Potential New Product Developments and Applications; s1

Monitoring International Trends posted December 2015

The NBA monitors international developments that may influence the management of blood and blood products in Australia. Our focus is on:

 Potential new product developments and applications;  Global regulatory and blood practice trends;  Events that may have an impact on global supply, demand and pricing, such as changes in company structure, capacity, organisation and ownership; and  Other emerging risks that could potentially put financial or other pressures on the Australian sector.

A selection of recent matters of interest appears below. Highlights include:

 Reports of presentations to the annual meeting of the American Society of Hematology, concerning developments in coagulation factors, RNAi therapeutics, treatments for sickle cell disease, gene therapy for blood disorders, length of storage of red blood cells, and a very portable diagnostic device (Section 1).  The availability of new agents with convenient oral or subcutaneous delivery which will make routine prophylaxis in hereditary angiodema more likely (Section 2).  CSL’s trial of its plasma-based CSL112 in the US to reduce the risk of a second heart attack (Section 2).  FDA approval of the first genetically engineered treatment for von Willebrand disease (Section 3).  Approval by the European Commission of the Sobi-Biogen long-acting recombinant Factor VIII, Elocta (Section 3).  CSL’s first shipment of Privigen to the US from Broadmeadows (Section 4).  Announcement by Grifols of its management succession plan (Section 4).  Mexico’s approval of Sanofi’s dengue vaccine (Section 5).  The FDA’s new guidance for blood banks, to protect the US blood supply during a future Ebola outbreak (Section 6).  New ways to deliver drugs (Section 7).  Attempts to develop a vaccine against MERS–CoV (Section 9).

Table of Contents

1. The 57th Annual Meeting and Exposition of the American Society of Hematology (ASH). Orlando, Florida, 5 to 8 December 2015.

Haemophilia a) CSL Behring reported the data from its Phase III PROLONG-9FP clinical program evaluating the efficacy and long-term safety of its investigational long-acting fusion protein linking recombinant coagulation factor IX with recombinant albumin (rIX-FP).

1 The data, from an ongoing extension study and two pivotal Phase III studies, assessed rIX-FP for routine prophylaxis in previously-treated adults with haemophilia B, at dosing intervals of up to 14 days. A second abstract reported efficacy and safety results for rIX-FP in patients undergoing surgery.

b) A study1 reported during a plenary session found that recombinant Factor VIII replacement products for severe haemophilia A appeared to increase inhibitor development 1.87-fold compared with plasma-derived products.

c) Biogen and Swedish Orphan Biovitrium in two poster sessions presented new data demonstrating that their long-acting products Elocta/Eloctate [recombinant human coagulation factor VIII, Fc fusion protein] and Alprolix (rFIXFc) may effectively manage target joint bleeding and maintain low annualised bleeding rates in people with severe haemophilia A and B2.

d) Alnylam Pharmaceuticals reported positive results from its continuing Phase 1 clinical study with fitusiran, the International Nonproprietary Name (INN) allocated to ALN- AT3. Fitusiran is an RNAi therapeutic which targets antithrombin (AT) with the goal of promoting sufficient thrombin generation to restore haemostasis. Results demonstrated that subcutaneous administration of fitusiran achieved potent and dose-dependent lowering of AT of up to 88 per cent. AT lowering was associated with statistically significant and clinically meaningful increases in thrombin generation and decreases in bleeding frequency in patients with haemophilia. In particular, fitusiran administration resulted in an 85 per cent reduction in median estimated annualized bleeding rates in nine evaluable patients. Fitusiran was found to be generally well tolerated to date, including no clinically significant increases in D- dimer, a biomarker of excessive clot formation. The company expects to begin pivotal studies of fitusiran in mid-2016. Sickle cell disease e) A study3 found the rate of vaso-occlusive crises is not significantly lower for children and adolescents with sickle cell anemia receiving prasugrel versus placebo. Eli Lilly and Daiichi Sankyo, the manufacturers of prasugrel, financed the study.

1 By Flora Peyvandi, associate professor of internal medicine at University of Milan and head of the internal medicine department and of the Angelo Bianchi Bonomi Haemophilia and Thrombosis Centre of Fondazione IRCCS Ca’ Granda, Ospedale Maggiore Policlinico in Milan, and colleagues. They conducted a multicentre, open-label, randomized study (in previously untreated patients with severe haemophilia A) to investigate whether the rate of inhibitory alloantibody development differed according to the source of Factor VIII replacement—plasma-derived or recombinant.

2 Kerlin, BA, et al.,”Long-term Efficacy of rFVIIIFc Prophylaxis in Pediatric, Adolescent, and Adult Subjects With Target Joints and Severe Hemophilia A“ and Shapiro, AD, et al.,”Analysis of Target Joint Bleeding With Prophylactic Use of Recombinant Factor IX Fc Fusion Protein in Patients With Severe Hemophilia B”.

3 By Matthew M. Heeney,from the Boston Children's Hospital, and colleagues. The research was published online 8 December in the New England Journal of Medicine to coincide with the meeting

2 f) Results of a placebo-controlled, double blind study of Global Blood Therapeutics’ GBT440 were reported4 to show that the small molecule haemoglobin modifier reduced haemolysis and improved anaemia without causing tissue hypoxia in patients with sickle cell disease. Treatment with GBT440 (Global Blood Therapeutics) also nearly eliminated all sickle cells in the peripheral blood of patients, according to researchers. GBT440 works to increase haemoglobin oxygen affinity.

g) One presentation reported on a trial sponsored by the US National Institutes of Health (NIH)5. TWiTCH evaluated hydroxyurea in its capacity to lower the risk of stroke in children with sickle cell disease (SCD) by improving blood flow in the brain. This was a prospective, randomized study involving 26 pediatric treatment centers around the US, and 120 children aged between 4 and 15, all with severe SCD. The TWiTCH trial was stopped early, because of clear results for hydroxyurea being at least as good as transfusion in maintaining blood flow to the brain, as measured by transcranial Doppler. (This was the primary endpoint of the trial). There was no significant difference in the incidence of strokes between the two treatment arms, and no significant problems observed from hydroxyurea on the study, which included follow-up through two years.

h) Another presentation6 reviewed results from a large international registry of 1,000 HLA-identical sibling transplants performed for patients with severe SCD. The perfectly-matched allogeneic transplants were carried out between 1986 and 2013, at 88 medical centers in 23 countries. The median age at transplant was 9 years. At three years after transplant, overall survival was 94 per cent. Paroxysmal nocturnal haemoglobinuria i) Clinical data from Alnylam Pharmaceutical’s ongoing Phase I/II study of its RNAi therapeutic ALN-CC5 targeting serum C5 were presented. These were from both the single-ascending dose and multiple-ascending dose parts of the ongoing study in healthy adult volunteers7. Akshay Vaishnaw, Executive Vice President and Chief Medical Officer of Alnylam, said soon after the meeting: "Based on encouraging data recently presented at ASH, we’ve now advanced ALN-CC5 into patients with PNH8,

4 Lehrer-Graiwer J, et al. Abstract 542.

5 Abstract 3. Presented by Dr Russell Ware

6 Abstract 541.Presented by Dr Barbara Cappelli

7 ALN-CC5 achieved up to 99 percent knockdown of serum C5 and up to 98 percent inhibition of serum sheep red blood cell haemolytic activity, an assay for complement activity; administration of ALN-CC5 resulted in low levels of residual C5, which – based on comparisons from separate studies – were at or below the estimated levels of free C5 observed at therapeutic doses of eculizumab, an approved anti-C5 monoclonal antibody; the effects of ALN-CC5 were found to be highly durable, with C5 knockdown and complement inhibition results supporting a once monthly and possibly a once quarterly subcutaneous dose regimen; and ALN-CC5 was shown to be generally well tolerated, with no clinically significant, drug-related adverse events to date.

