Monitoring International Trendsposted September 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:

The European Commission granted CSL Behring marketing authorization in all European Union (EU) member states for Respreeza (a purified Alpha-1 protein derived from human plasma) to treat the hereditary condition Alpha-1 antitrypsin deficiency (AATD). (Section 2)

ADMA Biologics, announced that the US Patent and Trademark Office (USPTO) had issued to it United States Patent 9,107,906, titled, 'Compositions And Methods For The Treatment of Immunodeficiency'. (Section 2)

Roche has gained fast-track designation from the US Food and Drug Administration (FDA) for its haemophilia drug ACE910. This is an investigational humanised bispecific monoclonal antibody engineered to mimic the function of factor VIII. (Section 2)

The FDA accepted Dimension Therapeutics’ investigational new drug (IND) application and granted orphan drug designation for its lead product candidate, DTX101, for the treatment of haemophilia B. (Section 2)

The FDA has expanded the use of Novartis’ Promacta (eltrombopag) to include children one year of age and older with the rare blood disorder chronic immune thrombocytopenia (ITP) who have not responded sufficiently to immunoglobulins, corticosteroids, or splenectomy. (Section 2)

From 1 July, Baxter International spun off part of its operations as Baxalta. Shire then made a private takeover bid followed by a public bid. The Baxalta Board rejected the advance, although there were suggestions that private talks were proceeding. (Section 3)

Gauss Surgical has raised $US 3.3 million to support its Triton System that gives a fast, real-time assessment of blood loss during surgery. (Section 3)

LFB USA of Framingham has opened a facility on its 383-acre Central Massachusetts farm for genetically altered rabbits that produce milk containing Factor VIIa, a protein used to treat haemophilia. (Section 3)

The US Biomedical Advanced Research and Development Authority (BARDA) has exercised a contract option for $US 15.5 million with start-up company Velico to back the development of its dried plasma technology. (Section 3)

Technavio's analysts forecast the global plasma therapeutics market to grow to 2019 at a compound annual growth rate of 12.10 per cent. (Section 3)

In the US, tick-borne babesiosis is thought to be the pathogen most often spread by blood transfusions. (Section 4)

Four researchers in India say that the expense of treating patients bitten by rabid dogs and monkeys can be substantially reduced by an eight-fold reduction in the quantity of immunoglobulin used and a five-fold reduction in the vaccine used. (Section 4)

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Korea’s Samsung Medical Center will overhaul its intensive care unit (ICU) system after its experience in the recent spread of the Middle East Respiratory Syndrome (MERS) coronavirus. (Section 4)

Canadian researchers reported that universal administration of tranexamic acid in patients undergoing hip or knee replacement surgery is safe and effective at reducing the incidence of red blood cell transfusion. (Section 5)

A recent review in the British Journal of Surgery concluded that: “The significance of preoperative anaemia appears underappreciated, and its detection should lead to routine investigation and treatment before elective surgery.” (Section 5)

The US Preventive Services Task Force (USPSTF) concluded that there is insufficient evidence to determine the balance of benefits and harms of routine screening for iron deficiency anaemia (IDA) in pregnant women or for the use of iron supplements during pregnancy to prevent adverse maternal health and birth outcomes. (Section 5)

A study suggested that after 5g of idarucizumab emergency surgery could be initiated rapidly in patients treated with Pradaxa (dabigatran etexilate mesylate). (Section 5)

The first patient has been enrolled in the trial to evaluate the safety of Eliquis versus warfarin or other vitamin K antagonists in patients with nonvalvular atrial fibrillation and a recent acute coronary syndrome or undergoing percutaneous coronary intervention (a stent). (Section 5)

Another study found that CSL Behring’s 4-factor prothrombin complex concentrate, Kcentra, reverses the anticoagulation effects of vitamin K antagonists at a faster rate than plasma in patients requiring emergency invasive procedures. (Section 5)

Visterra of Massachusetts and the Serum Institute of India have entered into a license agreement for the development, manufacture and commercialization of VIS513 in countries on the Indian subcontinent. This is a humanized monoclonal antibody engineered to bind and neutralize all four serotypes of the dengue virus. (Section 8)

Researchers found that drugs developed to treat sepsis could successfully treat dengue fever in mice. (Section 8)

Chinese researchers reported that while temporary poultry market closures can reduce environmental levels of H7N9 and other avian flu viruses, contamination quickly returns to pre closure levels, when markets re-open. (Section 8)

Between 4 and 18 September, there were 18 new MERS cases reported in Saudi Arabia, 15 of them in Riyadh, with links to an ongoing hospital outbreak at King Abdulaziz Medical City. 158 illnesses had been reported in Riyadh since 21 July. (Section 8)

An experimental vaccine given six weeks before exposure to MERS-CoV fully protects rhesus macaques from disease. (Section 8)

Researchers (led from the Chinese Center for Disease Control and Prevention) sequenced the genome of a MERS-CoV strain introduced to China in May after first reaching South Korea. They concluded that the Chinese and South Korean MERS-CoV strain resulted from recombination between MERS viruses which probably occurred in mid to late 2014. (Section 8)

In Saudi Arabia, the Ministry of Agriculture announced 7,700 out of 233,000 camels in the Kingdom have been infected with the MERS coronavirus. (Section 8)

A team from The University of Texas Medical Branch at Galveston and Profectus BioSciences reported in Nature that it had developed a quick-acting Ebola vaccine that it claims to be safe and effective with a single dose. (Section 8)

Inovio Pharmaceuticals announced that the first patient has been dosed in a Phase I trial of Pennvax-GP, the company’s DNA vaccine for HIV. (Section 8)

The Queensland Government says it will contact the parents of children who are not properly vaccinated to encourage them to get their vaccinations up to date. (Section 8)

The US Centers for Disease Control and Prevention (CDC) has been encouraging more states to publish vaccination statistics online. (Section 8)

By 2 September there had been eight cases of measles reported on the University of Queensland campus at St Lucia since July. The Metro North Public Health unit set up a five-day on-campus vaccination clinic. (Section 8)

