new data, including four oral presentations, contribute to the Bristol-Myers Squibb and Pfizer Alliance’s research in non-valvular atrial fibrillation (NVAF) and venous thromboembolism (VTE) in patients treated with their anticoagulant Eliquis. Abstracts include new data analyses from the Phase III study, ARISTOTLE, as well as a number of real-world data analyses35.

p) Portola Pharmaceuticals has completed enrolment of 7,500 patients in the Phase III APEX (Acute Medically Ill VTE Prevention with Extended Duration Betrixaban) Study. This trial is evaluating betrixaban, an oral, once-daily Factor Xa inhibitor anticoagulant, for extended-duration prevention of venous thromboembolism (VTE),

haemoglobin concentrations after the switch from recombinant human erythropoietin, whereas average haemoglobin decreased in the lower-dose arms. "This research lays the foundation for future longer-term trials that will examine whether GSK1278863 can manage anaemia in patients with CKD with a reduced incidence of cardiovascular events and death," said Dr. Holdstock.35 Presentations were;

1. On Phase III Clinical Trial Subanalyses, Polypharmacy and the impact of apixaban on adverse clinical events in patients with atrial

fibrillation: insights from the ARISTOTLE trial (poster) Efficacy and safety of apixaban compared with warfarin in patients with atrial fibrillation and

normal renal function over time: insights from the ARISTOTLE trial (poster) Efficacy and safety of apixaban compared with warfarin in patients with peripheral artery

disease and nonvalvular atrial fibrillation: insights from the ARISTOTLE trial (poster) Intracranial Hemorrhage in Patients with Atrial fibrillation in the ARISTOTLE trial: clinical

characteristics and associated outcomes (oral presentation by Renato D, Lopes)2. On Real-World Data Analyses Poor quality of warfarin therapy is associated with elevated risk of myocardial infarction in

patients with atrial fibrillation. Results from the FinWAF registry with 54,568 patients (poster) Real-world comparison of major bleeding risk among nonvalvular atrial fibrillation patients

newly initiated on warfarin versus apixaban 5 mg BID, dabigatran 150 mg BID, or rivaroxaban 20 mg QD (oral presentation by Shital Kamble)

Comparison of major bleeding risk and associated costs among newly anticoagulated nonvalvular atrial fibrillation patients (oral presentation by Steve Deitelzweig)

Comparison of major bleeding risk and healthcare costs among treatment-naïve nonvalvular atrial fibrillation patients initiating apixaban, dabigatran, rivaroxaban, or warfarin (poster)

Clinical and demographic characteristics according to dosage among new initiators and/or switchers from warfarin nonvalvular atrial fibrillation patients on apixaban, dabigatran and rivaroxaban (poster)

Real-world assessment of patients switching from warfarin to non-vitamin K oral anticoagulants (NOACs) using MarketScan EarlyView data (poster)

Comparison of all-cause and bleeding-related hospitalizations among nonvalvular atrial fibrillation patients receiving oral anticoagulants (poster)

The profile of new users of warfarin and non-vitamin K oral anticoagulants in patients with nonvalvular atrial fibrillation (poster)

Outcomes associated with warfarin time in therapeutic range among nonvalvular atrial fibrillation patients treated in an integrated healthcare delivery system in the U.S. (poster)

Risk of stroke, bleeding events and mortality is strongly associated with the quality of warfarin therapy. Results from the FinWAF registry with 54,568 patients (oral presentation by Mika Lehto)

Is major bleeding risk for oral anticoagulants similar among newly initiated nonvalvular atrial fibrillation patients? ( E-Abstract Session)

Venous thromboembolism recurrence and bleeding risk among cancer patients using a large commercial database (poster)

Hospitalization rates and healthcare costs among nonvalvular atrial fibrillation patients who were naïve users of novel oral anticoagulants (poster)

Healthcare costs following stroke and major bleeding events in nonvalvular atrial fibrillation patients (poster)

13

or blood clots, in acute medically ill patients who are hospitalized for conditions, such as heart failure, stroke, infection and pulmonary disease. The company expects to report top-line data at the end of the first quarter of 2016, and hopes to submit a New Drug Application to the FDA in the second half of 2016 under Fast Track designation.

q) A new hydrogel inspired by the venom of a South American viper has been shown in the lab to stop bleeding within six seconds. "It’s interesting that you can take something so deadly and turn it into something that has the potential to save lives," says Rice University chemist Jeffrey Hartgerink36.