3 where clinical activity can be measured toward LDH9, a key disease biomarker. If successful in lowering LDH levels, we believe that ALN-CC5 could emerge as a differentiated approach to address the continued unmet needs that exist for patients with PNH and other complement mediated diseases. We look forward to the continued clinical advancement of ALN-CC5 and expect to report initial PNH patient data in mid-2016 ahead of an anticipated 2017 Phase 3 start.”

j) Alexion Pharmaceuticals announced that researchers presented data from the International Paroxysmal Nocturnal Hemoglobinuria (PNH) Registry10 that advance the understanding of PNH and the long-term management of the disease, including the progression of symptoms in untreated patients with PNH and the continued benefits of the company’s Soliris (eculizumab) treatment irrespective of transfusion history. Researchers also presented data from a long-term follow-up study evaluating the effectiveness of Soliris in preventing thrombotic microangiopathy (TMA) in patients with atypical hemolytic uremic syndrome (aHUS). Both PNH and aHUS are severe, ultra-rare diseases caused by chronic uncontrolled complement activation. Other k) Bluebird Bio presented further data on a subgroup of four of the 13 patients with beta-thalassemia major on whom it is testing LentiGlobin BB305. These four have a genetic variation called beta-zero beta-zero that leaves them unable to make any of the oxygen-carrying molecule beta-globin. On 5 November, the company said three of the patients hadn’t responded as well to its drug as patients without the variation, which caused Bluebird’s share price to fall 22 per cent. At ASH, Bluebird emphasised11 that the group had been able to reduce the volume of transfusions they needed. The company will start a separate trial for similar hard-to-treat patients, and continue testing the therapy in patients without the variation. Five patients without the genetic variation and who can make a limited amount of the oxygen transporting molecule haven’t needed transfusions for between 7.1 to 16.4 months after therapy12.

8 Paroxysmal nocturnal haemoglobinuria. Alnylam has begun the final phase (Part C) of its Phase I/II clinical trial with ALN-CC5, a subcutaneously administered RNAi therapeutic targeting complement component C5 for the treatment of complement-mediated diseases. Part C is being conducted in patients with paroxysmal nocturnal hemoglobinuria (PNH). It will evaluate the safety and tolerability of multiple doses of ALN-CC5 and will measure its clinical activity, including knockdown of serum C5 levels, levels of residual C5, inhibition of serum haemolytic activity, and reduction of lactate dehydrogenase (LDH), a measure of red blood cell haemolysis.

9 lactate dehydrogenase

10 Three posters were presented at ASH from the International PNH Registry, a prospective, worldwide, observational study of patients with PNH that has so far enrolled more than 4,000 patients.

11 Abstract #201: “Update of Results from the Northstar Study (HGB-204): A Phase 1/2 Study of Gene Therapy for β-Thalassemia Major via Transplantation of Autologous Hematopoietic Stem Cells Transduced Ex Vivo with a Lentiviral βA-T87Q-Globin Vector (LentiGlobin BB305 Drug Product)” .An oral presentation was given by Mark C. Walters, University of California at San Francisco Benioff Children’s Hospital.

4 l) A number of other papers also reported on gene therapy trials in blood disorders.13

m) Janssen Pharmaceuticals and Bayer HealthCare announced the results from a real- world study in 5000 patients showing that, in people with deep vein thrombosis (DVT), the rates of major bleeding and recurrent blood clots for Xarelto (rivaroxaban) in routine clinical practice were generally consistent with those observed in Phase III research. Patients on Xarelto also had shorter hospital stays than those given standard anticoagulation14.

n) A report15 of a randomized, controlled clinical trial compared the oxygen delivery of short-storage versus longer-storage red blood cells (RBC) as measured by transfused patients' blood lactate levels16. The trial included 290 patients between the ages of six months and five years who visited a university hospital urgent care facility in Kampala, Uganda, for treatment of severe anemia marked by elevated blood lactate levels. Participants were randomly assigned to receive either RBCs stored for one to 10 days, or RBCs stored for 25 to 35 days. Patients were monitored during the transfusion and for a further 24 hours. The number of patients achieving the desired blood lactate level of less than or equal to 3mM was not statistically different between the two groups17. Brain oxygen levels increased in recipients of shorter-storage and longer-storage RBCs to the same extent.

12 The one-time treatment involves removing a patient’s stem cells that make red blood cells, modifying them with a normal gene to manufacture a protein that fights beta-thalassemia, and then infusing them back into the body.

13 Eg Abstract 259: “Safety and Clinical Benefit of Lentiviral Hematopoietic Stem Cell Gene Therapy for Wiskott-Aldrich Syndrome”, delivered by Francesca Ferrua, San Raffaele Telethon Institute for Gene Therapy (TIGET), Milan, and Abstract 261 “Lentiviral Hematopoietic Stem Cell Gene Therapy for Older Patients with X-Linked Severe Combined Immunodeficiency”, delivered by Suk See De Ravin, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland.

14 Principal investigator was Professor Alexander G. G. Turpie, of McMaster University and Hamilton Health Sciences, Ontario. The study was simultaneously published in Lancet Hematology.

15 “Tissue Oxygenation by Transfusion in Severe Anemia with Lactic Acidosis (TOTAL): A Prospective, Randomized, Non-Inferiority Trial of Blood Storage Duration” was presented orally by Walter Dzik, Massachusetts General Hospital, Boston. Christine M. Cserti-Gazdewich, University Health Network, Toronto, presented to the press conference.

16 When tissue oxygen levels are critically low, lactate levels jncrease, and when tissues are successfully re-oxygenated, lactate levels may fall.

17Of those who received shorter-storage blood, 58 percent reached this desired outcome compared to 61 percent of those who received longer-storage blood.

5 o) Researchers presented ongoing work18 on the HemeChip, a small mobile device to detect genetic blood disorders. "While sickle cell newborn screening is standard in the US, very few infants are screened in Africa because of the high cost and level of skill needed to run traditional tests," explained project researcher Dr Little, Associate Professor at the Case Western Reserve University School of Medicine. "This new mobile technology provides an easy to use, cost-effective tool that takes us closer to standardizing newborn screenings on mobile devices, thus simplifying diagnosis. It could make a huge difference in developing nations worldwide, enabling early treatment for this disease." Hemechip uses a battery-powered technique known as cellulose acetate electrophoresis to identify varying types of haemoglobin, a protein that helps red blood cells transport oxygen throughout the body.

2. Other product news Here 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.

a) La Jolla Pharmaceutical Company has been conducting a Phase 1 clinical trial of LJPC-401, its novel formulation of hepcidin19. The trial is a is a multicentre, open- label, dose-escalation trial evaluating the safety, tolerability and effect on serum iron parameters, and pharmacokinetics of LJPC-401 in patients at risk of iron overload due to hereditary haemochromatosis (HH),or beta thalassemia or sickle cell disease (SCD).

b) Baxalta announced the submission of a Clinical Trial Application (CTA) to the UK Medicines and Healthcare Products Regulatory Agency (MHRA) to initiate a first-in- human clinical trial to evaluate the safety and efficacy of BAX 826, an investigational, extended half-life recombinant Factor VIII (rFVIII) treatment for hemophilia A. "We are advancing a number of approaches, including BAX 826 as well as our gene therapy program, to evaluate potential new options for hemophilia patients that can offer efficacy while also easing the treatment burden with a goal of once-weekly or even less frequent infusions," said John Orloff, head of Research and Development and chief scientific officer, Baxalta. The open-label, dose-finding study of BAX 826 aims to enroll 30 patients; Baxalta expects to begin treating participants in the study by early 2016. BAX 826 is a next-generation rFVIII treatment based on the full length ADVATE [Antihemophilic Factor (Recombinant)] molecule. The compound is modified using proprietary polysialic acid (PSA) technology licensed from Xenetic Biosciences, to extend its circulating half-life.

c) Cerus Corporation announced that Smilow Cancer Hospital at Yale-New Haven has enrolled the first patient in the Phase IV INTERCEPT Platelets Entering Routine Use (PIPER) study, a prospective, open-label, non-inferiority, post-marketing surveillance

18 Ung R, Alapan Y, Noman Hasan M, et al. “Point-of-Care Screening For Sickle Cell Disease By a Mobile Micro-Electrophoresis Platform”.