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Europe has been reporting that refugees are bringing cutaneous diphtheria with them. (Section 8)

Table of Contents

1. Products________________________________________________________________4

Haemophilia treatments___________________________________________________________4

Other___________________________________________________________________________6

2. Regulatory______________________________________________________________6

3. Market structure and company news________________________________________8

4. Country-specific events___________________________________________________10

5. Safety and patient blood management______________________________________11

Appropriate transfusion__________________________________________________________11

Treating iron deficiency___________________________________________________________12

Other._________________________________________________________________________12

6. Research______________________________________________________________13

7. Legal actions and enquiries_______________________________________________13

8. Infectious diseases______________________________________________________13

Mosquito-borne diseases: dengue, chikungunya and malaria____________________________13

Influenza: strains, spread, prevention and treatment___________________________________14

MERS-CoV (Middle East Respiratory Syndrome-Coronoavirus)____________________________14

Other diseases: occurrence, prevention and treatment_________________________________15

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.

Haemophilia treatmentsa) Biogen and Swedish Orphan Biovitrium announced that newly published clinical data

demonstrate that people on extended-interval prophylaxis regimens with ELOCTATE1 for haemophilia A experienced low bleeding rates. The interim results of the ASPIRE Phase III, open-label extension study appeared in the online edition of Haemophilia, the journal of the World Federation of Hemophilia, the European Association for Haemophilia and Allied Disorders, and the Hemostasis & Thrombosis Research Society. Participants who completed the Phase III A-LONG and Kids A-LONG studies were able to participate in ASPIRE. The results to date show the

1 Antihaemophilic Factor VIII (Recombinant), Fc Fusion Protein

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majority of participants in ASPIRE maintained or extended their dosing intervals between treatments compared with the A-LONG and Kids A-LONG studies. At the time of the interim analysis, the median time in the ASPIRE study was 80.9 weeks for adults and adolescents completing the A-LONG study, and 23.9 weeks for children completing the Kids A-LONG study. Inhibitor development is the primary endpoint of ASPIRE and no inhibitors were reported in any treatment groups. Of the adults and adolescents who had previously been treated prophylactically and who remained in the study through the interim analysis (n=128), 72 per cent maintained their prophylactic dosing interval and 22 per cent lengthened and six per cent shortened the time between infusions. There were no reports of serious allergic reactions or vascular clots. The most common adverse events (incidence of greater than or equal to five per cent) included nasopharyngitis (common cold), arthralgia (joint pain) and upper respiratory infection.

b) Biogen announced that new clinical data support the long-term safety and efficacy of ALPROLIX2 in people with severe haemophilia B treated for up to two years. Participants in the Phase III, open-label extension study, B-YOND, maintained low bleeding rates with one to two week prophylaxis regimens, according to data from an interim analysis presented for the first time at the 67th Annual Meeting of the National Hemophilia Foundation (NHF) in Dallas. B-YOND is a multi-year study for participants with severe haemophilia B who completed the Phase III B-LONG or Kids B-LONG studies. In this interim analysis, the median time on ALPROLIX during B-YOND was 27.6 months for the 93 adults/adolescents involved, but only 47.7 weeks for 23 children under the age of 12 who were involved. The study’s primary endpoint is inhibitor development, and no inhibitors have been reported to-date. According to the interim analysis, adults and adolescents treated prophylactically maintained protection against bleeding episodes with infusions every one to two weeks. The most common adverse events (incidence of greater than or equal to five per cent) included headache, common cold and vomiting for adults and adolescents. For children under age 12, falls, common cold and seasonal allergy were the most common adverse events. From the beginning of B-LONG or Kids-B-LONG until the B-YOND interim data analysis, the cumulative median time on ALPROLIX was 171.6 weeks for adults and adolescents, and 95.3 weeks for children under age 12. ALPROLIX , a recombinant clotting factor therapy with prolonged circulation in the body, is approved in the United States, Canada, Australia and Japan. The therapy was developed using a process called Fc fusion, which is designed to prolong a therapy’s circulation in the body using a naturally occurring pathway. While Fc fusion has been used for more than 15 years, Biogen is the only company to apply it to the treatment of haemophilia. Development of neutralizing antibodies (inhibitors) to ALPROLIX may occur following administration of treatment. Common adverse reactions (incidence of greater than or equal to 1 per cent) from the registrational B-LONG study were headache and oral paresthesia (an abnormal sensation in the mouth).

c) CSL Behring announced that the first patient had been enrolled in Malaysia in its 54-patient Phase II/III clinical trial of CSL 6893, the company's recombinant fusion protein linking coagulation factor VIIa with albumin (rVIIa-FP). The trial will test the pharmacokinetics, efficacy, and safety for on-demand treatment in patients with congenital haemophilia A or B who have developed an inhibitor to factor VIII or factor IX replacement therapy4. Preclinical studies in healthy volunteers have confirmed that CSL689 has favourable pharmacokinetic properties compared with the commercially

2 Coagulation Factor IX (Recombinant), Fc Fusion Protein3 This Phase II/III study is part of the PROLONG-7FP clinical development program, which aims to demonstrate the therapeutic advantages of rVIIa-FP in patients with haemophilia A or haemophilia B who have developed inhibitors as well as in patients with congenital FVII deficiency. A Phase I pharmacokinetic study in patients with congenital FVII deficiency is ongoing.

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available recombinant FVIIa product currently available. In a phase I study it demonstrated good tolerance, and a three-to four-fold increase in half-life compared with the commercial product. The US Food and Drug Administration (FDA) awarded Orphan Drug Designation5 to rVIIa-FP for the treatment and prophylaxis of bleeding episodes in patients with congenital haemophilia and inhibitors to coagulation factor VIII or IX. The European Commission granted Orphan Drug Designations for rVIIa-FP for the treatment of patients with haemophilia A or B who have developed an inhibitor as well as for the treatment of congenital factor VII deficiency.

d) Barbara A. Konkle, professor of medicine at Puget Sound Blood Center and University of Washington, and her colleagues wrote of BAX 855: “Patients with hemophilia A who adopt a prophylactic regimen can reduce their bleeding rate, and thus reduce the probability of developing chronic arthropathy, which leads to disability”. A Phase II/III study showed BAX 855, a pegylated, full-length recombinant Factor VIII, to be safe and effective for biweekly prophylactic treatment6.

