Monitoring International Trendsposted July 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:

Baxter International separated from Baxalta, with the latter now responsible for haemophilia treatments and immunoglobulins, amongst other products. (Section 3)

The US Department of Health and Human Services on 1 July launched a National Ebola Training and Education Center to ensure that health care providers and facilities are properly prepared to identify, isolate, transport, and treat patients with Ebola and other disease threats. (Section 4)

Synthetic Blood will be tested in the UK in 2017. (Section 5) A study published in the journal Pediatrics claims that massaging the umbilical cord of

babies born prematurely, via cesarean section, helps improve the level of red blood cells in the infant. (Section 5)

A new study confirms that anticoagulant bridging is of little benefit and increases bleeding risk in patients taken off warfarin prior to elective surgery. (Section 5)

Researchers at the University of New South Wales developed a gene-editing technique that could lead to new treatments for sickle cell anemia and other blood disorders. (Section 6)

A study of the incidence of transfusion transmitted dengue in Brazil concluded that “during seasonal epidemics, substantial proportions of asymptomatic donors with infection are donating blood, and recipients are receiving RNA-positive blood components". (Section 8)

Vanderbilt University Medical Center's James Crowe, and his team reported the first large panel of antibody treatments against chikungunya. (Section 8)

South Korea’s case total of MERS reached 186 with 36 deaths. There is hope that the outbreak in the republic is over. (Section 8)

Saudi Arabia has again declined to issue Hajj visas to pilgrims from countries which have experienced an Ebola outbreak. (Section 8)

Contents1. Products.........................................................................................................................................2

Haemophilia treatments................................................................................................................2

Alpha-1 Antitrypsin........................................................................................................................5

Other.............................................................................................................................................6

2. Regulatory.....................................................................................................................................7

Plasma and recombinant products................................................................................................7

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Other.............................................................................................................................................7

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...............................................................................................................11

Other...........................................................................................................................................12

6. Research......................................................................................................................................12

7. Legal actions and enquiries..........................................................................................................13

8. Infectious diseases.......................................................................................................................13

Mosquito-borne diseases: dengue, chikungunya, zika, malaria and West Nile virus...................14

Influenza: strains, spread, prevention and treatment.................................................................15

MERS-CoV....................................................................................................................................16

Ebola...........................................................................................................................................17

Other diseases: occurrence, prevention and treatment..............................................................18

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) The International Society of Thrombosis and Haemostasis Congress(ISTH) in

Toronto in June was told that CSL Behring’s investigational recombinant Factor VIII-SingleChain demonstrated strong efficacy and a good safety profile in a large cohort of patients with severe haemophilia A.1 The novel B-domain truncated rFVIII was also reported to show superior pharmacokinetic activity to Baxter’s Advate. Prior studies had shown that the rFVIII-SingleChain product has higher binding affinity to von Willebrand Factor, a longer half-life, a lower clearance, and a higher mean residence time than Advate. Ingrid Pabinger-Fasching2, of the Medical University of Vienna, and colleagues conducted the open-label, multicentre AFFINITY study. 146 patients

1 Mahlangu J, et al. Abstract LB008. “rVIII-SingleChain, results of the pivotal phase I/III PK, efficacy and safety clinical trial in adults and adolescents with severe hemophilia A”. Presented at: International Society of Thrombosis and Haemostasis 2015 XXV Congress; June 20-25, 2015; Toronto. Posters on rVIII single chain presented by CSL Behring at the conference were: “The FVIII plasma activity of rVIII-SingleChain can be measured in both the one-stage and chromogenic substrate assays”, E-Poster # PO089; “Physicochemical characterization of recombinant single-chain factor VIII (rVIII-SingleChain)” E-Poster # PO146; “Population pharmacokinetic model of recombinant single-chain factor VIII (rVIII-SingleChain) in patients with hemophilia A”, E-Poster # PO241; “Efficacy and safety of rVIII-SingleChain in surgical prophylaxis”, E-Poster # PO258; and “rVIII-SingleChain pharmacokinetics in adults, adolescents and children”. E-Poster # PO262.

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received prophylactic treatment and 27 received on-demand treatment. Of 830 treated bleeds, 81 per cent were controlled by one infusion of rVIII-SingleChain and 94 per cent were successfully controlled with no more than two infusions. There was no inhibitor development observed. The most common adverse events included naso-pharyngitis, arthralgia and headache.

b) CSL also updated the conference on its recombinant fusion protein linking coagulation factor IX with albumin3, its recombinant fusion protein linking activated coagulation factor VIIa with albumin4, on a variety of topics concerning FVIII and von Willebrand factor5, on its recombinant von Willebrand factor–albumin fusion product6, and on pasteurization in plasma-derived products7.

c) Christopher Walsh, director of the Hemophilia Program at Mount Sinai School of Medicine, New York, commented recently that a “hot” area of haemophilia research is factor mimetics. In December, researchers presented to a conference the results from a phase I/II trial of ACE910, a first-in-class factor mimetic. ACE910 is a humanized bispecific monoclonal antibody designed to bind factors IXa and X

2 In her press release, she said “In this large-scale study, we observed relatively low annualized bleeding rates and a median of zero spontaneous bleeding events with rVIII-SingleChain for routine prophylaxis for patients with hemophilia A. As the first and only single chain recombinant factor product, rVIII-SingleChain has the potential to offer improved protection from bleeding with less frequent dosing, and an excellent safety profile thus far.” 3 “Efficacy, pharmacokinetics (PK) and safety results of a phase 3 clinical study of recombinant fusion protein linking coagulation factor IX with albumin (rIX-FP) in previously treated children with hemophilia B”, Oral Communication # OR346; “Efficacy and safety results of a phase 3 pivotal clinical study of recombinant fusion protein linking coagulation factor IX with albumin (rIX-FP) in previously treated patients with hemophilia B”, Oral Communication # OR347; “Population pharmacokinetics (PK) of recombinant fusion protein linking coagulation factor IX with recombinant albumin (rIX-FP) in adult and pediatric patients with severe hemophilia B”, Oral Communication # OR350; “Tissue distribution of rIX-FP after intravenous application to rodents”, E-Poster # PO152;“Structural characterization of recombinant factor IX fusion protein linked with human albumin (rIX-FP)”, E-Poster # PO144; and “Efficacy and safety of recombinant fusion protein linking coagulation factor IX with albumin (rIX-FP) in previously treated patients with hemophilia B undergoing a surgical procedure”, E-Poster # PO253;4FVIIa (rFVIIa) in a novel monkey model of acquired factor VIII inhibitors”, E-Poster # PO596. “A recombinant fusion protein linking activated coagulation factor VIIa with albumin (rVIIa-FP) binds to neonatal Fc receptor and tissue factor in vitro”, Oral Communication # AS016; “Dosing of rVIIa-FP in clinical studies in hemophilia with inhibitors and factor VII deficiency”, E-Poster # PO257; “The recombinant fusion protein linking activated factor VIIa to human albumin (rVIIa-FP) provides superior bleeding protection compared to recombinant5 “A phase III, open-label, multicenter study to evaluate pharmacokinetics of a plasma-derived von Willebrand factor/factor VIII (VWF/FVIII) concentrate in pediatric subjects with haemophilia A (SWIFTLY-HA study)”, E-Poster # PO206; “A phase III open-label, multi-center study with a plasma-derived von Willebrand factor/factor VIII concentrate to assess the pharmacokinetics, efficacy, and safety in pediatric subjects with von Willebrand disease (SWIFTLY-VWD study)”, E-Poster # PO629; “Molar specific activity of Factor VIII concentrates”, E-Poster # PO194; “High-purity, plasma-derived, pasteurized factor VIII concentrate in the treatment of patients with haemophilia A: update of a long-term observational study”, E-Poster # PO195; and“A phase III, open-label, multicentre study to evaluate efficacy and safety of a plasma-derived von Willebrand factor/factor VIII concentrate in pediatric subjects with hemophilia A (SWIFTLY-HA study)”, E-Poster # PO249.6 “Improved resolution of high molecular weight multimers of recombinant von Willebrand factor–albumin fusion product by agarose electrophoresis/western blotting”, E-Poster # PO673“An open-label, multi-center extension study to assess the efficacy and safety of a plasma-derived von Willebrand factor/factor VIII (VWF/FVIII) concentrate in pediatric, adolescent, and adult subjects with von Willebrand disease”, E-Poster # PO643; “Plasma-derived, purified, pasteurized von Willebrand factor/factor VIII concentrate in the treatment of patients with von Willebrand disease and haemophilia A: update of a long-term observational study”, E-Poster # PO647.7“Inactivation of emerging viruses by pasteurization in plasma-derived medicinal products”, E-Poster # PO605