19 Hepcidin is a naturally occurring peptide hormone that is the body’s regulator of iron absorption and distribution. Hepcidin prevents excessive iron accumulation in vital organs, such as the liver and heart, where it can cause significant damage and even lead to death.

6 study. The PIPER study is expected to enrol around 3,000 patients at up to 20 US hospitals20.

d) Hereditary angiodema is caused by low levels of functional C1-inhibitor. It is not a common disease, but has been an alarming one, leading as it does to acute attacks with major swelling which can be life-threatening. In recent years plasma derived C1- inhibitor replacement drugs Cinryze and Berinert have become available so therapy has been satisfactory, assuming diagnosis is both timely and accurate, which is not always the case. They are also efficacious and safe as prophylactic agents, but they require twice-weekly intravenous administration. New agents with convenient oral or subcutaneous delivery are becoming available, so routine prophylaxis is expected to become more common, replacing the emphasis on on-demand treatment. New agents include BioCryst's avoralstat and BCX-7353, Dyax's DX-2930, and CSL Behring's CSL-830.

e) CSL believes its plasma-based drug CSL112 could greatly reduce the risk of a second heart attack among sufferers21. It works by rapidly removing cholesterol from the arteries of heart attack patients. CSL is carrying out a phase IIb trial of CSL112 in 1200 heart attack patients in the US. Half the patients have been given a treatment of CSL112 — four infusions once a week for a fortnight — and half have been given a placebo22. CSL will now monitor the incidence of a second heart attack among the group over the next year. If the results prove successful, CSL will launch a phase III trial involving more than 10,000 patients in mid-2017.

f) Arch Therapeutics has clearance to begin a clinical trial in Western Europe for its AC5 surgical haemostatic device. The trial will examine bleeding wounds created during a dermatological procedure in fewer than 50 patients. The endpoints include product-related adverse effects and time to haemostasis.

g) ProMetic Life Sciences will conduct a double-blind placebo controlled phase II clinical trial in patients suffering from cystic fibrosis (CF) and related diabetes and liver steatosis, using its compound PBI-4050. CF is a condition which compromises pulmonary, pancreatic and hepatic functions. “PBI-4050 has been shown to significantly reduce fibrosis in several key organs in preclinical models and this, irrespective of how the injuries were induced or whether they were acute or chronic in nature”, stated Dr Lyne Gagnon, VP of R&D preclinical at ProMetic. “For this reason and because of the positive effects recently observed in type 2 diabetic patients, we believe that PBI-4050 could provide significant clinical benefits to patients affected by this medical condition”.

20 The PIPER study will monitor the transfusion of conventional and INTERCEPT-treated platelets in hematology/oncology patients. PIPER will evaluate the incidence of severe pulmonary adverse events requiring assisted mechanical ventilation, a clinical concern in transfusion medicine as it relates to repeated platelet transfusions in patient populations at risk for lung injury.

21 About 735,000 people in the US and 55,000 people in Australia have a heart attack each year. Of these about 15 per cent will have a second heart attack.

22 A separate sub-group trial involving patients suffering from moderate renal failure will run alongside the main CSL112 trial.

7 3. Regulatory The NBA monitors overseas regulatory decisions on products, processes or procedures which are or may be of relevance to its responsibilities.

a) The US Food and Drug Administration (FDA) has approved the first genetically engineered treatment for von Willebrand disease, the most common inherited bleeding disorder. Vonvendi, made by Baxalta, has been approved for treating patients aged 18 and older. Baxalta says the drug should be available in 2016, and that its price has not yet been determined.

b) Bayer said that the European Committee for Medicinal Products for Human Use or CHMP has recommended BAY 81-897323 for approval in the EU for the treatment and prophylaxis of bleeding in patients with haemophilia A for all age groups. A final decision will be made by the European Commission.

c) Swedish Orphan Biovitrum and Biogen announced that the European Commission has approved Elocta (rFVIIIFc) for the treatment of haemophilia A in all 28 European Union member states, as well as Iceland, Liechtenstein and Norway. Elocta, a recombinant factor VIII Fc fusion protein with an extended half-life, will be the first haemophilia A treatment in the EU to offer prolonged protection against bleeding episodes with prophylactic injections every three to five days. Elocta is indicated for both on-demand and prophylaxis treatment of people with haemophilia A of all ages24.

d) Green Cross Corporation, a South Korean biopharmaceutical company, submitted its Biologics License Application for IVIG-SN (human normal immunoglobulin G for intravenous administration) to the FDA. The application was submitted for the treatment of primary immunodeficiency diseases (PID), a class of inherited genetic disorders that causes an individual to have a deficient or absent immune system.

e) The FDA cleared the use in civilian trauma settings of the XSTAT 30 wound dressing, an expandable, multi-sponge dressing used to control severe, life- threatening bleeding from wounds in areas such as the groin or armpit where a tourniquet cannot be placed. The clearance expands the device's indication from use by the military only. XSTAT 30 is cleared for use in patients at high risk for immediate, life-threatening, and severe haemorrhagic shock and non-compressible junctional wounds, when definitive care at an emergency care facility cannot be achieved within minutes. XSTAT 30 is not indicated for use in certain parts of the chest, abdomen, pelvis or tissue above the collarbone. The dressing can be used for up to four hours25. The FDA cleared XSTAT 30 through the 510(k) review process

23 BAY 81-8973 is Bayer's new unmodified full-length recombinant factor VIII compound. In clinical trials, it controlled bleeds and protected from bleeds in hemophilia A patients when used prophylactically two or three times per week.

24 The EC approval was based on data from Elocta's pivotal, phase III A-LONG clinical study, which demonstrated the efficacy, safety and pharmacokinetics of rFVIIIFc in previously treated males 12 years of age and older with severe haemophilia A, and from the phase III Kids A-LONG clinical study, which demonstrated the efficacy and safety of rFVIIIFc in previously treated male children with haemophilia A under 12 years of age. Elocta is the trade name for rFVIIIFc in Sobi's territory, which is also approved under the name Eloctate® [Antihemophilic Factor (Recombinant), Fc Fusion Protein] for the treatment of haemophilia A in the U.S., Canada, Australia, New Zealand and Japan.

8 after the manufacturer demonstrated the product was substantially equivalent to the XSTAT, which was granted marketing authorization for battlefield use in April 2014.

f) European and US regulators have been investigating whether a defective blood- clotting test device affected a trial involving Bayer's anti-blood clotting drug Xarelto (rivaroxaban). The Rocket AF trial compared Xarelto with warfarin for the prevention of strokes and systemic embolisms in patients with irregular heartbeat.

g) Boehringer Ingelheim announced that it had received final approval from the FDA for its Pradaxa (dabigatran etexilate mesylate) to be used to prevent deep vein thrombosis or pulmonary embolism in patients who have had hip replacement surgery. The approval is for a new use for the drug, which was launched in 2010. “This milestone represents the fourth FDA-approved indication for PRADAXA in five years — a testament to the company’s continued leadership in the evolution of anticoagulation care for patients and clinicians,” Boehringer Ingelheim’s SVP medicine and regulatory Dr. Sabine Luik said. “PRADAXA has the longest real-world experience of any novel oral anticoagulant”.

h) Boehringer Ingelheim’s Praxbind, which reverses the effects of its anticoagulant Pradaxa, has been approved in Europe. The European Commission’s approval is based on data from an interim analysis of the RE-VERSE AD study, where the drug showed complete and sustained reversal for at least 12 hours in almost all patients. As Praxbind works only to reverse the effects of Pradaxa, it could give Boerhinger’s drug an edge in the crowded Novel Oral Anti-Coagulant market, as there has been no approved antidote to the Factor Xa inhibitors. US firm Portola Pharmaceuticals is working on andexanet alfa, but it is still some way from approval.