6. ResearchA wide range of scientific research has some potential to affect the use of blood and blood products. However, research projects have time horizons which vary from “useful tomorrow” to “at least ten years away”. Likelihood of success of particular projects varies, and even research which achieves its desired scientific outcomes may not lead to scaled-up production, clinical trials, regulatory approval and market development.

a) Scientists described in the journal Cell Stem Cell a promising new way for producing red blood cells, at volumes greater than current methods typically yield. Dr. Vijay Sankaran, assistant professor of paediatrics at Boston Children’s Hospital, and his colleagues37 took blood stem cells, and performed genetic surgery on them to make them more likely to produce more red blood cells. They turned off a particular gene, identified in previous studies, that is linked to lower levels of red blood cells. This resulted in a tripling of the number of red blood cells compared with control stem cells that were simply allowed to grow in a lab dish.

b) Doctors at Great Ormond Street Hospital in London used genetically engineered immune cells from a donor to kill cancerous cells in the bone marrow of a one-year-old girl with leukaemia.

c) Scientists from ANU’s John Curtin School of Medical Research, the Garvan Institute of Medical Research and US biotechnology company Genentech have identified the gene that causes inflammations leading to sepsis, a bodily response to infections that

Comparison of hospital length of stay and costs between nonvalvular atrial fibrillation patients treated with either apixaban or warfarin (poster)An early assessment of hospital readmissions among nonvalvular atrial fibrillation treated with the new oral anticoagulants, apixaban, dabigatran, and rivaroxaban (poster)

36 Hartgerink and his team created a nanofiber hydrogel including batroxobin, a venom found in two species of South American pit viper. Rice researchers have been working on injectable hydrogel scaffolds built from peptide sequences that mimic natural processes to heal wounds with natural tissue. The baxtrobin used isn't derived from snakes, but is produced by genetically modified bacteria and then purified to rid it of other dangerous toxins. By mixing their baxtrobin and nanofibers and loading them into a syringe, the researchers had an injectable liquid they called SB50. As the liquid is injected at the site of a wound, the nanofibers assemble themselves into a gel andbleeding ceases. "Batroxobin is an enzyme with similar function to thrombin, but its function is not blocked by heparin," says Hartgerink. "This is important because surgical bleeding in patients taking heparin can be a serious problem. The use of batroxobin allows us to get around this problem because it can immediately start the clotting process, regardless of whether heparin is there or not."Batroxobin is already approved for use by the US Food and Drug Administration, though Rice's new hydrogel is not. The researchers say several more years of testing are needed before it is cleared for clinical use. The research findings were published in the journal ACS Biomaterials Science and Engineering.37 from Dana-Farber/Boston Children's Cancer and Blood Disorders Center

14

can worsen a patient's condition and cause vital organs to shut down38. A research paper on the findings was published in Nature in September.

d) Scientists have developed a small prototype of a surgically implantable artificial kidney that uses a silicon nanofilter to remove toxins, salts and other molecules from the blood. The researchers said it could offer a promising alternative to kidney transplantation or dialysis for people with end stage renal disease (ESRD). Shuvo Roy, from the University of California, San Francisco said: "We aim to conduct clinical trials on an implantable, engineered organ in this decade, and we are coordinating our efforts with both the NIH (US National Institutes of Health) and the US Food and Drug Administration." The research was presented at the American Society of Nephrology Kidney Week.

e) Chinese scientists used a precise genome modification tool (CRISPR/Cas9) to insert a human albumin coding sequence into a pig gene that enables the pigs to produce human serum albumin, a protein made by the liver. “The pig albumin shares about 80 percent of its characteristics with human albumin at the amino acid level, but the 20 percent difference means we cannot use it directly in patients,” said Zhang Pumin, a co-author of the resulting research paper39 and a researcher at Beijing Proteome Research Centre. “The next step is to industrialize the product,” Zhang continued. “If we can use pigs as a factory for human albumin, it will provide an infinite amount for medical use.” Zhao Jianguo, a researcher at the Institute of Zoology of the Chinese Academy of Sciences said “The commercial prospect is promising. Using pigs as a reactor to produce an essential substance for medical use is a field full of possibilities.”