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simultaneously, thus mimicking the factor VIII cofactor function in haemophilia. "ACE910 mimics the function of the protein without being a factor," said Dr Walsh. ACE910 was tested in 18 patients with severe haemophilia A, eleven of whom had inhibitors. After 12 weeks of treatment, once-weekly subcutaneously delivered ACE910 was well tolerated and significantly reduced the annualized bleeding rate during treatment, compared with the rate seen in the 6-month period prior to enrolment in the trial. All patients with prior bleeding events experienced reductions in their annualized bleeding rate. The treatment was effective in patients with inhibitors. No patient developed an inhibitor to ACE910. In the opinion of Dr Walsh, ACE910 is significant for a number of reasons. "You have a drug that doesn't cause an inhibitor, according to what they have seen; it seems to be equivalent to factor VIII; and it can be given subcutaneously and at a fairly long interval," he said8.

d) Roche announced further encouraging data from study of ACE910 in adults and adolescents with severe haemophilia A. At the International Society on Thrombosis and Haemostasis meeting in Toronto, data was reported9 from a Phase I extension study to show that reduction in bleeding rates was maintained after a follow-up of 5.6 to 18.5 months. This was a follow-up of the Phase I study presented at the annual meeting of the American Society of Hematology (ASH) in 2014. This new data suggested that once-weekly subcutaneous administration of ACE910 had a promising continuing prophylactic efficacy profile in people with severe haemophilia A, while the tolerability profile of ACE910 was consistent with that previously observed. Sandra Horning, Roche’s Chief Medical Officer and Head of Global Product Development, said: “Our goal is to initiate a Phase III trial in patients with factor VIII inhibitors by the end of 2015 and a Phase III trial in patients without inhibitors in 2016.”

e) Several companies are testing inhibitors of another plasma protein, TFPI. "They are using different schemes—monoclonal antibodies in some settings, fusion peptides, binding antibodies, and aptamers," said Dr Walsh. In vitro experiments reported in December show that two TFPI antagonistic peptides together completely inhibit TFPI. Another study published in January, of the anti-TFPI antibody concizumab, showed a favourable safety profile after single intravenous or subcutaneous dosing. The researchers found a concentration-dependent procoagulant effect, requiring further study, so it will be some years before we can expect these drugs in the clinic.

f) At the International Society on Thrombosis and Haemostasis Congress in Toronto, Baxalta reported in an oral presentation continued progress on the Phase I/II open-label clinical trial10 assessing the safety and optimal dosing level of BAX 335, the company’s investigational factor IX (FIX) gene therapy treatment for haemophilia B. BAX 335 provides a mechanism for a haemophilia B patient’s own liver to begin producing FIX over an extended period following a single dose of treatment. Baxalta uses the Biological Nano Particle (BNP) platform obtained through the collaboration and subsequent acquisition of Chatham Therapeutics11. Seven patients in three

8 SeeMuto A, Yoshihashi K, Takeda M, Kitazawa T, Soeda T, Igawa T, Sakamoto Y, Haraya K, Kawabe Y, Shima M, Yoshioka A, Hattori K. “Anti-factor IXa/X bispecific antibody (ACE910): hemostatic potency against ongoing bleeds in a hemophilia A model and the possibility of routine supplementation”. J Thromb Haemost. 2014 Feb;12(2):206-13.9 in an oral presentation by Dr. Keiji Nogami from Nara Medical University in Japan (Abstract 1283; 22 June 2015).10 The clinical trial is assessing the safety of ascending doses of BAX 335 to determine the optimal single dose in up to 16 US adults with hemophilia B. The primary endpoint is the safety of a single dose of BAX 335 administered intravenously. Secondary endpoints include evaluation of the optimal dose to achieve stable therapeutic plasma FIX activity, as well as pharmacokinetics and immune response to treatment. See www.clinicaltrials.gov, Identifier #01687608.11 In April 2014, Baxter acquired Chatham Therapeutics,an affiliate of Asklepios BioPharmaceutical. Chatham’s Biological Nano Particles (BNP), an advanced recombinant adeno-associated virus-(rAAV-) based gene therapy technology, has shown potential therapeutic activity in early studies.

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sequentially-ascending dosing cohorts had been treated in the trial with evidence of a dose-related response. No patients had developed FIX inhibitors at the time of reporting. In the second dosing cohort two patients had experienced no bleeds without regular infusions of FIX and one of these patients has had sustained FIX expression levels of 20-25 percent for 12 months. In the highest dose cohort expression levels had peaked above 50 per cent, but the two patients in this cohort experienced an immune response which led to decreased FIX expression, and one of the patients resuming FIX infusions. Baxalta said it continues to address the immune responses observed while working to maintain target trough levels.

g) In a poster session at the International Society on Thrombosis and Haemostasis Congress in Toronto, Catalyst Biosciences announced positive results from a Phase I trial of CB 813d/PF-05280602, its next-generation and long-acting coagulation Factor VIIa. Single doses were well tolerated by haemophilia A and B patients, and there were no instances of antibody response or thrombosis. The drug reduced aPTT (activated partial thromboplastin time) and PT (prothrombin time) for up to two days after administration.

h) Alnylam Pharmaceuticals, at the International Society on Thrombosis and Haemostasis Congress, presented new positive data from its continuing Phase I study of ALN-AT3, its RNAi therapeutic targeting anti thrombin (AT) for the treatment of haemophilia and rare bleeding disorders.

i) At the International Society on Thrombosis and Haemostasis Congress, Novo Nordisk released the latest interim data from an extension trial, which showed that in a Phase III study turoctocog alfa, variously known as Zonovate or NovoEight, provided long-term efficacy and safety in the prophylaxis and treatment of bleeds in people with severe haemophilia A.12

Alpha-1 Antitrypsinj) Arrowhead Research Corporation of Pasadena dosed the first patient in Part B of a