Othere) Bio Products Laboratory (BPL) announced on 1 September that the first subject had

enrolled in SCIG03, a Phase III clinical trial evaluating the safety and pharmacokinetics of Subgam VF, 16% liquid immunoglobulin for the treatment of primary immunodeficiency7. This is a US trial and will form the basis of a biologics license application for marketing authorization in the US.

f) Share prices of Sangamo BioSciences rose in response to its announcement that the US National Institute of Health's Recombinant DNA Advisory Committee had unanimously approved the protocol of a Phase 1 study of one of the company's ZFP Therapeutics as a potential cure for haemophilia B. The Factor IX program will be the first clinical trial of in vivo genome editing and the first therapeutic application of Sangamo's In Vivo Protein Replacement Platform (IVPRP)8. Sangamo expects to file an Investigational New Drug (IND) application with the FDA by the end of 2015 and to initiate a Phase 1 study in 2016.

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 CSL Behring marketing authorization in all European Union (EU) member states for Respreeza (a purified Alpha-1 protein

4 Development of inhibitory antibodies against factor VIII or factor IX partially or completely blocks the efficacy of factor replacement therapy. The incidence of inhibitors in individuals with haemophilia A is estimated to be up to 33 per cent and in haemophilia B between one and 6 per cent. The most recent World Federation of Hemophilia (WFH) survey identified more than 4,753 patients with haemophilia A and 248 with haemophilia B who have developed an inhibitor worldwide.5 Orphan designation gives the company benefits such as tax credits for qualified clinical testing and exemption from certain application fees.6 Konkle BA, et al. Blood. 2015;doi:10.1182/blood-2015-03-6308977 The trial is titled, “A Phase III, Multicenter, Open-Label Study to Evaluate the Pharmacokinetics and Safety of Subgam VF in Primary Immunodeficiency Diseases” (clinicaltrials.gov identifier, NCT01884311).8 IVPRP technology employs the albumin gene locus, a liver-specific genomic "safe harbor" site. Zinc finger nucleases (ZFNs) can be used to edit the locus to accept and express any therapeutic gene. The liver will continue to produce therapeutic levels of the corrected protein such as factor VIII or IX to treat haemophilia. Since the liver produces albumin in excess of the body’s requirements, capturing a small portion of the albumin gene's capacity is enough to produce the replacement protein at a therapeutic level.

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derived from human plasma) to treat the hereditary condition Alpha-1 antitrypsin deficiency (AATD). The main function of the Alpha-1 antitrypsin protein is to protect the lungs from inflammation. This particular Alpha-1 proteinase inhibitor has been shown in a prospective double blind, placebo controlled trial (the RAPID study) to reduce significantly the loss of lung tissue by slowing the progression of emphysema due to AATD.

b) ADMA Biologics announced that the U.S. Patent and Trademark Office (USPTO) had issued United States Patent 9,107,906, titled, 'Compositions And Methods For The Treatment of Immunodeficiency'. It relates to the use of human plasma immunoglobulin compositions containing select antibody titres specific for a plurality of respiratory pathogens; methods of identifying human donors and donor samples for use in the compositions; methods of manufacturing the compositions; and methods of utilizing the compositions by prophylactic and or therapeutic treatments (e.g. passive immunization). The patent extends to January 20359.

c) Roche has gained fast-track designation10 from the FDA for its haemophilia drug ACE910. This is an investigational humanised bispecific monoclonal antibody engineered to mimic the function of factor VIII. It is a new approach to treating haemophilia, independent of whether or not patients have developed inhibitors. In the Phase I/II study11 ACE910 was administered as a weekly subcutaneous injection to patients with severe haemophilia A, with or without inhibitors. The drug appeared safe and effective for prophylaxis. Further trials of the drug, including for paediatric patients, will go into 2016. Separate Phase III trials will be conducted for patients with and without inhibitors.

d) The FDA accepted Dimension Therapeutics’ investigational new drug (IND) application and granted orphan drug designation12 for its lead product candidate, DTX101, for the treatment of haemophilia B. Dimension will conduct a multi-centre Phase I/II study to evaluate DTX101 in adult patients with moderate/severe to severe haemophilia B. DTX101 is designed to deliver blood clotting Factor IX (FIX) gene expression. The current standard of care involves chronic replacement of FIX protein through intravenous infusion.

e) The FDA approved AstraZeneca’s Brilinta tablets at a 60 mg dose that would be taken along with aspirin beyond a year after a heart attack. The drug had originally been approved at a higher dose for use during the year following a heart attack. European cardiologists recently endorsed the longer use of Brilinta and other blood clot preventers, with large clinical studies having found decreased heart risk from use of dual blood thinners for more than the first year after an attack.

f) La Jolla Pharmaceutical Company announced that the European Medicines Agency (EMA) Committee for Orphan Medicinal Products (COMP) issued a positive opinion

9 Adam Grossman, President and CEO of ADMA Biologics, said: "The issuance of ADMA's patent validates the differentiated, unique and novel way ADMA approaches immune globulin products. ADMA's goal is to ensure adherence to all FDA standards and produce an IG product with consistent lot to lot potency of polyclonal anti pathogen antibodies…. This is a major milestone for our company as it provides us the ability to protect our lead product candidate and at the same time supports development of a wide range of other therapeutic IG products for patients with immunodeficiency and related diseases. The company will continue to aggressively pursue additional proprietary rights encompassing this technology."10 Fast-track designation has been available in the US since 2012. It allows the FDA to hasten the development and review of drugs where early trials suggest significant improvement over current therapies.11 The Phase I/II study was study conducted with Japanese and Caucasian healthy volunteers as well as Japanese haemophilia A patients. Bleeding was completely controlled in nine out of 18 patients.12 The FDA Office of Orphan Products Development grants orphan designation to drugs and biologics expected to be used for treatment of diseases or conditions that affect fewer than 200,000 people in the US. The designation provides certain benefits such as tax credits for qualified clinical trials costs, and exemption from FDA user fees. If approved, the drug quality for seven years of market exclusivity.