f) A study at Umeå University in Sweden, recently published in the journal Cancer Cell, found a new RNA test of blood platelets can be used to detect, classify and pinpoint the location of cancer by analyzsing a sample equivalent to one drop of blood. Researchers say they have been able to identify cancer with 96 per cent accuracy.

g) Researchers at the University of Cambridge found that DNA shed in the bloodstream can track cancers while they evolve and respond to treatment, according to a new study. Their study was published in the journal Nature Communications.

h) Researchers at the Spanish National Cancer Research Centre (CNIO) have found the genetic link between Diamond-Blackfan anaemia and cancer predisposition, in particular to lymphoma40.

i) The bacterium that causes Q fever, an infectious disease that humans contract from animals, is associated with an increased risk of lymphoma, according to a study published in Blood41. Q fever is caused by infection with Coxiella burnetii, a bacterium primarily transmitted through the excrement of cattle, sheep, and goats.

38 The researchers found that the protein Gasdermin-D was critical to the development of sepsis, and then spent more than a year isolating the gene that produced it. Ordinarily a dormant part of a cell, Gasdermin-D becomes active when an enzyme known as capase-11 cuts the chemical cap off the protein, causing a chemical reaction leading to a cell's self-destruction. Capase-11 itself is triggered by the invasion of cells by molecules known as lipopolysaccharides, or LPS, which come from the surface of some bacteria. ANU Professor Simon Foote said: "This offers the potential for therapy, because all you need is a drug that inhibits the function of this particular enzyme….."It still means we have to treat the infection, but the overwhelming response from the host no longer occurs." One requirement for the necessary drug will be that it has to act quickly enough to combat the rapid development of sepsis. Genentech senior scientist Nobuhiko Kayagaki said the benefits of the research would stretch beyond the treatment of sepsis. He said: "The identification of Gasdermin-D can give us a better understanding not only of lethal sepsis, but also of multiple other inflammatory diseases."39 published by Scientific Reports, an online open-access journal from the publishers of Nature40 Manuel Serrano et al., “Partial Loss of Rpl11 in Adult Mice Recapitulates Diamond-Blackfan Anemia and Promotes Lymphomagenesis”, CellReports,DOI: http://dx.doi.org/10.1016/j.celrep.2015.09.03841 2015; doi:10.1182/blood-2015-04-639617

15

j) Endonovo Therapeutics has developed a large-scale method for the expansion of umbilical cord blood. Umbilical cord blood is a good source of hematopoietic stem cells for stem cell transplants because the newborn’s immune system is immature and the stem cells have a lower probability of inducing an adverse immune response in patients. A perfect immunological match between donor and recipient is not necessary, as it is in bone marrow transplants. Endonovo's technology consists of the co-culturing of cord blood mononuclear cells with a portion of the umbilical cord in a three-dimensional rotating wall vessel (RWV) bioreactor, allowing for the expansion of hematopoietic stem cells. This technology permits a tenfold increase in adult stem cell transplants.

k) Eugene Boland, chief scientist with US technology development company Techshot Inc, has developed a process for manufacturing large human blood vessels. The vessels are spun using an electrospinner to apply an electric field to a thin liquid stream of natural and synthetic polymers similar to material used in biodegradable sutures. The polymers are spun around a rotating mandrel, creating a tube. “While it looks solid, it’s actually 98 percent porous,” Boland said. The artificial vessels are printed with stem cells taken from the patient’s fat cells. Within nine to 18 months, the body will have absorbed the artificial vessel and the stem cells will have created a natural blood vessel. Boland had to identify a natural material that could be used in both the US and European market. He eventually selected salmon fibrinogen. “Salmon fibrinogen is more than 99 percent similar to human fibrinogen,” Boland said. As an added bonus, “there are no known disease states that cross species from fish to human.” Techshot received $US 1.15 million in funding from the Pentagon’s Defense Health Program for the project. Pre-clinical trials on the vessels are expected to begin late this year, with clinical trials in human patients expected to begin in 2017.