4. Market structure and company news The 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) CSL Behring has opened an office in Moscow and says it is looking for ways to partner with the government. CEO Paul Perreault said in a statement that it may be possible to transfer CSL Behring's plasma collection technology to Russia, and added he can see a point at which the firm might set up some of its plasma collection technology or manufacturing there. Novo Nordisk and AstraZeneca both opened manufacturing operations in Russia this year. Russian President Vladimir Putin insists that those companies that want to profit from his country's growth will need to invest and transfer technology there.

b) CSL is undertaking a $A 210 million expansion of its Broadmeadows plant. It will produce albumin from blood collected from CSL's American collection centres for the first time. Initial separation of blood into its plasma components happens at the

25 The device is available in packages of one or three syringe-style applicators containing 92 compressed, cellulose sponges that have an absorbent coating. The sponges expand and swell to fill the wound cavity, creating a temporary physical barrier to blood flow. The number of sponges needed for effective hemorrhage control will vary, depending on the size and depth of the wound. Each applicator can absorb about a pint of blood, and up to three applicators may be used on a patient. XSTAT 30 is manufactured by RevMedX, of Oregon.

9 company's Kankakee/Illinois factory before it is sent to global plants to be prepared for export. CSL is experiencing significant demand in China. Its sales of albumin rose 16 per cent in constant currency terms in the 2014 financial year-its third consecutive year of double-digit growth. The Victorian government made an undisclosed contribution to the investment26.

c) CSL has shipped to the US the first production of Prvigen from its Broadmeadows plant. This Australian facility producing Privigen has the capacity to manufacture products with an export value of $A 2 billion or more annually.

d) Pfizer and Allergan are merging in a $US 160 billion deal. Pfizer said it expected the merger to result in savings of $US 2 billion in the first three years. The effective tax rate the enlarged company will pay will be between 17 and 18 per cent after the deal closes, compared with the 26 per cent that Pfizer had to pay the American IRS in 2014. The new company will be the world’s largest drug company.

e) Baxalta announced the official opening of its global innovation centre in Cambridge, Massachusetts. Baxalta’s innovation efforts focus on therapies in haematology, immunology and oncology. The company expands its pieline based on an external innovation model, sourcing compounds externally through in-licensing or acquisitions. The company has about 40 programs in development, and plans to launch 20 new products by 2020. It sees its advantages as an experienced leadership team, existing global capabilities and footprint in more than 100 countries.

f) Cerus Corporation signed a three-year deal to supply the Mississippi Valley Regional Blood Center with its INTERCEPT Blood System for platelets and plasma. The Center is based in Davenport, Iowa, and is the exclusive provider of blood products to 88 hospitals in Illinois, Iowa, Missouri, and Wisconsin.

g) KaloBios Pharmaceuticals announced it was acquiring worldwide rights to a compound being developed for the treatment of Chagas disease. It is purchasing the rights to Benznidazole from privately held Savant Neglected Diseases LLC for an upfront payment of $US 2 million, regulatory milestones and a royalty based on product sales.

h) A patent application filed27 by Google Life Sciences28 is for a needle-free blood draw device for use in any sort of diagnostic including blood glucose or for use in a handheld device. The method relies upon a negative pressure barrel that would release microparticles with enough force to pierce the skin and elicit tiny blood droplets. The vacuum barrel would then draw in at least part of that blood.

26 In its submission to the Innovation Inquiry, CSL warned that Australia was not an attractive location for "entrepreneurial manufacturing" or commercialising intellectual property because of high corporate tax rates, declining skills, high labour costs and complex government interactions.

27 The date of original filing was May 2014, but it is U.S. Patent and Trademark policy to publish patent filings 18 months after an application is made.

28 Google announced in August that it would become parent company Alphabet ($GOOG) that houses companies including the search engine-oriented Google and med tech-based Google Life Sciences.

10 i) Humacyte, of Research Triangle Park, North Carolina, has raised $US 150 million in financing from a group of global investors. The funds will support the company’s Phase III clinical trials for its HumaGraft treatment, which is intended for patients undergoing hemodialysis29. In 2014 the FDA assigned fast track status to HumaGraft30.

j) ProMetic and Omnio have entered into an agreement under which ProMetic has secured exclusive license rights to both issued and pending patents for the use of plasminogen31 related to wound healing. ProMetic also gained access to preclinical data and proof of concept efficacy data in patients. Pierre Laurin, President and CEO of ProMetic commented: "Dr Ny and his esteemed colleagues at Omnio have decades of hands-on experience demonstrating the ability of plasminogen to accelerate the healing of otherwise very hard-to-treat wounds. Combining their unique knowhow with our own clinical experience from our ongoing US plasminogen clinical trial bodes very well for improving the future management of diabetic wounds”.

k) ProMetic Life Sciences has entered into a strategic partnership with ProThera Biologics for the development and commercialization of human plasma-derived Inter- alpha Inhibitor Proteins32. The agreements provide ProMetic with global, exclusive intellectual property rights to commercialize products for two clinical indications and both companies have strategic interest in the other's IAIP-related therapeutic areas through a royalty-bearing cross-license agreement. ProMetic and ProThera each will perform development services in order to advance IAIP to the clinic by 2017. ProMetic has received an initial 11.25 per cent equity stake in ProThera with such equity position to be increased to 22.5 per cent following the achievement of an

29 Hemodialysis performs the job of the kidneys in patients experiencing kidney failure – the last stage of chronic kidney disease. It filters blood removing excess water and waste, then returns the blood to the patient.

30 This is for drugs that have the potential to offer significant improvement in treatment compared with products already on the market.

31 Plasminogen is synthesized by the liver and circulates in the blood. Activated plasminogen, plasmin, is a fundamental component of the fibrinolytic system and is the main enzyme involved in the lysis of blood clots and clearance of extravasated fibrin. Plasminogen is involved in wound healing, cell migration, tissue remodelling, angiogenesis and embryogenesis.

32 ProMetic describes Inter-alpha Inhibitor Proteins thus: Inter-alpha Inhibitor Proteins (IAIP) are a family of naturally occurring proteins found in high concentration in human plasma and play an important role in the regulation of host immune response. Research shows that IAIP play a key role in fighting acute inflammatory diseases including whole-body inflammation (shock syndrome or sepsis), due to infection, trauma or injury. IAIP exert their effects through multiple anti-inflammatory pathways, but importantly they function by binding to, and neutralizing, the toxic effects of extracellular histones released from dying cells. There is now a broad and growing recognition that IAIP are one of the body's first lines of defence against severe inflammation and they serve as important immunomodulators. IAIP treatment has been shown to be effective in many pre-clinical models of acute inflammatory disease and decreased IAIP levels in patients correlate with increased morbidity and mortality for multiple diseases.