Phase 1 clinical trial13 of ARC-AAT. This is Arrowhead's RNAi-based drug candidate for the treatment of liver disease associated with alpha-1 antitrypsin deficiency14 (AATD) that was recently granted orphan drug designation by the US Food and Drug Administration (FDA). The clinical trial is initially enrolling patients at a single centre in Australia although Arrowhead will open additional sites for enrolment in Europe, if regulatory permission is forthcoming. "The goal of treatment with ARC-AAT is to halt progression and possibly reverse the liver injury and fibrosis associated with AATD, which currently has no approved therapy short of liver transplant’, said Bruce D. Given, Arrowhead's Chief Operating Officer.

k) Kamada reported the publication in Pediatric Diabetes15 of positive data from a Phase I/II trial of its intravenous Alpha1-Proteinase Inhibitor–Human (AAT), to treat recently diagnosed type 1 diabetes (T1D) paediatric patients. The authors concluded: “Notably, this is the first study to demonstrate profound safety of multiple intravenous doses of AAT therapy for non-AAT-deficient pediatric individuals with recent onset T1D while maintaining glycemic control and demonstrating less of a decrease in C-

Baxalta plans to evaluate the gene therapy technology in the treatment of haemophilia A.12 Lentz S, Kempton CL, Janic D, et al. “Interim results from a large multinational extension trial (guardian™2) using turoctocog alfa for prophylaxis and treatment of bleeding in patients with severe haemophilia A”. Abstract presented at: International Society on Thrombosis and Haemostasis (ISTH) 2015 Congress; June 20-25, 2015; Toronto, Canada. 13 The ongoing Phase 1 trial of ARC-AAT is a multi-centre, randomized, placebo-controlled, double-blind, single dose-escalation, first-in-human study to evaluate the safety, tolerability and pharmacokinetics of ARC-AAT and the effect on circulating AAT levels.14 AATD is a hereditary condition marked by a lack of the alpha-1 antitrypsin protein, whose main function is to protect the lungs from inflammation.15 Rachmiel et al., “Alpha-1 antitrypsin therapy is safe and well tolerated in children and adolescents with recent onset type 1 diabetes mellitus”.

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Peptide levels.” Eran Schenker, Kamada’s Vice President-Medical Director explained that “the scientific rationale for Glassia to treat T1D is based on the anti-inflammatory and immunomodulation activities that AAT holds”. Kamada continues to enrol patients in its Phase II/III trial.

l) Kamada and Baxalta are collaborating on a Phase I/II clinical trial in Israel of Kamada's alpha-1 antitrypsin treatment for the prevention of lung transplant rejection. Baxalta holds distribution rights to intravenous alpha-1 antitrypsin for all indications in the US, Canada, Australia and New Zealand.

Otherm) Pfizer announced enrolment had begun in the RESET16 Phase III trial assessing the

efficacy and safety of rivipansel for the treatment of vaso-occlusive crisis in patients six years or older hospitalized with sickle cell disease.

n) During major injuries to the torso, compression of injuries to prevent bleeding can make damage to major organs worse. Inability to stop bleeding is the most common cause of death from combat-related injuries and a major cause of death in car accidents. Now researchers have created a sprayable foam that forms a barrier and stops bleeding17. The foam was manufactured from chitosan, a biopolymer derived from shrimp shells and other crustaceans. Chitosan is already in use in other non-foam wound dressings. The chitosan foam stopped 90 per cent of blood loss in tests with pigs.

o) XBiotech announced on 1 July the treatment of the first patient in its Phase I/II clinical study to evaluate dosing, safety and efficacy of a novel antibody therapy intended to treat all forms of Staphylococcus aureus infections, including Methicillin-resistant S. aureus (MRSA).18 The study is expected to be completed early in 2016. The drug, 514G3, was developed from a human donor with natural antibodies effective at neutralizing MRSA and non-MRSA forms of S. aureus. It can be used without concern about strain-specific resistance to various antibiotics. As a human monoclonal antibody, the company expects it to be tolerated without the side effects or risks of antibiotics. For more details on the study, go to www.clinicaltrials.gov.

p) Pfizer enrolled the first patient in a Phase IIb clinical trial of its investigational Staphylococcus aureus multi-antigen vaccine in adults undergoing elective spinal fusion surgery19.

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

16 Rivipansel: Evaluating Safety, Efficacy and Time to Discharge. Rivipansel has both Orphan Drug and Fast Track status from the US Food and Drug Administration (FDA). 17Matthew B. Dowling, Ian C. MacIntire, Joseph C. White, Mayur Narayan, Michael J. Duggan, David R. King, and Srinivasa R. Raghavan, “Sprayable Foams Based on an Amphiphilic Biopolymer for Control of Hemorrhage Without Compression”, ACS Biomater. Sci. Eng., 2015, 1 (6), pp 440–447 DOI: 10.1021/acsbiomaterials.5b00067. Publication Date (Web): May 29, 201518 The company said the first patient to enter the study had confirmed MRSA bacteremia that was life threatening, but that within 24 hours of receiving a single, low dose of the therapy, the patient had no fever and white blood cell counts began to normalize. In addition to methicillin, MRSA have acquired resistance to antibiotics that include erythromycin, clindamycin, ciprofloxacin and tetracycline among others.19 Surgical Site Infections (SSIs) caused by S. aureus account for approximately 20 percent of all SSIs in the US, and are associated with an estimated annual treatment cost of $US 12.3 billion nationally. Patients who acquire such infections due to antibiotic resistant (MRSA) or antibiotic sensitive (MSSA) S.aureus have worse clinical outcomes, including increased mortality, than non-infected patients.

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Plasma and recombinant productsa) ADMA Biologics received Notice of Allowance20 from the US Patent and Trademark

Office for US patent application 14/592,721 concerning its lead product candidate RI-002, a plasma-based biologic for the treatment and prevention of infection, especially in primary immunodeficiency (PI). The patent was entitled Compositions and Methods for the Treatment of Immunodeficiency. RI-002 is a polyclonal, intravenous immunoglobulin (IVIg), derived from human plasma containing naturally occurring polyclonal antibodies (e.g., Streptococcus pneumoniae, H. influenza type B, Cytomegalovirus (CMV), measles, tetanus, etc.) as well as standardized, high levels of antibodies to respiratory syncytial virus (RSV).

b) The Israeli Patent Office has issued the patent titled, “System for Pulmonary Delivery of Alpha-1 Proteinase Inhibitor” under patent number, 193318. The patent is co-owned by Kamada and Pari Pharma, the producers of the eFlow nebulizer system. This patent application has been approved in Europe, Russia and Australia. A company statement said: “Based on the encouraging and important lung function outcomes from our European Phase II/III clinical trial of our inhaled AAT to treat AAT Deficient (AATD) patients, we are proceeding with our plan to submit the Marketing Authorization Application to the European Medicines Agency (EMA) by the end of this year.”

Otherc) Daiichi Sankyo’s once-daily blood thinner Lixiana (edoxaban) has been approved for

use in the EU to prevent stroke and systemic embolism in adult patients with nonvalvular atrial fibrillation with one or more risk factors, such as congestive heart failure or hypertension, as well as to treat and prevent deep vein thrombosis (DVT) and pulmonary embolism (PE).The drug is already marketed in the US, Japan and Switzerland.

d) Green Cross of South Korea, announced that its phase I clinical trial plan to extend the indications for Hepabig-gene has received approval from the Ministry of Food and Drug Safety. Hepabig-gene is a genetically-recombined hepatitis B antibiotic drug. The company carried out Phase II clinical trials in 2014 to evaluate the safety and efficacy of the drug in liver transplant patients who have underlying medical conditions of HBV infection, or for preventing the recurrence of HBV infection following a liver transplant. A company spokesman said: “Until now, no country or company in the world has succeeded in the commercialization of a gene recombinant hepatitis B antibody treatment. So, Hepabig-gene is highly likely to be the world’s first gene recombinant hepatitis B antibiotic medicine, if it is proven safe and effective.” The FDA and the European Medicine Agency (EMA) granted orphan drug status for Hepabig-gene in 2013, because it could improve safety, effectiveness, and convenience compared with plasma-based products.