7. Infectious diseasesThe NBA takes an interest in infectious diseases because: the presence of disease in individual donors (e.g. influenza), or potential disease resulting from travel (e.g. malaria) means a donor must be deferred; temporary disease burden within a community (e.g. dengue in North Queensland) may limit blood collection in the community for a time; and some people may not be permitted to donate at all (e.g. people who lived in the UK for a period critical in the history of vCJD). Blood donations are tested for a number of diseases (e.g. HIV and Hepatitis B), but there are also emerging infectious diseases for which it may become necessary to test in the future (e.g. Chagas disease, and the tick-borne babesiosis and Lyme disease).

Mosquito-borne disease: dengue, malaria, chikungunyaa) A new study42 identifies a target for a transmission-blocking vaccine that interferes

with infection of the mosquito after it feeds on the blood of hosts infected with the dengue virus. Tonya Colpitts43, Michael Conway44 and colleagues report that CRVP379 is required during dengue infection in mosquito cells and in live mosquitoes, and that there is a direct correlation between the amount of CRVP379 expressed in the mosquito gut (where infection begins) and the level of dengue virus infection in the gut and in whole mosquitoes45. They demonstrated that CRVP379 interacts with the protein prohibitin, generally considered to be a DENV receptor in mosquitoes. When the researchers fed Aedes mosquitoes antibodies able to recognize CRVP379, potentially blocking the interaction of the protein with either

42 published on October 22nd in PLOS Pathogens43 from the University of South Carolina School of Medicine in Columbia44 from the Central Michigan University College of Medicine in Mt Pleasant45 CRVP379 levels also seem to be correlated with infection in the case of two related viruses, West Nile and Yellow Fever, suggesting it may be possible to block their transmission by similar means

16

DENV or prohibitin, they discovered that this inhibits DENV infection of the mosquitoes. In considering the potential suitability of CRVP379 as a vaccine target, the researchers noted that the protein lacks similarities to human proteins (which if present could lead to undesired auto-immune reactions against a potential human vaccine). Furthermore, they were able to detect antibodies against CRVP379 in human blood samples showing that the protein can call forth an immune response in humans. They are currently investigating whether levels of these antibodies correlate with protection against DENV infection and disease severity upon infection.

b) A global consortium of laboratories has been studying the differences between dengue viruses. It has concluded46 that while the established view that there are four genetically-distinct types of the virus can still be justified, far more important are the differences in their antigenic properties, sometimes described as the ‘coats’ that the viruses wear to help human immune systems identify them47. Senior author Professor Derek Smith, from the Department of Zoology at Cambridge University, said: “This discovery is in many ways similar to when researchers first began using the microscope – it will give us a new way of looking at dengue and in much closer detail than before. Now we can ask–and potentially answer–the interesting questions about how the virus evolves and, importantly, why a first dengue infection is often mild while many second infections are life-threatening.”48 Researchers say that mapping the global variation of dengue viruses is important for understanding where vaccines under development will be protective; and it may assist in determining which strain to include in specific vaccination programmes and to follow the virus as it evolves.

c) GlaxoSmithKline’s Mosquirix is a malaria vaccine designed for use in African babies and toddlers. While it will probably be rolled out, its limited efficacy in trials was disappointing. Now scientists have offered a genetic explanation. A study funded by the US National Institutes of Health (NIH) has found that genetic variability in a protein found on malaria parasites could help explain the limited efficacy, because, while the protein comes in different forms, the vaccine incorporates only one variant49.

d) Ivermectin, a drug developed to kill parasitic worms, is being trialled in Burkina Faso50 to see if administering it to selected village populations reduces the incidence of malaria by killing mosquitoes.

e) The QIMR Berghofer Medical Research Institute in Brisbane will work further on development of new drugs to fight malaria with the support of a $A10 million investment announced by federal Trade and Investment Minister Andrew Robb and Premier of Queensland Annastacia Palaszczuk as part of the Northern Australia Investment Forum. 