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recommending LJPC-401, La Jolla’s novel formulation of hepcidin, for designation as an orphan medicinal product13 for the treatment of chronic iron overload14 requiring chelation therapy15. The final opinion, which is subject to review and approval by the European Commission (EC), may include all or a subset of these conditions.

g) The FDA has expanded the use of Novartis’ Promacta (eltrombopag) to include children 1 year of age and older with the rare blood disorder chronic immune thrombocytopenia (ITP) who have not responded sufficiently to immunoglobulins, corticosteroids, or splenectomy. The updated label also includes a new oral suspension formulation for younger children who may not be able to swallow tablets. Promacta was approved by the FDA as a tablet formulation in June 2015 for children 6 years of age and older and in 2008 for use in adult patients with the same condition.

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) From 1 July, Baxter International spun off part of its operations as Baxalta. It retained a stake, which it is planning to dispose of in a tax-free manner over 18 months.

b) Baxalta R&D chief John Orloff told the Boston Business Journal that his company's new hub in Cambridge, Massachusetts, will be far from a traditional research campus. Baxalta plans to have 350 R&D workers at the site by 2016, but the company isn't building lab space there, keeping its in-house discovery unit in Europe. The Cambridge facility will be Baxalta's deal making hub looking for partnerships to widen the company's pipeline. Orloff told the Journal: "Our whole approach is one based on external innovation."

c) Soon after Baxalta was spun off by Baxter International, Shire made a private takeover bid followed by a public bid. The Baxalta Board rejected the advance, although there were suggestions that talks were proceeding in private. Meanwhile, Baxalta was reported to be interested in acquiring Ariad Pharmaceuticals16, which already has Iclusig (an FDA approved cancer drug) on the market, with another therapy in trials. Ariad’s share price rose dramatically on news of the offer, but Baxalta was soon reported to have abandoned takeover talks.

d) Shire CEO Flemming Ornskov was reported to have said that he would cut costs by £1 billion if his new £19 billion bid to acquire Baxalta is successful. As much as half the cuts were expected to result from overlapping research and development operations.

e) Shire was said to have back-up plans for acquisitions if its bid for Baxter failed, but its own falling share price presented problems.

13 To achieve orphan status in the European Union (EU), a drug must be for the treatment of a life-threatening or chronically debilitating condition that affects no more than five in 10,000 people in the EU and for which no satisfactory treatments exist or, ir they do exist, the new drug will be of significant benefit to those affected by that condition. 14 Chronic iron overload occurs in patients suffering from beta thalassemia, sickle cell disease and hereditary haemochromatosis (HH). Beta thalassemia and sickle cell disease often require frequent and life-long blood transfusions, which can cause excessive iron accumulation in the body, which is toxic to vital organs. HH is a disease caused by a genetic deficiency in hepcidin production, resulting in excessive iron accumulation.15 Iron chelators bind to and help clear excessive iron from the body. They can, however, cause toxicity, including kidney failure, liver failure or gastrointestinal haemorrhage.16 At a reported offer price of $US 2 billion.

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f) In 2014, Shire bought Cinryze, a drug for hereditary angioedema (HAE)17, from ViroPharma. The drug, derived from human plasma, is a C1 esterase inhibitor and has been supplied by Sanquin. Shire has renegotiated its terms with Sanquin so it can use other contractors to increase its supply. Cinryze generated $US 503 million in revenue for Shire last year, compared with $US 364 million from its other HAE drug, Firazyr.

g) Shire has returned rights to Sangamo’s experimental gene editing programs for haemophilia A and B to the California company, and kept the rights to a prospective treatment for Huntington’s disease and another unspecified program. Rights to other targets that were part of the original 2012 deal have also been handed back to Sangamo. Shire still has a right of first negotiation to re-acquire the haemophilia programs in the future. Sangamo claims that the new arrangements will enable it to “accelerate the development” of its haemophilia A and B programs, and that it will. file papers by the end of the year to begin the first trial for its haemophilia B treatment18.

h) Gauss Surgical has raised $US 3.3 million to support its Triton System that gives a fast, real-time assessment of blood loss during surgery and can reduce the perceived need for transfusion. The system is already in use at a number of US hospitals19.

i) South Korean biopharmaceuticals company Green Cross has opened its eighth US blood centre, this time in San Antonio, Texas.

j) Novo Nordisk is investing DKK 500 million in a new raw material warehouse in Denmark.

k) Sweden Orphan Biovitrium (Sobi) has opened a new European and Benelux office in Brussels. Europe accounts for sixty per cent of Sobi’s annual product sales.

l) NovoNordisk and the Langer Laboratory at the Massachusetts Institute of Technology are collaborating on the next generation of drug delivery devices for the administration of peptides.

m) LFB USA of Framingham has opened a facility on its 383-acre Central Massachusetts for genetically altered rabbits that produce milk containing Factor VIIa, a protein used to treat haemophilia. LFB’s French parent company, LFB SA, is already in the final stages of testing its Factor VIIa in humans, using material made in rabbits in France. The company also has a herd of more than 1,000 genetically engineered (transgenic) goats, capable of producing the human clot-busting protein antithrombin III in their milk. The protein is sold under the name ATryn by another LFB subsidiary, rEVO Biologics, to prevent clotting problems before surgery or childbirth in patients who lack antithrombin. rEVO is hoping to expand its use by testing the protein as a treatment for the pregnancy ailment pre-eclampsia. rEvo had had an initial public offering of $US 50 million planned, but withdrew it on 9 September citing market conditions. It had planned to list on the Nasdaq as RBIO.