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) Abeona Therapeutics provided an update on the development of its proprietary SDF (salt diafiltration) process of extracting and purifying plasma proteins from human plasma. Through one of its planned contract manufacturers, Abeona has run multiple

20 A Notice of Allowance is issued after the USPTO makes a determination that claims in a patent application are deemed to represent patentable subject matter

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batches of its two-step salt precipitation process and confirmed that output fractions contain significantly higher levels of alpha-1 protease inhibitor and immunoglobulins than the Cohn process. Abeona says it expects the process to facilitate the isolation of ultra-orphan proteins, including plasminogen, fibrinogen, Factor H and von Willebrand's factor. Abeona will be seeking a meeting with the FDA to discuss further development and a clinical pathway for its products. Jeffrey Davis, Chief Operating Officer, said: "While continuing to optimize downstream steps, we have initiated a program to confirm chromatography steps for our IVIG product, and continue to analyze the SDF fractions to identify ultra-orphan protein products for which our process is particularly well-suited."

b) Alnylam Pharmaceutical announced plans to webcast its annual summer series of "RNAi Roundtables21" in July, August, and September. The will include presentations by Alnylam scientists, clinical collaborators, and patient advocates. Events are webcast live on the Investors section of the company's website, www.alnylam.com. An audio replay is later posted on the website. The 2015 RNAi Roundtable topics scheduled include ALN-AT3 for the treatment of Hemophilia and Rare Bleeding Disorders22; ALN-HBV for the treatment of Hepatitis B Virus (HBV) Infection23; and ALN-AAT for the treatment of AAT Deficiency-associated liver disease24.

c) Soon after Baxalta’s split from Baxter, analyst Karen Anderson25 wrote of the company’s prospects: Advate (and older, smaller product Recombinate) represent approximately 40% of Baxalta's revenue, and competition is rising. Advate's prophylaxis label and conversion of patients previously on plasma-derived products have allowed it to achieve strong growth. However, Biogen (BIIB) launched long-acting product Eloctate in the United States in 2014, which can support a three-to five-day dosing schedule (Advate can be given every three days), Novo Nordisk (NVO) is launching a me-too Advate in 2015, and Bayer (BAYRY) and Novo could both launch long-acting products in the next few years. We think Advate's strong safety profile and Baxalta's pipeline investments will help shield the firm from competitive threats in the near term, but long-term threats look more challenging. Baxalta should gain approval for twice-weekly Factor VIII protein BAX 855 in late 2015, but more convenient (perhaps once-monthly) treatments from Roche (RHHBY) and Alnylam (ALNY) could reach the market as early as 2018, as both are rapidly moving to late-stage development. We think this is a significant step up in convenience and the probability of approval for these competitors remains higher than the probability that Baxalta's earlier-stage gene therapy treatments will successfully reach the market. In immunology, Baxalta's prospects look brighter, with expanding plasma fractionation capacity and differentiated products. HyQvia, a long-acting version of immunoglobulin product Gammagard, is launching in the U.S. and

21 RNAi (RNA interference) represents a breakthrough in understanding how genes are turned on and off in cells, and a novel approach to drug discovery and development. RNAi is a natural process of gene silencing that occurs in plants and mammals. Small interfering RNA (siRNA), the molecules that mediate RNAi and constitute Alnylam's RNAi therapeutic platform, silence specific mRNAs, thus preventing disease-causing proteins from being made. 22 Wednesday, July 22, 9:00 – 10:30 a.m. ET (US). One of the guest speakers will be Margaret Ragni, Professor of Medicine, Division Hematology/ Oncology, University of Pittsburgh, and Director, Hemophilia Center of Western Pennsylvania.23 Tuesday, July 28, 4:00 – 5:00 p.m. ET (US). The guest speaker is Edward Gane, Professor of Medicine, University of Auckland, and Chief Hepatologist, Transplant Physician, Deputy Director of New Zealand Liver Transplant Unit, Auckland City Hospital.24 Friday, August 14, 2:00 – 3:00 p.m. ET (US). The guest speaker is Jeffrey Teckman, Professor, Department of Pediatrics, St. Louis University School of Medicine.25 In her article “Baxalta still holds a narrow moat, but hemophilia competition weighs on future growth.” http://analysisreport.morningstar.com/stock/research/c-report?t=XNYS:BXLT&region=usa&culture=en-US&productcode=MLE&cur=

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Europe. HyQvia's improved convenience should translate into market share gains and better pricing power.

d) In Switzerland Biogen announced its intention of building an advanced next generation biologics manufacturing facility in the Commune of Luterbach.

e) Sanguine Corporation (of Atlanta) obtained shareholder approval to change its name to New Alliance BioSciences. President Frank Marra said:, “The world of oxygen therapeutics has progressed tremendously over the past five years and encompasses exponentially more indications other than just blood substitution and transfusions. We feel that the name Sanguine no longer reflects the broader scope of our research and development efforts.” The company is focussed on development and commercialization of perfluorocarbon-based therapies and medical devices. Its lead product, PHER-02, is an intravenous perfluorocarbon emulsion that dissolves and delivers oxygen to tissues.

f) NuvOx Pharma (of Tucson, Arizona) has completed a licensing agreement with the University of Pittsburgh for a patent application entitled, “Treatment of Acute Complications of Sickle Cell Disease.” Inventors on the patent are Evan Unge and David Wilson from NuvOx, and Solomon Ofori-Acqua, from the University of Pittsburgh. NuvOx will have exclusive rights to develop a novel nanotechnology product for treatment of acute complications related to Sickle Cell Disease.

g) UK health communications consultancy Pegasus won the ‘Excellence in Patient/Consumer Health Programmes’ award at Communiqué Awards 2015 with its campaign for CSL Behring presenting “Faces of HAE26”. Judges described the campaign as “brave”, “really focussed on the patient” and “delivering real measurable outcomes that show true behavioural change.”

h) Benitec Biopharma27 and China-based Biomics Biotechnologies announced Benitec has acquired the full rights to the pre-clinical ddRNAi-based Hepatitis B therapeutic program, Hepbarna, which had been under development as a joint venture between them. Benitec will pay Biomics $A 2.5 million upfront with a further $A 3.5 million upon successful commercialization of the program. Biomics will receive a single-digit royalty on net sales once the product is marketed. Benitec’s CEO Dr. Peter French commented: “Benitec… plans to continue to explore opportunities to work with Biomics in utilizing RNA interference to target other important diseases”. Along with its HBV pre-clinical program, Benitec is developing a treatment for hepatitis C with efficacy data expected in late 2015.

i) Kamada reported that revenue during the first half of 2015 is in line with its plans at $US 28 million. “We are on track to achieve our full year 2015 revenue projections28 and to achieve our annual Glassia sales target worldwide, a significant part of which is secured with orders already received from Baxalta,” said Gil Efron, Deputy Chief Executive and Chief Financial Officer of Kamada.

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.