11 early-stage development milestone. Further, ProMetic will exclusively manufacture IAIP for clinical trial requirements and commercial sales for all indications.

l) Privately held Hawaii Biotech announced that the US Army awarded the company a Small Business Innovation Research Phase I contract to develop an effective dengue vaccine to protect military personnel. Hawaii’s Big Island has been managing a dengue outbreak this year.

m) In Cambridge, Massachusetts, Flagship Ventures launched Rubius Therapeutics, to develop functionalized red blood cells for the treatment of a number of serious diseases33. Flagship has made an initial capital commitment of $US 25 million to enable Rubius to enter clinical testing. Rubius says red-cell therapeutics (RCTs) possess pharmacodynamic and pharmacokinetic advantages over traditional therapeutics, not least because of their inherent ability to engage and modulate the immune system and circulate for extended periods in the body. "Red blood cells can now be produced in culture and engineered to possess enormous biotherapeutic properties," said Harvey Lodish, professor of biology and bioengineering at MIT who has joined the firm's board of directors. "They spend as much as four months in circulation, providing an opportunity for long and tunable therapeutic treatments. Red cells also have profound effects on the immune system and may ultimately transform the way we treat autoimmune diseases and allergies." Avak Kahvejian, founding CEO of Rubius and partner in Flagship VentureLabs, said: "Through its rapid prototyping capability, Rubius has generated and tested over 50 different RCTs for a wide array of indications including autoimmunity, oncology and infectious disease. The company is now poised to drive lead programs into the clinic, build a drug pipeline and further develop the Rubius Erythrocyte Design (RED) platform. We are expanding our R&D and management teams, and setting the stage for our next phase of growth." The company has broad patent protection of its platform and therapeutic products. Itis currently testing RCTs in animal models.

n) Grifols has reached an agreement with MassBiologics (MBL) of the University of Massachusetts Medical School that gives Grifols exclusive rights to market and distribute MBL's tetanus and diphtheria toxoids adsorbed (Td) vaccine34 in the US other than in Massachusetts. Grifols now offers two tetanus therapies in the US. For tetanus-prone wounds in persons with incomplete or unknown history of tetanus immunization, Grifols HyperTET S/D (tetanus immune globulin [human], derived from human plasma) is the sole product on the US market that provides immediate, passive immunity against tetanus; the Td vaccine is a complementary therapy that yields longer-term, active immunity for tetanus.

o) Akebia Therapeutics has signed a deal with Mitsubishi Tanabe Pharma Corp., based in Osaka, under which MTPC will have the rights to sell Akebia's aanemia drug in Japan, Taiwan, South Korea, Indonesia, India and other Asian countries. The Japanese company will pay Akebia tiered royalty payments on sales of vadadustat. Mitsubishi will also pay $US 60 million toward the Phase III trial of the drug on top of

33 Erytech in Lyon (France) have already developed a potential therapy for certain cancers using this method of drug delivery to a phase II trial stage.

34 MassBiologics' Td vaccine was licensed by the FDA in 1970. The vaccine is indicated for active immunization for the prevention of tetanus and diphtheria and is approved for use in people seven years of age and older.

12 a $US 40 million up-front payment. Vadadustat mimics the way the body reacts to high altitudes by blocking the hypoxia inducible factor, the main way the body regulates the production of red blood cells. Akebia says that method of maintaining haemoglobin levels is safer than erythropoiesis stimulating agents (ESAs) such as Epogen, Aranesp or Procrit. Akebia reported final results from a mid-stage, 94- patient trial in September.

p) The Board of Directors of Grifols has unanimously approved the 'succession plan' proposed by Víctor Grifols Roura, the incumbent Chairman and Chief Executive Officer of the company. From 1 January 2017 Victor Grifols Roura will be succeeded by his brother, Raimon Grifols, and his son, Víctor Grifols Deu, who will become joint and several chief executive officers of the company. Víctor Grifols will continue holding his position as non-executive chairman of the board of directors. The succession plan establishes 2016 as a transition year in order that the handover is carried out smoothly.

q) Biogen and Arsia Therapeutics are collaborating to improve administration of drugs for haemophilia patients by enabling subcutaneous versions of treatments that are currently subject to intravenous infusion. Biogen will utilize Arsia’s proprietary formulation technology. Arsia will receive an upfront payment and could be eligible to receive development, regulatory, launch and sales milestones of up to $100 million if multiple products are successfully commercialized. Arsia may also receive royalties on certain products arising from the collaboration.

r) Dr. Reddy's Laboratories completed the purchase of worldwide exclusive intellectual property rights for Fondaparinux sodium, its generic anti-coagulant drug from its Australian partner, Alchemia Limited, for $US 17.5 million.

5. Country-specific events The 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) Saudi Arabia’s first plasma fractionation plant is expected to fulfil 30 per cent of the Kingdom’s requirements for blood products. The plant is being funded by the Public Investment Fund with French expertise.

b) Mexico has approved the use of Sanofi’s dengue vaccine, Dengvaxia. Some 40,000 people will receive the treatment in an initial phase. The vaccine will be available only to children over the age of nine, and adults under 49 who live in areas where the disease is endemic.

c) The US Centers for Disease Control and Prevention (CDC) in the 2014 STD Surveillance Report says that reported cases of three nationally notifiable sexually transmitted diseases–chlamydia, gonorrhea, and syphilis–have increased for the first time since 200635. STDs continue to affect young people36—particularly women--most severely, but increasing rates among men contributed to the overall increases in

35 The 1.4 million reported cases of chlamydia, a rate of 456.1 cases per 100,000 population, is up 2.8 per cent since 2013. Rates of primary and secondary syphilis–the most infectious stages of syphilis– and gonorrhea have both increased since 2013, by 15.1 per cent and 5.1 per cent, respectively. In 2014, there were 350,062 reported cases of gonorrhea (a rate of 110.7 per 100,000) and 19,999 reported cases of primary and secondary syphilis (for a rate of 6.3 per 100,000).

13 2014 across all three diseases. Jonathan Mermin, director of CDC’s National Center for HIV/AIDS, Viral Hepatitis, STD, and Tuberculosis Prevention, said: “STDs affect people in all walks of life, particularly young women and men, but these data suggest an increasing burden among gay and bisexual men.”37

d) Chinese regulators in the field of academic publishing for scientific articles have banned dishonest practices. The directive forbids Chinese scientists from using a third party to write journal articles, or to submit articles, or to substantially revise articles. It bans providing fake peer review information, or giving authorship to scientists who have not substantially contributed to the research. The directive from the country's leading science organizations and ministries, including the Chinese Academy of Sciences and the Ministry of Education, comes after several international science journals this year rejected or retracted submissions from Chinese scientists, citing academic dishonesty38.

e) Cerus Corporation announced that the INTERCEPT Blood System for platelets and plasma has been approved for commercialization in Brazil by the Agência Nacional de Vigilância Sanitária (ANVISA). This is the first time that a system to inactivate pathogens in platelet and plasma components will be available in Brazil. “With serious outbreaks of viruses such as dengue, zika, and chikungunya becoming more common in Brazil, transmission of pathogens via blood transfusion remains an ongoing threat,” commented Carol Moore, SVP, Regulatory Affairs and Quality at Cerus.

f) The New Zealand Ministry for Primary Industries (MPI) Director General issued a statement warning of a potential risk associated with imported frozen berries following four human cases of hepatitis A. "Australian officials recalled imported frozen berries there in February [2015]. Recent outbreaks in other countries also suggest this link," he said. The Ministry has established a surveillance program, including additional testing, focussed on imported frozen berries. The ministry said fresh berries or products containing frozen berries had not been implicated in its investigation.

6. Safety and patient blood management We follow current issues in patient safety and achieving favourable patient outcomes.