17 Hereditary Angioedema is an inherited blood disorder characterised by episodic attacks of swelling that affect the face, extremities, genitals, gastrointestinal tract and upper airways.18 There are seven groups known to be hoping to use either gene therapy, or, in Sangamo’s case, gene editing, for treating haemophilia. Sangamo’s treatment would make use of zinc finger proteins which are thought, theoretically at least, to be able to deliver a permanent fix by making genetic corrections that would be passed on to other cells. The other six are: Baxalta, Biogen, Dimension Therapeutics/Bayer, Spark Therapeutics/Pfizer, UniQure, and BioMarin Pharmaceutical. Some are using different types of adeno-associated virus and lentivirus vectors, which may call forth varying immune responses, and each have their purported strengths and weaknesses. Others are delivering different types of genes with these vectors. Baxalta and Spark, for instance, are using mutant therapeutic genes meant to clot blood much faster than normal—which might produce unpredictable results. A possible problem with gene therapies using adeno-associated virus is that they may have to be repeated at regular intervals. 19 An iPad camera photographs the surgical canister or surgical sponges used. Images are analysed via algorithms to assess the haemoglobin content and to assess blood loss regardless of the presence of saline or irrigation fluid, lighting variations and the rupture of red cells.

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n) The US Biomedical Advanced Research and Development Authority (BARDA) has exercised a contract option for $US 15.5 million with start-up Velico to back the development of its dried plasma technology. BARDA is building on a 2012 commitment it made to Velico for $US 8.9 million.

o) Cerus Corporation reported a $US 16 million second quarter loss. On 2 September, the Chief Scientific Officer of Cerus Corporation, Laurence Corash, was reported to have purchased shares of the company $US 96,330. Over the month up to and including that date he had reported four purchases of the company shares for a total of $US 901,400.

p) Novo Nordisk announced that the company is investing 500 million Danish kroner in a new 19,000 m2 warehouse in Hillerød, Denmark. The warehouse will handle all inbound raw materials for Novo Nordisk's production in Denmark and will have a capacity of around 17,000 pallets. The warehouse is expected to be fully operational by the end of 2017. 

q) Technavio's analysts forecast the global plasma therapeutics market to grow at a compound annual growth rate of 12.10 per cent over the period to 201920.

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, tick-borne babesiosis is thought to be the pathogen most often spread by blood transfusions21, but there is no large-scale, FDA-approved way to test for Babesia in the 5 million transfusions annually. The prescription drugs azithromycin and atovaquone usually fight off a babesiosis infection quite quickly. However, in high-risk groups (the elderly, people without a spleen, the immune-compromised including cancer patients on immunosuppressive drugs) the mortality rate can be as high as 20 per cent. The risk to the blood supply comes from donors who are asymptomatic, which is one quarter of infected adults and half of infected children, whose infections can last months or years. The Centres for Disease Control (CDC) recorded 3,862 cases of babesiosis in the US from 2011-2013. About three-quarters were in the elderly. Babesiosis cases always spike during the summer. Five states (Rhode Island, Massachusetts, Connecticut, New York, and New Jersey) together account for more than 85 per cent of cases. Infections also appear across the Northeast and the Midwest. In 1994, it was found that about one in 601 tested blood transfusions in Connecticut resulted in a babesiosis infection. Since then the FDA believes there have been “expanding areas of transmission and infections”. While examining blood under a microscope can allow an expert to identify parasites present, this is not a feasible method on a large scale. Two US companies (IGeneX and Imugen) are each developing two types of tests to detect babesiosis, looking either for Babesia microbes directly by detecting their DNA in a person’s blood, or for antibodies that a person generates to fight Babesia. Before approving a test the FDA will need to know it works and is reliable, without too many false positive or negative results. The expected plan, if tests are approved, will be mandatory antibody screening in donors across fifty States, with additional DNA testing in high-risk States.

b) In the US, the Centers for Medicare and Medicaid Services (CMS) extended for a third year the new technology add-on payment (NTAP)22 for Kcentra (CSL Behring’s

20 Global Plasma Therapeutics Market 2015-201921 Edouard Vannier and Peter J. Krause, “Human Babesiosis” N Engl J Med 2012; 366:2397-2407 (June 21, 2012) DOI: 10.1056/NEJMra120201822 CMS implemented its NTAP policy in 2001 to encourage timely access to innovative therapies for Medicare beneficiaries as hospital inpatients, where this is not adequately covered under the

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Prothrombin Complex Concentrate [Human]). The NTAP will now be available to the end of September 2016 for eligible Medicare beneficiaries treated as hospital inpatients. Kcentra is the only non-activated 4-factor prothrombin complex concentrate (4F-PCC) approved by the FDA for the urgent reversal of acquired coagulation factor deficiency induced by Vitamin K antagonist (e.g. warfarin) therapy in adult patients with acute major bleeding or in need of an urgent surgery or invasive procedure. Unlike fresh frozen plasma (FFP), the most widely used agent in the US for warfarin reversal, Kcentra does not require thawing or blood-type matching and can be administered more quickly and with lower volume than FFP. Kcentra was first approved for use in the US in April 2013, and received its NTAP designation on 1 October the following year.

c) In the US, the Governor of Georgia opened the Georgia BioScience Training Center at Stanton Springs. The $US 14-million state-owned biotech training centre arose from the negotiations to encourage Baxter International, now Baxalta, to the state. The centre, operated by Georgia Quick Start, will provide customized training to meet Baxalta’s start-up training needs. Although Baxalta will be given preferential use for several years other companies coming to or expanding in Georgia will also be able to use the centre to train employees on technical equipment.

d) Four researchers in India say that the expense of treating patients bitten by rabid dogs and monkeys can be substantially reduced by an eight-fold reduction in the quantity of immunoglobulin used and a five-fold reduction in the vaccine used23. They found the key was injecting directly into the wound.

e) The University of Bristol and NHS Blood and Transplant are partners in a new £3M Blood and Transplant Research Unit. It will assist the development of new red blood cell products to support the transfusion needs of patients with rare blood groups and those with complex and life-limiting conditions like sickle cell disease and thalassemia. The Unit’s research will include a clinical trial of small volumes of artificial blood in human volunteers. The Unit is one of four new Blood and Transplant Research Units [BTRU] for which the National Institute for Health Research [NIHR] has committed £15.1 million of funding through a competitive process. The units are all partnerships between universities and NHS Blood and Transplant [NHSBT], and focus on rapid translation of research findings into routine practice.

f) Korea’s Samsung Medical Center will overhaul its intensive care unit (ICU) system after its experience in the recent spread of the Middle East Respiratory Syndrome (MERS) coronavirus.