26 Hereditary angiodema27 Benitec Biopharma Limited is an ASX-listed biotechnology company which has developed a patented gene-silencing technology called ddRNAi or 'expressed RNAi'. Based in Sydney, with labs in California and collaborators and licensees around the world, the company is developing ddRNAi-based therapeutics for chronic and life-threatening human conditions including Hepatitis C and B, drug resistant lung cancer and wet Age-related Macular Degeneration. Benitec has also licensed ddRNAi to other biopharmaceutical companies for applications including HIV/AIDS.28 In the range of $US 70 million to $US 73 million

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a) The US Department of Health and Human Services (HHS) on 1 July launched a National Ebola Training and Education Center to ensure that health care providers and facilities are properly prepared to identify, isolate, transport, and treat patients with Ebola and other disease threats. The Center is a collaborative effort among HHS’ Office of the Assistant Secretary for Preparedness and Response (ASPR), the Centers for Disease Control and Prevention (CDC) and three academic institutions: Emory University in Atlanta, Georgia; University of Nebraska Medical Center/ Nebraska Medicine in Omaha, Nebraska29; and Bellevue Hospital Center in New York City. The two government agencies will provide $US 12 million over the next five years to the academic institutions. This initiative is in addition to the nine regional ebola treatment centres that HHS recently announced as part of a national network of 55 Ebola treatment centres.

b) In the US the Connecticut Agricultural Experiment Station has added two new diseases to its testing program for tick-borne illnesses30, and with new molecular methods has cut the testing time from three weeks to three days or less.

c) In New Zealand, PHARMAC is moving to have Xyntha as the preferred brand of recombinant Factor VIII, while also maintaining funding for other currently-funded haemophilia products for patients who cannot receive Xyntha for clinical reasons31. The changes are to take effect from 1 September.

d) In Saudi Arabia, 9.417 cases of sickle cell anaemia have been reported in the last decade, bringing the number of people living with the disorder to 145,750. The Ministry of Health says sickle cell anaemia is one of the genetic disorders included in its “Healthy Marital Program”, primarily aimed at minimizing the spread of genetic diseases and therefore treatment costs. The ministry conducts five tests for disorders and diseases including thalassemia, hepatitis B and C, and HIV at 130 medical centers Kingdom-wide for couples preparing to marry.

e) Saudi authorities have made meningitis vaccination compulsory for all people planning to enter the country for Hajj this year.

f) Canadian Blood Services' Cord Blood Bank has been officially launched. Five hospital sites in four cities are partners–Ottawa (2), Brampton, Edmonton and Vancouver.

g) The Welsh Government has confirmed the Welsh Blood Service, which covers South, Mid and West Wales, will merge with North Wales’ NHS Blood and Transplant Service to form a single body from May 2016. A spokesman for the Welsh Government said there will be long-term savings of £596,000 annually. Cath O’Brien, director of the Welsh Blood Service, said: “We are looking forward to extending our first-class services to life-saving donors across the whole of Wales…From May 2016 every donor who donates in Wales will be primarily supporting the patients of Welsh hospitals.

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

29 Emory University and Nebraska Medical Center have been working with CDC for the last six months to train over 460 health care workers from 87 health care systems, including 37 designated Ebola treatment centres, on all aspects of infection control and patient care for individuals with Ebola. Emory University and Nebraska Medical Center are offering additional training opportunities in the northern hemisphere summer for up to 400 staff from Ebola assessment hospitals.30 The Tick Testing Program began in 1990 as a service to district health departments. Testing was previously limited to the Lyme disease agent, but now includes testing for Anaplasma phagocytophilum, the bacteria that cause human granulocytic anaplasmosis, for which 3.6 percent of ticks in the state have tested positive this year, and for Babesia microti, a protozoa that causes babesiosis, for which 12 percent of ticks have tested positive this year.31 The other brands will be available through application to a Haemophilia Treatments Panel established and co-ordinated by PHARMAC.

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Appropriate transfusiona) A recent study32 concluded that “perioperative allogeneic blood transfusion is

associated with decreased recurrence-free and overall survival following resection of gastric cancer, independent of adverse clinicopathologic factors. This supports the judicious use of perioperative transfusion during resection of gastric cancer.”

b) NHS Blood and Transplant (NHSBT) research published in The Lancet on 11 July showed that changing clinical thresholds for blood transfusions could safely produce significant savings for the NHS. The first reported multicentre randomised trial compared red blood cell transfusion strategies for Acute Upper Gastrointestinal Bleeding33 (AUGIB). The TRIGGER pilot study compared liberal and restrictive policies for red blood cell transfusions in patients with AUGIB. It found no significant difference in clinical outcomes between the two patient groups. A large cluster randomised trial to changes clinical practice guidelines is seen as the next step. Acute upper gastrointestinal bleeding accounts for 70,000 hospital admissions per year and 11 per cent of all red blood cell units transfused in England. It is the single leading clinical indication for transfusions for red blood cells.

c) Synthetic blood will be tested in the UK in 2017. The National Health Service plans a small safety trial in 20 people. The NHS has created lab-grown red blood cells. These can be made from bone marrow or umbilical cord stem cells, but the challenge has been to produce enough red blood cells from stem cells to do a full transfusion.

Treating iron deficiencyd) Early clinical trials are evaluating an innovative therapeutic protein which may

eventually lead to better treatment for anaemia of chronic disease. These trials are part of the EU-funded EUROCALIN project. The drug (PRS-080) works by mobilising iron trapped in iron storage cells. Data from the initial phase of these clinical trials are expected before the end of 2015, when the EUROCALIN34 project is due for completion.

e) A study35 published in the journal Pediatrics claims that massaging the umbilical cord of babies born prematurely, via caesarean section, helps improve the level of red blood cells in the infant. The benefits of doing so appeared to be greater than the standard practice of waiting for 60 seconds to cut the umbilical cord.

Other.f) A new study36 confirms that anticoagulant bridging is of little benefit and increases

bleeding risk in patients taken off warfarin prior to elective surgery, reported haematologist Stephan Moll, of the University of North Carolina. He was not involved with the study, but he called the findings "practice changing." He said: "It has increasingly become clear that patients at low or moderate risk for thromboembolism-either atrial fibrillation patients or DVT or PE patients on warfarin-do not need low-molecular-weight heparin bridging when warfarin is temporarily interrupted for surgical interventions," he said. "It leads to more bleeding, yet no benefit”.

32 Malcolm H. Squires, “Effect of Perioperative Transfusion on Recurrence and Survival after Gastric Cancer Resection: A 7-Institution Analysis of 765 Patients from the US Gastric Cancer Collaborative”, Journal of the American College of Surgeons, Published Online: June 21, 2015 DOI: http://dx.doi.org/10.1016/j.jamcollsurg.2015.06.01233 Lead researcher Dr Vipul Jairath, an NIHR Clinical Trials Fellow and Consultant Gastroenterologist at Oxford University Hospitals.34 The EUROCALIN project, which began in August 2011, brought together ten companies and academic institutions from across Europe to bring the new protein treatment for ACD sufferers through the first stages of clinical evaluation.35 Lead researcher Dr. Anup C. Katheria,36 by James D. Douketis of McMaster University, and colleagues. The study was published online in the New England Journal of Medicine.to coincide with its presentation at the International Society on Thrombosis and Hemostasis (ISTH) 2015 Congress in Toronto.