36 Despite being a relatively small portion of the sexually active population, young people between the ages of 15 and 24 accounted for the highest rates of chlamydia and gonorrhea in 2014 and almost two thirds of all reported cases. 37 Primary and secondary syphilis among men who have sex with men (MSM) has been increasing since at least 2000. In 2014, rates increased among MSM, who account for 83 percent of reported cases among men when the sex of the partner is known. More than half of MSM (51 percent) diagnosed with syphilis in 2014 were also HIV-positive. 38 In March, BioMed retracted 43 papers after an investigation that raised suspicions of fake peer reviews. Chinese state media said 41 of the papers came from Chinese scientists. In August Berlin- based publisher Springer retracted 64 articles-nearly all by Chinese authors-because of false peer reviews. Chinese state media reported more recently that an investigation by the Chinese Association for Science and Technology had found that fake peer reviews were "a tip of the iceberg" and that the buying and selling of journal articles was common.

14 a) The FDA has issued new guidance for blood banks and related establishments, to protect the US blood supply during a future Ebola outbreak. The recommendations are to apply when at least one country has current widespread transmission. In that case donor questionnaires should be updated to assess donor risk for the Ebola virus39. When donor screening reveals possible exposure to the Ebola virus, the FDA recommends blood banks and related establishments defer donation.40 When a blood bank or related establishment has collected blood or blood components from a donor who should have been deferred for risks related to residency, travel, or close contact, the establishment should quarantine and destroy all undistributed blood and blood components from the donor. The establishment should also notify consignees who received the supplies that they should do the same. Upon learning a donor was later diagnosed as having the Ebola virus, the establishment should contact the FDA and appropriate state and local health authorities. If the affected blood products were transfused, consignees should also notify the physician of record for each recipient. All undistributed blood and blood components from the donor should be quarantined and destroyed.

b) Researchers in Sweden found that heart surgery patients given blood stored for more than six weeks faced no greater harm than those who received blood donated within the previous two weeks. Study author Dr. Ulrik Sartipy, an associate professor in the department of molecular medicine and surgery at the Karolinska Institute in Stockholm, said: "In our study, which is by far the biggest of its kind, including all heart surgery patients in all of Sweden over a 16-year period, we find no evidence that prolonged storage of blood units has negative effects on patient survival or risk of complications."41

c) A study42 in 251 patients by Ariela Marshall, from the Mayo Clinic in Rochester, Minnesota, and colleagues found that about 20 per cent of patients given fresh frozen plasma (FFP) to reverse warfarin anticoagulation develop pulmonary complications43, with the highest risk seen with more than three units of FFP44.

39 The FDA recommends screening for History of Ebola virus infection: history of residence in or travel in the past 8 weeks to a country with widespread transmission of the Ebola virus; history of close contact in the past 8 weeks with a person confirmed to have the Ebola virus or any person under investigation for infection; and history of notification by a public health authority that the prospective donor may have been exposed in the past 8 weeks to a person with the virus. 40 For a donor who has resided in or visited a country with widespread transmission, defer the donation for 8 weeks from the date of departure; for a donor with a history of Ebola infection, defer the donation indefinitely or until additional data regarding the persistence of the virus in survivors becomes available; for a donor who has had close contact with any person under investigation for Ebola infection, or who has been confirmed infected, defer donation for 8 weeks after the last contact.; and for a donor who has been notified by a public health authority that he or she might have been exposed to the Ebola virus, defer the donation for 8 weeks following the possible exposure. 41 The findings were reported in a research letter published in the 20 October issue of Journal of the American Medical Association. 42 Published online 8 December in the Journal of Thrombosis and Haemostasis.

15 7. Research A 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) A study from the Jacobs School of Engineering at the University of California at San Diego reports that nanoparticles can be an effective delivery system for drugs in the treatment of cardiovascular disease and systemic bacterial infections. A biodegradable polymer was used to create the nanoparticle cores as the body can metabolize them after the drugs are delivered. The engineers disguised nanoparticles as human platelets. Cloaking also increases binding to the damaged blood vessels preferentially, meaning they automatically prefer the damaged areas in the body.

b) Researchers at the University of British Columbia have developed self-propelled particles capable of delivering coagulants against the flow of blood to treat severe bleeding. Christian Kastrup, an assistant professor in the Department of Biochemistry and Molecular Biology and the Michael Smith Laboratories said: “Bleeding is the number one killer of young people, and maternal death from postpartum haemorrhage can be as high as one in 50 births in low resource settings……. People have developed hundreds of agents that can clot blood but the issue is that it’s hard to push these therapies against severe blood flow, especially far enough upstream to reach the leaking vessels. Here, for the first time, we’ve come up with an agent that can do that.” The team created gas-generating calcium carbonate micro-particles that are applied in powder form. They release carbon dioxide gas, to propel them toward the source of bleeding. The carbonate forms porous micro particles that can bind with the clotting tranexamic acid, and transport it through wounds and deep into the damaged tissue.

c) In another experiment Assistant Professor Kastrup and his graduate students injected platelets with DNA and other ingredients needed to make RNA. The RNA, when extracted from the platelets and immersed in a soup of cellular biochemicals, produced proteins that glowed when exposed to certain types of light. This experiment45 suggests platelets could be fortified with useful genes, eg making platelets even better at blood clotting, programmed to release more coagulation enzymes. They could also be developed to release RNA or proteins that decrease inflammation.

d) Researchers from the Global Medical Science Center at the Fukushima’s Medical University have signed a Memorandum of Understanding with Pluristem therapeutics to develop future therapies. They will use Pluristem’s placenta-based PLX-R18 cell

43 including 12 per cent transfusion-associated circulatory overload (TACO), 1per cent transfusion- related acute lung injury (TRALI), and 7 per cent pulmonary oedema that did not meet the criteria for TACO 44 After controlling for age, sex, initial systolic blood pressure, and intravenous fluids given in the emergency department, receipt of more than three units of FFP remained significantly associated with pulmonary complications.

45 described in an article in the German chemistry journal Angewandte Chemie International Edition

16 therapy to investigate a treatment for Acute Radiation Syndrome (ARS). “Fukushima researchers intend to study our cells for repair of bone marrow function within the context of acute radiation syndrome, and of cancer treatment using high levels of radiation,” said Karine Kleinhaus, Managing Director of Pluristem. “PLX-R18 cells are designed to repair production of the three blood cell types produced by the bone marrow: red cells, white cells and platelets.” The research collaboration is supported by the US National Institutes of Health (NIH), concurrently investigating PLX-R18 in preclinical tests in animal models. PLX-R18 is Pluristem’s second placental-derived cell therapy product in development, the other being PLX-PAD. Both are made using the firm’s patented 3D manufacturing process.

e) In the US, researchers at Lawrence Livermore National Laboratory are using 3D bioprinting to print 'living' blood vessels. "It's going to change the way we do biology," said Lab research engineer Monica Moya, the project's principal investigator. "This technology can take biology from the traditional petri dish to a 3D physiologically relevant tissue patch with functional vasculature."

f) A study46 by researchers from Otago and Japan suggests the appetite-regulating hormone ghrelin could eventually be used clinically for the early treatment of critical limb ischemia (CLI)47. Otago physiology department researchers Dr Rajesh Katare, Dr Daryl Schwenke and colleagues have shown administering ghrelin daily over two weeks markedly improved blood flow in affected limbs. They found ghrelin, also known as the ‘‘hunger hormone'', promoted growth of new structurally and functionally normal blood vessels, improved cell survival, and decreased tissue fibrosis. Further animal-related research will be conducted with human trials some years away.

g) A study by researchers at Griffith University suggests that unconjugated bilirubin48, an endogenous antioxidant, may protect the heart against ischemia reperfusion injury49. “Inflammation is the main culprit of damage to the body, and is caused by over-active white blood cells that release free radicals. It appears our natural bilirubin can protect from these free radicals during chronic inflammatory diseases like cardiovascular disease, kidney disease, and diabetes,” said lead author Andrew Bulmer. “We believe that this protection could be related to recently identified anti-oxidative property of the bilirubin molecule.”