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

Appropriate transfusiona) Canadian researchers reported24 that universal administration of tranexamic acid in

patients undergoing hip or knee replacement surgery is safe and effective at reducing

Medicare Severity Diagnosis-Related Groups (MS-DRGs). To qualify for an NTAP, the drug must be new and inadequately paid for under existing MS-DRGs and provide a significant clinical improvement over existing therapies. CMS will continue to reimburse hospitals an additional amount, up to $US 1,587.50, for cases involving Kcentra that exceed the MS-DRG payment amount. 23 OK Bharti et al., “Local infiltration of rabies immunoglobulins without systemic intramuscular administration: An alternative cost effective approach for passive immunization against rabies”, Human Vaccines and Immunotherapeutics, online ahead of print, 28 August. PMID:26317441 (PubMed)24 James E. Baker et al., “Universal tranexamic acid therapy to minimize transfusion for major joint arthroplasty: a retrospective analysis of protocol implementation”, Canadian Journal of Anesthesia/Journal canadien d’anesthésie, 2015; DOI: 10.1007/s12630-015-0460-6

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the incidence of red blood cell transfusion. One of the researchers, Dr Gregory Hare of St Michael’s Hospital, said of future work: “We plan to continue following our patients over time and have now accumulated data on about 2000 patients. We continue to observe reduced rates of red blood cell transfusion and no increase in adverse events. As part of our ongoing quality assurance program, we have developed a computer based real-time database to continue collecting data on patients who receive TXA peri-operatively; to ensure that transfusion rates remain low and that no increase in adverse events are observed over time.”

b) Researchers examining transfusion practice queried New York State’s Statewide Planning and Research Cooperative System for elective oesophagectomy, gastrectomy, and pancreatectomy for malignancy from 2001 to 2013. They concluded that: “Significant variation in perioperative blood transfusion utilization is present at both the surgeon and hospital level. These findings are unexplained by patient-level factors and other known hospital characteristics, suggesting that variation is due to provider preferences and/or lack of standardized transfusion protocols. Implementing institutional transfusion guidelines is necessary to limit unwarranted variation and reduce infectious complication rates.”25

Treating iron deficiencyc) A recent review in the British Journal of Surgery concluded that: “The significance of

preoperative anaemia appears underappreciated, and its detection should lead to routine investigation and treatment before elective surgery. The risks of unnecessary blood transfusion are increasingly being recognized. Strategic adoption of patient blood management in surgical practice is recommended, and will reduce costs and improve outcomes in surgery”26.

d) The US Preventive Services Task Force (USPSTF) concluded that there is insufficient evidence to determine the balance of benefits and harms of routine screening for iron deficiency anaemia (IDA) in pregnant women or for the use of iron supplements during pregnancy to prevent adverse maternal health and birth outcomes27. The task force also considered evidence on the benefits and harms of screening for IDA in young children ages 6 to 24 months. It found there is not enough evidence to determine whether there was on balance benefit.

Other.e) The European Society of Cardiology Congress in London was told that results from an

interim analysis of the Phase III RE-VERSE AD study showed that after 5g of idarucizumab emergency surgery could be initiated rapidly in patients treated with Pradaxa (dabigatran etexilate mesylate). Patients could be urgently brought to surgical procedures, with a median time of 1.7 hours between administration of idarucizumab and start of procedure. No bleeding complications were reported in the 24 hours after surgery. Jerrold Levy, RE-VERSE AD investigator28, said: "Dabigatran already has a short half-life of around 12 hours, allowing for normal surgery to be performed in a reasonable time after stopping the drug in many patients. But in case of an emergency situation, we need to go to the operating room sooner. The data now presented show that immediately reversing dabigatran with idarucizumab would allow for rapid normalization of clotting and faster initiation of surgery in case it is needed."

25 Christopher T Aquina, et al., “Significant Variation in Blood Transfusion Practice Persists following Upper GI Cancer Resection” Journal of Gastrointestinal Surgery online: 12 August 201526 Clevenger, B, Mallett, S V, Klein, A A. and Richards, T (2015), “Patient blood management to reduce surgical risk”. Br J Surg. doi: 10.1002/bjs.989827 www.uspreventiveservicestaskforce.org 28 and Professor of Anesthesiology and Co-Director of the Cardiothoracic Intensive Care Unit, Duke University Medical Center, North Carolina.

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f) Bristol-Myers Squibb and Pfizer announced that the first patient has been enrolled into the Phase IV clinical trial, AUGUSTUS. This will evaluate the safety of Eliquis versus warfarin or other vitamin K antagonists in patients with nonvalvular atrial fibrillation (NVAF) and a recent acute coronary syndrome or undergoing percutaneous coronary intervention (a stent).

g) A randomized study of 168 patients found that CSL Behring’s 4-factor prothrombin complex concentrate (4F-PCC), Kcentra, reverses the anticoagulation effects of vitamin K antagonists (VKA) at a faster rate than plasma in patients requiring emergency invasive procedures29. This reinforces the findings of an earlier but smaller randomized trial with 20 patients30.