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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 found that in thalassemia, low bioavailability of the amino acid arginine could be a factor in pulmonary hypertension, the increase of blood pressure in the pulmonary artery, pulmonary vein or pulmonary capillaries.37 In earlier work, the authors had found arginine deficiency to be a significant factor in acute pain episodes of sickle cell disease38. A Phase II trial in 2013 found that arginine therapy reduced use of pain medications and hospitalization during these acute episodes. First author Claudia R. Morris, associate professor of paediatrics and emergency medicine at Emory University School of Medicine and the Emory Children’s Center for Cystic Fibrosis and Airways Disease Research, said: “We are finding that arginine dysregulation is an important hematologic mechanism beyond sickle cell disease. This new study shows that it plays a role in thalassemia patients as well and may contribute to cardiopulmonary dysfunction. Interventions aimed at restoring arginine bioavailability could be a promising area of focus for new therapeutics.”

b) Johnson & Johnson announced on 1 July that scientists at Beth Israel Deaconess Medical Center (BIDMC), Crucell Holland BV39, and other collaborators had published40 results from a preclinical study of an HIV vaccine regimen used in non-human primates. The study suggests that a “heterologous prime-boost” vaccine regimen, which first primes the immune system, then boosts the immune system to increase the response, could ultimately prove to be a strategy for protecting against global human immunodeficiency virus (HIV-1) infection. The pre-clinical data form the basis of vaccine regimens being evaluated in an international Phase I/IIa clinical trial for safety and immunogenicity in healthy, HIV-uninfected volunteers. "We are very encouraged by the results of this preclinical HIV vaccine study, and the findings lead to a clear path forward for evaluating this HIV vaccine candidate in humans," said lead author Dan H. Barouch, Director of the Center for Virology and Vaccine Research at BIDMC and Professor of Medicine at Harvard Medical School. The phase I/IIa study is currently enrolling 400 volunteers in the US and Rwanda to evaluate heterologous prime-boost regimens, with sites in South Africa, Uganda and Thailand to join soon.

c) Axon Neuroscieces’ vaccine for Alzheimer’s disease patients has passed a Phase 1 safety trial, according to the company. The vaccine is designed to stimulate patients‘ immune systems to attack diseased tau proteins41.

37 Morris, C. R., Kim, H.-Y., Klings, E. S., Wood, J., Porter, J. B., Trachtenberg, F., Sweeters, N., Olivieri, N. F., Kwiatkowski, J. L., Virzi, L., Hassell, K., Taher, A., Neufeld, E. J., Thompson, A. A., Larkin, S., Suh, J. H., Vichinsky, E. P., Kuypers, F. A. and the Thalassemia Clinical Research Network (2015) “Dysregulated arginine metabolism and cardiopulmonary dysfunction in patients with thalassaemia”. British Journal of Haematology, 169: 887–898. doi: 10.1111/bjh.1345238 A deficiency of nitric oxide, a vasodilator, has been identified in sickle cell disease and may contribute to episodes of blocked vessels and pain, and arginine is a building block of nitric oxide.39 Crucell Holland B.V. is one of the Janssen Pharmaceutical Companies of Johnson & Johnson. It is engaged in research, development and production of vaccines.40 in the online edition of Science41 Results were presented at the Alzheimer’s Association International Conference (AAIC) in July in, Washington, DC.

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d) A study42 led by Nancy J Wandersee, from Medical College of Wisconsin in Milwaukee, and colleagues found omega-3 fatty acid supplementation in mice suffering sickle cell disease decreased the stiffness of red cells and increased the deformability of the cells.

e) Researchers from the Food Fortification Initiative and Emory University in the US looked at the impact in 32 countries of fortifying wheat flour alone or in combination with maize flour with at least iron, folic acid, vitamin A or vitamin B12. They concluded that fortifying flour with micronutrients can be effective in decreasing national prevalence of anaemia43.

f) Researchers at the University of New South Wales developed a gene-editing technique that could lead to new treatments for sickle cell anemia and other blood disorders44. They can alter a single letter of the human red blood cell DNA to make adult haemoglobin more closely resemble foetal haemoglobin. The technique introduces a naturally occurring genetic mutation back into the cells. This increases the production of oxygen-carrying haemoglobin.

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) In South Korea, family members of Middle East respiratory syndrome victims have been filing lawsuits against hospitals and government. The plaintiffs claimed that the government and hospitals failed to block the spread of the virus and kept crucial information on MERS patients confidential, despite knowing MERS was infectious. There are also plaintiffs who were quarantined but uninfected, now seeking compensation.grounds.

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

42 Nancy J. Wandersee, Jamie L. Maciaszek, Katie M. Giger, Madelyn S. Hansonc, Suilan Zheng, YiHe Guo, Barbara Mickelsong, Cheryl A. Hillery, George Lykotrafitis, Philip S. Low, Neil Hogg, “Dietary supplementation with docosahexanoic acid (DHA) increases red blood cell membrane flexibility in mice with sickle cell disease”, Blood Cells, Molecules, and Diseases, Volume 54, Issue 2, February 2015, Pages 183–18843 J. S. Barkley, K. S. Wheeler and H. Pachon, “Anaemia prevalence may be reduced among countries that fortify flour”, British Journal of Nutrition, Published online ahead of print, doi:10.1017/S0007114515001646 44 Crossley M, Wienert B, Funnell APW. “Editing the genome to introduce a beneficial naturally occurring mutation associated with increased fetal globin”. Nature Communications. 2015.

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Mosquito-borne diseases: dengue, chikungunya, zika, malaria and West Nile virusa) A report from Singapore announced that researchers at Duke-NUS Graduate Medical

School45 have identified an antibody that can kill all strains of the dengue serotype DENV-2, one of two common serotypes in Singapore46. Having discovered the DENV-1 antibody in 2012 and the DENV-3 antibody in February this year the scientists are on their way to developing a drug cocktail to kill all four dengue serotypes. Another Duke-NUS team has found a way to identify which DENV-2 strains may lead to an epidemic.

b) In Malaysia the total number of dengue cases reported from the beginning of January to 27 June was 56,533 compared with 42,229 for the same period last year. Deaths from dengue in the first half of this year totalled 162, compared with 82 in the same period last year. The Ministry of Defence through the Malaysian Armed Forces (MAF) together with Pharmaniaga and Bavarian Nordic is to carry out dengue vaccine research and development.

c) A study47 in Brazil of the incidence of transfusion transmitted dengue has concluded that “during seasonal epidemics, substantial proportions of asymptomatic donors with infection are donating blood, and recipients are receiving RNA-positive blood components".

d) A recent paper48 supported the possibility of sexual transmission of the zika virus.e) Vanderbilt University Medical Center's James Crowe49 and his team reported the first

large panel of antibody treatments against chikungunya.50 Using blood from a previously infected person, researchers found chikungunya antibody-secreting cells, and then processed them to retrieve their DNA and antibody genes. The team has so far isolated three dozen chikungunya antibodies. "Amazingly even decades after an infection, people still have cells in their blood making antibodies for chikungunya," Crowe said. The team aims to be testing one or more of the antibodies in human beings in about a year.

f) Sanofi is trialling two potential malaria treatments, OZ439/Piperaquine and OZ439/Ferroquine. These are single, fixed-dose combination therapies independent of artemisin, and were developed in partnership with non-profit organisation Medicines for Malaria.

g) A study51 led by researchers at Harvard T.H. Chan School of Public Health has discovered that a specific malaria parasite protein (calcineurin) is essential for parasite invasion into red blood cells. Parasite calcineurin is therefore suggested as a focus for the development of new antimalarial drugs. Human calcineurin is already a