8. Legal matters The 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.

46 Published in the journal Endocrinology 47 an advanced form of peripheral artery disease, involving the severe obstruction of blood flow to the extremities. Major amputations are often required, and in half of the cases, death results within five years. The leading risk factors are diabetes, obesity and age.

48 Bilirubin is the yellow pigmented breakdown product of heme catabolism, caused by the body's clearance of aged red blood cells, which contain hemoglobin.

49 The study was published in the January 2016 issue of the International Journal of Cardiology.

17 a) A New Jersey man says Janssen Research sold anti-stroke drug Xarelto without warning the public of its dangerous potential side effects50. He complained he developed life-threatening gastrointestinal bleeding on 28 February, some six months after he started taking the drug. He claims that the defendants negligently and/or fraudulently represented that the drug was tested and found safe. He seeks a jury trial and damages of more than $75,00051.

9. Infectious diseases The NBA takes an interest in infectious diseases because: the presence of disease in individual donors (e.g. influenza), or potential disease resulting from travel (e.g. malaria) means a donor must be deferred; temporary disease burden within a community (e.g. dengue in North Queensland) may limit blood collection in the community for a time; and some people may not be permitted to donate at all (e.g. people who lived in the UK for a period critical in the history of vCJD). Blood donations are tested for a number of diseases (e.g. HIV and Hepatitis B), but there are also emerging infectious diseases for which it may become necessary to test in the future (e.g. Chagas disease, and the tick-borne babesiosis and Lyme disease). Mosquito-borne disease: malaria, chikungunya, dengue, Ross River virus a) A study of malaria infection among children in the East Sepik Province of Papua New Guinea suggested a strategy to reduce infections by Plasmodium vivax and Plasmodium ovale. Study leader was Dr Leanne Robinson of the Population Heath and Immunity Division of the Walter and Eliza Hall Institute52. Robinson and a consortium of Australian, Swiss, UK and Spanish researchers showed that adding primaquine to a cocktail of standard antimalarial drugs dramatically reduces relapse rates among children. Primaquine targets a phase in the life cycle of both P. vivax and P. ovale parasites, called a hypnozoite, which lies dormant in liver cells.

b) The Australian Institute of Tropical Health and Medicine at James Cook University in North Queensland is a collaborating recipient of a grant to further develop a malaria vaccine. Funds from the Bill and Melinda Gates Foundation will also be with other scientists in the Walter and Eliza Hall Institute in Melbourne, and in US institutions. “There is an urgent need for a broadly effective vaccine to attack all strains, species and life stages of malaria,” AITHM Director Louis Schofield said. “However, this is a major challenge: five malaria parasite species infect humans, and the parasites are complex and hard to target. Some forms infect people through the bite of a mosquito; 50 Stuart Elfenbein filed a lawsuit on 23 November in the U.S. District Court for the Eastern District of Louisiana against Janssen Research & Development, formerly known as Johnson & Johnson Pharmaceutical Research and Development; Janssen Ortho; Janssen Pharmaceuticals Inc., formerly known as Janssen Pharmaceutica Inc. or Ortho-McNeil-Janssen Pharmaceuticals Inc.; Bayer Healthcare Pharmaceuticals Inc.; Bayer Pharma AG; Bayer Corp.; Bayer Healthcare; and Bayer AG, alleging fraud and negligence. U.S. District Court for the Eastern District Case number 2:15-cv-06264

51 He is represented by attorneys William L. Bross, W. Lewis Garrison Jr., Kathryn Harrington, Taylor Bartlett and Jeanie Sleadd of Heninger Garrison Davis in Birmingham, Alabama

52 Leanne J. Robinson et al., “Strategies for Understanding and Reducing the Plasmodium vivax and Plasmodium ovale Hypnozoite Reservoir in Papua New Guinean Children: A Randomised Placebo- Controlled Trial and Mathematical Model”, PloS Medicine,

18 other forms proliferate in the blood and cause disease, and yet different forms are passed from human to mosquitoes to complete the cycle. Our prototype vaccine attempts to overcome these barriers by attacking most species and stages in the malaria life cycle”.

c) Scientists have produced a strain of mosquitoes carrying genes that block malaria transmission, with the idea that they could breed with other members of their species in the wild and produce offspring that cannot spread the disease53. They used gene- editing on a species called Anopheles stephensi that spreads malaria in urban India. "It can spread through a population with great efficiency, increasing from 1 percent to more than 99 percent in 10 generations, or about one season for mosquitoes," University of California-San Diego biologist Valentino Gantz said. One group of scientists in 2014 said it created a strain carrying a gene leading nearly all offspring to be male, which could cause wild populations to plummet. In contrast, this new development only prevents mosquitoes from carrying malaria so should generate less ecological damage.

d) Researchers at Washington University School of Medicine in St. Louis have identified in mice “broadly neutralizing” antibodies that protect against infection by multiple, distantly related arthritogenic alphaviruses – including Chikungunya – that cause fever and debilitating joint pain54. Senior author Michael Diamond, a professor of medicine and director of the Division of Infectious Diseases and Vaccine Development in the Center for Human Immunology and Immunotherapy Programs said: “What we’ve identified here are antibodies that actually neutralize several different alphaviruses.” The researchers found ten antibodies that react against three or more alphaviruses, and also identified a small piece of the alphavirus called an epitope that is identical across the arthritogenic alphavirus family.

e) A joint research project by scientists at the University of Queensland and the University of Sydney has discovered a virus, carried by Aedes vigilax mosquitoes, which may make it harder for them to become infected with disease-causing viruses such as Ross River virus. Parramatta River virus appears not to infect humans or animals. The scientists are now looking to see if the same or similar virus is carried by the Aedes egypti mosquito responsible for transmitting dengue.

f) The number of confirmed cases of Ross River virus rose in Queensland this year. In the Wide Bay region, for instance, there have been 185 confirmed cases, compared with 149 in 2014. Influenza: strains, spread, prevention and treatment g) At the Ninth Vaccine & International Society of Vaccines Congress in Seoul, Vaxart’s representatives reported success in two vaccine studies, an oral norovirus vaccine and an H1N1 influenza tablet. Vaxart CEO, Wouter Latour, said: "The second presentation highlighted data from a recent Phase 1 clinical study demonstrating that Vaxart’s H1N1 influenza tablet vaccine generated neutralizing antibodies in 92 percent of subjects after a single dose.” He explained: “Vaxart’s lead programs include tablet vaccine candidates for seasonal influenza, norovirus and Respiratory

53 The research was published in the Proceedings of the National Academy of Sciences.

54 JM Fox et al., “Broadly neutralizing alphavirus antibodies bind an epitope on E2 and inhibit entry and egress”, Cell. online 5 November, 2015

19 Syncytial Virus. The vaccines are based on a versatile vector-based platform that is designed to be suitable for a wide range of infectious diseases.” The advantage of Vaxart’s temperature-stable tablets is that they can be shipped and stored without refrigeration. They are easier to distribute than injectable vaccines, which can cause needle stick injury and medical waste.

h) In Expert Review of Vaccines, Dr Michael Jarvis (a molecular virologist from Plymouth University School of Biomedical Sciences) identified self-disseminating vaccines as one potential way forward to deal with future pandemics of animal origin, with potential to cut off such diseases at the animal source before they spread to human populations. Self-disseminating vaccines use virus-based vectors-viruses that are unique to individual species but which have no significant impact on that species' health. This facilitates vaccination across populations where it is difficult to inoculate every animal.