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) Researchers from New York University Polytechnic School of Engineering received a grant of $US 368,000 from the US Army Research Laboratory to study over the course of the next three years applications for hydrogels31 to treat wounds, including the delivery of drugs. Hydrogels have been used as wound dressings in the past, and this team is hoping to improve upon those functions by mimicking biochemical processes found in nature.

7. Legal actions and enquiriesThe NBA is interested in the implications for Australia of any proceedings against companies, governments and professional practitioners in relation to blood and blood products; or of relevant public enquiries.

a) A jury awarded $US4 million to an Alabama couple who sued LifeSouth Community Blood Center after the husband contracted HIV through contaminated blood administered during open heart surgery.

8. 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

29 Lancet 2015;385:2077-2087. The study was led by Dr Joshua Goldstein, an attending physician in the Department of Emergency Medicine at Massachusetts General Hospital and an associate professor of surgery at Harvard Medical School. His team came from 33 hospitals in the US, Europe and Asia.30 Vox Sang 2010;99:251-26031 A hydrogel is a polymeric material which can hold large amounts of water in its 3-D structural network. It acts as the gel equivalent of a sponge.

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become necessary to test in the future (e.g. Chagas disease, and the tick-borne babesiosis and Lyme disease).

Mosquito-borne diseases: dengue, chikungunya and malariaa) As New Delhi copes with an increasing number of dengue cases, the type 4 strain

emerged at first as the dominant strain in the city, then type 2 began to dominate.b) Visterra of Massachusetts and the Serum Institute of India have entered into a

license agreement for the development, manufacture and commercialization of VIS513 in countries on the Indian subcontinent. Visterra’s VIS513 is humanized monoclonal antibody engineered using Visterra’s Hierotope technology. The antibody was designed to bind and neutralize all four serotypes of the dengue virus. Preclinical trials found a rapid reduction in viral titres after a single systemic administration.

c) Researchers from the University of Queensland’s School of Chemistry and Molecular Biosciences and the Australian Infectious Disease Research Centre, led by Professor Paul Young, found that drugs developed to treat sepsis could successfully treat dengue fever in mice32. With safety trials already complete, human clinical trials could soon follow.

d) Researchers from Yale University have found they can slow the development of the malaria parasite inside blood cells by changing its gene expression33. They hope that even drug-resistant strains can be dealt with this way.

e) The University of Oxford’s spin-out company Oxitec, which is commercialising technology to control disease-carrying insects and pests, has been sold to synthetic biology specialist Intrexon Corporation for US$160 million. Oxitec breeds genetically modified insects whose progeny die before reproducing. ‘Sterile’ strains are mass reared and released in an attempt to remove particular insect species eg mosquitos carrying dengue. Trials in Grand Cayman, Brazil and Panama have all shown Aedes Aegypti mosquito population reductions of more than 90 per cent, with the modified mosquito the first GM insect approved as safe for use in Brazil. Oxitec has received approval for open field trials in Brazil and the US to control the Mediterranean fruit fly and the diamond back moth.

Influenza: strains, spread, prevention and treatmentf) Vaxart reported that its H1N1 influenza tablet vaccine developed protective immunity

based on Haemagglutinin Inhibition Assay (HAI) with HAI titer increases comparable with increases demonstrated by current FDA-approved influenza vaccines34. The company said its tablet vaccine also demonstrated a favourable safety and tolerability profile.

g) At the end of August, the Australian Medical Association Queensland (AMAQ) said the State was on the brink of an influenza epidemic. There had been more than 12,000 confirmed cases in 2015 until August 16. Almost half had been diagnosed between August 1 and 16 and 92 people had been hospitalised. Official flu statistics were thought to be the tip of the iceberg, with only about one person in 10 who gets the flu having a swab. The main strain causing problems is said to have been the Brisbane B strain, not in the (subsidised) Southern Hemisphere 3-strain vaccine this year, although it will be included in 2016..

32 Naphak Modhiran, Paul R. Young et.al.,” Dengue virus NS1 protein activates cells via Toll-like receptor 4 and disrupts endothelial cell monolayer integrity” Science Translational Medicine 9 Sep 2015: Vol. 7, Issue 304, pp. 304ra142, DOI: 10.1126/scitranslmed.aaa386333 Aprajita Garg, Sidney Altman et al., “Targeting protein translation, RNA splicing, and degradation by morpholino-based conjugates in Plasmodium falciparum”, Proceedings of the National Academy of Sciences, Published online before print September 8, 2015, doi: 10.1073/pnas.151586411234 David Liebowitz et al., “High titre neutralising antibodies to influenza after oral tablet immunisation: a phase 1, randomised, placebo-controlled trial”, The Lancet Infectious Diseases, Volume 15, No. 9, p1041–1048, September 2015. DOI: http://dx.doi.org/10.1016/S1473-3099(15)00266-2

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h) Chinese researchers reported that while temporary poultry market closures can reduce environmental levels of H7N9 and other avian flu viruses, contamination quickly returns to pre closure levels, when markets re-open35.

MERS-CoV (Middle East Respiratory Syndrome-Coronoavirus)i) MERS-CoV has continued to spread in Saudi Arabia, with some hospitals

contributing to the spread36. By 28 September the case total in Saudi Arabia since 2012 was 1,246 with 532 fatalities.

j) Around three million Muslims from all over the world attended Islam's holiest sites in Mecca and Medina for the Hajj season. On 26 August, the World Health Organisation (WHO) warned Pakistan that there are high chances of the MERS-CoV virus being transported back to the country by returning pilgrims.

k) In preparation for the annual Hajj pilgrimage beginning on 22 September, Saudi Arabia imposed a ban on individuals who have been in contact with MERS patients from performing the pilgrimage. The Kingdom also reported imposed a ban on sacrificing camels as part of the Hajj rituals this year.

l) Saudi Arabian health officials announced a plan to compensate the families of people who die from MERS-CoV within the country37. A royal decree had been issued to pay the compensation, which amounts to $US 133,300 per family.