45 Led by research fellow Guntur Fibriansah and associate professor Shee-Mei Lok(of the Duke NUS Emerging Infectious Diseases Programme)46Guntur Fibriansah, Kristie D. Ibarra, Thiam-Seng Ng, Scott A. Smith, Joanne L. Tan, Xin-Ni Lim, Justin S. G. Ooi, Victor A. Kostyuchenko, Jiaqi Wang, Aravinda M. de Silva, Eva Harris, James E. Crowe Jr., and Shee-Mei Lok, “Cryo-EM structure of an antibody that neutralizes dengue virus type 2 by locking E protein dimers”, Science 3 July 2015: 88-91.DOI:10.1126/science.aaa8651 47 Sabino EC, et al., “Transfusion-Transmission of Dengue Virus and Associated Clinical Symptomatology during the 2012 Epidemic in Brazil”,J Infect Dis. 2015; doi:10.1093/infdis/jiv326; editorial, Levi JE. J Infect Dis. 2015;doi:10.1093/infdis/jiv322.48 Didier Musso, Claudine Roche, Emilie Robin, Tuxuan Nhan, Anita Teissier, Van-Mai Cao-Lormeau, “Potential Sexual Transmission of Zika Virus” Emerging Infectious Diseases, Vol. 21, No. 2, February 2015 DOI:http://dx.doi.org/10.3201/eid2102.14136349 Ann Scott Carell Professor and director of the Vanderbilt Vaccine Center50 Smith S, Silva L, Fox J, Flyak A, Kose N, Sapparapu G. “Isolation and Characterization of Broad and Ultrapotent Human Monoclonal Antibodies with Therapeutic Activity against Chikungunya Virus”. Cell Host & Microbe, 2015.51 Aditya S. Paul, Sudeshna Saha, Klemens Engelberg, Rays H.Y. Jiang, Bradley I. Coleman, Aziz L. Kosber, Chun-Ti Chen, Markus Ganter, Nicole Espy, Tim W. Gilberger, Marc-Jan Gubbels, Manoj T. Duraisingh. “Parasite Calcineurin Regulates Host Cell Recognition and Attachment by Apicomplexans”. Cell Host & Microbe, online 25 June 2015; DOI: 10.1016/j.chom.2015.06.003

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target for drugs treating rheumatoid arthritis and lupus. Senior author Manoj Duraisingh52 commented: "As drug resistance is a major problem for malaria control and eradication, it is critical that that we continue to develop new antimalarials that act against previously unexploited targets in the parasite to keep priming the drug pipeline."

h) In the US, a clinical trial of a West Nile Virus vaccine is being sponsored by the National Institute of Allergy and Infectious Diseases (NIAID), part of the National Institutes of Health. The vaccine was developed by scientists at the Oregon National Primate Research Center at Oregon Health & Science University in Portland, funded with a $US 7.2 million grant from NIAID, awarded in 2009. The vaccine is being tested in a Phase 1 clinical trial at Duke University in Durham, North Carolina, one of NIAID’s Vaccine and Treatment Evaluation Units (VTEUs).The OHSU team, led by Mark Slifka, created the vaccine, HydroVax-001, with a hydrogen peroxide-based process that renders the virus inactive but maintains key immune-system triggering surface structures. Because it is inactivated, it could be used in a immunologically vulnerable groups.

Influenza: strains, spread, prevention and treatmenti) On 10 July a woman in Yunnan province, China, died after contracting H5N6 avian

flu. In May last year, a man from southwest China’s Sichuan Province died after contracting H5N6 in the world’s first known human infection with the strain. The virus had previously been isolated to waterfowls and wild ducks.

j) Also on 10 July China reported five new H7N9 avian influenza infections, as well as four deaths. The events had occurred in June. The total for June was a decrease from the 15 cases and 6 deaths that China reported in May. The additional infections took the global H7N9 case total to 685.

k) In England, The Department for Environment, Food and Rural Affairs ordered 170,000 birds to be culled after finding signs of avian flu at a poultry farm in Lancaster. It was reported to be H7N7.

l) BiondVax Pharmaceuticals announced positive preliminary results from its Phase II trial of M-001, its candidate for a universal influenza vaccine. The company said that M-001 is well tolerated and enhances antibody responses to multiple flu strains when administered as a primer in a 1 mg dose.

m) Research by Rockefeller University scientists and their colleagues has suggested a new path towards a universal flu vaccine53. "While the conventional flu vaccine protects only against specific strains, usually three of them, our experiments show that by including modified antibodies within the vaccine it may be possible to elicit broad protection against many strains simultaneously," says senior study author Jeffrey Ravetch54, "We believe these results may represent a preliminary step toward a universal flu vaccine, one that is effective against a broad range of the flu viruses."

n) Researchers from the University of Melbourne, in conjunction with colleagues at Fudan University in China, investigated the immune response of patients to the first outbreak of the avian flu H7N9 They identified the ‘killer’ CD8+ T cells as having given optimal protection against the influenza virus. Associate Professor Kedzierska from the University of Melbourne says this suggests the potential of moving from vaccines for specific influenza strains toward developing a vaccine component based on T-cells, and the optimal immune responses witnessed in the patients who recovered quickest in the study. She said that ‘killer’ T cells target an interior ‘conserved’ part of the virus which does not change when the virus mutates. When the ‘killer’ T cells recognise these same ‘conserved’ parts in a new virus, they kill the early infection." Nobel Laureate Professor Peter Doherty, one of the lead authors of

52 The John LaPorte Given Professor of Immunology and Infectious Diseases53 In a paper published 2 July in Cell54 Theresa and Eugene M. Lang Professor and head of the Leonard Wagner Laboratory of Molecular Genetics and Immunology.

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the study from the University of Melbourne, said “After spending the past 40 years working on the virus-specific ‘killer’ T cells, this is the first study from our group that shows their role in protecting people against a new human influenza A virus”.

o) Canadian research has found55 that a new drug, Vasculotide, prevented fluid from entering the lungs of mice who'd been given three different strains of flu. It kept them from dying by targeting the symptom not the virus. Dr Warren Lee, of both St. Michael's Keenan Research Centre for Biomedical Sciences and the University of Toronto said the drug could be effective in humans because the mechanism of blood vessels leaking into the lungs is common to all animals. The drug, unlike antiviral drugs, worked even if administered several days after infection began.

p) Visterra presented new preclinical data for VIS410 at the 4th International Society for Influenza and Other Respiratory Virus Diseases Antiviral Group (isirv-Antiviral Group) Conference at the University of Texas at Austin, in June56. VIS410 is Visterra’s novel monoclonal antibody against H7N957. Visterra conducted preclinical studies and a Phase 1 clinical trial of VIS410. The company then initiated a placebo-controlled Phase II challenge trial of VIS410 in healthy subjects administered an influenza virus before receiving either VIS410 or placebo.