i) A study at the University of Helsinki suggests that genomic information from circulating influenza viruses can help in producing better targeted seasonal vaccines55. Scientists developed an approach for reliable real-time tracking and prediction of viral evolution based on whole-genome sequences of influenza viruses.

j) Eight countries, including Japan and Morocco, suspended imports of French poultry after the H5N1 bird flu virus was found in southwestern France, where many foie gras and poultry producers are located. France has also detected low pathogenic H5N3 bird flu.

k) Nigeria has been reporting outbreaks of H5N1, and Vietnam has been confirming outbreaks of H5N6. Human cases of avian influenza A(H7N9) are continuing to occur on the Chinese mainland. MERS-CoV (Middle East Respiratory Syndrome-Coronoavirus) l) At 17 December Saudi Arabia had since 2012 had 1278 cases of laboratory- confirmed MERS-CoV, including 550 deaths (42.9 per cent) and 728 recoveries (56.9 per cent), to that time. 12 per cent of infections had been acquired in the healthcare setting as health care workers, 33 per cent had been acquired in the healthcare setting as patients, 14 per cent had been acquired by household contact, 38 per cent were primary cases, and 3 percent were unclassified. Globally, since September 2012, the World Health Organisation (WHO) had been notified of 1620 laboratory- confirmed cases of infection with MERS-CoV, including at least 581 related deaths.

m) Hemispherx Biopharma Europe NV/SA, received a positive opinion for its new Middle East Respiratory Syndrome (MERS) treatment from Europe’s Committee on Medical Products (COMP). COMP recommended that the company’s Alergon N Injection receive orphan medical product designation for MERS. "Alferon has great experimental potential as an early onset therapeutic for this dread disease,” Hemispherx President Tom Equels said. “Hemispherx is dedicated to making Alferon available for MERS clinical trials, emergency uses and early access programs consistent with all applicable laws.”

n) GeneOne Life Science, which partnered with Inovio Pharmaceuticals to develop a MERS vaccine (GLS-5300) filed an Investigational New Drug Application (IND) for

55 Researchers from the Institute for Molecular Medicine Finland analysed thousands of complete genome sequences of influenza A(H1N1) and A(H3N2) strains representing different geographic regions. They collaborated with researchers from Singapore and UK.

20 GLS-5300 with the FDA. The companies expected to move quickly into a phase I clinical trial in healthy volunteers. In a preclinical study reported in Science Translational Medicine, the vaccine has been shown to induce 100 per cent protection from a live virus challenge in mice, camels and monkeys, or non-human primates. In monkeys, all vaccinated animals in the study were protected from symptoms of MERS when challenged with a live MERS virus.

o) Purdue University researchers have identified molecules that inhibit the activity of an essential enzyme in the MERS virus56.

p) Studies looking for potential reservoirs for MERS-CoV found that the virus is widespread in camels57 in Nigeria but not in bats58 in Egypt and Lebanon. The virus infecting camels in Nigeria is a distinct strain from the virus in the Middle East. In the bat study, researchers identified other coronaviruses in various samples from wild bats, but not MERS-CoV.

q) European scientists have genetically engineered a smallpox virus, Modified Vaccinia Ankara–MVA, to display Mers virus spike protein on its surface59. The MERS spike protein is thought to be a major target for the immune response. Scientists believe that cloaking MVA with this spike would train the immune system to recognize and kill MERS. The vaccine was able to protect camels from developing MERS symptoms. Scientists hope to test the vaccine in humans at risk from infection and also to stop the spread of infection in camels. Another experimental vaccine for camels has shown some promise, while a new study has found five variants of the MERS coronavirus to have been circulating between camels and people.

Ebola virus disease r) Experts from the [US] National Eye Institute [NEI] travelled to Liberia to investigate the long-term effects of Ebola on the eye among hundreds of survivors following the 2014 outbreak. Based on literature reports from the 1990s, it was expected that some survivors of the latest Ebola epidemic would develop uveitis, an inflammatory eye disease. NEI's investigation is part of a larger study called PREVAIL III (Partnership for Research on Ebola Vaccines in Liberia) sponsored by NIAID [National Institute of Allergy and Infectious Diseases] and the Liberian Ministry of Health. The goal is to understand the long-term health implications of Ebola virus disease among those who survived acute infection with the virus, many of whom report a variety of ailments from headaches and tinnitus, to joint and muscle pain, eye fatigue, and blurry vision. Ebola is known to linger in the eye after a person’s blood is virus-free. This does not necessarily put other people at risk of becoming infected because the virus is inside the eye, not on the surface. There is not yet evidence that live virus is present in survivors' tears. But transmission associated with the eye could be a concern in the future if eye surgery should be needed.

56 Andrew Mesecar and Arjun Ghosh in the Journal of Biological Chemistry 57 1o December, Eurosurveillance 58 9 December Emerging Infectious Diseases

59 A report appeared in the journal Science

21 s) Bavarian Nordic began a new staged Phase III clinical study of the Ebola prime-boost vaccine (its MVA-BN Filo vaccine) in combination with the Ad26.ZEBOV vaccine from Crucell Holland, a subsidiary of Johnson & Johnson. The study is designed to evaluate the safety and immunogenicity of the combination regimen. The trial is being coordinated by the London School of Hygiene and Tropical Medicine and sponsored by Janssen, also a Johnson and Johnson subsidiary.

t) Canadian company Medicago was awarded a contract by the Public Health Agency of Canada (PHAC) to develop two antibodies to fight the Sudan strain of the Ebola virus. Medicago will produce these antibodies at its facility in Quebec City. This will build on existing work directed at the Zaire strain which is responsible for the recent outbreak in West Africa. The Sudan strain has previously been associated with large- scale outbreaks in Africa. Medicago's technology uses plants as miniature factories that can quickly produce large quantities of vaccines or antibodies.

u) Gilead has been working on an experimental anti-viral for Ebola. The Scots nurse who was readmitted to London’s Royal Free hospital with late complications from Ebola agreed to receive it. GS-5734, a novel nucleotide analogue in development for the potential treatment of Ebola, was discovered as part of Gilead’s programme to screen compounds in its libraries for activity against a range of potential emerging viruses. Gilead announced that in animal studies treatment initiated on day three post-infection with Ebola led to 100 per cent survival of the monkeys. The company went on to initiate a Phase I clinical trial in healthy human volunteers to determine the safety, tolerability and pharmacokinetics of the drug.

v) A clinical trial of a new Ebola vaccine (ChAd3-EBO-Z)60 has found that it is well tolerated and stimulates strong immune responses in adults in Mali, West Africa and in Baltimore61. If the vaccine is found to be safe and effective, it could offer crucial protection for contacts of patients with confirmed Ebola disease in future epidemics, helping to interrupt transmission. Larger trials of the vaccine sponsored, by GSK Biologicals, have already begun. Other diseases: occurrence, prevention and treatment w) Sanofi Pasteur launched an injectable trivalent inactivated polio vaccine under the name ShanIPV. The vaccine will be manufactured by SanofiPasteur’s affiliate Shantha Biotechnics, based in Hyderabad. A release issued by this company said: “Keeping with WHO’s Global endgame strategy, India is introducing an additional dose of IPV at 14 weeks of age. This is to be given in addition to the regular oral polio vaccine.”

x) In India nine per cent of all paediatric tuberculosis patients are resistant to rifampicin, one of the first-line drugs used in the treatment of the disease.

60 developed by the Vaccine Research Center (VRC) of the National Institute of Allergy and Infectious Diseases (NIAID), part of the US National Institutes of Health, and GlaxoSmithKline (GSK). Other key partners in the study included the University of Oxford’s Jenner Institute and the World Health Organization.

61 according to a study published in the journal Lancet Infectious Disease