m) An experimental vaccine given six weeks before exposure to MERS-CoV fully protects rhesus macaques from disease38. The vaccine also generates potentially protective MERS-CoV antibodies in blood drawn from vaccinated camels. The research team was led by NIH-funded University of Pennsylvania scientists.39 Funding was also provided by Inovio Pharmaceuticals.

n) Novavax has also said it is developing a MERS vaccine, based on the company’s protein nanoparticle vaccine technology.

o) Researchers led from the Chinese Center for Disease Control and Prevention sequenced the genome of a MERS-CoV strain introduced to China in May after first reaching South Korea. They concluded that the Chinese and South Korean MERS-CoV strain resulted from recombination between MERS viruses which probably occurred in mid to late 201440. Columbia University's virologist Ian Lipkin said in his commentary that coronaviruses such as MERS-CoV are known for their

35 Yuan J et al. “Effect of live poultry market closure on avian influenza A(H7N9) virus activity in Guangzhou, China, 2014”. Emerg Infect Dis. October 2015. http://dx.doi.org/10.3201/eid2110.15062336 As at noon on 30 August, there had been in Saudi Arabia since June 2012 a total of: 1178 laboratory confirmed cases of MERS-CoV, including 507 deaths, 609 recoveries, and 62 currently active cases (including 9 on home isolation). In the previous 48 hours there had been 5 newly confirmed cases of MERS-CoV infection reported and 5 new fatalities. Since the beginning of August 2015, there had been a total of 121 cases of MERS-CoV infection confirmed by Saudi Arabia, of which all but 7 were reported in Riyadh (114 total). It had become clear that cases and deaths were clustered aound Riyadh’s King Fahd Hospital in the King Abdul Aziz Medical City. The emergency ward at the hospital was temporarily closed. By 13 September, there was speculation about a Medina hospital cluster. Between 4 and 18 September, there were 18 new MERS cases reported in Saudi Arabia, 15 of them in Riyadh, with links to the ongoing hospital outbreak at King Abdulaziz Medical City. By then 158 illnesses had been reported in Riyadh since 21 July.37 This includes families of people from other countries who fall ill with MERS-CoV in Saudi Arabia and die, including foreign healthcare workers. 38 K. Muthumani et al. “A synthetic consensus anti-Spike protein DNA vaccine induces protective immunity against Middle East Respiratory Syndrome Coronavirus in non-human primates”. Science Translational Medicine DOI: 10.1126/scitranslmed.aac7462 (2015)39 Collaborators included researchers from NIH’s National Institute of Allergy and Infectious Diseases; Public Health Agency of Canada; Inovio Pharmaceuticals; the University of Washington; and the University of South Florida.40 Wang Y et al., 8 September 2015. “Origin and possible genetic recombination of the Middle East respiratory syndrome coronavirus from the first imported case in China: phylogenetics and coalescence analysis”. mBio 6(5):e01280-15. doi:10.1128/mBio.01280-15.

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recombination capabilities and that it "would not be surprising … if recombination were to occur in MERS-CoV and to result in enhanced transmission or virulence."

p) In Saudi Arabia, the Ministry of Agriculture announced 7,700 out of 233,000 camels in the Kingdom have been infected with the MERS coronavirus. Forty survey teams and 200 veterinarians had examined 32,000 samples from 8,000 camels, with results suggesting that 81.5 per cent of camels are immune to the virus, while 3.3 per cent carry or spread it.

Other diseases: occurrence, prevention and treatmentt) Sierra Leone began vaccinating 200 people against Ebola, after a woman died five

days into what the country hoped was its 42 day countdown to being Ebola free. By 8 September three further cases had emerged.

u) A team from The University of Texas Medical Branch at Galveston and Profectus BioSciences reported in Nature that it had developed a quick-acting Ebola vaccine that it claims to be safe and effective with a single dose.

v) Inovio Pharmaceuticals announced that the first patient has been dosed in a Phase I trial to evaluate safety and tolerability41 of Pennvax-GP, the company’s DNA vaccine for HIV. The trial will measure immune responses in four groups of healthy subjects receiving the vaccine with or without an immune activator (IL-12) and administered into muscle or skin using Inovio’s Cellectra delivery technology.

w) The Queensland Government says it will contact the parents of children who are not properly vaccinated to encourage them to get their vaccinations up to date. The Health Minister wants to raise the vaccination rate for children to 95 per cent. The Commonwealth Child Care Benefit will from 1 January require children to be immunised.

x) The US Centers for Disease Control and Prevention (CDC) has been encouraging more states to publish vaccination statistics online. Dr. Anne Schuchat of the CDC said parents could weigh their child's risk of vaccine-preventable illnesses at specific schools or school districts, and the data could help health officials identify pockets of unvaccinated children. At present, only 21 states publish vaccination rates for individual schools, school districts, counties or areas of the state42.

y) Biopharmaceutical company CureVac, and the not-for-profit International AIDS Vaccine Initiative (IAVI) will together develop AIDS vaccines, to be delivered via CureVac's messenger RNA technology.

z) Duke University has received $US 20 million in grants from the National Institutes of Health to develop an HIV vaccine.

aa) The Champaign-Urbana campus of the University of Illinois has had over 100 cases of mumps. Since two doses of the MMR vaccine offer only 85 per cent protection, the CDC and the Illinois Department of Public Health recommended everyone in the community get a third shot to increase their immunity level to 95 per cent.

bb) By 2 September there had been eight cases of measles reported on the University of Queensland campus at St Lucia since July. The Metro North Public Health unit set up a five-day on-campus vaccination clinic.

cc) Europe has been reporting that refugees from Syria are bringing cutaneous diphtheria with them.

41 The trial is conducted by the HIV Vaccine Trials Network and funded by the US National Institute of Allergy and Infectious Diseases (NIAID).42 All states require children to be vaccinated against diseases such as measles and polio before going to kindergarten, but permit exemptions on medical grounds. Many allow exemptions for religious or philosophical reasons iIn Idaho 6.5 per cent of kindergartners have exemptions). Following a measles outbreak this year, California dropped religious and philosophical exemptions for school children.

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