46 Results were published in the journal Science47 Researchers from the Dengue Antigenic Cartography Consortium, writing in today’s edition of Science, analysed 47 strains of dengue virus with 148 samples taken from both humans and primates to see whether they indeed fit into four distinct types. The researchers found a significant amount of antigenic difference within each dengue serotype – in fact, the amount of difference within each serotype was of a similar order to that between the different types. This implies that an individual infected with one type may not be protected against antigenically different viruses of the same type, and that in some cases the individual may be protected against some antigenically similar strains of a different type.48 An unusual characteristic of dengue is that in some cases when an individual becomes infected for a second time, rather than being immune to infection, the disease can be much more severe. One hypothesis to explain this is that the antibodies produced in response to infection with one strain of the virus somehow allow viruses of a different strain to enter undetected into cells, implying that antigenic differences between the serotypes are important.49 The study was published in The New England Journal of Medicine.50 By researchers from Colorado State University and the Institut de Recherche en Sciences de la Santé in Burkina Faso.

17

f) Japanese drug giant Eisai has entered into a joint development programme with the Liverpool School of Tropical Medicine and the University of Liverpool for preclinical development of the novel antimalarial candidate E209. Eisai has also signed a joint development programme with non-profit public-private product development partnership Medicines for Malaria Venture, to discover antimalarial candidate compounds with novel modes of action effective against parasites resistant to existing treatments. Each of the projects has been awarded a grant by the Global Health Innovative Technology Fund, an international non-profit organisation.

g) A collaboration of Indian and American scientists51 has identified a malarial parasite protein that can be used to develop antibodies when displayed on novel nanoparticles. This has the potential to prevent the parasite from multiplying in the human host and also inhibits transmission through mosquitoes.

h) Researchers at the University of Texas Medical Branch at Galveston, in partnership with a commercial lab, are developing a new and relatively inexpensive test for chikungunya. It uses a virus related to chikungunya, but it will replicate only in mosquitoes and not in vertebrates. Most diagnostic tests for chikungunya use chikungunya virus that has been inactivated, and have to be carried out in higher-level containment labs.

Influenza: strains, spread, prevention and treatmenta) Hyperimmune intravenous immunoglobulin treatment appeared to significantly

increase hemagglutination inhibition antibody titer concentrations in patients with influenza, according to an ongoing trial52. Researchers wrote: “This trial is seeking to evaluate the efficacy and safety of anti-influenza hIVIG in patients hospitalized with severe influenza beginning with the 2014-2015 Northern Hemisphere influenza season….Due to the ongoing threat of antigenic drift, one major challenge of such a trial will be the need to keep the antibody specificity of the manufactured IVIG product contemporaneous with circulating virus subtypes throughout the projected course of the study over two or more influenza seasons.”

MERS-CoV (Middle East Respiratory Syndrome-Coronoavirus)a) At 4 November there had been 1275 laboratory-confrmed cases of MERS-CoV in

Saudi Arabia, with 546 deaths. Globally, between September 2012 and 5 November 2015, WHO had been notified of 1637 laboratory-confirmed cases of infection with MERS-CoV, including at least 632 related deaths.

b) A study reported in the Centers for Disease Control and Prevention (CDC) publication, Emerging Infectious Diseases53, suggests a number of risk factors for MERS. Researchers said: “Using multivariable analysis, we found that direct exposure to dromedary camels during the 2 weeks before illness onset, as well as diabetes mellitus, heart disease, and smoking, were each independently associated with MERS-CoV illness. Further investigation is needed to better understand animal-to-human transmission of MERS-CoV”. This study excluded people who had caught MERS in family or healthcare settings. Hospitals have been a major contributor to transmission because of inadequate infection control. There has also been a cluster of cases among 36 female janitors sharing a three-bedroom apartment east of Riyadh.