MERS-CoVr) Between 19 and 30 June 2015, the Kingdom of Saudi Arabia notified WHO of 6

additional cases of Middle East respiratory syndrome coronavirus (MERS-CoV) infection. Globally, since September 2012, WHO had by 30 June been notified of 1,363 laboratory-confirmed cases of infection with MERS-CoV, including at least 487 related deaths.

s) With MERS in mind Saudi Arabia has advised immunocompromised58 pilgrims to postpone their plans for performing Hajj this season.

t) In South Korea, health authorities on 5 July reported an additional case of MERS, raising the total number of people infected with the virus to 186. If this patient were found to have contracted MERS at the Samsung Medical Centre, the number of people infected with the virus at SMC would rise to 91. Of the total 25 medical staffers infected with MERS, 13 had so far contracted the virus at SMC. Meanwhile, the death toll from MERS remained at 34. By 10 July the total number of deaths had reached 36, with case numbers stable at 186. Over 560 people remained in isolation.

u) A South Korean woman was diagnosed with MERS in early July, a week after her quarantine was over. While her symptoms may have been delayed, she may instead have been exposed to the virus when she went to the hospital for cancer treatment shortly after her quarantine period expired.

v) In January 2015, the Philippines had its first case of MERS, in a nurse returning from working in Saudi Arabia. Then a foreigner who arrived from Dubai on 19 June was admitted to a government hospital on 4 July with MERS. Both patients recovered.

55 The study was published in Scientific Reports56 The presentations of data related to VIS410 were: Tatiana Baranovich, a postdoctoral fellow at St. Jude Children’s Research Hospital in Memphis presented “VIS410 Monoclonal Antibody Demonstrates Potent Efficacy Against Neuraminidase Inhibitors-Susceptible and-Resistant Influenza A (H7N9) Viruses and Protects Mice from Development of ARDS.” José M. Trevejo, Visterra’s Vice President of Development presented “VIS410, a Broadly Neutralizing Antibody to Influenza A: Characterization and Potential for ADE.” 57 VIS410 is actually a broad spectrum human monoclonal antibody designed to neutralize all strains of influenza A, including newly emerging strains. By inhibiting hemagglutinin-mediated cell membrane fusion, it blocks viral replication. Visterra is developing VIS410 for one-off administration to patients hospitalized with seasonal or pandemic influenza A.58 Mentioning the elderly, pregnant women, HIV patients and children below the age of five

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w) Scientists from the University of Maryland School of Medicine and Regeneron Pharmaceuticals report they have together found and validated two therapeutics that show promise in animal models of preventing and treating MERS59.

x) Purdue University researchers reported that they have found molecules that shut down the activity of an enzyme essential to MERS virus replication60.

y) Researchers from Ludwig-Maximilians-Universität München61 have now demonstrated, in a preclinical setting, the protective effect of their candidate vaccine against MERS. They are now planning a clinical trial. The vaccine, MVA-MERS-S, was developed in collaboration with colleagues at Marburg University and the Erasmus Medical Centre in Rotterdam.

z) Researchers at the University of Minnesota have found two mutations that likely allowed MERS-CoV, to transmit from bats to humans62.

aa) The Australasian College for Infection Prevention and Control (ACIPC) said in June that all hospital emergency departments should update standard admission procedures to include travel history checks.

Ebolabb) Liberia on 2 July confirmed a third Ebola case, two months after it was declared

Ebola free.cc) Saudi Arabia has again declined to issue Hajj visas to pilgrims from countries which

have experienced an Ebola outbreakdd) Researchers at The Scripps Research Institute (TSRI) identified new immune

molecules that protect against Marburg virus, a relative of Ebola virus. "These antibodies attack a new site on Marburg virus we had not seen before," said Erica Ollmann Saphire, senior author of the new study, professor at TSRI and director of the Viral Hemorrhagic Fever Immunotherapeutic Consortium. The new antibodies were developed through a partnership including Integrated Biotherapeutics, Mapp Biopharmaceutical and Emergent BioSolutions as well as the Institute.63 Funding came from multiple sources: the US National Institutes of Health (NIH) National Institute of Allergy and Infectious Diseases (four grants), a pre-doctoral fellowship from the National Science Foundation, a postdoctoral fellowship from the Japan Society for Promotion of Science, the Uehara Memorial Foundation, and an Investigators in the Pathogenesis of Infectious Disease award from the Burroughs Wellcome Fund.

ee) Researchers identified 30 FDA-approved drugs that appeared to kill the Ebola virus in cultured cells, including an antidepressant (Zoloft) and a heart disease drug (Vascor) which also prevented the virus from reproducing in rodents64.

ff) A team led by associate professor Marco Salemi of the University of Florida’s Department of Pathology and Emerging Pathogens Institute, in collaboration with the Italian Institute of Health, has allayed concern that Ebola could spread through air65.

59 The two antibodies, REGN3051 and REGN3048, showed an ability to neutralize the virus. Lead researcher on the study was assistant professor Matthew B. Frieman, and the Proceedings of the National Academy of Sciences (PNAS).60 Sakshi Tomar, Melanie L. Johnston, Sarah E. St. John, Heather L. Osswald, Prasanth R. Nyalapatla, Lake N. Paul, Arun K. Ghosh, Mark R. Denison and Andrew D. Mesecar, “Ligand-induced dimerization of MERS coronavirus nsp5 protease (3CLpro): implications for nsp5 regulation and the development of antivirals”, Journal of Biological Chemistry, 8 June 2015, doi: 10.1074/jbc.M115.651463 61led by Professor Gerd Sutter, who holds the Chair of Virology at LMU's Institute for Infectious Diseases and Zoonoses. The work was reported in the Journal of Virology.62 See Journal of Virology63 The study "Protective mAbs and Cross-reactive mAbs Raised by Immunization with Engineered Marburg Virus GPs," was published online ahead of print in the journal PloS Pathogens.64 See Science Translational Medicine65The study was published in Nature Scientific Reports

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Other diseases: occurrence, prevention and treatmentgg) A study66 found that after antiretroviral therapy, latent HIV cells 'wake up' only once a

week, much less than previously thought. Professor Miles Davenport from the Kirby Institute at the University of New South Wales said this means the number of latent HIV cells needed to produce a 1-year remission period and a suspension of drug therapy would need to be reduced by around 50-70 times.

hh) NSW Health was reported to have suspended six Sydney dentists and cautioned another six over poor sterilisation practices that may have exposed thousands of patients to HIV and hepatitis over the past decade. NSW Health director of health protection Jeremy McAnulty urged all patients to visit their GP to be tested for HIV as well as Hepatitis A, B and C as a precaution.

ii) The NT's Centre for Disease Control (CDC) reported in mid-July that there had been 134 reported cases of syphilis in the Central Australia, Barkly and Katherine regions since July last year67. Children as young as 12 have tested positive but the majority of the notified cases are reported to be in Indigenous people aged 15 to 19. CDC spokesman Dr Matthew Thalanany said it was important doctors tried to determine the sexual partners of anyone that tested positive for the disease. "It's a very delicate matter, it's difficult, but it is necessary," he said. "It's necessary we get to know who all the contacts are and we get to test them." The disease can spread from mother to unborn baby, potentially causing severe health problems for the child and even death. Three babies tested positive in the past financial year. NT Health Minister John Elferink said: "Any child under the age of consent who develops a sexually transmitted disease is subject to an investigation and prosecutions are launched.

jj) Scientists at The University of Texas Health Science Center at Houston have found that grass plants can bind, take up and transport infectious prions68. “There is no proof of transmission from wild animals and plants to humans,” said lead author Claudio Soto69, “but it’s a possibility that needs to be explored and people need to be aware of it. Prions have a long incubation period.”

66 Published in PLoS Pathogens67 up from 15 reported cases in the 2013-14 financial year.68 Article published 26 May in Cell Reports69 professor of neurology at UTHealth Medical School and director of the UTHealth George and Cynthia W. Mitchell Center for Alzheimer’s Disease and Other Brain Related Illnesses.

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