51 From theTata Institute of Fundamental Research (TIFR), Mumbai and the University of Maryland School of Medicine, Baltimore. The work was reported in Malaria Journal.52 Davey RT Jr, et al. “Anti-influenza hIVIG increases HAI antibody titers” J Clin Infect Dis . 2015;doi:10.1093/infdis/jiv453. October 7, 201553 Alraddadi BM, Watson JT, Almarashi A, Abedi GR, Turkistani A, Sadran M, et al. “Risk factors for primary Middle East respiratory syndrome Coronavirus illness in humans, Saudi Arabia, 2014”. Emerg Infect Dis.2016 January [ahead of print] <http://dx.doi.org/10.3201/eid2201.151340>

18

c) A University of Southampton study has suggested that copper can be used to stop the spread and transmission of respiratory viruses that are connected to Middle East respiratory syndrome (MERS) and severe acute respiratory syndrome (SARS). Scientists found human coronavirus 229E stayed infectious when it was placed on common surface materials for multiple days. When the virus was placed on copper, it was quickly destroyed.

d) GeneOne Life Science and the Walter Reed Army Institute of Research (WRAIR) recently developed a partnership to create a vaccine against MERS. The agreement is specifically to further GLS-5300, the DNA vaccine from GeneOne. The human trial of this vaccine will be the first for a MERS treatment or vaccine.

Ebola virus diseasea) London’s Royal Free Hospital discharged the nurse who had suffered meningitis as a

follow-on from earlier Ebola.

Other diseases: occurrence, prevention and treatmenta) India recorded the largest number of tuberculosis cases in the world in 2014.

Globally there was a marked increase in TB notifications for the first time since 2007. The World Health Organisation’s Global Tuberculosis Report 2015, said that of the 9.6 million new TB cases in 2014, 58 per cent were in the South-East Asia and Western Pacific regions. India, Indonesia and China had the largest number of cases in 2014. Nigeria, Pakistan and South Africa also had significant numbers of TB cases last year. Around 1.5 million people were known to have died from the disease in 2014, including 140,000 children. The annual total of new TB cases, which had been about 5.7 million until 2013, rose to slightly more than 6 million in 2014, mostly due to a 29 per cent increase in notifications in India, which followed the introduction of a policy of mandatory notification in May 2012, creation of a national web-based reporting system in June 2012 and intensified efforts to engage the private health sector.

b) Researchers at Harvard’s T.H. Chan School of Public Health have called for a "biosocial" approach to fighting tuberculosis that incorporates interventions in areas such as nutrition, urban planning, occupational health, addiction recovery, and mental health services. "Despite increased funding for tuberculosis programs over the past 15 years, progress has been woefully slow," said senior author Rifat Atun54.

c) Scientists at the University of North Carolina have identified a new virus, similar to SARS, which can jump from Chinese horseshoe bats to humans without mutating55. There is no treatment for the virus, named SHC014-CoV, which crosses the species divide without the need to mutate. It is not known if the disease has the ability to spread from human to human. Senior study author, Dr Ralph Baric said: “Studies have predicted the existence of nearly 5,000 coronaviruses in bat populations and some of these have the potential to emerge as human pathogens”. The research highlights an ongoing debate over the US government's decision to suspend all gain of function experiments on certain agents, which is claimed to have stalled the development of vaccines or treatments for these pathogens should there be an outbreak. In addition, the team discovered the new virus also replicates as well as SARS-CoV in primary human lung cells, the preferred target for infection. 

d) Queensland Health said in November that 2015 had seen an increase in syphilis notifications in both Northern Queensland and the South East Queensland metropolitan areas.

54 The study was published online 26 October in The Lancet.55 The findings were reported in the journal Nature Medicine.

19

e) Professor Basil Donovan, of the Sydney-based Kirby Institute, said a syphilis outbreak that started in northern Queensland in 2011 had swept across the Top End. Ten babies had died as a result of congenital syphilis since the outbreak began. The Kirby Institute's national surveillance system showed 2,000 new cases were diagnosed in 2014. As of October 30, another 1,972 cases had been recorded in 2015, making it the most severe Australian outbreak in 30 years. The two groups affected are northern Aboriginal communities and urban gay communities.

f) University of Massachusetts Medical School researchers are making progress towards pre-exposure prophylaxis in Lyme disease territory, every spring for protection through high tick season. It would use monoclonal antibodies.

20